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Synthesis of β2,2-Amino Acids by Stereoselective Alkylation of Isoserine Derivatives Followed by Nucleophilic Ring Opening of Quaternary Sulfamidates
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Synthesis of β2,2-Amino Acids by Stereoselective Alkylation of Isoserine Derivatives Followed by Nucleophilic Ring Opening of Quaternary Sulfamidates
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  • Pablo Tovillas
    Pablo Tovillas
    Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
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  • Claudio D. Navo
    Claudio D. Navo
    Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160 Derio, Spain
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    Orcidhttps://orcid.org/0000-0003-0161-412X
  • Paula Oroz
    Paula Oroz
    Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
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  • Alberto Avenoza
    Alberto Avenoza
    Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
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  • Francisco Corzana
    Francisco Corzana
    Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
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    Orcidhttps://orcid.org/0000-0001-5597-8127
  • María M. Zurbano
    María M. Zurbano
    Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
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  • Gonzalo Jiménez-Osés
    Gonzalo Jiménez-Osés
    Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160 Derio, Spain
    Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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    Orcidhttps://orcid.org/0000-0003-0105-4337
  • Jesús H. Busto*
    Jesús H. Busto
    Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0003-4403-4790
  • Jesús M. Peregrina*
    Jesús M. Peregrina
    Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0003-3778-7065
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The Journal of Organic Chemistry

Cite this: J. Org. Chem. 2022, 87, 13, 8730–8743
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https://doi.org/10.1021/acs.joc.2c01034
Published June 22, 2022

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Abstract

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Chiral bicyclic N,O-acetal isoserine derivatives have been synthesized by an acid-catalyzed tandem N,O-acetalization/intramolecular transcarbamoylation reaction between conveniently protected l-isoserine and 2,2,3,3-tetramethoxybutane. The delicate balance of the steric interactions between the different functional groups on each possible diastereoisomer controls their thermodynamic stability and hence the experimental product distribution. These chiral isoserine derivatives undergo diastereoselective alkylation at the α position, proceeding with either retention or inversion of the configuration depending on the relative configuration of the stereocenters. Quantum mechanical calculations revealed that a concave-face alkylation is favored due to smaller torsional and steric interactions at the bicyclic scaffold. This synthetic methodology gives access to chiral β2,2-amino acids, attractive compounds bearing a quaternary stereocenter at the α position with applications in peptidomimetic and medicinal chemistry. Thus, enantiopure α-alkylisoserine derivatives were produced upon acidic hydrolysis of these alkylated scaffolds. In addition, α-benzylisoserine was readily transformed into a five-membered ring cyclic sulfamidate, which was ring opened regioselectively with representative nucleophiles to yield other types of enantiopure β2,2-amino acids such as α-benzyl-α-heterofunctionalized-β-alanines and α-benzylnorlanthionine derivatives.

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Introduction

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The synthesis of enantiomerically and diastereomerically pure compounds is still one of the main challenges faced by organic chemists. In this context, the use of chiral auxiliaries that are covalently bound to the substrate and subsequently removed is an effective strategy in asymmetric synthesis. (1,2) Both chiral oxazolidinones (Evans’ oxazolidinones) and oxazolidines (N,O-acetals) have been extensively used as efficient chiral auxiliaries in asymmetric synthesis. (3−5) By combining both strategies, we designed a chiral oxazolidine–-oxazolidinone-fused bicyclic scaffold, readily accessible from N-Boc-protected serine and threonine esters by diastereoselective reaction with 2,2,3,3-tetramethoxybutane (TMB) and catalytic amounts of p-toluenesulfonic acid (TsOH·H2O). (6) These chiral derivatives displayed exceptional diastereoselectivities in the alkylation at their α position with different electrophiles. The alkylation occurs with total retention of the configuration due to the high pyramidalization of the enolate intermediate and allows the synthesis of a wide variety of chiral quaternary α-alkylserine and threonine derivatives (Scheme 1). (7,8) Conversely, when these scaffolds were synthesized from unusual (allo-threonine) or unnatural (α-methylserine) amino acids, the reaction under the same conditions resulted in a complete loss of stereoselectivity toward N,O-acetals formation. (9) As inferred from the computational studies, slight variations on the three-dimensional arrangement of the exocyclic substituents of the bicyclic compounds notably affect the thermodynamical stability of the corresponding isomers and hence determine the stereochemical outcome. With this in mind, we envisioned the use of non-natural amino acid isoserine to form the corresponding bicyclic N,O-acetals and therefore provide access to chiral quaternary β2,2-amino acids (Scheme 1). During the past decades, β-amino acids have become research targets in the chemical biology field, (10−13) and thus, there has been continuous interest in the synthetic chemistry. (14−17) However, despite the many reported methods to obtain enantioenriched β2- and β3-amino acids, only a few synthetic routes for the asymmetric synthesis of β2,2-amino acids have been reported, (18,19) and the synthesis remains a challenge in organic synthesis. (20,21) The importance of this type of amino acid is due to the existence of a quaternary stereocenter at the α position, which plays a significant role in the conformational behavior with implications in their use as peptidomimetic units and as key targets in the synthesis of Taxol analogues and β-lactams with antibiotic activity. (20,21) In this regard, the nucleophilic ring opening of α-methylisoserine sulfamidates has been extensively used by our group to access a wide variety of β2,2-amino acid derivatives. (22,23)

Scheme 1

Scheme 1. Synthesis of (S)-α-Alkylserine from Protected l-Ser (previous work) and (R)- and (S)-α-Alkylisoserines from Protected l-isoSer (this work) via Diastereoselective Formation of Bicyclic Acetals and Alkylation Followed by Hydrolysis
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Results and Discussion

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Formation of Bicyclic N,O-Acetal Isoserine Derivatives

N-Boc-l-isoserine methyl ester (Boc-l-isoSer-OMe, 1) was readily synthesized from commercially available l-isoserine. (24) The reaction of Boc-l-isoSer-OMe with 2,2,3,3-tetramethoxybutane (TMB), freshly prepared from butan-2,3-dione, (25) was then assayed in the presence of catalytic amounts of diverse acids under different reaction conditions (Scheme 2 and Supporting Information). In all cases, four different products were obtained in different ratios, corresponding to bicyclic N,O-acetal diastereomers 2 and 3, and a mixture of two nonseparable methylene-oxazolidinone isomers 4. This byproduct is likely formed by an in situ acid-catalyzed elimination reaction from compounds 2 and 3, as previously observed in the formation of allo-threonine-derived bicyclic N,O-acetal. (9) The optimized conditions for N,O-acetal formation required treatment with 0.2 equiv of p-toluenesulfonic acid (TsOH·H2O) or camphorsulfonic acid (CSA·H2O), affording isolated bicyclic compounds 2 and 3 in moderate yields (55% and 32%, respectively) and diastereomeric ratios (∼2:1). The conditions using CSA were applied to scale up the reaction starting from 13.7 mmol of 1 to obtain bicyclic systems 2/3 in 85% yield with a 63:37 ratio, respectively (entry 15, Table S1, Supporting Information). Because these two bicyclic compounds 2 and 3 are the key derivatives to start the synthetic routes that allow the synthesis of important β2,2-amino acids, we need to have them not only in large quantities but also in sufficient diastereomeric purity. Therefore, we achieved a suitable chromatographic separation that led to a high diastereomeric purity (dr 98:2) for each of them, measured by 1H NMR (Supporting Information).

Scheme 2

Scheme 2. Formation of Bicyclic N,O-Acetal Isoserine Derivatives 2 and 3
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Bicyclic compounds 2 and 3 were assessed by complete NMR analysis, including 2D NOESY experiments, which allowed us to determine the absolute configuration of the new stereocenters created upon the bicyclic acetal formation. Considering that the configuration of the α-carbon of the starting isoserine derivative remains unaffected, the medium-size NOE cross-peaks observed for the bridgehead methyl group linked to the C7a carbon (Me7a) with H2 and H3a protons as well as with the methoxy group linked to C7 carbon (OMe) confirmed that bicyclic compound 2 exhibited a (2S,7R,7aS)-configuration. This finding was corroborated by X-ray analysis of a monocrystal of compound 2 obtained by slow crystallization in CH2Cl2/hexane (Supporting Information). On the other hand, the NOE cross-peaks observed for Me7a with the methyl ester and the methoxy (OMe) groups confirmed the (2S,7S,7aR)-configuration of bicyclic compound 3 (Figure 1). Of note, the major compound 2 displays an absolute configuration equivalent to that of the major products obtained from natural amino acids (Ser and Thr), whereas the minor compound 3 exhibits reverse configurations at both C7 and C7a.

Figure 1

Figure 1. (A) ORTEP3 diagram of compound 2 obtained by X-ray diffraction analysis showing thermal ellipsoids at the 75% probability level, and 2D NOESY NMR (400 MHz) experiments for compounds 2 (B) and 3 (C) in CDCl3 at 298 K.

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Mechanism of the Formation of Compounds 2–4

The proposed mechanism for this reaction is similar to that described for the thermodynamically controlled formation of related bicyclic N,O-acetals (6,9) from Boc-l-Ser-OMe: acid-catalyzed formation of the five-membered N,O-acetal followed by formation of the fused O,O-acetalic carbamate driven by tert-butyl group cleavage. To provide a rationale for the experimental outcome, we evaluated the thermal stability of all of the possible stereoisomers of the final bicyclic compounds using quantum mechanics calculations. Bicyclic diastereoisomers I–IV were optimized in implicit toluene solvent (see computation details and Supporting Information); the calculated minimum-energy structures along with their relative free Gibbs energies (ΔG) and populations (p) are depicted in Figure 2. Consistent with our previous observations and with the 2D NOESY NMR experiments, all of the calculated isoserine-derived bicyclic diastereoisomers I–IV show a highly pyramidalized bridgehead N atom resulting from the conformational restrains imposed by the bicyclic structure. Structures III and I, corresponding to compounds 2 and 3, respectively, are ca. 3–4 kcal mol–1 more stable than structures II and IV due to the smaller steric interactions between the OMe group and the N,O-acetalic oxygen (O1) as well as between Me7 and Me7a. On the other hand, structure III (compound 2) is just 0.8 kcal mol–1 more stable than structure I (compound 3), reflecting their very similar thermostability as observed experimentally. In fact, a theoretical ∼3:1 ratio of compounds 2 and 3 was predicted from the Boltzmann distribution of all conformers and stereoisomers calculated at the experimental reaction temperature (115 °C) from their free energies, which matches the experimentally observed ratio. In accordance with their comparable energies, both disatereomers, I and III, display very similar three-dimensional arrangements, the main difference being the outward and inward presentation of the ester group with respect to the bicyclic scaffold, respectively.

Figure 2

Figure 2. Lowest energy structures for the four possible bicyclic diastereomers (I–IV) obtained upon reaction of Boc-l-isoSer-OMe 1 with TMB calculated with PCM(toluene)/M06-2X/6-31+G(d,p). Relative free Gibbs energies at 388 K (ΔG) are given in kcal mol–1, and relative populations (p) at the same temperature derived from ΔG are shown in parentheses. Dark and light red arrows indicate high or low steric hindrance, respectively.

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The acid-catalyzed elimination process leading to enecarbamates 4 was also investigated computationally (see Supporting Information). Protonation at O1 in I (compound 3) and III (compound 2) was found to promote the spontaneous cleavage of the O1–C7a bond and formation of an 2-oxo-2,5-dihydrooxazol-3-ium cation; subsequent deprotonation of the methyl group adjacent to that carbocation yields the experimentally observed methylene-oxazolidinones 4.

Diastereoselective Alkylation of Derivatives 2 and 3

Considering the good results obtained with bicyclic N,O-acetal acids derived from serine and threonine, (6) we assayed the alkylation of both chiral isoserine-derived compounds 2 and 3 as an entry to quaternary α-alkyl-β2-amino acids. Optimized conditions required treatment of 2 with methyl iodide (MeI, a) at low temperature in the presence of lithium hexamethyldisilazide (LHMDS) as a base and hexamethylphosphoramide (HMPA) as an additive to obtain α-methylated derivative 5a in good yield (95%) as a 83:17 mixture of diastereoisomers (Scheme 3 and Supporting Information).

Scheme 3

Scheme 3. Diastereoselective Alkylation of Chiral Bicyclic Acetals 2 and 3
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The absolute configuration of α-methylated compound 5a was determined by a 2D NOESY NMR experiment (Figure 3). The medium-size NOE cross-peaks observed for the Me7a group with a H3a proton and OMe along with the cross-peak Me2-H3b confirmed that bicyclic 5a displays a (2R,7R,7aS)-configuration. Thus, methylation of compound 2 occurs with inversion of the configuration at the C2 carbon, contrary to the alkylation of bicyclic N,O-acetals derived from Ser/Thr. (6) On the other hand, the diastereoselective alkylation of chiral building block 3 with MeI (a) under the same conditions led to α-methylated bicyclic compound 6a in 5 min in a good yield (94%) and with a similar diastereoselectivity (82:18, Scheme 3). Surprisingly, methylated bicyclic compound 6a displays the same spectroscopy data (including 2D NOESY) as bicyclic compound 5a, but it showed the opposite sign in its specific rotation value. Therefore, a (2S,7S,7aR)-configuration is inferred from these data (Figure 3), indicating that, in this case, methylation occurs with retention of configuration at the C2 carbon. Hence, the major alkylation products from 2 and 3 (compounds 5a and 6a) are enantiomers to each other.

Figure 3

Figure 3. Two-dimensional NOESY NMR experiment for compounds 5a or 6a performed with 400 MHz equipment using CDCl3 as solvent at 298 K.

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The scope of the diastereoselective alkylation of compound 2 was expanded using ethyl triflate (b), benzyl iodide (c), and allyl iodide (d) to obtain alkylated bicyclic compounds 5b (92%, dr 85:15), 5c (91%, dr 80:20), and 5d (93%, dr 87:13) with good yields and diastereoselectivities. Similarly, the diastereoselective alkylation of compound 3 was also carried out with benzyl iodide (c), giving alkylated bicyclic compound 6c in an 89% yield and a diastereomeric ratio of 80:20. As in the alkylation of compounds 2 and 3 with MeI to give the methylated bicyclic compounds 5a and 6a, respectively, the benzylated compounds 5c and 6c are also enantiomers. Importantly, the final alkylated compounds 5a–d and 6a,c were purified using the corresponding chromatographic columns to achieve high diastereomeric purity for all of them (Scheme 3).

Stereochemical Outcome of the Alkylation Reaction

The stereochemical course of the alkylation reactions involves an inversion of the configuration at the reacting carbon for bicyclic compound 2 and a retention of configuration at the same position for bicyclic compound 3. This perplexing behavior observed for apparently very similar substrates was analyzed quantum mechanically (Figure 4A and Figure S3 in the Supporting Information) using bromomethane as a computationally tractable alkylating reagent in implicit THF solvent (see computation details and Supporting Information). Due to the experimental usage of HMPA, which has a superior ability to effectively solvate lithium cations, (26) bare enolates were considered. Similarly to serine-derived N,O-acetal enolate, (6) enolate (2proS,7R,7aS)-2′ displays a noticeable nonplanar (pyramidalized) character (α = 32°) according to the out-of-plane angle between the C2–CO2Me bond and the O1–C2–C3 plane (Figure 4B). This feature usually leads to retention of configuration of the stereocenter upon alkylation, so it is reasonable to think that the highly pyramidalized enolate must invert prior to alkylation to fulfill the experimental observation. In fact, the inverted enolate 2′_epi, which also exhibits a highly pyramidalized character (α = 28°), showed a slightly higher stability (ΔΔG = −0.8 kcal mol–1) than 2′ due to the release of torsional strain on the bicyclic scaffold upon deprotonation. Inspection of the Newman projection along the N4–C7a bonds revealed that both rings in enolate 2′ are more eclipsed than those in 2′_epi, as reflected by the smaller dihedral angles (Figure 4B). The activation barrier calculated for the pyramidal inversion of enolate 2′ (2′_TSinv) was exceedingly small (1.2 kcal mol–1), indicating a very fast interconversion between both enolates. The geometries of the minimum-energy transition structures (TS) for the C-alkylation of both enolates by the convex (2′_TSMeBr) and concave (2′_epi_TSMeBr) faces revealed a significant pyramidalization for both cases (α = 35° and 29°, respectively). Considering the rapid interconversion between reactant enolates 2′ and 2′_epi and the irreversible formation of products, the Curtin–Hammett principle can be applied. In this context, the difference in transition state energies (ΔΔG‡ = 0.9 kcal mol–1) indicates a preference for the sterically more-hindered concave (Si) face (2′_epi_TSMeBr). This difference leads to a theoretical kinetic 93:7 ratio for products 5a and 5a_epi, predicted from the Boltzmann distribution of all calculated alkylation TSs at the experimental reaction temperature (−78 °C), which is in good agreement with the experimental results. This preference for the apparently more hindered concave (Si) face can also be rationalized by the lower torsional strain around the bridgehead atoms upon enolate formation and alkylation, which is a common trend in fused five-membered bicyclic compound scaffolds. (6,27−29)

Figure 4

Figure 4. Minimum-energy pathways for the alkylation reaction of enolates 2′ (A) with bromomethane calculated with PCM(THF)/M06-2X/6-31+G(d,p). Free Gibbs energies (ΔG) calculated at 195 K are given in kcal mol–1. (B) Newman projections from N4 to C7a of the lowest energy structures for enolates 2′ and 2′_epi and transition states 2′_TSMeBr and 2′_epi_TSMeBr. Torsional strain is represented through the dihedral angles highlighted in cyan and magenta. Dihedral angles closer to 60° correspond to more staggered conformations. Pyramidalization is represented through the out-of-plane angle (in light brown) between the C2–CO2Me bond and the O1–C2–C3 plane. Angles close to 0° correspond to planarity.

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On the other hand, deprotonation of compound 3 leads to enolate (2proS,7S,7aR)-3′, which turns out to be enantiomer of enolate (2proR,7R,7aS)-2′_epi (Figure S3 in the Supporting Information). Therefore, both minimum-energy pathways starting from either 3′ or 2′ are geometrically and energetically equivalent (see Figure 4A and Figure S3 in the Supporting Information), and an analogous conclusion can be drawn. Since enolate 3′ is the most stable intermediate in this case, the alkylation reaction proceeds with retention of the configuration toward compound 6a (enantiomer of 5a), and the epimeric compound 6a_epi is formed as a minor product under Curtin–Hammett conditions.

Synthesis of α-Substituted Isoserines

Representative α-alkylated bicyclic acetals 5a, 5b, 5c, 6a, and 6c were subjected to acidic hydrolysis with 6 M HCl to obtain β-amino acid (R)-α-methylisoserine 7a, (R)-α-ethylisoserine 7b, (R)-α-benzylisoserine 7c, (S)-α-methylisoserine 8a, and (S)-α-benzylisoserine 8c, respectively, in good yields as hydrochloride salts (Scheme 4). In some cases (7a–c and 8a,c), the corresponding amino acid hydrochlorides were treated with propylene oxide to obtain free β-amino acids to compare their physical data with previously published data. Thus, the experimental data obtained for free (R)- and (S)-α-methylisoserine 7a and 8a as well as for β-amino acids 7b and 7c agree with those previously reported in the literature, (30) confirming the stereochemical outcome of the diastereoselective alkylation reactions. We tried to determine the enantiomeric purity of these Cα-tetrasubstituted β-amino acids using chiral HPLC without success. Fortunately, in the case of amino acids 7c and 8c (enantiomers), the enantiomeric purity could be measured by NMR using a chiral lanthanide shift reagent. In particular, a samarium(III) complex with (S,S)-ethylenediamine-N,N′-disuccinate allowed the separation of the signal (doublet) corresponding to a benzylic proton, demonstrating that the enantiomeric purity was >95:5 (Figure S20 in the Supporting Information). Considering the ability of non-natural β2,2-amino acids, (30) particularly α-methylisoserine, to induce folded conformations when incorporated into peptides and the few reported methods to synthesize them, (22) the methodology reported herein represents a valuable alternative.

Scheme 4

Scheme 4. Hydrolysis of Chiral Bicyclic Acetals 5a–c and 6a,c To Obtain Enantiomerically Pure (R)- and (S)-α-Alkylisoserines
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α-Substituted Isoserines as Precursors of β2,2-Amino Acids via Sulfamidate Chemistry

Five-membered cyclic sulfamidates are well-known valuable synthetic intermediates in organic chemistry for the regio- and stereoselective synthesis of a wide variety of chemicals. (31) Although the synthesis and reactivity of sulfamidates have been described in detail, (32,33) such derivatives are mostly monosubstituted or 1,2-disubstituted. In contrast, little is known about hindered sulfamidates. Our group has widely studied sulfamidates derived not only from serine, (34) isoserine, and α-methylserine (24) but also from α-methylisoserine. (22) Those building blocks were subjected to further nucleophilic ring-opening reactions to obtain unnatural amino acid derivatives, glycosyl amino acids, peptides, and glycopeptides. (23,34,35) On this basis, we envisioned to further explore the scope of a new class of hindered sulfamidates in ring-opening reactions with a variety of nucleophiles. As a representative example, the amino and acid groups of α-benzylisoserine (α-Bn-isoSer, 7c) were conveniently protected as a tert-butyl carbamate and a methyl ester, respectively, to obtain compound 9. Sulfamidate 10 was then generated using a modified protocol (22) involving the use of thionyl chloride (SOCl2) and pyridine (py) in acetonitrile (MeCN) as a solvent followed by oxidation of the cyclic sulfamidite intermediate with ruthenium tetraoxide (RuO4), generated in situ from ruthenium trichloride monohydrate (RuCl3·H2O) and sodium periodate (NaIO4) (Scheme 5). The structure of sulfamidate 10 was determined by X-ray analysis (Figure 5 and Supporting Information).

Scheme 5

Scheme 5. Conversion of (R)-α-Benzylisoserine 7c into Cyclic Sulfamidate 10
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Figure 5

Figure 5. ORTEP3 diagram of sulfamidate 10 obtained by X-ray diffraction analysis showing thermal ellipsoids at the 75% probability level.

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Chiral sulfamidate 10 was ring opened with different nucleophiles as an entry to various α-benzyl-β2-amino acids (Scheme 6). Reaction with sodium azide (NaN3) in DMF at room temperature followed by treatment with an aqueous 20% H2SO4 solution gave protected α-azido-α-benzyl-β-amino acid derivative 11, which was then hydrogenated to obtain N-Boc-protected methyl α-benzyl-2,3-diaminopropanoate 12. Finally, acidic hydrolysis of compound 12 with 6 M HCl yielded α-benzyl-α,β-diaminopropanoic acid 16 (α-Bn-DAP) as a hydrochloride salt. Using a similar protocol, when sulfamidate 10 was treated with phenylthiolate (PhS–), phenylselenolate (PhSe–), and fluoride (F–) followed by addition of 20% H2SO4, the corresponding ring-opening products 13, 14, and 15 were readily obtained in good yields. The competitive elimination reaction frequently observed in α-methylisoserine-derived sulfamidates (22,35) occurred only when fluoride was used as a nucleophile, and a phenyl acrylate derivative was obtained as a byproduct (21%). Ring-opening products 13, 14, and 15 were hydrolyzed with 6 M HCl to give β2,2-amino acids 17 (α-Bn-SPh-isoCys), 18 (α-Bn-SePh-isoSec), and 19 (α-Bn-α-F-β-Ala), respectively, as hydrochloride salts (Scheme 6). The absolute configuration of the ring-opening products and β2,2-amino acids was determined by comparing their optical properties with those reported in the literature, (36−40) demonstrating that the ring-opening reactions occur with inversion of the configuration at the chiral tetrasubstituted carbon center.

Scheme 6

Scheme 6. Nucleophilic Ring-Opening Reactions of Sulfamidate 10 Followed by Acid Hydrolysis To Obtain β2,2-Amino Acids 16–19
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Finally, sulfamidate 10 was reacted with Boc-Cys-OMe and a Cys-containing model tetrapeptide (Ac-Cys-Gly-Val-Ala-NH2) to obtain protected α-benzylnorlanthionine derivative 20 and a modified tetrapeptide 21 in 88% and 49% yields, respectively (Scheme 7). The good yield obtained for α-benzylnorlanthionine derivative 20 from cyclic sulfamidate 10 derived from α-Bn-isoSer using DBU as a base is similar to other ring-opening reactions of cyclic sulfamidates such as α-Me-isoSer derivatives. On the other hand, the yield of the synthesis of tetrapeptide 21 decreases, probably due to the large size of the nucleophile used to carry out the ring-opening reaction of cyclic sulfamidate 10. The α-benzylnorlanthionine scaffold is a mimetic of naturally occurring cross-linker bis-amino acid lanthionine, commonly found in peptidoglycans of certain Fusobacterium species (41) and antimicrobial lanthipeptides. (42,43)

Scheme 7

Scheme 7. Nucleophilic Ring-Opening Reactions of Sulfamidate 10 To Obtain α-Bn-norLan 20 and α-Bn-norLan-Containing Peptide 21
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Conclusion

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This report covers the synthesis of a diversity of enantiomerically pure β2,2-amino acids, considered challenging in organic synthesis, using a straightforward synthetic methodology from l-isoserine. The strategy involves the formation and subsequent diastereoselective alkylation of chiral bicyclic N,O-acetals to obtain α-alkylisoserine derivatives. Remarkably, these derivatives are alkylated with either retention or inversion of configuration depending on the relative configuration of the stereocenters. The alkylation mechanism involves a highly pyramidalized chiral enolate, which can undergo a fast pyramidal inversion. Alkylation occurs preferably by the ostensibly most-hindered concave face due to the reduced torsional strain at the bicyclic scaffold in the alkylation transition structure. As a synthetic application, a variety of enantiomerically pure quaternary α-alkylisoserines were synthesized. Further, α-benzylisoserine served as a template to generate a chiral sulfamidate scaffold that was adequately prepared to undergo stereospecific nucleophilic ring-opening reactions with inversion of the configuration at the stereogenic tetrasubstituted carbon center. This sulfamidate provided easy access to four representative β2,2-amino acids derived from α-benzyl-β-alanine incorporating amino, phenylthio, phenylselenyl, or fluoro groups at the α position as well as the bis-amino acid α-benzylnorlanthionine and a α-benzylnorlanthionine-containing peptide.

Experimental Section

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General and Experimental Methods

Commercial reagents were used without further purification. Analytical thin layer chromatography (TLC) was performed on Macherey-Nagel precoated aluminum sheets with a 0.20 mm thickness of silica gel 60 with fluorescent indicator UV254. TLC plates were visualized with UV light and by staining with a potassium permanganate solution (0.75 g f KMnO4, 5 g of K2CO3, and 0.63 mL of 10% NaOH in 100 mL of water) or a ninhydrin solution (1.5 g of ninhydrin in 100 mL of n-butanol and 3.0 mL of acetic acid). Column chromatography was performed on silica gel (230–400 mesh). 1H and 13C{1H} NMR spectra were measured with a 300 or 400 MHz spectrometer with TMS as the internal standard. Multiplicities are quoted as singlet (s), broad singlet (br s), doublet (d), doublet of doublets (dd), triplet (t), or multiplet (m). Spectra were assigned using COSY and HSQC experiments. The results of these experiments were processed with MestreNova software. High-resolution electrospray mass (ESI) spectra were recorded on a microTOF spectrometer; accurate mass measurements were achieved using sodium formate as an external reference.

Two-Dimensional NMR Experiments

Spectra were assigned using COSY and edited-HSQC experiments (blue color for CH2 and red color for CH and CH3 groups). NOESY experiments were recorded on a 400 MHz spectrometer at 298 K. The experiments were conducted using phase-sensitive ge-2D NOESY spectra. The number of scans used was 16, and the mixing time was 800 ms.

Disatereoselective Formation of Bicyclic N,O-Acetals 2 and 3

In a round-bottom flask, (S)-N-Boc-isoserine methyl ester (200 mg, 0.91 mmol) was dissolved in toluene (4 mL). Then, TMB (330 mg, 1.82 mmol) and CSA·H2O (46 mg, 0.18 mmol) were added. The solution was stirred under reflux in an oil bath for 1 h, until the starting materials disappeared. The reaction mixture was cooled to room temperature, diluted with diethyl ether (10 mL), and quenched with an aqueous saturated NaHCO3 solution (10 mL). The aqueous phase was extracted with diethyl ether (2 × 10 mL), and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was removed, and the crude product was purified by column chromatography (hexane/EtOAc, 7:3) to give bicyclic N,O-acetals 2 (123 mg, 55%) and 3 (74 mg, 33%) together with compounds 4 (29 mg, 13%) as yellow oils. This synthetic procedure was scaled up to obtain N,O-acetals 2 and 3 in gram quantities after column chromatography; 1.78 g of 2 (53%, dr 98:2, Rf = 0.33) and 1.07 g of 3 (32%, dr 99:1, Rf = 0.27) using the following conditions: (S)-N-Boc-isoserine methyl ester (3.00 g, 13.7 mmol), toluene (60 mL), TMB (4.97 g, 27.4 mmol), and CSA·H2O (693 mg, 2.74 mmol). The solution was stirred under reflux for 1 h, until the starting materials disappeared.
Methyl (2S,7R,7aS)-7-Methoxy-7,7a-dimethyl-5-oxotetrahydro-5H-oxazolo[4,3-b]oxazole-2-carboxylate (2)
[α]D25 = −127.3 (c 1.00, CHCl3). HRMS (ESI) m/z [M + H]+ calcd for C10H16NO6: 246.0972. Found: 246.0973. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.56 (dd, J = 8.6, 2.7 Hz, 1H, H2), 4.23 (dd, J = 12.7, 2.7 Hz, 1H, H3), 3.75 (s, 3H, CO2CH3), 3.66 (dd, J = 12.7, 8.6 Hz, 1H, H3), 3.48 (s, 3H, OCH3), 1.75 (s, 3H, CH3), 1.42 (s, 3H, CH3). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 171.2 (CO2Me), 160.1 (C5), 107.8 (C7), 102.7 (C7a), 73.3 (C2), 52.6 (CO2CH3), 51.1 (OCH3), 49.6 (C3), 18.3 (CH3), 15.9 (CH3).
Methyl (2S,7S,7aR)-7-Methoxy-7,7a-dimethyl-5-oxotetrahydro-5H-oxazolo[4,3-b]oxazole-2-carboxylate (3)
[α]D25 = −27.6 (c 1.00, CHCl3). HRMS (ESI) m/z [M + H]+ calcd for C10H16NO6: 246.0972. Found: 246.0966. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.44–4.37 (m, 2H, H2, H3), 3.8 (s, 3H, CO2CH3), 3.46 (s, 3H, OCH3), 3.44–3.36 (m, 1H, H3), 1.63 (s, 3H, CH3), 1.47 (s, 3H, CH3). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 170.9 (CO2Me), 160.4 (C5), 107.7 (C7), 102.4 (C7a), 73.3 (C2), 52.7 (CO2CH3), 51.1 (OCH3), 49.0 (C3), 18.0 (CH3), 15.7 (CH3).
Methyl (2S)-2-Hydroxy-3-((5S)-5-methoxy-5-methyl-4-methylene-2-oxooxazolidin-3-yl)propanoate and Ethyl (2S)-2-Hydroxy-3-((5R)-5-methoxy-5-methyl-4-methylene-2-oxooxazolidin-3-yl)propanoate (4)
HRMS (ESI) m/z [M + Na]+ calcd for C10H15NNaO6: 268.0792. Found: 268.0803. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.56 (dd, 1H, J = 8.2, 3.1 Hz, CH2═C), 4.52–4.44 (m, 1H, H2), 4.39 (t, 1H, J = 3.1 Hz, CH2═C), 3.92–3.74 (m, 5H, CO2CH3, OH, H3), 3.26 (s, 3H, OCH3), 3.15 (dd, 1H, J = 10.0 Hz, J = 4.0 Hz, H3), 1.67 (s, 3H, CH3). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 173.0 (CO2Me), 154.7 and 154.8 (C5), 143.7 and 143.8 (CH2═C), 106.0 and 106.1 (C7), 84.6 and 84.8 (CH2═C), 67.8 (C2), 53.1 and 53.2 (CO2CH3), 50.6 and 50.7 (OCH3), 44.7 (C3), 26.0 (CH3).

General Procedure for Diastereoselective Alkylation of Bicyclic N,O-Acetals

In a Schlenk flask, the bicyclic N,O-acetal (2 or 3) (100 mg, 0.4 mmol) was dissolved in dry THF (10 mL) under inert atmosphere conditions. Then, HMPA (285 μL, 1.65 mmol) was added, and the mixture was cooled to −78 °C. Afterward, the alkylating agent (1.25 mmol) was charged, and LHDMS (815 μL, 0.8 mmol) was added dropwise. After 5 min, the reaction was quenched with an aqueous saturated NH4Cl solution (10 mL) and warmed up to room temperature. The mixture was diluted with Et2O (25 mL), and the aqueous phase was extracted with Et2O (2 × 25 mL). The combined organic phase was dried over anhydrous Na2SO4, and the solvent was evaporated. The crude reaction corresponds to a mixture of both diastereoisomers, which were subjected to purification by column chromatography to obtain the major product as a colorless oil.
Methyl (2R,7R,7aS)-7-Methoxy-2,7,7a-trimethyl-5-oxotetrahydro-5H-oxazolo[4,3-b]oxazole-2-carboxylate (5a)
Yield of the alkylation of compound 2 with MeI was 95% with a diastereoselectivity of 83:17. After column chromatography (CHCl3/toluene/EtOAc 8:1.75:0.25), compound 5a was obtained in an 86% yield (89 mg) with a dr > 99:1. [α]D25 = −118.2 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C11H17NNaO6: 282.0948. Found: 282.0946. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.04 (d, 1H, J = 12.5 Hz, H3), 3.80 (s, 3H, CO2CH3), 3.70 (d, 1H, J = 12.5 Hz, H3), 3.46 (s, 3H, OCH3), 1.64 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.40 (s, 3H, CH3). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 173.1 (CO2Me), 160.9 (C5), 107.5 (C7), 102.6 (C7a), 81.5 (C2), 54.4 (C3), 52.9 (CO2CH3), 51.1 (OCH3), 25.1 (CH3), 17.8 (CH3), 16.0 (CH3).
Methyl (2S,7S,7aR)-7-Methoxy-2,7,7a-trimethyl-5-oxotetrahydro-5H-oxazolo[4,3-b]oxazole-2-carboxylate (6a)
Yield of the alkylation of compound 3 with MeI was 94% with a diastereoselectivity of 82:18. After column chromatography (CHCl3/toluene/EtOAc 8:1.75:0.25), compound 6a (enantiomer of 5a) was obtained in an 86% yield (87 mg) with a dr of 98:2. [α]D25 = +97.9 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C11H17NNaO6: 282.0944. Found: 282.0948. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.04 (d, 1H, J = 12.5 Hz, H3), 3.80 (s, 3H, CO2CH3), 3.70 (d, 1H, J = 12.5 Hz, H3), 3.46 (s, 3H, OCH3), 1.64 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.40 (s, 3H, CH3). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 173.1 (CO2Me), 160.9 (C5), 107.5 (C7), 102.6 (C7a), 81.5 (C2), 54.4 (C3), 52.9 (CO2CH3), 51.1 (OCH3), 25.1 (CH3), 17.8 (CH3), 16.0 (CH3).
Methyl (2R,7R,7aS)-2-Ethyl-7-methoxy-7,7a-dimethyl-5-oxotetrahydro-5H-oxazolo[4,3-b]oxazole-2-carboxylate (5b)
Yield of the alkylation of compound 2 with ethyl trifluoromethanesulfonate was 92% with a diastereoselectivity of 85:15. After column chromatography (CHCl3/toluene/EtOAc 8:1.75:0.25), compound 5b was obtained in an 81% yield (22 mg, from 0.1 mmol of 2) with a dr of 95:5. [α]D25 = −82.3 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C12H19NO6Na: 296.1105. Found: 296.1105. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.05 (d, 1H, J = 12.6 Hz, H3), 3.81 (s, 3H, CO2CH3), 3.71 (d, 1H, J = 9.2 Hz, H3), 3.46 (s, 3H, OCH3), 1.89–1.84 (m, 1H, CH2CH3), 1.70–1.58 (m, 1H, CH2CH3), 1.67 (s, 3H, CH3), 1.39 (s, 3H, CH3), 0.88 (t, 3H, J = 7.4 Hz, CH3CH2). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 173.0 (CO2Me), 160.7 (C5), 107.3 (C7), 102.3 (C7a), 85.2 (C2), 53.0 (C3), 52.7 (CO2CH3), 51.0 (OCH3), 31.7 (CH2CH3), 17.6 (CH3), 16.0 (CH3), 8.4 (CH3CH2).
Methyl (2R,7R,7aS)-2-Benzyl-7-methoxy-7,7a-dimethyl-5-oxotetrahydro-5H-oxazolo[4,3-b]oxazole-2-carboxylate (5c)
Yield of the alkylation of compound 2 with benzyl iodide was 91% with a diastereoselectivity of 80:20. After column chromatography (CHCl3/toluene/EtOAc 8:1.75:0.25), compound 5c was obtained in a 73% yield (101 mg) with a dr > 99:1. [α]D25 = −89.7 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C17H21NO6Na: 358.1262. Found: 358.1276. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.30–7.24 (m, 3H, PhCH2), 7.12 (dd, J = 7.8, 1.8 Hz, 2H, PhCH2), 4.24 (d, 1H, J = 12.8 Hz, H3), 3.74 (s, 3H, CO2CH3), 3.67 (d, 1H, J = 8.9 Hz, H3), 3.46 (s, 3H, OCH3), 3.09 (d, 1H, J = 12.0 Hz, CH2Ph), 2.99 (d, 1H, J = 12.0 Hz, CH2Ph), 1.71 (s, 3H, CH3), 1.37 (s, 3H, CH3). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 172.4 (CO2Me), 160.7 (C5), 134.4, 129.8, 128.5, 127.4, (Ph), 107.2 (C7), 102.7 (C7a), 85.1 (C2), 52.7 (C3), 52.6 (CO2CH3), 51.0 (OCH3), 44.6 (PhCH2), 17.5 (CH3), 16.0 (CH3).
Methyl (2S,7S,7aR)-2-Benzyl-7-methoxy-7,7a-dimethyl-5-oxotetrahydro-5H-oxazolo[4,3-b]oxazole-2-carboxylate (6c)
The yield of the alkylation of compound 3 with benzyl iodide was 89% with a diastereoselectivity of 80:20. After column chromatography (CHCl3/toluene/EtOAc 8:1.75:0.25), compound 6c (enantiomer of 5c) was obtained in a 68% yield (95 mg) with a dr of 98:2. [α]D25 = +78.5 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C17H21NO6Na: 358.1262. Found: 358.1263. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.30–7.24 (m, 3H, PhCH2), 7.12 (dd, J = 7.8, 1.8 Hz, 2H, PhCH2), 4.23 (d, 1H, J = 12.9 Hz, H3), 3.73 (s, 3H, CO2CH3), 3.69 (d, 1H, J = 8.9 Hz, H3), 3.46 (s, 3H, OCH3), 3.09 (d, 1H, J = 13.8 Hz, CH2Ph), 2.97 (d, 1H, J = 13.8 Hz, CH2Ph), 1.71 (s, 3H, CH3), 1.36 (s, 3H, CH3).
Methyl (2R,7R,7aS)-2-Allyl-7-methoxy-7,7a-dimethyl-5-oxotetrahydro-5H-oxazolo[4,3-b]oxazole-2-carboxylate (5d)
Yield of the alkylation of compound 2 with allyl iodide was 93% with a diastereoselectivity of 87:13. After column chromatography (CHCl3/toluene/EtOAc 8:1.75:0.25), compound 5d was obtained in an 85% yield (25 mg, from 0.1 mmol of 2) with a dr > 99:1. [α]D25 = −184.3 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C13H19NO6Na: 308.1105. Found: 308.1109. 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.68–5.59 (m, 1H, CH2CH═CH2), 5.17–5.12 (m, 2H, CH2CH═CH2), 4.11 (d, 1H, J = 12.7 Hz, H3), 3.80 (s, 3H, CO2CH3), 3.68 (d, 1H, J = 12.7 Hz, H3), 3.46 (s, 3H, OCH3), 2.55–2.38 (m, 2H, CH2CH═CH2), 1.66 (s, 3H, CH3), 1.39 (s, 3H, CH3). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 172.4 (CO2Me), 160.5 (C5), 130.7 (CH2CH═CH2), 120.5 (CH2CH═CH2), 107.4 (C7), 102.6 (C7a), 84.4 (C2), 52.8 (CO2CH3), 52.6 (C3), 51.1 (OCH3), 42.7 (CH2CH═CH2), 17.7 (CH3), 16.1 (CH3).

General Procedure for Hydrolysis of Alkylated Bicyclic N,O-Acetals

The corresponding alkylated compound (0.4 mmol of 5a–c or 6a,c) was charged in a round-bottom flask with an aqueous 6 M solution of HCl (5 mL). The mixture was stirred for 14 h under reflux in an oil bath. The solvent was evaporated; the residue was dissolved in water (10 mL) and extracted with EtOAc (10 mL). The aqueous phase was evaporated, and the amino acid hydrochloride salt was obtained and treated with ethanol/propylene oxide (3:1, 4 mL) to give the free amino acid as a white solid.
(R)-3-Amino-2-hydroxy-2-methylpropanoic Acid (7a)
Yield 98% (46 mg), ee 96%. [α]D25 = −7.2 (c 1.00, H2O). HRMS (ESI) m/z [M + H]+ calcd for C4H10NO3: 120.0655. Found: 120.0659. 1H NMR (D2O, 400 MHz): δ (ppm) 3.36 (d, 1H, J = 13.2 Hz, Hβ), 3.26 (d, 1H, J = 13.2 Hz, Hβ), 1.54 (s, 3H, CH3). 13C{1H} NMR (D2O, 100 MHz): δ (ppm) 176.3 (CO2H), 59.5 (Cα), 45.7 (Cβ), 22.6 (CH3). These data are consistent with those reported previously. (22)
(S)-3-Amino-2-hydroxy-2-methylpropanoic Acid (8a)
Yield 96% (44 mg), ee 94%. [α]D25 = +6.8 (c 1.00, H2O). HRMS (ESI) m/z [M + H]+ calcd for C4H10NO3: 120.0655. Found: 120.0654. 1H NMR (D2O, 400 MHz): δ (ppm) 3.36 (d, 1H, J = 13.2 Hz, Hβ), 3.26 (d, 1H, J = 13.2 Hz, Hβ), 1.54 (s, 3H, CH3). 13C{1H} NMR (D2O, 100 MHz): δ (ppm) 176.3 (CO2H), 59.5 (Cα), 45.7 (Cβ), 22.6 (CH3). These data are consistent with those reported previously.24 (22)
(R)-3-Amino-2-ethyl-2-hydroxypropanoic Acid (7b)
Yield 94% (46 mg), ee 86%. [α]D25 = −18.0 (c 1.00, H2O). HRMS (ESI) m/z [M + H]+ calcd for C5H12NO3: 134.0812. Found: 134.0816. 1H NMR (D2O, 400 MHz): δ (ppm) 3.30 (d, 1H, J = 13.3 Hz, Hβ), 3.05 (d, 1H, J = 13.3 Hz, Hβ), 1.79–1.70 (m, 1H, CH2CH3), 1.66–1.57 (m, 1H, CH2CH3), 0.81 (t, 3H, J = 7.5 Hz, CH3CH2). 13C{1H} NMR (D2O, 100 MHz): δ (ppm) 176.0 (CO2H), 75.7 (Cα), 45.4 (Cβ), 29.8 (CH2CH3), 6.8 (CH3CH2).
(R)-3-Amino-2-benzyl-2-hydroxypropanoic Acid (7c)
Yield 97% (71 mg), ee 96%. [α]D25 = −24.2 (c 1.00, H2O). HRMS (ESI) m/z [M + H]+ calcd for C10H14NO3: 196.0968. Found: 196.0970. 1H NMR (D2O, 400 MHz): δ (ppm) 7.31–7.24 (m, 3H, PhCH2), 7.18 (dd, 2H, J = 7.8, 1.8 Hz, PhCH2), 3.45 (d, 1H, J = 13.4 Hz, Hβ), 3.13 (d, 1H, J = 13.4 Hz, Hβ), 3.07 (d, 1H, J = 13.7 Hz, CH2Ph), 2.95 (d, 1H, J = 13.7 Hz, CH2Ph). 13C{1H} NMR (D2O, 100 MHz): δ (ppm) 174.7 (CO2H), 134.1, 130.2, 128.6, 127.6, (Ph), 75.8 (Cα), 45.2 (Cβ), 42.9 (PhCH2).
(S)-3-Amino-2-benzyl-2-hydroxypropanoic Acid (8c)
Yield 90% (50 mg), ee 96%. [α]D25 = +22.4 (c 1.00, H2O). HRMS (ESI) m/z [M + H]+ calcd for C10H14NO3: 196.0968. Found: 196.0965. 1H NMR (D2O, 400 MHz): δ (ppm) 7.31–7.20 (m, 5H, PhCH2), 3.25 (d, 1H, J = 13.2 Hz, Hβ), 3.01 (d, 1H, J = 13.5 Hz, Hβ), 3.01 (d, 1H, J = 13.5 Hz, CH2Ph), 2.94 (d, 1H, J = 13.2 Hz, CH2Ph).
Methyl (R)-2-Benzyl-3-((tert-butoxycarbonyl)amino)-2-hydroxy-propanoate (9)
In a round-bottom flask, methanol (2.4 mL) was cooled to 0 °C and acetyl chloride (0.4 mL) was added dropwise. Then, compound 7c (100 mg, 0.48 mmol) was added, and the reaction was stirred under reflux in an oil bath until the starting materials disappeared (2 h). The solvent was removed, and methyl (R)-3-amino-2-benzyl-2-hydroxy-propanoate was obtained as a colorless oil without purification with column chromatography. Yield 98% (105 mg). [α]D25 = −15.2 (c 1.00, H2O). HRMS (ESI) m/z [M + H]+ calcd for C11H16NO3: 210.1125. Found: 210.1126. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.30–7.23 (m, 3H, PhCH2), 7.20–7.17 (m, 2H, PhCH2), 3.73 (s, 3H, CO2Me), 3.36 (d, 1H, J = 13.1 Hz, Hβ), 3.09–3.03 (m, 3H, CH2Ph, Hβ). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 172.5 (CO2Me), 134.3, 129.9, 128.0, 127.0 (Ph), 75.4 (Cα), 52.0 (OMe), 44.8 (Cβ), 43.4 (PhCH2). Methyl (R)-3-amino-2-benzyl-2-hydroxy-propanoate (100 mg, 0.48 mmol) was dissolved in THF (32 mL), and N2CO3·10H2O (279 mg, 1.05 mmol) and Boc2O (136 mg, 0.62 mmol) were added to the solution. Then, water (8 mL) was added, and the mixture was stirred overnight. After this time, the solvent was removed and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and dried over anhydrous Na2SO4, and the solvent was evaporated. The crude product was purified by column chromatography (hexane/EtOAc 9:1), giving the final product 9 as a colorless oil. Yield 84% (124 mg). [α]D25 = −57.7 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C16H23NO5Na: 332.1468. Found: 332.1471. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.19–7.15 (m, 3H, PhCH2), 7.11–7.08 (m, 2H, J = 7.9, 1.8 Hz, PhCH2), 4.70 (br s, 1H, NH), 3.66 (s, 3H, CO2Me), 3.73–3.65 (m, 1H, Hβ), 3.38 (br s, 1H, OH), 3.20 (dd, 1H, J = 13.8, 4.5 Hz, Hβ), 2.98 (d, 1H, J = 13.6 Hz, CH2Ph), 2.84 (d, 1H, J = 13.6 Hz, CH2Ph), 1.35 (s, 9H, Boc). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 174.7 (CO2Me), 156.0 (CO2C(CH3)3), 135.1, 130.0, 128.3, 127.1 (Ph), 79.7 (Cα), 78.3 (CO2C(CH3)3), 52.8 (OMe), 47.7 (Cβ), 42.5 (PhCH2), 28.3 (C(CH3)3).
3-(tert-Butyl) 5-Methyl (R)-5-Benzyl-1,2,3-oxathiazolidine-3,5-dicarboxylate 2,2-dioxide (10)
To a solution of thionyl chloride (30.0 μL, 0.42 mmol) in dry acetonitrile (5 mL) was added another solution of compound 9 (100 mg, 0.32 mmol) in dry acetonitrile (2 mL) dropwise at −40 °C. The reaction was stirred for 45 min, and then pyridine (130 μL, 1.62 mmol) was added. The mixture was stirred until the starting materials disappeared (2 h). At that time, the reaction was quenched with water, warmed to room temperature, and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed under vacuum; the product was dissolved in acetonitrile (5 mL) and cooled to 0 °C. Ruthenium(III) chloride hydrate (2 mg, 0.005 mmol), sodium periodate (104 mg, 0.49 mmol), and water (5 mL) were added. The mixture was stirred for 2 h at 0 °C, and the aqueous phase was extracted with Et2O (3 × 5 mL). The organic phases were combined, washed with a saturated solution of NaHCO3, and dried over anhydrous Na2SO4. The solvent was evaporated, and the crude product was purified by column chromatography (hexane/EtOAc, 8:2), giving the final product 10 as a colorless oil. Yield 71% (85 mg). [α]D25 = −19.8 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C16H21NO7SNa: 394.0931. Found: 394.0930. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.28–7.22 (m, 3H, PhCH2), 7.12 (dd, 2H, J = 7.3, 2.3 Hz, PhCH2), 4.33 (d, 1H, J = 10.5 Hz, Hβ), 3.91 (d, 1H, J = 10.5 Hz, Hβ), 3.69 (s, 3H, CO2Me), 3.30 (m, 2H, CH2Ph), 1.46 (s, 9H, Boc). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 168.0 (CO2Me), 148.2 (CO2(CH3)3), 131.7, 130.1, 128.9, 128.2 (Ph), 86.1 (Cα), 85.3 (CO2C(CH3)3), 53.6 (OMe), 51.2 (Cβ), 42.2 (PhCH2), 27.9 (C(CH3)3).
Methyl (S)-2-Azido-2-benzyl-3-((tert-butoxycarbonyl)amino)propanoate (11)
Cyclic sulfamidate 10 (40 mg, 0.11 mmol) and sodium azide (32 mg, 0.49 mmol) were dissolved in DMF (4 mL) and stirred at 25 °C for 1 h until the starting material disappeared. After that time, the solvent was evaporated, and the residue was dissolved in a mixture of 20% aq. H2SO4 and CH2Cl2 (1:1, 5 mL). This mixture was stirred for 2 h at room temperature, and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was evaporated, and the crude product was purified by column chromatography (hexane/EtOAc, 7:3) to obtain the final product 11 as a colorless oil (30 mg, 83%). [α]D25 = +9.9 (c 1.00, CHCl3) HRMS (ESI) m/z [M + Na]+ calcd for C16H22N4O4Na: 357.1533. Found: 357.1532. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.29–7.17 (m, 3H, PhCH2), 7.12 (dd, 2H, J = 7.2, 1.9, PhCH2), 4.75 (br s, 1H, NH), 3.71 (s, 3H, CO2Me), 3.55 (dd, 1H, J = 14.0, 6.7 Hz, Hβ), 3.29 (dd, 1H, J = 14.0, 6.4 Hz, Hβ), 3.12 (d, 1H, J = 13.7 Hz, CH2Ph), 2.94 (d, 1H, J = 13.8 Hz, CH2Ph), 1.37 (s, 9H, Boc). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 170.9 (CO2Me), 155.6 (CO2C(CH3)3), 134.0, 130.1, 128.6, 127.6 (Ph), 80.0 (Cα), 70.8 (CO2C(CH3)3), 52.9 (OMe), 46.2 (Cβ), 41.1 (PhCH2), 28.3 (C(CH3)3).
Methyl (S)-2-Amino-2-benzyl-3-((tert-butoxycarbonyl)amino)propanoate (12)
Into a Schlenk reactor, palladium on carbon (3 mg, 10% mass) was suspended in methanol (4 mL) and prehydrogenated for 10 min. Then, compound 11 was dissolved in methanol (4 mL) and added to the catalyst in one portion (30 mg, 0.10 mmol). The reaction was stirred at room temperature for 2 h until the starting product disappeared. The mixture was filtered through diatomaceous earth and concentrated in vacuo, and the crude product was purified by column chromatography (hexane/EtOAc, 3:7) to obtain the final product 12 as a colorless oil (23 mg, 83%). [α]D25 = +9.3 (c 1.00, CHCl3). HRMS (ESI) m/z [M + H]+ calcd for C16H25N2O4: 309.1809. Found: 309.1818. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.25–7.16 (m, 3H, PhCH2), 7.10–7.02 (m, 2H, PhCH2), 4.85 (br s, 1H, NHBoc), 3.65 (s, 3H, CO2Me), 3.46 (dd, 1H, J = 13.6, 6.1 Hz, Hβ), 3.26 (dd, 1H, J = 13.6, 6.5 Hz, Hβ), 3.08 (d, 1H, J = 13.4 Hz, CH2Ph), 2.71 (d, 1H, J = 13.4 Hz, CH2Ph), 1.60 (br s, 2H, NH2), 1.37 (s, 9H, Boc). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 175.4 (CO2Me), 156.0 (C(CH3)3), 79.6 (Cα), 135.5, 129.9, 128.5, 127.2 (Ph), 62.5 (CO2C(CH3)3), 52.3 (OMe), 48.4 (Cβ), 43.2 (PhCH2), 28.4 (C(CH3)3).
Methyl (S)-2-Benzyl-3-((tert-butoxycarbonyl)amino)-2-(phenylthio)propanoate (13)
Cyclic sulfamidate 10 (38 mg, 0.116 mmol), DBU (18 μL, 0.122 mmol), and thiophenol (13 μL, 0.128 mmol) were dissolved in DMF (4 mL) and stirred at 50 °C in an oil bath until the starting materials disappeared (2 h). Then, the solvent was removed under vacuum; the residue was dissolved in a mixture of CH2Cl2 and 20% aq. H2SO4 (1:1, 5 mL) and stirred for 3 h. After that time, the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed, and the crude product was purified by column chromatography (hexane/EtOAc, 9:1) to obtain the final product 13 as a colorless oil (39 mg, 95%). [α]D25 = −30.1 (c 1.00, CHCl3). HRMS (ESI) m/z [M + H]+ calcd for C22H28NO4S: 402.1733. Found: 402.1726. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.46–7.08 (m, 10H, PhCH2, PhS), 5.07 (br s, 1H, NH), 3.55 (s, 3H, CO2Me), 3.45–3.39 (m, 1H, Hβ), 3.27–3.21 (m, 2H, CH2Ph, Hβ), 2.97 (d, 1H, J = 13.7 Hz, CH2Ph), 1.41 (s, 9H, Boc). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 171.8 (CO2Me), 155.7 (CO2C(CH3)3), 137.0, 135.3, 130.2, 129.9, 129.1, 129.0, 128.4, 127.6, 127.3, 127.2, (Ph), 79.5 (Cα), 60.0 (CO2C(CH3)3), 52.1 (OMe), 42.6 (Cβ), 40.3 (PhCH2), 28.4 (C(CH3)3).
Methyl (S)-2-Benzyl-3-((tert-butoxycarbonyl)amino)-2-(phenylselanyl)propanoate (14)
Cyclic sulfamidate 10 (37 mg, 0.10 mmol), triethylamine (35 μL, 0.25 mmol), and freshly distilled benzeneselenol (9 μL, 0.08 mmol) were dissolved in DMF (2 mL) and stirred at 50 °C in an oil bath until the starting materials disappeared by TLC monitoring (30 min). Then, the solvent was removed, and the residue was dissolved in a mixture of CH2Cl2 and 20% aq. H2SO4 (1:1, 5 mL) and stirred for 3 h. After that time, the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed, and the crude product was purified by column chromatography (hexane/EtOAc, 9:1) to obtain the final product 14 as a colorless oil (39 mg, 88%). [α]D25 = −49.7 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C22H27NNaO4Se: 472.0998. Found: 472.1009. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.66 (d, 2H, J = 7.5 Hz, SePh), 7.53–7.41 (m, 1H, SePh), 7.37 (dd, 2H, J = 8.3. 6.8 Hz, SePh), 7.34–7.12 (m, 5H, PhCH2), 5.19 (br s, 1H, NH), 3.66 (s, 3H, CO2Me), 3.61–3.47 (m, 2H, Hβ), 3.39 (d, 1H, J = 13.8 Hz, CH2Ph), 3.14 (d, 1H, J = 13.4 Hz, CH2Ph), 1.51 (s, 9H, Boc). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 172.9 (CO2Me), 155.7 (CO2C(CH3)3), 138.3, 136.0, 130.1, 129.7, 129.0, 128.5, 127.2, 126.1 (Ph), 79.5 (Cα), 55.2 (CO2C(CH3)3), 52.1 (OMe), 44.1 (Cβ), 40.9 (PhCH2), 28.4 (C(CH3)3).
Methyl (S)-2-Benzyl-3-((tert-butoxycarbonyl)amino)-2-fluoropropanoate (15)
Cyclic sulfamidate 10 (30 mg, 0.08 mmol) and 1 M solution of tetrabutylammonium fluoride in THF (105 μL, 0.105 mmol) were dissolved in DMF (2 mL) and stirred at 25 °C until the starting materials disappeared by TLC monitoring (5 h). Then, the solvent was removed, and the residue was dissolved in a mixture of CH2Cl2 and 20% aq. H2SO4 (1:1, 5 mL) and stirred for 3 h. After that time, the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed to give a mixture of two compounds in a ratio 79/21. The major compound was the desired product 15, which was accompanied with a side product arising from an elimination reaction [methyl (E)-2-(((tert-butoxycarbonyl)amino)methyl)-3-phenyl acrylate] (15b). The mixture was purified by column chromatography (hexane/EtOAc, 8:2) to obtain compounds 15 (19 mg, 76%) and 15b (4 mg, 17%), both as colorless oils. Data for compound 15: [α]D25 = +15.5 (c 1.00, CHCl3). HRMS (ESI) m/z [M + Na]+ calcd for C16H22FNNaO4: 334.1425. Found: 334.1428. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.33–7.17 (m, 5H, PhCH2), 4.88 (br s, 1H, NH), 3.85 (ddd, 1H, J = 12.9, 11.8, 7.5 Hz, Hβ), 3.73 (s, 3H, CO2Me), 3.52 (‘t’d, 1H, J = 14.8, 5.3 Hz, Hβ), 3.39–3.13 (m, 2H, CH2Ph), 1.47 (s, 9H, Boc). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 169.6 (CO2Me), 155.6 (CO2C(CH3)3), 133.7, 130.1, 128.5, 128.1, 127.4 (Ph), 97.0 (d, J = 190.3 Hz, Cα), 80.0 (CO2C(CH3)3), 52.6 (OMe), 45.9 (d, J = 23.2 Hz, Cβ), 40.6 (d, J = 20.9 Hz, PhCH2), 28.3 (C(CH3)3). 19F{1H} NMR (CDCl3, 282 MHz): −167.8. Data for compound 15b: HRMS (ESI) m/z [M + Na]+ calcd for C16H21NNaO4: 314.1363. Found: 314.1369. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.79 (s, 1H, CH═C), 7.54–7.32 (m, 5H, PhCH2), 5.06 (br s, 1H, NH), 4.22 (d, 2H, J = 5.9 Hz, Hβ), 3.85 (s, 3H, CO2Me), 1.44 (s, 9H, Boc). Physical data agree to those previously reported. (44)

General Procedure for Hydrolysis of Ring-Opening Products

Method A: The corresponding ring-opening compound (0.04 mmol of 13 or 15) was charged in a round-bottom flask with an aqueous 6 M solution of HCl (1 mL). The mixture was stirred for 14 h under reflux in an oil bath. The solvent was evaporated; the residue was dissolved in water (3 mL) and washed with EtOAc (3 mL). The aqueous phase was evaporated, and the corresponding amino acid hydrochloride salt (17 or 19) was obtained as a white solid. Method B: The ring-opening compound 12 (0.04 mmol) was dissolved in MeOH (2 mL), and LiOH·H2O (0.4 mmol) was added. The reaction mixture was stirred at room temperature until the starting materials disappeared by TLC monitoring (3 h). Then, an aqueous 2 M solution of HCl was added to give pH 2. The aqueous phase was evaporated, and the amino acid hydrochloride salt 16 was obtained as a white solid. Method C: The ring-opening compound 14 (0.04 mmol) was dissolved in MeOH (2 mL), and LiOH·H2O (0.4 mmol) was added. The reaction mixture was stirred at room temperature until the starting materials disappeared by TLC monitoring (3 h). An aqueous 2 M solution of HCl was added to adjust the pH to 6, and then CH2Cl2 (1 mL) and TFA (1 mL) were added. The mixture was stirred at room temperature for 1 h, and the solution was concentrated in vacuo to afford amino acid hydrochloride salt 18.
(S)-2,3-Diamino-2-benzylpropanoic Acid Hydrochloride (16)
Yield 96% (6 mg). [α]D25 = +11.8 (c 1.00, H2O). HRMS (ESI) m/z [M]+ calcd for C10H15N2O2: 195.1128. Found: 195.1135. 1H NMR (D2O, 400 MHz): δ (ppm) 7.60–7.39 (m, 3H, PhCH2), 7.33 (dd, 2H, J = 7.1, 2.4 Hz, PhCH2), 3.67–3–55 (m, 2H, Hβ), 3.52 (d, 1H, J = 14.2, CH2Ph), 3.20 (d, 1H, J = 14.2, CH2Ph). 13C{1H} NMR (D2O, 100 MHz) δ (ppm): 171.2 (CO2H), 131.8, 130.3, 129.5, 128.7 (Ph), 61.5 (Cα), 42.9 (Cβ), 39.5 (PhCH2).
(S)-3-Amino-2-benzyl-2-(phenylthio)propanoic Acid Hydrochloride (17)
Yield 89% (7 mg). [α]D25 = +20.0 (c 1.00, H2O). HRMS (ESI) m/z [M]+ calcd for C16H18NO2S: 288.1053. Found: 288.1046. 1H NMR (D2O, 400 MHz): δ (ppm) 7.53 (d, 2H, J = 6.8 Hz, PhS), 7.46–7.40 (m, 3H, PhS), 7.31–7.16 (m, 5H, PhCH2), 3.21 (d, 1H, J = 14.0 Hz, CH2Ph), 2.89–2.75 (m, 2H, CH2Ph, Hβ), 2.62 (d, 1H, J = 14.1 Hz, Hβ). 13C{1H} NMR (D2O, 100 MHz): δ (ppm) 176.4 (CO2H), 136.5, 136.4, 130.0, 129.8, 129.7, 129.3, 128.5, 127.1 (Ph), 63.3 (Cα), 42.8 (Cβ), 41.0 (PhCH2).
(S)-3-Amino-2-benzyl-2-(phenylselanyl)propanoic Acid Hydrochloride (18)
Yield 92% (10 mg). [α]D25 = +18.2 (c 1.00, H2O). HRMS (ESI) m/z [M]+ calcd for C16H18NO2Se: 336.0497. Found: 336.0497. 1H NMR (D2O, 400 MHz): δ (ppm) 7.62 (d, 2H, J = 7.4 Hz, PhSe), 7.43 (t, 1H, J = 7.4 Hz, PhSe), 7.34 (t, 2H, J = 7.4 Hz, PhSe), 7.27–7.22 (m, 3H, PhCH2), 7.14 (d, 2H, J = 6.9 Hz, PhCH2), 3.48 (d, 1H, J = 12.0 Hz, CH2Ph), 3.11 (d, 1H, J = 12.0 Hz, Hβ), 2.96 (d, 1H, J = 16.0 Hz, CH2Ph), 2.90 (d, 1H, J = 16.0 Hz, Hβ). 13C{1H} NMR (D2O, 100 MHz): δ (ppm) 174.8 (CO2H), 137.8, 135.4, 130.4, 129.9, 129.7, 128.8, 127.7, 124.8 (Ph), 54.5 (Cα), 42.7 (Cβ), 41.3 (PhCH2).
(S)-3-Amino-2-benzyl-2-fluoropropanoic Acid Hydrochloride (19)
Yield 92% (7 mg). [α]D25 = +13.5 (c 1.00, H2O). HRMS (ESI) m/z [M]+ calcd for C10H13FNO2: 198.0925. Found: 198.0931. 1H NMR (D2O, 400 MHz): δ (ppm) 7.27–7.23 (m, 3H, PhCH2), 7.17 (d, 2H, J = 7.1 Hz, PhCH2), 3.58–3.46 (m, 1H, Hβ), 3.34 (‘t’, 1H, J = 13.0 Hz, Hβ), 3.17–3.11 (m, 2H, CH2Ph). 13C{1H} NMR (D2O, 100 MHz): δ (ppm) 172.4 (d, J = 24.6 Hz, CO2H), 133.4, 130.2, 128.6, 127.7 (Ph), 95.3 (d, J = 189.9 Hz, Cα), 44.1 (d, J = 22.5 Hz, Cβ), 40.5 (d, J = 21.1 Hz, PhCH2). 19F{1H} NMR (D2O, 282 MHz): −165.3.
Methyl (S)-2-Benzyl-3-((tert-butoxycarbonyl)amino)-2-(((R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)thio)propanoate (20)
Sulfamidate 10 (20 mg, 0.05 mmol), DBU (9 μL, 0.06 mmol), and N-Boc-l-Cys-OMe (13 mg, 0.05 mmol) were dissolved in DMF (2 mL) and stirred at room temperature until the starting materials disappeared (2 h). Then, the solvent was eliminated, and the residue was dissolved in a mixture of CH2Cl2 and H2SO4 20% aq. (1:1, 4 mL) and stirred for 3 h. After that time, the aqueous phase was extracted with CH2Cl2 (3 × 4 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed, and the crude product was purified by column chromatography (hexane/EtOAc, 7:3) to obtain the final product 20 as a colorless oil. Yield 88% (25 mg). [α]D25 = −18.0 (c 1.00, H2O). HRMS (ESI) m/z [M + Na]+ calcd for C25H38N2NaO8S: 549.2241. Found: 549.2244. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.37–6.93 (m, 5H, PhCH2), 4.45 (s, 1H, Hαcys), 3.71 (s, 6H, 2 CO2Me), 3.56–3.29 (m, 2H, CH2Ph), 3.22 (dd, 1H, J = 13.6, 7.2, Hz, Hβ), 3.06–2.86 (m, 3H, 2Hβcys, Hβ), 1.39 (s, 9H, Boc), 1.38 (s, 9H, Boc). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm): 171.9 (CO2Me), 171.1 (CO2Me), 155.8 (CO2C(CH3)3), 155.2 (CO2C(CH3)3), 135.0, 130.0, 128.5, 127.4 (Ph), 80.3 (CO2C(CH3)3), 79.7 (CO2C(CH3)3), 77.2 (Cα), 52.7 (OMe), 52.6 (OMe), 54.5 (Cαcys), 42.9 (Cβ), 42.7 (Cβ), 31.6 (PhCH2), 28.4 (C(CH3)3), 28.3 (C(CH3)3).
Methyl (2S,5S,11R,14S)-11-Acetamido-1-amino-14-benzyl-14-(((tert-butoxycarbonyl)amino)methyl)-5-isopropyl-2-methyl-1,4,7,10-tetraoxo-13-thia-3,6,9-triazapentadecan-15-oate (21)
Sulfamidate 10 (19 mg, 0.05 mmol), Et3N (21 μL, 0.15 mmol), and Ac-CGVA-NH2 (24 mg, 0.06 mmol) were dissolved in DMF (2 mL). The reaction was stirred at room temperature followed by analytical RP-HPLC. After semipreparative RP-HPLC purification, peptide 21 was obtained as a white solid using the following conditions: a Phenomenex Luna C18(2) column (10 μ, 250 mm × 21.2 mm) and a dual-absorbance detector with a flow rate of 20 mL/min. Retention time (Rt) = 34.02 min (gradient: acetonitrile/water + 0.1% TFA (22.5:77.5) → (77.5:22.5), 37 min, λ = 212 nm). Yield 49% (17 mg). UPLC-MS: Rt = 4.92 min (Acquity UPLC BEH 1.7 μm C18, 2.1 × 100 mm (gradient: acetonitrile/water + 0.1% formic acid (5:95) → (100:0), 10 min, 0.45 mL/min, λ = 212 nm, 254 nm)). HRMS (ESI) m/z [M + Na]+ calcd for C31H48N6NaO9S: 703.3096. Found: 703.3084. 1H NMR (DMF-d7, 400 MHz): δ (ppm) 8.67 (t, 1H, J = 5.8 Hz, NH), 8.58 (d, 1H, J = 7.4 Hz, NH), 8.14 (t, 1H, J = 7.5 Hz, NH), 7.99 (t, 1H, J = 8.2 Hz, NH), 7.44–7.15 (m, 7H, Ph, NH2), 7.17 (t, 1H, J = 5.8 Hz, NH), 4.64 (t, 1H, J = 9.7 Hz, HαLan), 4.57–4.51 (m, 1H, HαAla), 4.48–4.33 (m, 1H, HαVal), 4.16 (dd, 1H, J = 16.9, 6.3 Hz, HβLan), 4.04–4.00 (m, 1H, HβLan), 3.64 (s, 2H, HαGly), 3.46 (s, 3H, OMe), 3.35 (d, 2H, J = 5.0 Hz, CH2Ph), 3.31 (dd, 1H, J = 8.2, 4.6 Hz, HβLan), 3.18–3.12 (m, 1H, HβCys), 2.38–2.28 (m, 1H, HβVal), 2.15 (s, 3H, NHCOCH3), 1.60 (s, 9H, NHBoc), 1.50 (d, 3H, J = 7.0 Hz, CH3Ala), 1.09 (dd, 6H, J = 12.8, 6.7 Hz, 2CH3Val). 13C{1H} NMR (DMF-d7, 100 MHz): δ (ppm) 174.8 (CO2Me), 172.0, 171.4, 171.0, 170.8, 169.7 (CON), 136.1 (C(CH3)3), 130.8, 130.3, 128.7, 128.4, 127.2 (Ph), 117.9 (CO2C(CH3)3), 77.2 (Cα), 58.9 (CαVal), 53.7 (Cαcys), 49.5 (CαAla), 43.1 (Cβ), 42.8 (CαGly), 39.2 (PhCH2), 30.8 (CβVal), 30.7 (CβLan), 28.1 (CO2C(CH3)3), 22.3 (NHCOCH3), 19.1 (CH3Val), 18.0 (CH3Val), 17.7 (CH3Ala).

Quantum Mechanical Calculations

Full geometry optimizations were carried out with Gaussian 16 (45) using the M06-2X hybrid functional (46) and 6-31+G(d,p) basis set in combination with ultrafine integration grids. Bulk solvent effects in toluene and tetrahydrofuran were considered implicitly through the IEF-PCM polarizable continuum model. (47) The possibility of different conformations was taken into account. Frequency analyses were carried out at the same level used in the geometry optimizations, and the nature of the stationary points was determined in each case according to the appropriate number of negative eigenvalues of the Hessian matrix. The quasiharmonic approximation reported by Truhlar et al. was used to replace the harmonic oscillator approximation for calculation of the vibrational contribution to enthalpy and entropy. (48) Scaled frequencies were not considered. Mass-weighted intrinsic reaction coordinate (IRC) calculations were carried out using the Gonzalez and Schlegel scheme (49,50) in order to ensure that the TSs indeed connected the appropriate reactants and products. The complex nature of the enolate inversion of 2′ to 2′_epi, which is also coupled with a conformational change at the oxazolidinone ring, caused the IRC calculations to fail in both the forward and the reverse directions. Gibbs free energies (ΔG) were used for the discussion on the relative stabilities of the considered structures. The lowest energy conformer for each calculated stationary point was considered in the discussion; all computed structures can be obtained from the authors upon request. Cartesian coordinates, electronic energies, entropies, enthalpies, Gibbs free energies, and lowest frequencies of the calculated structures are available in the Supporting Information.

X-ray Diffraction Analysis

CCDC 2122265–2122266 contain the supplementary crystallographic data for this paper. The SHELXL97 program (51) was used for refinement of the ecrystal structures, and hydrogen atoms were fitted at theoretical positions.

Determination of the Enantiomeric Purity of β-Amino Acids 7c and 8c

Following a recent but slightly modified procedure, (52,53) the corresponding amino acid 7c, 8c, or a mixture of both was dissolved in D2O to prepare a 0.05 M solution. The pH of these three solutions was adjusted to 10 with a 1 M KOH solution in D2O. Then, a solution of 8 mg/mL of samarium(III) complex with (S,S)-ethylenediamine-N,N′-disuccinate in D2O was prepared, and 0.2 mL of this solution was added to each of the corresponding NMR tubes containing 0.5 mL of a solution of amino acids 7c, 8c, or a mixture of both. The 1H NMR experiments were registered in a 400 MHz spectrometer at 298 K. Under these conditions, the doublet corresponding to the CHaHbPh signal appears separated by 0.02 ppm for both enantiomers, allowing their integration. Thus, in the case of β-amino acid 7c, this signal appears at 2.63 ppm (d, 1H, J = 13.7 Hz), while the same signal in the case of β-amino acid 8c appears at 2.65 ppm (d, 1H, J = 13.6 Hz). Taking into account that in the spectrum of each amino acid no signals of the other enantiomer were observed, we conclude that the enantiomeric purity for each of them is >95:5 (Supporting Information).

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c01034.

  • Additional experimental details, computational data and copies of 1H and 13C NMR spectra as well as 2D NMR spectra (COSY, edited-HSQC and NOESY) for all new compounds (PDF)

  • FAIR data, including the primary NMR FID files, for compounds 2 and 3 (ZIP)

Accession Codes

CCDC 2122265–2122266 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Author Information

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  • Corresponding Authors
  • Authors
    • Pablo Tovillas - Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
    • Claudio D. Navo - Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160 Derio, Spain;  Orcidhttps://orcid.org/0000-0003-0161-412X
    • Paula Oroz - Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
    • Alberto Avenoza - Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
    • Francisco Corzana - Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain;  Orcidhttps://orcid.org/0000-0001-5597-8127
    • María M. Zurbano - Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, La Rioja, Spain
    • Gonzalo Jiménez-Osés - Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160 Derio, Spain;  Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain;  Orcidhttps://orcid.org/0000-0003-0105-4337
  • Author Contributions

    P.T. and C.D.N.: These authors contributed equally to this work.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank the Agencia Estatal Investigación of Spain (AEI; RTI2018-099592-B-C21 and RTI2018-099592-B-C22 projects and FPI grant of P.T.), the Mizutani Foundation for Glycoscience (grant 200077), and the EU (Marie-Sklodowska Curie ITN, DIRNANO, grant agreement no. 956544). We also thank Universidad de La Rioja (Beronia cluster) for computer support. Part of this work corresponds to the Doctoral Thesis of Pablo Tovillas. (54)

References

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This article references 54 other publications.

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    A review. The use of peptidomimetics has emerged as a powerful means for overcoming the limitations inherent in the phys. characteristics of peptides thus improving their therapeutic potential. A peptidomimetic approach that has emerged in recent years with significant potential, is the use of β-amino acids. β-Amino acids are similar to α-amino acids in that they contain an N-terminus and a C-terminus. However, in β-amino acids two carbon atoms sep. these functional termini. β-Amino acids, with a specific side chain, can exist as the R or S isomers at either the α (C2) carbon or the β (C3) carbon. This results in a total of 4 possible diastereoisomers for any given side chain. The flexibility to generate a vast range of stereo- and regioisomers, together with the possibility of disubstitution, significantly expands the structural diversity of β-amino acids thereby providing enormous scope for mol. design. The incorporation of β-amino acids has been successful in creating peptidomimetics that not only have potent biol. activity, but are also resistant to proteolysis. This article reviews the rapidly expanding applications of β-amino acids in the design of bioactive peptide analogs ranging from receptor agonists and antagonists, MHC-binding peptides, antimicrobial peptides and peptidase inhibitors. Given their structural diversity taken together with the ease of synthesis and incorporation into peptide sequences using std. solid-phase peptide synthesis techniques, β-amino acids have the potential to form a new platform technol. for peptidomimetic design and synthesis.
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    Abele, S.; Seebach, D. Preparation of Achiral and of Enantiopure Geminally Disubstituted β-Amino Acids for β-Peptide Synthesis. Eur. J. Org. Chem. 2000, 2000, 1– 15,  DOI: 10.1002/(SICI)1099-0690(200001)2000:1<1::AID-EJOC1>3.0.CO;2-6
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    Wang, K.; Yu, J.; Shao, Y.; Tang, S.; Sun, J. Forming All-Carbon Quaternary Stereocenters by Organocatalytic Aminomethylation: Concise Access to β 2,2-Amino Acids. Angew. Chem., Int. Ed. 2020, 59, 23516– 23520,  DOI: 10.1002/anie.202009892
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    Forming All-Carbon Quaternary Stereocenters by Organocatalytic Aminomethylation: Concise Access to β2,2-Amino Acids
    Wang, Kai; Yu, Jianliang; Shao, Ying; Tang, Shengbiao; Sun, Jiangtao
    Angewandte Chemie, International Edition (2020), 59 (52), 23516-23520CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The asym. synthesis of β2,2-amino acids remains a formidable challenge in org. synthesis. Here a novel organocatalytic enantioselective aminomethylation of ketenes with stable and readily available N,O-acetals is reported, providing β2,2-amino esters bearing an all-carbon quaternary stereogenic center in high enantiomeric ratios with a catalytic amt. of chiral phosphoric acid [e.g., ketene I + acetal II → III (76%, 97:3 e.r.) in cyclohexane in presence of chiral phosphoric acid]. Typically, this transformation probably proceeds through an asym. counter-anion-directed catalysis. As a result, a concise, practical, and atom-economic protocol toward rapidly access to β2,2-amino acids has been developed.
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    Eitzinger, A.; Winter, M.; Schörgenhumer, J.; Waser, M. Quaternary β 2,2-Amino Acid Derivatives by Asymmetric Addition of Isoxazolidin-5-Ones to: para-Quinone Methides. Chem. Commun. 2020, 56, 579– 582,  DOI: 10.1039/C9CC09239K
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    Quaternary β2,2-amino acid derivatives by asymmetric addition of isoxazolidin-5-ones to para-quinone methides
    Eitzinger, Andreas; Winter, Michael; Schoergenhumer, Johannes; Waser, Mario
    Chemical Communications (Cambridge, United Kingdom) (2020), 56 (4), 579-582CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    The highly enantioselective (>99.5% ee) synthesis of a new class of densely functionalized β2,2-amino acid derivs. by reacting isoxazolidin-5-ones with para-quinone methides in the presence of chiral ammonium salt phase-transfer catalysts was developed. The reaction proceeds with exceptionally low catalyst loadings down to 20 ppm on gram scale and the utilization of the primary addn. products towards further manipulations was demonstrated for selected examples.
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    Avenoza, A.; Busto, J. H.; Corzana, F.; Jiménez-Osés, G.; Peregrina, J. M. SN2 vs. E2 on Quaternary Centres: An Application to the Synthesis of Enantiopure β 2,2-Amino Acids. Chem. Commun. 2004, 980– 981,  DOI: 10.1039/B400282B
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    Chemical Communications (Cambridge, United Kingdom) (2004), (8), 980-981CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    SN2 and E2 competing reactions in cyclic sulfamidates can be modulated by the change of an amide group to an ester group attached to the quaternary carbon activated for the nucleophilic attack, allowing an easy approach to enantiopure α,α-disubstituted β-amino acids.
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    Mazo, N.; García-González, I.; Navo, C. D.; Corzana, F.; Jiménez-Osés, G.; Avenoza, A.; Busto, J. H.; Peregrina, J. M. Synthesis of Mixed α/β2,2 -Peptides by Site-Selective Ring-Opening of Cyclic Quaternary Sulfamidates. Org. Lett. 2015, 17, 5804– 5807,  DOI: 10.1021/acs.orglett.5b02927
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    Synthesis of Mixed α/β2,2-Peptides by Site-Selective Ring-Opening of Cyclic Quaternary Sulfamidates
    Mazo, Nuria; Garcia-Gonzalez, Ivan; Navo, Claudio D.; Corzana, Francisco; Jimenez-Oses, Gonzalo; Avenoza, Alberto; Busto, Jesus H.; Peregrina, Jesus M.
    Organic Letters (2015), 17 (23), 5804-5807CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A method for site- and stereoselective peptide modification using a cyclic sulfamidate scaffold contg. peptides is described. A peptide synthesis strategy allowing the rapid generation of mixed α/β-peptides incorporating a sulfamidate residue, derived from 2-methylisoserine, has been generalized. The unique electrophilic nature of this scaffold for nucleophilic substitution at a quaternary center with total inversion of its configuration, which was demonstrated computationally, allows for site-selective conjugation with various nucleophiles, such as anomeric thiocarbohydrates and pyridines. This strategy provides rapid access to complex thioglyco-α/β-conjugates and charged α/β-peptides.
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    Tovillas, P.; García-González, I.; Oroz, P.; Mazo, N.; Avenoza, A.; Corzana, F.; Jiménez-Osés, G.; Busto, J. H.; Peregrina, J. M. Tn Antigen Mimics by Ring-Opening of Chiral Cyclic Sulfamidates with Carbohydrate C1-S-and C1-O-Nucleophiles. J. Org. Chem. 2018, 83, 4973– 4980,  DOI: 10.1021/acs.joc.7b03225
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    Tovillas, Pablo; Garcia, Ivan; Oroz, Paula; Mazo, Nuria; Avenoza, Alberto; Corzana, Francisco; Jimenez-Oses, Gonzalo; Busto, Jesus H.; Peregrina, Jesus M.
    Journal of Organic Chemistry (2018), 83 (9), 4973-4980CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Starting from com. available (S)-isoserine and effectively accessible (S)-α-methylserine, enantiopure cyclic sulfamidates have been prepd. as chiral building blocks for the synthesis of various S- and O-glycosylated amino acid derivs., including unnatural variants of the Tn antigen, through highly chemo-, regio-, and stereoselective nucleophilic ring-opening reactions with carbohydrate C1-S- and C1-O-nucleophiles.
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    Montchamp, Jean-Luc; Tian, Feng; Hart, Matthew E.; Frost, J. W.
    Journal of Organic Chemistry (1996), 61 (11), 3897-3899CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Vicinal diequatorial diols are selectively protected as 2,3-butane bisacetals (BBA) upon refluxing polyols in methanol soln. with 2,2,3,3-tetramethoxybutane (TMB), tri-Me orthoformate, and catalytic camphorsulfonic acid. TMB reagent is prepd. inexpensively on a large scale and conveniently purified by distn. In addn. to its selectivity, BBA protection affords products in moderate to high yields that are generally cryst. and display diagnostic NMR spectra. Use of BBA protection is illustrated for polyols ranging from carbohydrates to carbocycles such as myo-inositol and quinic acid.
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    Hexamethylphosphoric triamide
    Normant, Henri
    Angewandte Chemie, International Edition in English (1967), 6 (12), 1046-67CODEN: ACIEAY; ISSN:0570-0833.
    A review, with 184 references, of the prepn., structure, and basicity of the title compd. (I), complexes of I with org. compds., Lewis acids, and organometallic compds., I as a solvent, the reaction of I with electrophiles and alkali metals, I as a catalyst in the prepn. of PhN:C:NPh, I (with electron donor properties) as a reaction medium, I as an electron acceptor in redn. reactions, and the use of I as a polymn. catalyst.
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    Gutiérrez-Jiménez, M. I.; Aydillo, C.; Navo, C. D.; Avenoza, A.; Corzana, F.; Jiménez-Osés, G.; Zurbano, M. M.; Busto, J. H.; Peregrina, J. M. Bifunctional Chiral Dehydroalanines for Peptide Coupling and Stereoselective S-Michael Addition. Org. Lett. 2016, 18, 2796– 2799,  DOI: 10.1021/acs.orglett.6b00840
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    Bifunctional chiral dehydroalanines for peptide coupling and stereoselective S-Michael addition
    Gutierrez-Jimenez, Marta I.; Aydillo, Carlos; Navo, Claudio D.; Avenoza, Alberto; Corzana, Francisco; Jimenez-Oses, Gonzalo; Zurbano, Maria M.; Busto, Jesus H.; Peregrina, Jesus M.
    Organic Letters (2016), 18 (12), 2796-2799CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A second generation of chiral bicyclic dehydroalanines easily accessible from serine has been developed. These scaffolds behaved as excellent S-Michael acceptors when tri-O-acetyl-2-acetamido-2-deoxy-1-thio-α-D-galactopyranose (abbreviated as GalNAc-α-SH) was used as a nucleophile. This addn. proceeds with total chemo- and stereoselectivity, complete atom economy, quickly, and at room temp., making it a true click reaction. The Michael adducts were easily transformed into S-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-L- and -D-cysteines, which can be regarded as mimics of the Tn antigen derived from L-Ser (α-D-GalNAc-L-Ser) and D-Ser (α-D-GalNAc-D-Ser), resp.
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    Wang, H.; Houk, K. N. Torsional Control of Stereoselectivities in Electrophilic Additions and Cycloadditions to Alkenes. Chem. Sci. 2014, 5, 462– 470,  DOI: 10.1039/C3SC52538D
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    Torsional control of stereoselectivities in electrophilic additions and cycloadditions to alkenes
    Wang, Hao; Houk, K. N.
    Chemical Science (2014), 5 (2), 462-470CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A review. Torsional effects control the π-facial stereoselectivities of a variety of synthetically important organicreactions. This review surveys theor. calcns. that have led to the understanding of the influence of the torsional effects on several types of stereoselective org. reactions, esp. electrophilic addns. and cycloaddns. to alkenes.
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    Schnermann, M. J.; Untiedt, N. L.; Jiménez-Osés, G.; Houk, K. N.; Overman, L. E. Forming Tertiary Organolithiums and Organocuprates from Nitrile Precursors and Their Bimolecular Reactions with Carbon Electrophiles to Form Quaternary Carbon Stereocenters. Angew. Chem., Int. Ed. 2012, 51, 9581– 9586,  DOI: 10.1002/anie.201205001
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    Forming Tertiary Organolithiums and Organocuprates from Nitrile Precursors and their Bimolecular Reactions with Carbon Electrophiles to Form Quaternary Carbon Stereocenters
    Schnermann, Martin J.; Untiedt, Nicholas L.; Jimenez-Oses, Gonzalo; Houk, Kendall N.; Overman, Larry E.
    Angewandte Chemie, International Edition (2012), 51 (38), 9581-9586, S9581/1-S9581/126CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A general procedure for the synthesis of tertiary trialkyl-substituted organolithiums and organocuprates was reported. These intermediates was employed in the stereocontrolled construction of quaternary carbon stereocenters.
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    Huang, Y.; Zhang, Y. B.; Chen, Z. C.; Xu, P. F. A Concise Synthesis of (R)- and (S)-α-Alkyl Isoserines from d- and l-Malic Acids. Tetrahedron Asymmetry 2006, 17, 3152– 3157,  DOI: 10.1016/j.tetasy.2006.11.033
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    A concise synthesis of (R)- and (S)-α-alkyl isoserines from D- and L-malic acids
    Huang, Yan; Zhang, Yong-Bo; Chen, Zhi-Ce; Xu, Peng-Fei
    Tetrahedron: Asymmetry (2006), 17 (22), 3152-3157CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
    A simple and diastereoselective method for the synthesis of (R)- and (S)-α-alkyl isoserines was developed in four steps starting from com. available D- and L-malic acid, resp. This approach featured stereo-controlled alkylation of 2-(2-tert-butyl-5-oxo-1,3-dioxolan-4-yl)acetic acid followed by a Curtius rearrangement.
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    Baig, R. B. N.; Nadagouda, M. N.; Varma, R. S. Cyclic Sulfamidates Enabled Syntheses of Amino Acids, Peptides, Carbohydrates and Natural Products. Aldrichimica Acta 2015, 48, 71– 80
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    Cohen, S. B.; Halcomb, R. L. Application of Serine- and Threonine-Derived Cyclic Sulfamidates for the Preparation of S-Linked Glycosyl Amino Acids in Solution- and Solid-Phase Peptide Synthesis. J. Am. Chem. Soc. 2002, 124, 2534– 2543,  DOI: 10.1021/ja011932l
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    Application of Serine- and Threonine-Derived Cyclic Sulfamidates for the Preparation of S-Linked Glycosyl Amino Acids in Solution- and Solid-Phase Peptide Synthesis
    Cohen, Scott B.; Halcomb, Randall L.
    Journal of the American Chemical Society (2002), 124 (11), 2534-2543CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Cyclic sulfamidates I (R = H, Me; R1 = H, CH2C6H4OMe-4) were synthesized from L-serine and allo-L-threonine. These cyclic sulfamidates reacted with a variety of unprotected 1-thio sugars in aq. bicarbonate buffer (pH 8) to afford the corresponding S-linked serine- and threonine-glycosyl amino acids with good diastereoselectivity (≥97%) after hydrolysis of the N-sulfates. For example, I (R = H, Me; R1 = H) reacted with 1-deoxy-1-thio-β-D-glucose sodium salt to give S-linked amino acids II. For dipeptide synthesis, sulfamidate ester I (R = H, R1 = CH2C6H4OMe-4) was hydrogenated to give the free acid, which, was, then, coupled with H-Leu-OH, followed by chemoselective ligation with 1-deoxy-1-thio-β-D-glucose sodium salt to afford an S-linked glycopeptide III in 80% yield. III was also efficiently synthesized on solid support by, first, coupling I (R = H, R1 = CH2C6H4OMe-4) in its free acid form with resin-bound L-leucine, followed by N-deprotection of the p-methoxybenzyl group, and then, chemoselective ligation with 1-deoxy-1-thio-β-D-glucose·Na salt. After deprotection and resin cleavage steps, III was obtained with 94% purity.
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    Jamieson, A. G.; Boutard, N.; Beauregard, K.; Bodas, M. S.; Ong, H.; Quiniou, C.; Chemtob, S.; Lubell, W. D. Positional Scanning for Peptide Secondary Structure by Systematic Solid-Phase Synthesis of Amino Lactam Peptides. J. Am. Chem. Soc. 2009, 131, 7917– 7927,  DOI: 10.1021/ja9010628
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    Positional scanning for peptide secondary structure by systematic solid-phase synthesis of amino lactam peptides
    Jamieson, Andrew G.; Boutard, Nicolas; Beauregard, Kim; Bodas, Mandar S.; Ong, Huy; Quiniou, Christiane; Chemtob, Sylvain; Lubell, William D.
    Journal of the American Chemical Society (2009), 131 (22), 7917-7927CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Incorporation of amino lactams into biol. active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection (Fmoc = 9-fluorenylmethyloxycarbonyl) strategy has been developed for the systematic synthesis of peptides contg. configurationally defined α- and β-amino γ-lactams. N-Alkylation of N-silyl peptides with five- and six-member cyclic sulfamidates (I) and (II) minimized bis-alkylation and provided N-alkyl peptides, which underwent lactam annulation under microwave heating. Employing this solid-phase protocol on the growth hormone secretagogue GHRP-6, as well as on the allosteric modulator of the IL-1 receptor 101.10, has furnished 16 amino lactam derivs. and validated the effectiveness of this approach on peptides bearing aliph., arom., branched, charged, and heteroat. side chains. The binding affinity IC50 values of the GHRP-6 lactam analogs on both the GHS-R1a and CD36 receptors are reported as well as inhibition of thymocyte proliferation measurements for the 101.10 lactam analogs. In these cases, lactam analogs were prepd. exhibiting similar or improved properties compared with the parent peptide. Considering the potential for amino lactams to induce peptide turn conformations, the effective method described herein for their supported construction on growing peptides, and for the systematical amino lactam scan of peptides, has proven useful for the rapid identification of the secondary structure necessary for peptide biol. activity.
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    De Luca, S.; Digilio, G.; Verdoliva, V.; Saviano, M.; Menchise, V.; Tovillas, P.; Jiménez-Osés, G.; Peregrina, J. M. A Late-Stage Synthetic Approach to Lanthionine-Containing Peptides via S-Alkylation on Cyclic Sulfamidates Promoted by Molecular Sieves. Org. Lett. 2018, 20, 7478– 7482,  DOI: 10.1021/acs.orglett.8b03254
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    A late-stage synthetic approach to lanthionine-containing peptides via S-alkylation on cyclic sulfamidates promoted by molecular sieves
    De Luca, Stefania; Digilio, Giuseppe; Verdoliva, Valentina; Saviano, Michele; Menchise, Valeria; Tovillas, Pablo; Jimenez-Oses, Gonzalo; Peregrina, Jesus M.
    Organic Letters (2018), 20 (23), 7478-7482CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A one-pot, high-yield procedure for synthesizing lanthionine-contg. peptides was developed. It relies on the S-alkylation of cysteine-contg. peptides with chiral cyclic sulfamidates. The key feature of this approach is the use of mild reaction conditions (only activated mol. sieves are employed as the catalyst), leading to good chemoselectivity and excellent stereochem. control. The potential of the new methodol. has been investigated by synthesizing the thioether ring of a natural antibiotic, Haloduracin β.
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    Navo, C. D.; Mazo, N.; Avenoza, A.; Busto, J. H.; Peregrina, J. M.; Jiménez-Osés, G. Substituent Effects on the Reactivity of Cyclic Tertiary Sulfamidates. J. Org. Chem. 2017, 82, 13250– 13255,  DOI: 10.1021/acs.joc.7b02352
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    Substituent Effects on the Reactivity of Cyclic Tertiary Sulfamidates
    Navo, Claudio D.; Mazo, Nuria; Avenoza, Alberto; Busto, Jesus H.; Peregrina, Jesus M.; Jimenez-Oses, Gonzalo
    Journal of Organic Chemistry (2017), 82 (24), 13250-13255CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    The reactivity of cyclic tertiary sulfamidates derived from α-methylisoserine strongly depends on the substitution at the C and N termini. These substrates are one of the very few examples able to undergo nucleophilic ring opening at a quaternary carbon with complete inversion of the configuration, as demonstrated both exptl. and computationally. When the sulfonamide is unprotected, the characteristic ring-opening reaction is completely silenced, which explains that the majority of the ring-opening reactions reported in the literature invoke N-alkyl or N-carbonyl-protected sulfamidates. Accumulation of neg. charge at the NSO3 moiety in the transition state, esp. when the sulfonamide NH is deprotonated, drastically raises the activation barrier for the nucleophilic attack. On the other hand, ester groups at the carboxylic position favor ring opening, whereas amides allow competition between the substitution and elimination pathways. Using pyridine as a nucleophilic probe, we have demonstrated both exptl. and computationally that a proper selection of the substitution scheme can enhance the synthetic scope of α-methylisoserine-derived sulfamidates, switching off and on the nucleophilic ring-opening in a controlled manner. This is particularly convenient for hybrid α/β-peptide synthesis, as demonstrated recently by our group.
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    Park, Y.; Kang, S.; Lee, Y. J.; Kim, T. S.; Jeong, B. S.; Park, H. G.; Jew, S. S. Highly Enantioselective Synthesis of (S)-α-Alkyl-α,β- Diaminopropionic Acids via Asymmetric Phase-Transfer Catalytic Alkylation of 2-Phenyl-2-Imidazoline-4-Carboxylic Acid Tert-Butyl Esters. Org. Lett. 2009, 11, 3738– 3741,  DOI: 10.1021/ol9013552
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    Highly Enantioselective Synthesis of (S)-α-Alkyl-α,β-diaminopropionic Acids via Asymmetric Phase-Transfer Catalytic Alkylation of 2-Phenyl-2-imidazoline-4-carboxylic Acid tert-Butyl Esters
    Park, Yohan; Kang, Sukhoon; Lee, Young Ju; Kim, Taek-Soo; Jeong, Byeong-Seon; Park, Hyeung-geun; Jew, Sang-sup
    Organic Letters (2009), 11 (16), 3738-3741CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    An efficient enantioselective synthetic method for (S)-α-alkyl-α,β-diaminopropionic acid is reported. The asym. phase-transfer catalytic alkylation of N(1)-Boc-2-phenyl-2-imidazoline-4-carboxylic acid tert-Bu ester in the presence of chiral quaternary ammonium catalyst gave the corresponding alkylated products (93-98% ee) which could be transformed to enantioenriched α-alkyl-α,β-diaminopropionic acids.
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  37. 37
    Castellanos, E.; Reyes-Rangel, G.; Juaristi, E. Diastereoselective Electrophilic Amination of Chiral 1-Benzoyl-2,3,5,6-Tetrahydro-3-Methyl-2-(1-Methylethyl)Pyrimidin-4(1H)-One for the Asymmetric Syntheses of α-Substituted α,β-Diaminopropanoic Acids. Helv. Chim. Acta 2004, 87, 1016– 1024,  DOI: 10.1002/hlca.200490073
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    Enantioselective syntheses of β-amino acids: Part 15. Diastereoselective electrophilic amination of chiral 1-benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one for the asymmetric syntheses of α-substituted α,β-diaminopropanoic acids
    Castellanos, Elena; Reyes-Rangel, Gloria; Juaristi, Eusebio
    Helvetica Chimica Acta (2004), 87 (4), 1016-1024CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
    The chiral compds. (R)- and (S)-1-benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one [(R)- and (S)-I], derived from (R)- and (S)-asparagine, resp., were used as convenient starting materials for the prepn. of the enantiomerically pure α-alkylated α,β-diamino acids (R)- and (S)-H2NCH2CR(NH2)CO2H (II; R = Me, Et, Bn). The chiral lithium enolates of (R)- and (S)-I were alkylated and the resulting diastereoisomeric products were aminated with di-tert-Bu azodicarboxylate (DBAD), giving rise to the diastereoisomerically pure (≥ 98%) compds. III (2R,5S) and corresponding 2S,5R isomers. The target compds. (R)- and (S)-II could then be obtained in good yields and high purities by a hydrolysis/hydrogenolysis/hydrolysis sequence.
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  38. 38
    Cadart, T.; Berthonneau, C.; Levacher, V.; Perrio, S.; Brière, J. F. Enantioselective Phase-Transfer Catalyzed α-Sulfanylation of Isoxazolidin-5-Ones: An Entry to β2,2-Amino Acid Derivatives. Chem. Eur. J. 2016, 22, 15261– 15264,  DOI: 10.1002/chem.201603910
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    Enantioselective Phase-Transfer Catalyzed α-Sulfanylation of Isoxazolidin-5-ones: An Entry to β2,2-Amino Acid Derivatives
    Cadart, Timothee; Berthonneau, Clement; Levacher, Vincent; Perrio, Stephane; Briere, Jean-Francois
    Chemistry - A European Journal (2016), 22 (43), 15261-15264CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    An unprecedented enantioselective α-functionalization of C4-substituted N-alkoxycarbonyl isoxazolidin-5-ones, readily available platforms from Meldrum's acid derivs., by N-sulfanylphthalimide (PhthSR) electrophiles was achieved upon an efficient phase-transfer catalytic approach, mediated by a com. N-spiro quaternary ammonium catalyst. Two catalytic activities of the in situ formed R4N+Phth- species were highlighted, the phtalimidate being involved in the anion metathesis event and likely as a Bronsted base. This sequence offers a straightforward access to α,α-disubstituted isoxazolidinones, which turned out to be useful precursors of α-sulfanyl-β2,2-amino acid derivs.
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    Edmonds, M. K.; Graichen, F. H. M.; Gardiner, J.; Abell, A. D. Enantioselective Synthesis of α-Fluorinated β2-Amino Acids. Org. Lett. 2008, 10, 885– 887,  DOI: 10.1021/ol703045z
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    Enantioselective synthesis of α-fluorinated β2-amino acids
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    Organic Letters (2008), 10 (5), 885-887CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    A methodol. for the enantioselective synthesis of α-fluorinated β2-amino acids has been developed from readily available carboxylic acids (I) (R1 = Ph, cyclohexyl). Conversion to the Evan's oxazolidinone followed by enantioselective fluorination and alkylation gave (II) (R1 = Ph, cyclohexyl) in high diastereomeric excess (>95%). Subsequent removal of the oxazolidinone and amination at the Bn-protected hydroxyl center gave optically active α-fluorinated β2-amino acids.
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    Peddie, V.; Pietsch, M.; Bromfield, K. M.; Pike, R. N.; Duggan, P. J.; Abell, A. D. Fluorinated β2- and β3-Amino Acids: Synthesis and Inhibition of α-Chymotrypsin. Synthesis 2010, 2010, 1845– 1859,  DOI: 10.1055/s-0029-1218743
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    Vasstrand, E. N.; Hofstad, T.; Endresen, C.; Jensen, H. B. Demonstration of Lanthionine as a Natural Constituent of the Peptidoglycan of Fusobacterium Nucleatum. Infect. Immun. 1979, 25, 775– 780,  DOI: 10.1128/iai.25.3.775-780.1979
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    Demonstration of lanthionine as a natural constituent of the peptidoglycan of Fusobacterium nucleatum
    Vasstrand, Endre N.; Hofstad, Tor; Endresen, Curt; Jensen, Harald B.
    Infection and Immunity (1979), 25 (3), 775-80CODEN: INFIBR; ISSN:0019-9567.
    Peptidoglycan was purified from the oral bacterium, F. nucleatum strain Fev 1, by boiling Na dodecyl sulfate and Pronase. The compn. of this peptidoglycan was similar to that of other gram-neg. bacteria, except that it lacked diaminopimelic acid. Lanthionine, the monosulfur analog of diaminopimelic acid, was identified as the diaminodicarboxylic acid of this peptidoglycan. It is assumed that lanthionine replaced diaminopimelic acid. Thus, the peptidoglycan of F. nucleatum Fev 1 is one of the few known sources of naturally occurring lanthionine.
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    Chatterjee, C.; Paul, M.; Xie, L.; van der Donk, W. A. Biosynthesis and Mode of Action of Lantibiotics. Chem. Rev. 2005, 105, 633– 683,  DOI: 10.1021/cr030105v
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    Biosynthesis and Mode of Action of Lantibiotics
    Chatterjee, Champak; Paul, Moushumi; Xie, Lili; Van der Donk, Wilfred A.
    Chemical Reviews (Washington, DC, United States) (2005), 105 (2), 633-683CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. The review discusses gene organization of lantibiotics-producing microorganisms; structures, biosynthesis, regulation of prodn., and mode of action of lantibiotics. Self immunity of the producing strains, lantibiotic engineering, and resistance against nisin are also discussed.
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    Tabor, A. B. The Challenge of the Lantibiotics: Synthetic Approaches to Thioether-Bridged Peptides. Org. Biomol. Chem. 2011, 9, 7606– 7628,  DOI: 10.1039/c1ob05946g
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    The challenge of the lantibiotics: synthetic approaches to thioether-bridged peptides
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    Organic & Biomolecular Chemistry (2011), 9 (22), 7606-7628CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    A review. The unique antibacterial properties and structural complexity of the lantibiotics has stimulated considerable interest in the development of methodol. for the synthesis of these peptides. One of the most challenging issues has been the synthesis of polycyclic peptides with multiple thioether bridges between side-chains, which are a characteristic feature of the lantibiotics. In this perspective, the different approaches to this problem, including soln.-phase synthesis, solid-phase synthesis, biomimetic approaches and biotransformation strategies, are reviewed, highlighting the advances resulting from each of these approaches.
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    Lühr, S.; Holz, J.; Zayas, O.; Wendisch, V.; Börner, A. Synthesis of Chiral β 2-Amino Acids by Asymmetric Hydrogenation. Tetrahedron Asymmetry 2012, 23, 1301– 1319,  DOI: 10.1016/j.tetasy.2012.08.010
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    Synthesis of chiral β2-amino acids by asymmetric hydrogenation
    Luehr, Susan; Holz, Jens; Zayas, Odalys; Wendisch, Volkmar; Boerner, Armin
    Tetrahedron: Asymmetry (2012), 23 (17), 1301-1319CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
    The synthesis of chiral β2-amino acids by homogeneous asym. hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α-aminomethylacrylates used as substrates were prepd. by a Baylis-Hillman reaction, followed by acylation and amination. For the asym. hydrogenation, a large variety of chiral, preferentially rhodium catalysts bearing com. available phosphorus ligands were tested. Conversions and enantioselectivities were dependent on the reaction conditions and varied strongly between the substrates used. A chiral N-α-phenylethyl group supports the stereoface discriminating ability of the chiral catalysts and thus a matching pair effect could be realized. In strong contrast, a chiral ester group has almost no effect in this respect. In some cases the use of the corresponding substrate acid was better in comparison to the use of its ester. After optimization of the hydrogenation conditions (chiral catalyst, H2-pressure, temp., solvent), full conversions and products with up to 99% ee were achieved.
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    Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16; Gaussian, Inc.: Wallingford CT, 2016.
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    Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Function. Theor. Chem. Acc. 2008, 120, 215– 241,  DOI: 10.1007/s00214-007-0310-x
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    The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals
    Zhao, Yan; Truhlar, Donald G.
    Theoretical Chemistry Accounts (2008), 120 (1-3), 215-241CODEN: TCACFW; ISSN:1432-881X. (Springer GmbH)
    We present two new hybrid meta exchange-correlation functionals, called M06 and M06-2X. The M06 functional is parametrized including both transition metals and nonmetals, whereas the M06-2X functional is a high-nonlocality functional with double the amt. of nonlocal exchange (2X), and it is parametrized only for nonmetals. The functionals, along with the previously published M06-L local functional and the M06-HF full-Hartree-Fock functionals, constitute the M06 suite of complementary functionals. We assess these four functionals by comparing their performance to that of 12 other functionals and Hartree-Fock theory for 403 energetic data in 29 diverse databases, including ten databases for thermochem., four databases for kinetics, eight databases for noncovalent interactions, three databases for transition metal bonding, one database for metal atom excitation energies, and three databases for mol. excitation energies. We also illustrate the performance of these 17 methods for three databases contg. 40 bond lengths and for databases contg. 38 vibrational frequencies and 15 vibrational zero point energies. We recommend the M06-2X functional for applications involving main-group thermochem., kinetics, noncovalent interactions, and electronic excitation energies to valence and Rydberg states. We recommend the M06 functional for application in organometallic and inorganometallic chem. and for noncovalent interactions.
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    Scalmani, G.; Frisch, M. J. Continuous Surface Charge Polarizable Continuum Models of Solvation. I. General Formalism. J. Chem. Phys. 2010, 132, 114110,  DOI: 10.1063/1.3359469
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    Continuous surface charge polarizable continuum models of solvation. I. General formalism
    Scalmani, Giovanni; Frisch, Michael J.
    Journal of Chemical Physics (2010), 132 (11), 114110/1-114110/15CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    Continuum solvation models are appealing because of the simplified yet accurate description they provide of the solvent effect on a solute, described either by quantum mech. or classical methods. The polarizable continuum model (PCM) family of solvation models is among the most widely used, although their application has been hampered by discontinuities and singularities arising from the discretization of the integral equations at the solute-solvent interface. In this contribution we introduce a continuous surface charge (CSC) approach that leads to a smooth and robust formalism for the PCM models. We start from the scheme proposed over ten years ago by York and Karplus and we generalize it in various ways, including the extension to analytic second derivs. with respect to at. positions. We propose an optimal discrete representation of the integral operators required for the detn. of the apparent surface charge. We achieve a clear sepn. between "model" and "cavity" which, together with simple generalizations of modern integral codes, is all that is required for an extensible and efficient implementation of the PCM models. Following this approach we are now able to introduce solvent effects on energies, structures, and vibrational frequencies (anal. first and second derivs. with respect to at. coordinates), magnetic properties (derivs. with respect of magnetic field using GIAOs), and in the calcn. more complex properties like frequency-dependent Raman activities, vibrational CD, and Raman optical activity. (c) 2010 American Institute of Physics.
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    Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Use of Solution-Phase Vibrational Frequencies in Continuum Models for the Free Energy of Solvation. J. Phys. Chem. B 2011, 115, 14556– 14562,  DOI: 10.1021/jp205508z
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    Use of Solution-Phase Vibrational Frequencies in Continuum Models for the Free Energy of Solvation
    Ribeiro, Raphael F.; Marenich, Aleksandr V.; Cramer, Christopher J.; Truhlar, Donald G.
    Journal of Physical Chemistry B (2011), 115 (49), 14556-14562CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    We find that vibrational contributions to a solute's free energy are in general insensitive to whether the solute vibrational frequencies are computed in the gas phase or in soln. In most cases, the difference is smaller than the intrinsic error in solvation free energies assocd. with the continuum approxn. to solvation modeling, although care must be taken to avoid spurious results assocd. with limitations in the quantum-mech. harmonic-oscillator approxn. for very low-frequency mol. vibrations. We compute solute vibrational partition functions in aq. and carbon tetrachloride soln. and compare them to gas-phase mol. partition functions computed with the same level of theory and the same quasiharmonic approxn. for the diverse and extensive set of mols. and ions included in the training set of the SMD continuum solvation model, and we find mean unsigned differences in vibrational contributions to the solute free energy of only about 0.2 kcal/mol. On the basis of these results and a review of the theory, we conclude, in contrast to previous work, that using partition functions computed for mols. optimized in soln. is a correct and useful approach for averaging over solute degrees of freedom when computing free energies of solutes in soln., and it is moreover recommended for cases where liq. and gas-phase solute structures differ appreciably or when stationary points present in liq. soln. do not exist in the gas phase, for which we provide some examples. When gas-phase and soln.-phase geometries and frequencies are similar, the use of gas-phase geometries and frequencies is a useful approxn.
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    Gonzalez, C.; Schlegel, H. B. An Improved Algorithm for Reaction Path Following. J. Chem. Phys. 1989, 90, 2154– 2161,  DOI: 10.1063/1.456010
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    An improved algorithm for reaction path following
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    Journal of Chemical Physics (1989), 90 (4), 2154-61CODEN: JCPSA6; ISSN:0021-9606.
    A new algorithm is presented for obtaining points on a steepest descent path from the transition state of the reactants and products. In mass-weighted coordinates, this path corresponds to the intrinsic reaction coordinate. Points on the reaction path are found by constrained optimizations involving all internal degrees of freedom of the mol. The points are optimized so that the segment of the reaction path between any two adjacent points is given by an arc of a circle, and so that the gradient at each point is tangent to the path. Only the transition vector and the energy gradients are needed to construct the path. The resulting path is continuous, differentiable and piecewise quadratic. In the limit of small step size, the present algorithm is shown to take a step with the correct tangent vector and curvature vector; hence, it is a second order algorithm. The method was tested on the following reactions: HCN → CNH, SiH2 + H2 → SiH4, CH4 + H → CH3 + H2, F- + CH3F → FCH3 + F-, and C2H5F → C2H4 + HF. Reaction paths calcd. with a step size of 0.4 a.u. are almost identical to those computed with a step size of 0.1 a.u. or smaller.
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    Gonzalez, C.; Schlegel, H. B. Reaction Path Following in Mass-Weighted Internal Coordinates. J. Phys. Chem. 1990, 94, 5523– 5527,  DOI: 10.1021/j100377a021
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    Reaction path following in mass-weighted internal coordinates
    Gonzalez, Carlos; Schlegel, H. Bernhard
    Journal of Physical Chemistry (1990), 94 (14), 5523-7CODEN: JPCHAX; ISSN:0022-3654.
    A previous algorithm for following reaction paths downhill (Chem. Phys. 1989), has been extended to use mass-weighted internal coordinates. Points on the reaction path are found by constrained optimizations involving the internal degrees of freedom of the mol. The points are optimized so that the segment of the reaction path between any two adjacent points is described by an arc of a circle in mass-weighted internal coordinates, and so that the gradients (in mass-weighted internals) at the end points of the arc are tangent to the path. The algorithm has the correct tangent vector and curvature vectors in the limit of small step size but requires only the transition vector and the energy gradients; the resulting path is continuous, differentiable, and piecewise quadratic. Reactions paths for CH4 + H → CH3 + H2, HCN → CNH, F- + CH3F → FCH3 + F-, and C2H5F → C2H4 + HF are calcd. and the results are compared to the paths obtained with mass-weighted Cartesians and with internal coordinates without mass-weighting.
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    Aizawa, S.-I.; Okano, M.; Kidani, T. Enantiomeric NMR signal separation behavior and mechanism of samarium(III) and neodymium(III) complexes with (S,S)-ethylenediamine-N,N′-disuccinate. Chirality 2017, 29, 273– 281,  DOI: 10.1002/chir.22681
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    Enantiomeric NMR signal separation behavior and mechanism of samarium(III) and neodymium(III) complexes with (S,S)-ethylenediamine-N,N'-disuccinate
    Aizawa, Sen-ichi; Okano, Masaru; Kidani, Takahiro
    Chirality (2017), 29 (6), 273-281CODEN: CHRLEP; ISSN:0899-0042. (Wiley-Liss, Inc.)
    Enantiomeric 1H and 13C NMR signal sepn. behaviors of various α-amino acids and DL-tartarate were investigated by using the samarium(III) and neodymium(III) complexes with (S,S)-ethylenediamine-N,N'-disuccinate as chiral shift reagents. A relatively smaller concn. ratio of the lanthanide(III) complex to substrates was suitable for the neodymium(III) complex compared with the samarium(III) one, striking a balance between relatively greater signal sepn. and broadening. To clarify the difference in the signal sepn. behavior, the chem. shifts of β-protons for fully bound D- and L-alanine (δb(D) and δb(L)) and their adduct formation consts. (Ks) were obtained for both metal complexes. Preference for D-alanine was similarly obsd. for both complexes, while it was revealed that the difference between the δb(D) and δb(L) values is the significant factor to det. the enantiomeric signal sepn. The neodymium(III) and samarium(III) complexes can be used complementarily for higher and smaller concn. ranges of substrates, resp., because the neodymium(III) complex gives the larger difference between the δb(D) and δb(L) values with greater signal broadening compared to the samarium(III) complex.
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    Aizawa, S.-I.; Okano, M. Enantiomeric NMR signal separation mechanism and prediction of separation behavior for a praseodymium(III) complex with (S,S)-ethylenediamine-N,N′-disuccinate. Magn. Reson. Chem. 2020, 58, 941– 948,  DOI: 10.1002/mrc.5062
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    Enantiomeric NMR signal separation mechanism and prediction of separation behavior for a praseodymium (III) complex with (S,S)-ethylenediamine-N,N-disuccinate
    Aizawa, Sen-ichi; Okano, Masaru
    Magnetic Resonance in Chemistry (2020), 58 (10), 941-948CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
    Because choice of chiral NMR (NMR) shift reagents and concn. conditions have been made empirically by trials and errors for chiral NMR analyses, the prediction of NMR signal sepn. behavior is an urgent issue. In this study, the sepn. of enantiomeric and enantiotopic 1H and 13C NMR signals for α-amino acids and tartaric acid was performed by using the praseodymium(III) complex with (S,S)-ethylenediamine-N,N'-disuccinate ((S,S)-EDDS). All the present D-amino acids exhibited larger downfield shift of their α-protons and α-carbons compared with those for the corresponding L-amino acids in common. This regularity is applicable to abs. configurational assignment and detn. of optical purity of amino acids. The chem. shifts of β-protons of D- and L-alanine fully bound with the Pr(III) ((S,S)-EDDS) complex (δbs) and the adduct formation consts. of both enantiomers (Ks) were obtained by dependences of the obsd. downfield shifts of the β-protons on the total concns. of the resp. enantiomers in the presence of a const. concn. of the Pr(III) complex. The difference in the K values was found to be predominant detg. factor for the enantiomeric signal sepn. The chem. shifts of both enantiomers (δs) and the enantiomeric signal sepns. (Δδs) under given conditions could be calcd. from the δb and K values. Furthermore, prediction of the signal sepn. behavior was enabled by using the calcd. δ values and the signal broadening obtained by dependences of the half-height widths of the obsd. signals on the bound/free substrate concn. ratios for the resp. enantiomers.
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  • Abstract

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    Scheme 1

    Scheme 1. Synthesis of (S)-α-Alkylserine from Protected l-Ser (previous work) and (R)- and (S)-α-Alkylisoserines from Protected l-isoSer (this work) via Diastereoselective Formation of Bicyclic Acetals and Alkylation Followed by Hydrolysis
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    Scheme 2

    Scheme 2. Formation of Bicyclic N,O-Acetal Isoserine Derivatives 2 and 3
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    Figure 1

    Figure 1. (A) ORTEP3 diagram of compound 2 obtained by X-ray diffraction analysis showing thermal ellipsoids at the 75% probability level, and 2D NOESY NMR (400 MHz) experiments for compounds 2 (B) and 3 (C) in CDCl3 at 298 K.

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    Figure 2

    Figure 2. Lowest energy structures for the four possible bicyclic diastereomers (I–IV) obtained upon reaction of Boc-l-isoSer-OMe 1 with TMB calculated with PCM(toluene)/M06-2X/6-31+G(d,p). Relative free Gibbs energies at 388 K (ΔG) are given in kcal mol–1, and relative populations (p) at the same temperature derived from ΔG are shown in parentheses. Dark and light red arrows indicate high or low steric hindrance, respectively.

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    Scheme 3

    Scheme 3. Diastereoselective Alkylation of Chiral Bicyclic Acetals 2 and 3
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    Figure 3

    Figure 3. Two-dimensional NOESY NMR experiment for compounds 5a or 6a performed with 400 MHz equipment using CDCl3 as solvent at 298 K.

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    Figure 4

    Figure 4. Minimum-energy pathways for the alkylation reaction of enolates 2′ (A) with bromomethane calculated with PCM(THF)/M06-2X/6-31+G(d,p). Free Gibbs energies (ΔG) calculated at 195 K are given in kcal mol–1. (B) Newman projections from N4 to C7a of the lowest energy structures for enolates 2′ and 2′_epi and transition states 2′_TSMeBr and 2′_epi_TSMeBr. Torsional strain is represented through the dihedral angles highlighted in cyan and magenta. Dihedral angles closer to 60° correspond to more staggered conformations. Pyramidalization is represented through the out-of-plane angle (in light brown) between the C2–CO2Me bond and the O1–C2–C3 plane. Angles close to 0° correspond to planarity.

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    Scheme 4

    Scheme 4. Hydrolysis of Chiral Bicyclic Acetals 5a–c and 6a,c To Obtain Enantiomerically Pure (R)- and (S)-α-Alkylisoserines
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    Scheme 5

    Scheme 5. Conversion of (R)-α-Benzylisoserine 7c into Cyclic Sulfamidate 10
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    Figure 5

    Figure 5. ORTEP3 diagram of sulfamidate 10 obtained by X-ray diffraction analysis showing thermal ellipsoids at the 75% probability level.

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    Scheme 6

    Scheme 6. Nucleophilic Ring-Opening Reactions of Sulfamidate 10 Followed by Acid Hydrolysis To Obtain β2,2-Amino Acids 16–19
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    Scheme 7

    Scheme 7. Nucleophilic Ring-Opening Reactions of Sulfamidate 10 To Obtain α-Bn-norLan 20 and α-Bn-norLan-Containing Peptide 21
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  • References

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      Role of the Countercation in Diastereoselective Alkylations of Pyramidalized Bicyclic Serine Enolates. An Easy Approach to α-Benzylserine
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      Journal of Organic Chemistry (2007), 72 (14), 5399-5402CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmt12htbw%253D&md5=afefaa294c56e5cd1082bfaf7a4271c1
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      A Double Diastereoselective Michael-Type Addition as an Entry to Conformationally Restricted Tn Antigen Mimics
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      Journal of Organic Chemistry (2013), 78 (21), 10968-10977CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      A totally stereocontrolled C-Michael addn. of serine-equiv. C-nucleophiles to tri-O-benzyl-2-nitro-D-galactal was used as the key step to synthesize several pyrano-[3,2-b]-pyrrole structures, e.g. I. These scaffolds could be regarded as conformationally restricted Tn antigen mimics, as we have demonstrated by biol. assays. The pyranose rings retain their 4C1 chair conformation, as shown by mol. modeling and NMR spectroscopy. The expected bioactivity was established by a competition-tailored enzyme-linked lectin assay using both soybean and Vicia villosa agglutinins as model lectins. The facile described synthetic route and the strategic combination of computational and exptl. techniques to reveal conformational features and bioactivity demonstrate the prepd. glycomimics to be promising candidates for further exploitation of this scaffold to give glycans for lectin blocking and vaccination.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFGku7rP&md5=67a66ee7f7f7529822a9e49882fcd3e0
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlOlurg%253D&md5=4e5b64d322a0c9622acb3a0238ffbd48
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntlGntbg%253D&md5=40cbf3f3d3c00ec8d6250adf407a663a
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      The origins of our nearly ten-year research program of chemical and biological investigations into peptides based on homologated proteinogenic amino acids are described. The road from the biopolymer poly[ethyl (R)-3-hydroxybutanoate] to the beta-peptides was primarily a step from organic synthesis methodology (the preparation of enantiomerically pure compounds (EPCs)) to supramolecular chemistry (higher-order structures maintained through non-covalent interactions). The performing of biochemical and biological tests on the beta- and gamma-peptides, which differ from natural peptides/proteins by a single or two additional CH(2) groups per amino acid, then led into bioorganic chemistry and medicinal chemistry. The individual chapters of this review article begin with descriptions of work on beta-amino acids, beta-peptides, and polymers (Nylon-3) that dates back to the 1960s, even to the times of Emil Fischer, but did not yield insights into structures or biological properties. The numerous, often highly physiologically active, or even toxic, natural products containing beta- and gamma-amino acid moieties are then presented. Chapters on the preparation of homologated amino acids with proteinogenic side chains, their coupling to provide the corresponding peptides, both in solution (including thioligation) and on the solid phase, their isolation by preparative HPLC, and their characterization by mass spectrometry (HR-MS and MS sequencing) follow. After that, their structures, predominantly determined by NMR spectroscopy in methanolic solution, are described: helices, pleated sheets, and turns, together with stack-, crankshaft-, paddlewheel-, and staircase-like patterns. The presence of the additional C--C bonds in the backbones of the new peptides did not give rise to a chaotic increase in their secondary structures as many protein specialists might have expected: while there are indeed more structure types than are observed in the alpha-peptide realm - three different helices (10/12-, 12-, and 14-helix) if we include oligomers of trans-2-aminocyclopentanecarboxylic acid, for example - the structures are already observable with chains made up of only four components, and, having now undergone a learning process, we are able to construct them by design. The structures of the shorter beta-peptides can also be reliably determined by molecular-dynamics calculations (in solution; GROMOS program package). Unlike in the case of the natural helices, these compounds' folding into secondary structures is not cooperative. In beta- and gamma-peptides, it is possible to introduce heteroatom substituents (such as halogen or OH) onto the backbones or to incorporate heteroatoms (NH, O) directly into the chain, and, thanks to this, it has been possible to study effects unobservable in the world of the alpha-peptides. Tests with proteolytic enzymes of all types (from mammals, microorganisms, yeasts) and in vivo examination (mice, rats, insects, plants) showed beta- and gamma-peptides to be completely stable towards proteolysis and, as demonstrated for two beta-peptides, extraordinarily stable towards metabolism, even when bearing functionalized side chains (such as those of Thr, Tyr, Trp, Lys, or Arg). The beta-peptides so far examined also normally display no or only very weak cytotoxic, antiproliferative, antimicrobial, hemolytic, immunogenic, or inflammatory properties either in cell cultures or in vivo. Even biological degradation by microbial colonies of the types found in sewage-treatment plants or in soil is very slow. That there are indeed interactions of beta- and gamma-peptides with biological systems, however, can be seen in the following findings: i) organ-specific distribution takes place after intravenous (i.v.) administration in rats, ii) transport through the intestines of rodents has been observed, iii) beta-peptides with positively charged side chains (Arg and Lys) settle on cell surfaces, are able to enter into mammalian cells (fibroplasts, keratinocytes, HeLa cells), and migrate into their cell nuclei (and nucleoli), and iv) in one case, it has already been established that a beta-peptide derivative can up- and down-regulate gene expression rates. Besides these less sharply definable interactions, it has also been possible to construct beta- and gamma-peptide agonists of naturally occurring peptide hormones, MHC-binding beta-peptides, or amphipathic beta-peptide inhibitors of membrane-bound proteins in a controlled fashion. Examples include somatostatin mimics and the suppression of cholesterol transport through the intestinal brush-border membrane (by the SR-BI-protein). The results so far obtained from investigations into peptides made up of homologues of the proteinogenic amino acids also represent a contribution to deepening of our knowledge of the natural peptides/proteins, while potential for biomedicinal application of this new class of substances has also been suggested.
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      Martinek, T. A.; Fülöp, F. Peptidic Foldamers: Ramping up Diversity. Chem. Soc. Rev. 2012, 41, 687– 702,  DOI: 10.1039/C1CS15097A
      12
      Peptidic foldamers: ramping up diversity
      Martinek, Tamas A.; Fueloep, Ferenc
      Chemical Society Reviews (2012), 41 (2), 687-702CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Non-natural folded polymers (foldamers) display considerable versatility, and the design of such mols. is of great current interest. In this respect, peptidic foldamers are perhaps the best-characterized systems, as they populate a no. of residue-controlled secondary structures, which have found various biol. applications and have also led to the creation of nanostructured materials. This crit. review covers recent developments related to diverse building blocks and modern foldamer design principles, such as the stereochem. patterning methods. The recent achievements concerning tertiary/quaternary structures and the self-assembling foldameric nanostructures are also addressed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFKisA%253D%253D&md5=c8f14d0329e1293895d260eab952de63
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      Horne, W. S.; Gellman, S. H. Foldamers with Heterogeneous Backbones. Acc. Chem. Res. 2008, 41, 1399– 1408,  DOI: 10.1021/ar800009n
      13
      Foldamers with Heterogeneous Backbones
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      Accounts of Chemical Research (2008), 41 (10), 1399-1408CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. The functions performed by proteins and nucleic acids provide the foundation for life. Chemists have recently begun to ask whether it is possible to design synthetic oligomers that approach the structural and functional complexities of these biopolymers. The study of foldamers, non-natural oligomers displaying discrete folding propensities, has demonstrated that there are several synthetic backbones that exhibit biopolymer-like conformational behavior. Early work in this area focused on oligomers comprised of a single type of monomer subunit, but recent efforts have highlighted the potential of mixed or "heterogeneous" backbones to expand the structural and functional repertoire of foldamers. In this Account, we illustrate the promise of heterogeneous backbone foldamers by focusing on examples contg. both α- and β-amino acid residues. Some β-residues bear protein-like side chains, while others have cyclic structures that confer conformational rigidity. The study of heterogeneous backbone foldamers has several advantages over that of their homogeneous backbone counterparts, including access to many new mol. shapes based on variations in the stoichiometries and patterns of the subunit combinations and improved prospects for side chain diversification. Recent efforts to develop α/β-peptide foldamers can be divided into two conceptually distinct classes. The first includes entities prepd. using a "block" strategy, in which α-peptide segments and β-peptide segments are combined to form a hybrid oligomer. The second class encompasses designs in which α- and β-amino acid monomers are interspersed in a regular pattern throughout an oligomer sequence. One α/β-peptide helical secondary structure, contg. C=O(i)···H-N(i+4) H-bonds analogous to those in the α-helix, has been shown via crystallog. to form helix bundle quaternary structures. Desirable biol. functions have been elicited from α/β-peptide foldamers. Efforts to mimic naturally occurring host-defense α-peptides have yielded new antimicrobial agents and have led to a reexamn. of the long-held views regarding structure-activity relationships among these α-peptides and their analogs. Foldamers offer new platforms for mimicry of the mol. surfaces involved in specific protein-protein recognition events; recent achievements in the prepn. of α/β-peptide inhibitors of the protein-protein interactions involved in apoptotic signaling (e.g., between Bcl-xL and pro-apoptotic partners) have revealed the benefits of employing heterogeneous backbones relative to homogeneous backbones for foldamer-based designs. These initial successes in the development of α/β-peptides exhibiting specific biol. activities highlight the potential of heterogeneous backbone foldamers for use in biomedical applications and provide guidelines for future studies into new target functions.
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    14. 14
      Sleebs, B. E.; Van Nguyen, T. T.; Hughes, A. B. Recent Advances in Stereoselective Synthesis and Application of β-Amino Acids. Org. Prep. Proced. Int. 2009, 41, 429– 478,  DOI: 10.1080/00304940903376028
      14
      Recent advances in stereoselective synthesis and application of β-amino acids
      Sleebs, Brad E.; Van Nguyen, T. T.; Hughes, Andrew B.
      Organic Preparations and Procedures International (2009), 41 (6), 429-478CODEN: OPPIAK; ISSN:0030-4948. (Taylor & Francis, Inc.)
      A review. This review gives detailed descriptions of the various methods of synthesis of β-amino acids. One method is homologation of α-amino acids. Other methods are enantioselective synthesis of β-amino acids via organocatalytic Mannich-type methods and conjugate addn. Also described are asym. Michael addn., enolate addn., enantioselective hydrogenation and redn. methods. Applications of β-amino acids in drug development are mentioned.
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    15. 15
      Juaristi, E.; Soloshonok, V. A. In Enantioselective Synthesis of β-Amino Acids; Juaristi, E., Soloshonok, V. A., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2005.
      There is no corresponding record for this reference.
    16. 16
      Huck, B. R.; Gellman, S. H. Synthesis of 2,2-Disubstituted Pyrrolidine-4-Carboxylic Acid Derivatives and Their Incorporation into β-Peptide Oligomers. J. Org. Chem. 2005, 70, 3353– 3362,  DOI: 10.1021/jo048639z
      16
      Synthesis of 2,2-Disubstituted Pyrrolidine-4-carboxylic Acid Derivatives and Their Incorporation into β-Peptide Oligomers
      Huck, Bayard R.; Gellman, Samuel H.
      Journal of Organic Chemistry (2005), 70 (9), 3353-3362CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      The authors have recently shown that members of a new class of β-peptides, oligomers of 2,2-disubstituted pyrrolidine-4-carboxylic acids, display discrete conformational preferences despite the impossibility of internal hydrogen bonding (Huck et al. J. Am. Chem. Soc. 2003, 125, 9035). Here, the authors describe the synthesis of a variety of 2,2-disubstituted pyrrolidine-4-carboxylic derivs. that bear a diverse set of side chains and protecting groups suitable for oligomer synthesis. In addn., coupling methods for construction of oligomers in soln. and on solid phases are discussed. Non-hydrogen bonded foldamers such as those generated from 2,2-disubstituted pyrrolidine-4-carboxylic acids may be useful in biomedical applications because the low intrinsic polarity of their backbones may promote bioavailability.
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    17. 17
      Steer, D.; Lew, R.; Perlmutter, P.; Smith, A.; Aguilar, M.-I. β-Amino Acids: Versatile Peptidomimetics. Curr. Med. Chem. 2002, 9, 811– 822,  DOI: 10.2174/0929867024606759
      17
      β-Amino acids: Versatile peptidomimetics
      Steer, David L.; Lew, Rebecca A.; Perlmutter, Patrick; Smith, A. Ian; Aguilar, Marie-Isabel
      Current Medicinal Chemistry (2002), 9 (8), 811-822CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers)
      A review. The use of peptidomimetics has emerged as a powerful means for overcoming the limitations inherent in the phys. characteristics of peptides thus improving their therapeutic potential. A peptidomimetic approach that has emerged in recent years with significant potential, is the use of β-amino acids. β-Amino acids are similar to α-amino acids in that they contain an N-terminus and a C-terminus. However, in β-amino acids two carbon atoms sep. these functional termini. β-Amino acids, with a specific side chain, can exist as the R or S isomers at either the α (C2) carbon or the β (C3) carbon. This results in a total of 4 possible diastereoisomers for any given side chain. The flexibility to generate a vast range of stereo- and regioisomers, together with the possibility of disubstitution, significantly expands the structural diversity of β-amino acids thereby providing enormous scope for mol. design. The incorporation of β-amino acids has been successful in creating peptidomimetics that not only have potent biol. activity, but are also resistant to proteolysis. This article reviews the rapidly expanding applications of β-amino acids in the design of bioactive peptide analogs ranging from receptor agonists and antagonists, MHC-binding peptides, antimicrobial peptides and peptidase inhibitors. Given their structural diversity taken together with the ease of synthesis and incorporation into peptide sequences using std. solid-phase peptide synthesis techniques, β-amino acids have the potential to form a new platform technol. for peptidomimetic design and synthesis.
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    18. 18
      Abele, S.; Seebach, D. Preparation of Achiral and of Enantiopure Geminally Disubstituted β-Amino Acids for β-Peptide Synthesis. Eur. J. Org. Chem. 2000, 2000, 1– 15,  DOI: 10.1002/(SICI)1099-0690(200001)2000:1<1::AID-EJOC1>3.0.CO;2-6
      There is no corresponding record for this reference.
    19. 19
      Christoffers, J.; Baro, A. In Quaternary Stereocenters; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
      There is no corresponding record for this reference.
    20. 20
      Wang, K.; Yu, J.; Shao, Y.; Tang, S.; Sun, J. Forming All-Carbon Quaternary Stereocenters by Organocatalytic Aminomethylation: Concise Access to β 2,2-Amino Acids. Angew. Chem., Int. Ed. 2020, 59, 23516– 23520,  DOI: 10.1002/anie.202009892
      20
      Forming All-Carbon Quaternary Stereocenters by Organocatalytic Aminomethylation: Concise Access to β2,2-Amino Acids
      Wang, Kai; Yu, Jianliang; Shao, Ying; Tang, Shengbiao; Sun, Jiangtao
      Angewandte Chemie, International Edition (2020), 59 (52), 23516-23520CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The asym. synthesis of β2,2-amino acids remains a formidable challenge in org. synthesis. Here a novel organocatalytic enantioselective aminomethylation of ketenes with stable and readily available N,O-acetals is reported, providing β2,2-amino esters bearing an all-carbon quaternary stereogenic center in high enantiomeric ratios with a catalytic amt. of chiral phosphoric acid [e.g., ketene I + acetal II → III (76%, 97:3 e.r.) in cyclohexane in presence of chiral phosphoric acid]. Typically, this transformation probably proceeds through an asym. counter-anion-directed catalysis. As a result, a concise, practical, and atom-economic protocol toward rapidly access to β2,2-amino acids has been developed.
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    21. 21
      Eitzinger, A.; Winter, M.; Schörgenhumer, J.; Waser, M. Quaternary β 2,2-Amino Acid Derivatives by Asymmetric Addition of Isoxazolidin-5-Ones to: para-Quinone Methides. Chem. Commun. 2020, 56, 579– 582,  DOI: 10.1039/C9CC09239K
      21
      Quaternary β2,2-amino acid derivatives by asymmetric addition of isoxazolidin-5-ones to para-quinone methides
      Eitzinger, Andreas; Winter, Michael; Schoergenhumer, Johannes; Waser, Mario
      Chemical Communications (Cambridge, United Kingdom) (2020), 56 (4), 579-582CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      The highly enantioselective (>99.5% ee) synthesis of a new class of densely functionalized β2,2-amino acid derivs. by reacting isoxazolidin-5-ones with para-quinone methides in the presence of chiral ammonium salt phase-transfer catalysts was developed. The reaction proceeds with exceptionally low catalyst loadings down to 20 ppm on gram scale and the utilization of the primary addn. products towards further manipulations was demonstrated for selected examples.
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      and references therein.

    22. 22
      Avenoza, A.; Busto, J. H.; Corzana, F.; Jiménez-Osés, G.; Peregrina, J. M. SN2 vs. E2 on Quaternary Centres: An Application to the Synthesis of Enantiopure β 2,2-Amino Acids. Chem. Commun. 2004, 980– 981,  DOI: 10.1039/B400282B
      22
      SN2 vs. E2 on quaternary centers: an application to the synthesis of enantiopure β2,2-amino acids
      Avenoza, Alberto; Busto, Jesus H.; Corzana, Francisco; Jimenez-Oses, Gonzalo; Peregrina, Jesus M.
      Chemical Communications (Cambridge, United Kingdom) (2004), (8), 980-981CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      SN2 and E2 competing reactions in cyclic sulfamidates can be modulated by the change of an amide group to an ester group attached to the quaternary carbon activated for the nucleophilic attack, allowing an easy approach to enantiopure α,α-disubstituted β-amino acids.
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    23. 23
      Mazo, N.; García-González, I.; Navo, C. D.; Corzana, F.; Jiménez-Osés, G.; Avenoza, A.; Busto, J. H.; Peregrina, J. M. Synthesis of Mixed α/β2,2 -Peptides by Site-Selective Ring-Opening of Cyclic Quaternary Sulfamidates. Org. Lett. 2015, 17, 5804– 5807,  DOI: 10.1021/acs.orglett.5b02927
      23
      Synthesis of Mixed α/β2,2-Peptides by Site-Selective Ring-Opening of Cyclic Quaternary Sulfamidates
      Mazo, Nuria; Garcia-Gonzalez, Ivan; Navo, Claudio D.; Corzana, Francisco; Jimenez-Oses, Gonzalo; Avenoza, Alberto; Busto, Jesus H.; Peregrina, Jesus M.
      Organic Letters (2015), 17 (23), 5804-5807CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A method for site- and stereoselective peptide modification using a cyclic sulfamidate scaffold contg. peptides is described. A peptide synthesis strategy allowing the rapid generation of mixed α/β-peptides incorporating a sulfamidate residue, derived from 2-methylisoserine, has been generalized. The unique electrophilic nature of this scaffold for nucleophilic substitution at a quaternary center with total inversion of its configuration, which was demonstrated computationally, allows for site-selective conjugation with various nucleophiles, such as anomeric thiocarbohydrates and pyridines. This strategy provides rapid access to complex thioglyco-α/β-conjugates and charged α/β-peptides.
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    24. 24
      Tovillas, P.; García-González, I.; Oroz, P.; Mazo, N.; Avenoza, A.; Corzana, F.; Jiménez-Osés, G.; Busto, J. H.; Peregrina, J. M. Tn Antigen Mimics by Ring-Opening of Chiral Cyclic Sulfamidates with Carbohydrate C1-S-and C1-O-Nucleophiles. J. Org. Chem. 2018, 83, 4973– 4980,  DOI: 10.1021/acs.joc.7b03225
      24
      Tn antigen mimics by ring-opening of chiral cyclic sulfamidates with carbohydrate C1-S- and C1-O-nucleophiles
      Tovillas, Pablo; Garcia, Ivan; Oroz, Paula; Mazo, Nuria; Avenoza, Alberto; Corzana, Francisco; Jimenez-Oses, Gonzalo; Busto, Jesus H.; Peregrina, Jesus M.
      Journal of Organic Chemistry (2018), 83 (9), 4973-4980CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Starting from com. available (S)-isoserine and effectively accessible (S)-α-methylserine, enantiopure cyclic sulfamidates have been prepd. as chiral building blocks for the synthesis of various S- and O-glycosylated amino acid derivs., including unnatural variants of the Tn antigen, through highly chemo-, regio-, and stereoselective nucleophilic ring-opening reactions with carbohydrate C1-S- and C1-O-nucleophiles.
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    25. 25
      Montchamp, J. L.; Tian, F.; Hart, M. E.; Frost, J. W. Butane 2,3-Bisacetal Protection of Vicinal Diequatorial Diols. J. Org. Chem. 1996, 61, 3897– 3899,  DOI: 10.1021/jo960170n
      25
      Butane 2,3-Bisacetal Protection of Vicinal Diequatorial Diols
      Montchamp, Jean-Luc; Tian, Feng; Hart, Matthew E.; Frost, J. W.
      Journal of Organic Chemistry (1996), 61 (11), 3897-3899CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Vicinal diequatorial diols are selectively protected as 2,3-butane bisacetals (BBA) upon refluxing polyols in methanol soln. with 2,2,3,3-tetramethoxybutane (TMB), tri-Me orthoformate, and catalytic camphorsulfonic acid. TMB reagent is prepd. inexpensively on a large scale and conveniently purified by distn. In addn. to its selectivity, BBA protection affords products in moderate to high yields that are generally cryst. and display diagnostic NMR spectra. Use of BBA protection is illustrated for polyols ranging from carbohydrates to carbocycles such as myo-inositol and quinic acid.
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    26. 26
      Normant, H. Hexamethylphosphoramide. Angew. Chem., Int. Ed. 1967, 6, 1046– 1067,  DOI: 10.1002/anie.196710461
      26
      Hexamethylphosphoric triamide
      Normant, Henri
      Angewandte Chemie, International Edition in English (1967), 6 (12), 1046-67CODEN: ACIEAY; ISSN:0570-0833.
      A review, with 184 references, of the prepn., structure, and basicity of the title compd. (I), complexes of I with org. compds., Lewis acids, and organometallic compds., I as a solvent, the reaction of I with electrophiles and alkali metals, I as a catalyst in the prepn. of PhN:C:NPh, I (with electron donor properties) as a reaction medium, I as an electron acceptor in redn. reactions, and the use of I as a polymn. catalyst.
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    27. 27
      Gutiérrez-Jiménez, M. I.; Aydillo, C.; Navo, C. D.; Avenoza, A.; Corzana, F.; Jiménez-Osés, G.; Zurbano, M. M.; Busto, J. H.; Peregrina, J. M. Bifunctional Chiral Dehydroalanines for Peptide Coupling and Stereoselective S-Michael Addition. Org. Lett. 2016, 18, 2796– 2799,  DOI: 10.1021/acs.orglett.6b00840
      27
      Bifunctional chiral dehydroalanines for peptide coupling and stereoselective S-Michael addition
      Gutierrez-Jimenez, Marta I.; Aydillo, Carlos; Navo, Claudio D.; Avenoza, Alberto; Corzana, Francisco; Jimenez-Oses, Gonzalo; Zurbano, Maria M.; Busto, Jesus H.; Peregrina, Jesus M.
      Organic Letters (2016), 18 (12), 2796-2799CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A second generation of chiral bicyclic dehydroalanines easily accessible from serine has been developed. These scaffolds behaved as excellent S-Michael acceptors when tri-O-acetyl-2-acetamido-2-deoxy-1-thio-α-D-galactopyranose (abbreviated as GalNAc-α-SH) was used as a nucleophile. This addn. proceeds with total chemo- and stereoselectivity, complete atom economy, quickly, and at room temp., making it a true click reaction. The Michael adducts were easily transformed into S-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-L- and -D-cysteines, which can be regarded as mimics of the Tn antigen derived from L-Ser (α-D-GalNAc-L-Ser) and D-Ser (α-D-GalNAc-D-Ser), resp.
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    28. 28
      Wang, H.; Houk, K. N. Torsional Control of Stereoselectivities in Electrophilic Additions and Cycloadditions to Alkenes. Chem. Sci. 2014, 5, 462– 470,  DOI: 10.1039/C3SC52538D
      28
      Torsional control of stereoselectivities in electrophilic additions and cycloadditions to alkenes
      Wang, Hao; Houk, K. N.
      Chemical Science (2014), 5 (2), 462-470CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A review. Torsional effects control the π-facial stereoselectivities of a variety of synthetically important organicreactions. This review surveys theor. calcns. that have led to the understanding of the influence of the torsional effects on several types of stereoselective org. reactions, esp. electrophilic addns. and cycloaddns. to alkenes.
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    29. 29
      Schnermann, M. J.; Untiedt, N. L.; Jiménez-Osés, G.; Houk, K. N.; Overman, L. E. Forming Tertiary Organolithiums and Organocuprates from Nitrile Precursors and Their Bimolecular Reactions with Carbon Electrophiles to Form Quaternary Carbon Stereocenters. Angew. Chem., Int. Ed. 2012, 51, 9581– 9586,  DOI: 10.1002/anie.201205001
      29
      Forming Tertiary Organolithiums and Organocuprates from Nitrile Precursors and their Bimolecular Reactions with Carbon Electrophiles to Form Quaternary Carbon Stereocenters
      Schnermann, Martin J.; Untiedt, Nicholas L.; Jimenez-Oses, Gonzalo; Houk, Kendall N.; Overman, Larry E.
      Angewandte Chemie, International Edition (2012), 51 (38), 9581-9586, S9581/1-S9581/126CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A general procedure for the synthesis of tertiary trialkyl-substituted organolithiums and organocuprates was reported. These intermediates was employed in the stereocontrolled construction of quaternary carbon stereocenters.
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    30. 30
      Huang, Y.; Zhang, Y. B.; Chen, Z. C.; Xu, P. F. A Concise Synthesis of (R)- and (S)-α-Alkyl Isoserines from d- and l-Malic Acids. Tetrahedron Asymmetry 2006, 17, 3152– 3157,  DOI: 10.1016/j.tetasy.2006.11.033
      30
      A concise synthesis of (R)- and (S)-α-alkyl isoserines from D- and L-malic acids
      Huang, Yan; Zhang, Yong-Bo; Chen, Zhi-Ce; Xu, Peng-Fei
      Tetrahedron: Asymmetry (2006), 17 (22), 3152-3157CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
      A simple and diastereoselective method for the synthesis of (R)- and (S)-α-alkyl isoserines was developed in four steps starting from com. available D- and L-malic acid, resp. This approach featured stereo-controlled alkylation of 2-(2-tert-butyl-5-oxo-1,3-dioxolan-4-yl)acetic acid followed by a Curtius rearrangement.
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    31. 31
      Baig, R. B. N.; Nadagouda, M. N.; Varma, R. S. Cyclic Sulfamidates Enabled Syntheses of Amino Acids, Peptides, Carbohydrates and Natural Products. Aldrichimica Acta 2015, 48, 71– 80
      There is no corresponding record for this reference.
    32. 32
      Cohen, S. B.; Halcomb, R. L. Application of Serine- and Threonine-Derived Cyclic Sulfamidates for the Preparation of S-Linked Glycosyl Amino Acids in Solution- and Solid-Phase Peptide Synthesis. J. Am. Chem. Soc. 2002, 124, 2534– 2543,  DOI: 10.1021/ja011932l
      32
      Application of Serine- and Threonine-Derived Cyclic Sulfamidates for the Preparation of S-Linked Glycosyl Amino Acids in Solution- and Solid-Phase Peptide Synthesis
      Cohen, Scott B.; Halcomb, Randall L.
      Journal of the American Chemical Society (2002), 124 (11), 2534-2543CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Cyclic sulfamidates I (R = H, Me; R1 = H, CH2C6H4OMe-4) were synthesized from L-serine and allo-L-threonine. These cyclic sulfamidates reacted with a variety of unprotected 1-thio sugars in aq. bicarbonate buffer (pH 8) to afford the corresponding S-linked serine- and threonine-glycosyl amino acids with good diastereoselectivity (≥97%) after hydrolysis of the N-sulfates. For example, I (R = H, Me; R1 = H) reacted with 1-deoxy-1-thio-β-D-glucose sodium salt to give S-linked amino acids II. For dipeptide synthesis, sulfamidate ester I (R = H, R1 = CH2C6H4OMe-4) was hydrogenated to give the free acid, which, was, then, coupled with H-Leu-OH, followed by chemoselective ligation with 1-deoxy-1-thio-β-D-glucose sodium salt to afford an S-linked glycopeptide III in 80% yield. III was also efficiently synthesized on solid support by, first, coupling I (R = H, R1 = CH2C6H4OMe-4) in its free acid form with resin-bound L-leucine, followed by N-deprotection of the p-methoxybenzyl group, and then, chemoselective ligation with 1-deoxy-1-thio-β-D-glucose·Na salt. After deprotection and resin cleavage steps, III was obtained with 94% purity.
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    33. 33
      Jamieson, A. G.; Boutard, N.; Beauregard, K.; Bodas, M. S.; Ong, H.; Quiniou, C.; Chemtob, S.; Lubell, W. D. Positional Scanning for Peptide Secondary Structure by Systematic Solid-Phase Synthesis of Amino Lactam Peptides. J. Am. Chem. Soc. 2009, 131, 7917– 7927,  DOI: 10.1021/ja9010628
      33
      Positional scanning for peptide secondary structure by systematic solid-phase synthesis of amino lactam peptides
      Jamieson, Andrew G.; Boutard, Nicolas; Beauregard, Kim; Bodas, Mandar S.; Ong, Huy; Quiniou, Christiane; Chemtob, Sylvain; Lubell, William D.
      Journal of the American Chemical Society (2009), 131 (22), 7917-7927CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Incorporation of amino lactams into biol. active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection (Fmoc = 9-fluorenylmethyloxycarbonyl) strategy has been developed for the systematic synthesis of peptides contg. configurationally defined α- and β-amino γ-lactams. N-Alkylation of N-silyl peptides with five- and six-member cyclic sulfamidates (I) and (II) minimized bis-alkylation and provided N-alkyl peptides, which underwent lactam annulation under microwave heating. Employing this solid-phase protocol on the growth hormone secretagogue GHRP-6, as well as on the allosteric modulator of the IL-1 receptor 101.10, has furnished 16 amino lactam derivs. and validated the effectiveness of this approach on peptides bearing aliph., arom., branched, charged, and heteroat. side chains. The binding affinity IC50 values of the GHRP-6 lactam analogs on both the GHS-R1a and CD36 receptors are reported as well as inhibition of thymocyte proliferation measurements for the 101.10 lactam analogs. In these cases, lactam analogs were prepd. exhibiting similar or improved properties compared with the parent peptide. Considering the potential for amino lactams to induce peptide turn conformations, the effective method described herein for their supported construction on growing peptides, and for the systematical amino lactam scan of peptides, has proven useful for the rapid identification of the secondary structure necessary for peptide biol. activity.
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    34. 34
      De Luca, S.; Digilio, G.; Verdoliva, V.; Saviano, M.; Menchise, V.; Tovillas, P.; Jiménez-Osés, G.; Peregrina, J. M. A Late-Stage Synthetic Approach to Lanthionine-Containing Peptides via S-Alkylation on Cyclic Sulfamidates Promoted by Molecular Sieves. Org. Lett. 2018, 20, 7478– 7482,  DOI: 10.1021/acs.orglett.8b03254
      34
      A late-stage synthetic approach to lanthionine-containing peptides via S-alkylation on cyclic sulfamidates promoted by molecular sieves
      De Luca, Stefania; Digilio, Giuseppe; Verdoliva, Valentina; Saviano, Michele; Menchise, Valeria; Tovillas, Pablo; Jimenez-Oses, Gonzalo; Peregrina, Jesus M.
      Organic Letters (2018), 20 (23), 7478-7482CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A one-pot, high-yield procedure for synthesizing lanthionine-contg. peptides was developed. It relies on the S-alkylation of cysteine-contg. peptides with chiral cyclic sulfamidates. The key feature of this approach is the use of mild reaction conditions (only activated mol. sieves are employed as the catalyst), leading to good chemoselectivity and excellent stereochem. control. The potential of the new methodol. has been investigated by synthesizing the thioether ring of a natural antibiotic, Haloduracin β.
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    35. 35
      Navo, C. D.; Mazo, N.; Avenoza, A.; Busto, J. H.; Peregrina, J. M.; Jiménez-Osés, G. Substituent Effects on the Reactivity of Cyclic Tertiary Sulfamidates. J. Org. Chem. 2017, 82, 13250– 13255,  DOI: 10.1021/acs.joc.7b02352
      35
      Substituent Effects on the Reactivity of Cyclic Tertiary Sulfamidates
      Navo, Claudio D.; Mazo, Nuria; Avenoza, Alberto; Busto, Jesus H.; Peregrina, Jesus M.; Jimenez-Oses, Gonzalo
      Journal of Organic Chemistry (2017), 82 (24), 13250-13255CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      The reactivity of cyclic tertiary sulfamidates derived from α-methylisoserine strongly depends on the substitution at the C and N termini. These substrates are one of the very few examples able to undergo nucleophilic ring opening at a quaternary carbon with complete inversion of the configuration, as demonstrated both exptl. and computationally. When the sulfonamide is unprotected, the characteristic ring-opening reaction is completely silenced, which explains that the majority of the ring-opening reactions reported in the literature invoke N-alkyl or N-carbonyl-protected sulfamidates. Accumulation of neg. charge at the NSO3 moiety in the transition state, esp. when the sulfonamide NH is deprotonated, drastically raises the activation barrier for the nucleophilic attack. On the other hand, ester groups at the carboxylic position favor ring opening, whereas amides allow competition between the substitution and elimination pathways. Using pyridine as a nucleophilic probe, we have demonstrated both exptl. and computationally that a proper selection of the substitution scheme can enhance the synthetic scope of α-methylisoserine-derived sulfamidates, switching off and on the nucleophilic ring-opening in a controlled manner. This is particularly convenient for hybrid α/β-peptide synthesis, as demonstrated recently by our group.
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    36. 36
      Park, Y.; Kang, S.; Lee, Y. J.; Kim, T. S.; Jeong, B. S.; Park, H. G.; Jew, S. S. Highly Enantioselective Synthesis of (S)-α-Alkyl-α,β- Diaminopropionic Acids via Asymmetric Phase-Transfer Catalytic Alkylation of 2-Phenyl-2-Imidazoline-4-Carboxylic Acid Tert-Butyl Esters. Org. Lett. 2009, 11, 3738– 3741,  DOI: 10.1021/ol9013552
      36
      Highly Enantioselective Synthesis of (S)-α-Alkyl-α,β-diaminopropionic Acids via Asymmetric Phase-Transfer Catalytic Alkylation of 2-Phenyl-2-imidazoline-4-carboxylic Acid tert-Butyl Esters
      Park, Yohan; Kang, Sukhoon; Lee, Young Ju; Kim, Taek-Soo; Jeong, Byeong-Seon; Park, Hyeung-geun; Jew, Sang-sup
      Organic Letters (2009), 11 (16), 3738-3741CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      An efficient enantioselective synthetic method for (S)-α-alkyl-α,β-diaminopropionic acid is reported. The asym. phase-transfer catalytic alkylation of N(1)-Boc-2-phenyl-2-imidazoline-4-carboxylic acid tert-Bu ester in the presence of chiral quaternary ammonium catalyst gave the corresponding alkylated products (93-98% ee) which could be transformed to enantioenriched α-alkyl-α,β-diaminopropionic acids.
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    37. 37
      Castellanos, E.; Reyes-Rangel, G.; Juaristi, E. Diastereoselective Electrophilic Amination of Chiral 1-Benzoyl-2,3,5,6-Tetrahydro-3-Methyl-2-(1-Methylethyl)Pyrimidin-4(1H)-One for the Asymmetric Syntheses of α-Substituted α,β-Diaminopropanoic Acids. Helv. Chim. Acta 2004, 87, 1016– 1024,  DOI: 10.1002/hlca.200490073
      37
      Enantioselective syntheses of β-amino acids: Part 15. Diastereoselective electrophilic amination of chiral 1-benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one for the asymmetric syntheses of α-substituted α,β-diaminopropanoic acids
      Castellanos, Elena; Reyes-Rangel, Gloria; Juaristi, Eusebio
      Helvetica Chimica Acta (2004), 87 (4), 1016-1024CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
      The chiral compds. (R)- and (S)-1-benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one [(R)- and (S)-I], derived from (R)- and (S)-asparagine, resp., were used as convenient starting materials for the prepn. of the enantiomerically pure α-alkylated α,β-diamino acids (R)- and (S)-H2NCH2CR(NH2)CO2H (II; R = Me, Et, Bn). The chiral lithium enolates of (R)- and (S)-I were alkylated and the resulting diastereoisomeric products were aminated with di-tert-Bu azodicarboxylate (DBAD), giving rise to the diastereoisomerically pure (≥ 98%) compds. III (2R,5S) and corresponding 2S,5R isomers. The target compds. (R)- and (S)-II could then be obtained in good yields and high purities by a hydrolysis/hydrogenolysis/hydrolysis sequence.
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    38. 38
      Cadart, T.; Berthonneau, C.; Levacher, V.; Perrio, S.; Brière, J. F. Enantioselective Phase-Transfer Catalyzed α-Sulfanylation of Isoxazolidin-5-Ones: An Entry to β2,2-Amino Acid Derivatives. Chem. Eur. J. 2016, 22, 15261– 15264,  DOI: 10.1002/chem.201603910
      38
      Enantioselective Phase-Transfer Catalyzed α-Sulfanylation of Isoxazolidin-5-ones: An Entry to β2,2-Amino Acid Derivatives
      Cadart, Timothee; Berthonneau, Clement; Levacher, Vincent; Perrio, Stephane; Briere, Jean-Francois
      Chemistry - A European Journal (2016), 22 (43), 15261-15264CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      An unprecedented enantioselective α-functionalization of C4-substituted N-alkoxycarbonyl isoxazolidin-5-ones, readily available platforms from Meldrum's acid derivs., by N-sulfanylphthalimide (PhthSR) electrophiles was achieved upon an efficient phase-transfer catalytic approach, mediated by a com. N-spiro quaternary ammonium catalyst. Two catalytic activities of the in situ formed R4N+Phth- species were highlighted, the phtalimidate being involved in the anion metathesis event and likely as a Bronsted base. This sequence offers a straightforward access to α,α-disubstituted isoxazolidinones, which turned out to be useful precursors of α-sulfanyl-β2,2-amino acid derivs.
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    39. 39
      Edmonds, M. K.; Graichen, F. H. M.; Gardiner, J.; Abell, A. D. Enantioselective Synthesis of α-Fluorinated β2-Amino Acids. Org. Lett. 2008, 10, 885– 887,  DOI: 10.1021/ol703045z
      39
      Enantioselective synthesis of α-fluorinated β2-amino acids
      Edmonds, Michael K.; Graichen, Florian H. M.; Gardiner, James; Abell, Andrew D.
      Organic Letters (2008), 10 (5), 885-887CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      A methodol. for the enantioselective synthesis of α-fluorinated β2-amino acids has been developed from readily available carboxylic acids (I) (R1 = Ph, cyclohexyl). Conversion to the Evan's oxazolidinone followed by enantioselective fluorination and alkylation gave (II) (R1 = Ph, cyclohexyl) in high diastereomeric excess (>95%). Subsequent removal of the oxazolidinone and amination at the Bn-protected hydroxyl center gave optically active α-fluorinated β2-amino acids.
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    40. 40
      Peddie, V.; Pietsch, M.; Bromfield, K. M.; Pike, R. N.; Duggan, P. J.; Abell, A. D. Fluorinated β2- and β3-Amino Acids: Synthesis and Inhibition of α-Chymotrypsin. Synthesis 2010, 2010, 1845– 1859,  DOI: 10.1055/s-0029-1218743
      There is no corresponding record for this reference.
    41. 41
      Vasstrand, E. N.; Hofstad, T.; Endresen, C.; Jensen, H. B. Demonstration of Lanthionine as a Natural Constituent of the Peptidoglycan of Fusobacterium Nucleatum. Infect. Immun. 1979, 25, 775– 780,  DOI: 10.1128/iai.25.3.775-780.1979
      41
      Demonstration of lanthionine as a natural constituent of the peptidoglycan of Fusobacterium nucleatum
      Vasstrand, Endre N.; Hofstad, Tor; Endresen, Curt; Jensen, Harald B.
      Infection and Immunity (1979), 25 (3), 775-80CODEN: INFIBR; ISSN:0019-9567.
      Peptidoglycan was purified from the oral bacterium, F. nucleatum strain Fev 1, by boiling Na dodecyl sulfate and Pronase. The compn. of this peptidoglycan was similar to that of other gram-neg. bacteria, except that it lacked diaminopimelic acid. Lanthionine, the monosulfur analog of diaminopimelic acid, was identified as the diaminodicarboxylic acid of this peptidoglycan. It is assumed that lanthionine replaced diaminopimelic acid. Thus, the peptidoglycan of F. nucleatum Fev 1 is one of the few known sources of naturally occurring lanthionine.
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    42. 42
      Chatterjee, C.; Paul, M.; Xie, L.; van der Donk, W. A. Biosynthesis and Mode of Action of Lantibiotics. Chem. Rev. 2005, 105, 633– 683,  DOI: 10.1021/cr030105v
      42
      Biosynthesis and Mode of Action of Lantibiotics
      Chatterjee, Champak; Paul, Moushumi; Xie, Lili; Van der Donk, Wilfred A.
      Chemical Reviews (Washington, DC, United States) (2005), 105 (2), 633-683CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. The review discusses gene organization of lantibiotics-producing microorganisms; structures, biosynthesis, regulation of prodn., and mode of action of lantibiotics. Self immunity of the producing strains, lantibiotic engineering, and resistance against nisin are also discussed.
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    43. 43
      Tabor, A. B. The Challenge of the Lantibiotics: Synthetic Approaches to Thioether-Bridged Peptides. Org. Biomol. Chem. 2011, 9, 7606– 7628,  DOI: 10.1039/c1ob05946g
      43
      The challenge of the lantibiotics: synthetic approaches to thioether-bridged peptides
      Tabor, Alethea B.
      Organic & Biomolecular Chemistry (2011), 9 (22), 7606-7628CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
      A review. The unique antibacterial properties and structural complexity of the lantibiotics has stimulated considerable interest in the development of methodol. for the synthesis of these peptides. One of the most challenging issues has been the synthesis of polycyclic peptides with multiple thioether bridges between side-chains, which are a characteristic feature of the lantibiotics. In this perspective, the different approaches to this problem, including soln.-phase synthesis, solid-phase synthesis, biomimetic approaches and biotransformation strategies, are reviewed, highlighting the advances resulting from each of these approaches.
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    44. 44
      Lühr, S.; Holz, J.; Zayas, O.; Wendisch, V.; Börner, A. Synthesis of Chiral β 2-Amino Acids by Asymmetric Hydrogenation. Tetrahedron Asymmetry 2012, 23, 1301– 1319,  DOI: 10.1016/j.tetasy.2012.08.010
      44
      Synthesis of chiral β2-amino acids by asymmetric hydrogenation
      Luehr, Susan; Holz, Jens; Zayas, Odalys; Wendisch, Volkmar; Boerner, Armin
      Tetrahedron: Asymmetry (2012), 23 (17), 1301-1319CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
      The synthesis of chiral β2-amino acids by homogeneous asym. hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α-aminomethylacrylates used as substrates were prepd. by a Baylis-Hillman reaction, followed by acylation and amination. For the asym. hydrogenation, a large variety of chiral, preferentially rhodium catalysts bearing com. available phosphorus ligands were tested. Conversions and enantioselectivities were dependent on the reaction conditions and varied strongly between the substrates used. A chiral N-α-phenylethyl group supports the stereoface discriminating ability of the chiral catalysts and thus a matching pair effect could be realized. In strong contrast, a chiral ester group has almost no effect in this respect. In some cases the use of the corresponding substrate acid was better in comparison to the use of its ester. After optimization of the hydrogenation conditions (chiral catalyst, H2-pressure, temp., solvent), full conversions and products with up to 99% ee were achieved.
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    45. 45
      Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16; Gaussian, Inc.: Wallingford CT, 2016.
      There is no corresponding record for this reference.
    46. 46
      Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Function. Theor. Chem. Acc. 2008, 120, 215– 241,  DOI: 10.1007/s00214-007-0310-x
      46
      The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals
      Zhao, Yan; Truhlar, Donald G.
      Theoretical Chemistry Accounts (2008), 120 (1-3), 215-241CODEN: TCACFW; ISSN:1432-881X. (Springer GmbH)
      We present two new hybrid meta exchange-correlation functionals, called M06 and M06-2X. The M06 functional is parametrized including both transition metals and nonmetals, whereas the M06-2X functional is a high-nonlocality functional with double the amt. of nonlocal exchange (2X), and it is parametrized only for nonmetals. The functionals, along with the previously published M06-L local functional and the M06-HF full-Hartree-Fock functionals, constitute the M06 suite of complementary functionals. We assess these four functionals by comparing their performance to that of 12 other functionals and Hartree-Fock theory for 403 energetic data in 29 diverse databases, including ten databases for thermochem., four databases for kinetics, eight databases for noncovalent interactions, three databases for transition metal bonding, one database for metal atom excitation energies, and three databases for mol. excitation energies. We also illustrate the performance of these 17 methods for three databases contg. 40 bond lengths and for databases contg. 38 vibrational frequencies and 15 vibrational zero point energies. We recommend the M06-2X functional for applications involving main-group thermochem., kinetics, noncovalent interactions, and electronic excitation energies to valence and Rydberg states. We recommend the M06 functional for application in organometallic and inorganometallic chem. and for noncovalent interactions.
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    47. 47
      Scalmani, G.; Frisch, M. J. Continuous Surface Charge Polarizable Continuum Models of Solvation. I. General Formalism. J. Chem. Phys. 2010, 132, 114110,  DOI: 10.1063/1.3359469
      47
      Continuous surface charge polarizable continuum models of solvation. I. General formalism
      Scalmani, Giovanni; Frisch, Michael J.
      Journal of Chemical Physics (2010), 132 (11), 114110/1-114110/15CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      Continuum solvation models are appealing because of the simplified yet accurate description they provide of the solvent effect on a solute, described either by quantum mech. or classical methods. The polarizable continuum model (PCM) family of solvation models is among the most widely used, although their application has been hampered by discontinuities and singularities arising from the discretization of the integral equations at the solute-solvent interface. In this contribution we introduce a continuous surface charge (CSC) approach that leads to a smooth and robust formalism for the PCM models. We start from the scheme proposed over ten years ago by York and Karplus and we generalize it in various ways, including the extension to analytic second derivs. with respect to at. positions. We propose an optimal discrete representation of the integral operators required for the detn. of the apparent surface charge. We achieve a clear sepn. between "model" and "cavity" which, together with simple generalizations of modern integral codes, is all that is required for an extensible and efficient implementation of the PCM models. Following this approach we are now able to introduce solvent effects on energies, structures, and vibrational frequencies (anal. first and second derivs. with respect to at. coordinates), magnetic properties (derivs. with respect of magnetic field using GIAOs), and in the calcn. more complex properties like frequency-dependent Raman activities, vibrational CD, and Raman optical activity. (c) 2010 American Institute of Physics.
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    48. 48
      Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Use of Solution-Phase Vibrational Frequencies in Continuum Models for the Free Energy of Solvation. J. Phys. Chem. B 2011, 115, 14556– 14562,  DOI: 10.1021/jp205508z
      48
      Use of Solution-Phase Vibrational Frequencies in Continuum Models for the Free Energy of Solvation
      Ribeiro, Raphael F.; Marenich, Aleksandr V.; Cramer, Christopher J.; Truhlar, Donald G.
      Journal of Physical Chemistry B (2011), 115 (49), 14556-14562CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      We find that vibrational contributions to a solute's free energy are in general insensitive to whether the solute vibrational frequencies are computed in the gas phase or in soln. In most cases, the difference is smaller than the intrinsic error in solvation free energies assocd. with the continuum approxn. to solvation modeling, although care must be taken to avoid spurious results assocd. with limitations in the quantum-mech. harmonic-oscillator approxn. for very low-frequency mol. vibrations. We compute solute vibrational partition functions in aq. and carbon tetrachloride soln. and compare them to gas-phase mol. partition functions computed with the same level of theory and the same quasiharmonic approxn. for the diverse and extensive set of mols. and ions included in the training set of the SMD continuum solvation model, and we find mean unsigned differences in vibrational contributions to the solute free energy of only about 0.2 kcal/mol. On the basis of these results and a review of the theory, we conclude, in contrast to previous work, that using partition functions computed for mols. optimized in soln. is a correct and useful approach for averaging over solute degrees of freedom when computing free energies of solutes in soln., and it is moreover recommended for cases where liq. and gas-phase solute structures differ appreciably or when stationary points present in liq. soln. do not exist in the gas phase, for which we provide some examples. When gas-phase and soln.-phase geometries and frequencies are similar, the use of gas-phase geometries and frequencies is a useful approxn.
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    49. 49
      Gonzalez, C.; Schlegel, H. B. An Improved Algorithm for Reaction Path Following. J. Chem. Phys. 1989, 90, 2154– 2161,  DOI: 10.1063/1.456010
      49
      An improved algorithm for reaction path following
      Gonzalez, Carlos; Schlegel, H. Bernhard
      Journal of Chemical Physics (1989), 90 (4), 2154-61CODEN: JCPSA6; ISSN:0021-9606.
      A new algorithm is presented for obtaining points on a steepest descent path from the transition state of the reactants and products. In mass-weighted coordinates, this path corresponds to the intrinsic reaction coordinate. Points on the reaction path are found by constrained optimizations involving all internal degrees of freedom of the mol. The points are optimized so that the segment of the reaction path between any two adjacent points is given by an arc of a circle, and so that the gradient at each point is tangent to the path. Only the transition vector and the energy gradients are needed to construct the path. The resulting path is continuous, differentiable and piecewise quadratic. In the limit of small step size, the present algorithm is shown to take a step with the correct tangent vector and curvature vector; hence, it is a second order algorithm. The method was tested on the following reactions: HCN → CNH, SiH2 + H2 → SiH4, CH4 + H → CH3 + H2, F- + CH3F → FCH3 + F-, and C2H5F → C2H4 + HF. Reaction paths calcd. with a step size of 0.4 a.u. are almost identical to those computed with a step size of 0.1 a.u. or smaller.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXhsVahtbk%253D&md5=17e5199cc364324ce3c55c6701342b58
    50. 50
      Gonzalez, C.; Schlegel, H. B. Reaction Path Following in Mass-Weighted Internal Coordinates. J. Phys. Chem. 1990, 94, 5523– 5527,  DOI: 10.1021/j100377a021
      50
      Reaction path following in mass-weighted internal coordinates
      Gonzalez, Carlos; Schlegel, H. Bernhard
      Journal of Physical Chemistry (1990), 94 (14), 5523-7CODEN: JPCHAX; ISSN:0022-3654.
      A previous algorithm for following reaction paths downhill (Chem. Phys. 1989), has been extended to use mass-weighted internal coordinates. Points on the reaction path are found by constrained optimizations involving the internal degrees of freedom of the mol. The points are optimized so that the segment of the reaction path between any two adjacent points is described by an arc of a circle in mass-weighted internal coordinates, and so that the gradients (in mass-weighted internals) at the end points of the arc are tangent to the path. The algorithm has the correct tangent vector and curvature vectors in the limit of small step size but requires only the transition vector and the energy gradients; the resulting path is continuous, differentiable, and piecewise quadratic. Reactions paths for CH4 + H → CH3 + H2, HCN → CNH, F- + CH3F → FCH3 + F-, and C2H5F → C2H4 + HF are calcd. and the results are compared to the paths obtained with mass-weighted Cartesians and with internal coordinates without mass-weighting.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXktl2rt78%253D&md5=8a002e8a34a7fb30c09567a3162a302a
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      Sheldrick, G. M. SHELXL97: Program for the Refinement of Crystal Structures; University of Göttingen: Göttingen, Germany, 1997.
      There is no corresponding record for this reference.
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      Aizawa, S.-I.; Okano, M.; Kidani, T. Enantiomeric NMR signal separation behavior and mechanism of samarium(III) and neodymium(III) complexes with (S,S)-ethylenediamine-N,N′-disuccinate. Chirality 2017, 29, 273– 281,  DOI: 10.1002/chir.22681
      52
      Enantiomeric NMR signal separation behavior and mechanism of samarium(III) and neodymium(III) complexes with (S,S)-ethylenediamine-N,N'-disuccinate
      Aizawa, Sen-ichi; Okano, Masaru; Kidani, Takahiro
      Chirality (2017), 29 (6), 273-281CODEN: CHRLEP; ISSN:0899-0042. (Wiley-Liss, Inc.)
      Enantiomeric 1H and 13C NMR signal sepn. behaviors of various α-amino acids and DL-tartarate were investigated by using the samarium(III) and neodymium(III) complexes with (S,S)-ethylenediamine-N,N'-disuccinate as chiral shift reagents. A relatively smaller concn. ratio of the lanthanide(III) complex to substrates was suitable for the neodymium(III) complex compared with the samarium(III) one, striking a balance between relatively greater signal sepn. and broadening. To clarify the difference in the signal sepn. behavior, the chem. shifts of β-protons for fully bound D- and L-alanine (δb(D) and δb(L)) and their adduct formation consts. (Ks) were obtained for both metal complexes. Preference for D-alanine was similarly obsd. for both complexes, while it was revealed that the difference between the δb(D) and δb(L) values is the significant factor to det. the enantiomeric signal sepn. The neodymium(III) and samarium(III) complexes can be used complementarily for higher and smaller concn. ranges of substrates, resp., because the neodymium(III) complex gives the larger difference between the δb(D) and δb(L) values with greater signal broadening compared to the samarium(III) complex.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvFCnur4%253D&md5=9867a4b8a3ea8f52335d90fb7e51cb2b
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      Aizawa, S.-I.; Okano, M. Enantiomeric NMR signal separation mechanism and prediction of separation behavior for a praseodymium(III) complex with (S,S)-ethylenediamine-N,N′-disuccinate. Magn. Reson. Chem. 2020, 58, 941– 948,  DOI: 10.1002/mrc.5062
      53
      Enantiomeric NMR signal separation mechanism and prediction of separation behavior for a praseodymium (III) complex with (S,S)-ethylenediamine-N,N-disuccinate
      Aizawa, Sen-ichi; Okano, Masaru
      Magnetic Resonance in Chemistry (2020), 58 (10), 941-948CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      Because choice of chiral NMR (NMR) shift reagents and concn. conditions have been made empirically by trials and errors for chiral NMR analyses, the prediction of NMR signal sepn. behavior is an urgent issue. In this study, the sepn. of enantiomeric and enantiotopic 1H and 13C NMR signals for α-amino acids and tartaric acid was performed by using the praseodymium(III) complex with (S,S)-ethylenediamine-N,N'-disuccinate ((S,S)-EDDS). All the present D-amino acids exhibited larger downfield shift of their α-protons and α-carbons compared with those for the corresponding L-amino acids in common. This regularity is applicable to abs. configurational assignment and detn. of optical purity of amino acids. The chem. shifts of β-protons of D- and L-alanine fully bound with the Pr(III) ((S,S)-EDDS) complex (δbs) and the adduct formation consts. of both enantiomers (Ks) were obtained by dependences of the obsd. downfield shifts of the β-protons on the total concns. of the resp. enantiomers in the presence of a const. concn. of the Pr(III) complex. The difference in the K values was found to be predominant detg. factor for the enantiomeric signal sepn. The chem. shifts of both enantiomers (δs) and the enantiomeric signal sepns. (Δδs) under given conditions could be calcd. from the δb and K values. Furthermore, prediction of the signal sepn. behavior was enabled by using the calcd. δ values and the signal broadening obtained by dependences of the half-height widths of the obsd. signals on the bound/free substrate concn. ratios for the resp. enantiomers.
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      Tovillas, P. Synthesis and reactivity of cyclic sulfamidates derived from amino acids. Ph.D. Dissertation, University of La Rioja, Logroño, La Rioja, Spain, 2021.
      There is no corresponding record for this reference.

  • Supporting Information

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