This Perspective presents a review and survey of the science and philosophy of my research career over the past five decades at Columbia as a physical organic chemist and photochemist. I explore the role of paradigms, structure, and geometric thinking in my own cognitive and intellectual development. The Perspective describes my investigations of high energy content molecules in electronically excited states and the development of electronic spin and supramolecular photochemistry chemistry. Current research dealing with the nuclear spin chemistry of H₂ incarcerated in buckyballs is illustrated. In the second part of this Perspective, I recount a personal role of the philosophy and history of science and the scientific communities’ use of paradigms in their every day research and intellectual activities. Examples are given of the crucial role of geometry and structure in the rapid development of organic chemistry and physical organic chemistry over the past century.

A novel derivative of 2′,4′-bridged nucleic acid, named hydroxamate-bridged nucleic acid (HxNA), containing a six-membered perhydro-1,2-oxazin-3-one ring, was designed and synthesized. The introduction of a carbonyl function along with an N–O linkage in the six-membered bridged structure is the unique structural feature of the novel 2′,4′-bridged nucleic acid analogue. The design was carried out to restrict the flexibility of the sugar moiety through the trigonal planarity of carbonyl function, which would improve the properties of the modification. The synthesized monomer was incorporated into oligonucleotides, and their properties were examined. The HxNA-modified oligonucleotides exhibited selectively high affinity toward complementary ssRNA. Furthermore, the nuclease resistance of the HxNA-modified oligonucleotide was found to be higher than that of the corresponding natural and 2′,4′-BNA/LNA-modified oligonucleotides. Interestingly, exposure of HxNA modified oligonucleotide to 3′-exonuclease resulted in gradual opening of the bridge, which stopped further digestion. Moreover, ring-opening of only one modification at the 3′-end of the oligonucleotides was observed, even if two or three HxNA modifications were present in the sequence. The results demonstrate the strong potential of the HxNA modification as a switch for the generation of highly nuclease-resistant RNA selective oligonucleotide in situ, which could have potential applications in antisense technology.

A stereoselective synthesis of the antibiotic (−)-virginiamycin M₂ is detailed. A convergent strategy was utilized that proceeded in 10 steps (longest linear sequence) from enantioenriched silane (S)-15. This reagent, which was prepared via a Rh(II)- or Cu(I)-catalyzed carbenoid Si–H insertion, was used to introduce the desired olefin geometry and stereocenters of the C1–C5 propionate subunit. A modified Negishi cross-coupling or an efficient alkoxide-directed titanium-mediated alkyne–alkyne reductive coupling strategy was utilized to assemble the trisubstituted (E,E)-diene. An underutilized late-stage SmI₂-mediated macrocyclization was employed to construct the 23-membered macrocycle scaffold of the natural product.

An intramolecular approach to generate compounds containing an arylnaphthalene lignan scaffold in high yields is presented. It involves a sequential intramolecular electrophilic attack of carbonyl on arylalkyne followed by benzannulation catalyzed by gold salt. AuCl₃ in combination with AgSbF₆ works better to effect this transformation. Selected products have been converted into arylnaphthalene lactone natural products such as justicidin E, taiwanin C, and retrojusticidin B.

The photoreactivity of (3-methyl-2H-azirin-2-yl)-phenylmethanone, 1, is wavelength-dependent (Singh et al. J. Am. Chem. Soc. 1972, 94, 1199−1206). Irradiation at short wavelengths yields 2P, whereas longer wavelengths produce 3P. Laser flash photolysis of 1 in acetonitrile using a 355 nm laser forms its triplet ketone (T_1K, broad absorption with λ_max ∼ 390–410 nm, τ ∼ 90 ns), which cleaves and yields triplet vinylnitrene 3 (broad absorption with λ_max ∼ 380–400 nm, τ = 2 μs). Calculations (B3LYP/6-31+G(d)) reveal that T_1K of 1 is located 67 kcal/mol above its ground state (S₀) and has a long C–N bond (1.58 Å), and the calculated transition state to form 3 is only 1 kcal/mol higher in energy than T_1K of 1. The calculations show that 3 has significant 1,3-carbon iminyl biradical character, which explains why 3 reacts efficiently with oxygen and decays by intersystem crossing to the singlet surface. Photolysis of 1 in argon matrixes at 14 K produced ketene imine 7, which presumably is formed from 3 intersystem crossing to 7. In comparison, photolysis of 1 in methanol with a 266 nm laser produces mainly ylide 2 (λ_max ∼ 380 nm, τ ∼ 6 μs, acetonitrile), which decays to form 2P. Ylide 2 is formed via singlet reactivity of 1, and calculations show that the first singlet excited state of the azirine chromophore (S_1A) is located 113 kcal/mol above its S₀ and that the singlet excited state of the ketone (S_1K) is 85 kcal/mol. Furthermore, the transition state for cleaving the C–C bond in 1 to form 2 is located 49 kcal/mol above the S₀ of 1. Thus, we theorize that internal conversion of S_1A to a vibrationally hot S₀ of 1 forms 2, whereas intersystem crossing from S_1K to T_1K results in 3.

Reaction conditions for the Ni(COD)₂/PCy₃ catalyzed cross-coupling of aryl neopentylglycolboronates with aryl mesylates were developed. By using optimized reaction conditions, Ni(COD)₂/PCy₃ was shown to be a versatile catalyst for the cross-coupling of a diversity of aryl neopentylglycolboronates with aryl and heteroaryl mesylates and sulfamates containing both electron-donating and electron-withdrawing substituents in their para, ortho, and meta positions in THF at room temperature. This Ni-catalyzed cross-coupling of aryl neopentylglycolboronates is also effective for the synthesis of heterobiaryls and biaryls containing electrophilic functionalities sensitive to organolithium and organomagnesium derivatives. In combination with the recently developed Ni-catalyzed neopentylglycolborylation, all Ni-catalyzed routes to functional biaryls and heterobiaryls are now easily accessible.

The formation of an identical linear tetrapyrrole observed in the course of photooxidation of meso-tetraarylporphyrin and its N-confused isomer can be explained as a result of 1,2- and 1,3-dioxygen addition, respectively, as substantiated by DFT calculations.

The first psico-oxetanocin analogue of the powerful antiviral natural product, oxetanocin A, has been readily synthesized from cis-2-butene-1,4-diol. Key 2-methyleneoxetane precursors were derived from β-lactones prepared by the carbonylation of epoxides. F⁺-mediated nucleobase incorporation provided the corresponding nucleosides in good yield but with low diastereoselectivity. Surprisingly, attempted exploitation of anchimeric assistance to increase the selectivity was not fruitful. A range of 2-methyleneoxetane and related 2-methylenetetrahydrofuran substrates was prepared to explore the basis for this. With one exception, these substrates also showed little stereoselectivity in nucleobase incorporation. Computational studies were undertaken to examine if neighboring group participation involving fused [4.2.0] or [4.3.0] intermediates is favorable.

We have developed a solvent-dependent method for the synthesis of novel benzo-δ-sultone scaffolds. A variety of benzylbenzo[e][1,2]oxathiin-4(3H)-one-2,2-dioxides were obtained in high yields in DMF using a one-pot, DBU-catalyzed condensation of 2-hydroxybenzaldehydes with a number of (E)-2-phenylethenesulfonyl chlorides. On the other hand, the initially prepared 2-formylphenyl-(E)-2-phenylethenesulfonate derivatives underwent DBU-catalyzed reactions to a series of 3-[methoxy(phenyl)methyl]benzo[e][1,2]oxathiine-2,2-dioxides in moderate to good yields in MeOH. These reactions presumably proceed via DBU-catalyzed O-sulfonylation/intramolecular Baylis–Hillman/1,3-H shift or dehydration tandem sequences, respectively.

1,2,3,4,8,9,10,11-Octaalkylpentacenes were synthesized in high yields from tetrahydropentacenes by the pentacene–DDQ adduct method in the presence of amine. Dehydro side-coupling reactions of pentacene derivatives proceeded to give the corresponding 6,6′-dipentacenyl derivatives in high yields in the presence of a catalytic amount of CSA and 0.5 equiv of DDQ. The structures of dehydro side-coupling products of substituted pentacenes were determined by NMR and X-ray analysis. The combination of acid and DDQ was necessary for the dehydro side coupling of substituted pentacenes.

Halogenated BODIPYs are important synthetic precursors and potential sensitizers for photodynamic therapy (PDT). Electrophilic bromination of pyrrolic-unsubstituted BODIPYs using bromine regioselectively generated mono- to heptabromoBODIPYs in a stepwise fashion in good to excellent yields. These resultant bromoBODIPYs were applied for regioselective substitution and Suzuki coupling reaction to generate BODIPYs 4, 5, 6, and 7 in good to excellent yields. According to NMR and X-ray analysis results, the stepwise bromination first takes place at 2,6-, then at 3,5-, and eventually at 1,7-positions, whereas the regioselective substitution occurs first at 3,5- then at 1,7-positions of the chromophore. The spectroscopic properties of these resultant BODIPYs were studied, which shows the potential application of these bromoBODIPYs as sensitizers for PDT.

Selective syn and anti diacetoxylations of alkenes have been achieved using a PhI(OAc)₂/BF₃·OEt₂ system in the presence and absence of water, respectively. A broad range of substrates including electron-deficient alkenes (such as α,β-unsaturated esters) could be elaborated efficiently at room temperature with this methodology, furnishing the desired products in good to excellent yields and diastereoselectivity. In particular, a multigram-scale diastereoselective diacetoxylation of methyl cinnamate (5.00 g) was also accomplished in a few hours, maintaining the same efficiency as small-scale reaction. This novel methodology provides an alternative approach for the preparation of various 1,2-diols.

A well-defined N-heterocyclic carbene based ruthenium complex was developed as a highly active precatalyst for the direct amide synthesis from alcohols and secondary amines. Notably, reaction of 1-hexanol and dibenzylamine afforded 60% of the corresponding amide using our catalytic system, while no amide formation was observed for this reaction with the previously reported catalytic systems. Unlike the previously reported amidation with less sterically hindered alcohols and amines, involvement of ester intermediates was observed.

The stereoselective amination of various chiral benzylic ethers using chlorosulfonyl isocyanate is developed, and the application of this method to the total synthesis of a potent antidepressant, (+)-sertraline, from readily available 1-naphthol is also described.

A series of new chiral macrocycles containing the trans-1,2-diaminocyclohexane (DACH) subunit and arene- and oligoethylene glycol-derived spacers has been prepared in enantiomerically pure form. Four of the macrocycles have been characterized by X-ray crystallography, which reveals a consistent mode of intramolecular N–H···N hydrogen bonding and conformational variations about the N-benzylic bonds. Most of the macrocycles were found to differentiate the enantiomers of mandelic acid (MA) by ¹H NMR spectroscopy in CDCl₃; within the series of macrocycles tested, enantiodiscrimination was promoted by (i) a meta-linkage geometry about the arene spacer, (ii) the presence of naphthalene- rather than phenylene-derived arene spacers, and (iii) increasing length of the oligoethylene glycol bridge. ¹H NMR titrations were performed with optically pure MA samples, and the data were fitted to a simultaneous 1:1 and 2:1 binding model, yielding estimates of 2:1 binding constants between some of the macrocycles and MA enantiomers. In several cases, NOESY spectra of the MA:macrocycle complexes show differential intramolecular correlations between protons adjacent to the amine and carboxylic acid groups of the macrocycles and MA enantiomers, respectively, thus demonstrating geometric differences between the diastereomeric intermolecular complexes. The three most effective macrocycles were employed as chiral solvating agents (CSAs) to determine the enantiomeric excess (ee) of 18 MA samples over a wide ee range and with very high accuracy (1% absolute error).

A series of amido pincer complexes of nickel were examined for their catalysis in the Kumada cross-coupling reaction. The P,N,O-pincer nickel complexes tested are active catalysts for the cross-coupling of aryl, heteroaryl, and vinyl chlorides with aryl Grignard reagents. The reactions can proceed at room temperature and tolerate functional groups in aryl chlorides with the aid of LiCl and ZnCl₂ additives.

Supramolecular calix[4]arene conjugate (L) has been developed as a sensitive and selective sensor for Zn²⁺ in HEPES buffer among the 12 metal ion by using fluorescence, absorption and ESI MS and also by visual fluorescent color. The structural, electronic, and emission properties of the calix[4]arene conjugates L and its zinc complex, [ZnL], have been demonstrated using ab initio density functional theory (DFT) combined with time-dependent density functional theory (TDDFT) calculations. The TDDFT calculations reveal the switch on fluorescence behavior of L is mainly due to the utilization of the lone pair of electrons on imine moiety by the Zn²⁺. The resultant fluorescent complex, [ZnL], has been used as a secondary sensing chemo-ensemble for the detection of −SH containing molecules by removing Zn²⁺ from [ZnL] and forming {Cys/DTT·Zn} adducts as equivalent to those present in metallothioneins. The displacement followed by the release of the coordinated zinc from its Cys/DTT complex by heavy metal ion (viz. Cd²⁺ and Hg²⁺), as in the metal detoxification process or by ROS (such as H₂O₂) as in the oxidative stress, has been well demonstrated using the conjugate L through the fluorescence intensity retrieval wherein the fluorescence intensity is the same as that observed with [ZnL], which in turn mimics the zinc sensing element (MTF) in biology.

Four generations of chemoenzymatic approaches to oseltamivir are presented. The first two generations relied on the use of cyclohexadiene-cis-diol derived enzymatically from bromobenzene. The third and fourth generation used the corresponding diol obtained from ethyl benzoate by fermentation with E. coli JM109(pDTG601a). Oseltamivir was obtained from ethyl benzoate by intersecting intermediate 39 (third-generation synthesis) and intermediate 45 (fourth-generation synthesis). Both of these advanced approaches benefited from symmetry considerations and translocation of the acrylate double bond with concomitant elimination of the C-1 hydroxyl. The syntheses are evaluated for overall efficiency by the use of efficiency metrics and compared with other syntheses of oseltamivir (both academic and industrial).

A method for the synthesis of 2-naphthols 4 is described. The carbonylative Stille coupling reactions of 2-bromobenzyl bromides with tributylallylstannane to produce 2-bromobenzyl β,γ-unsaturated ketones 2 in satisfactory to excellent yields has been achieved. The isomerization of 2-bromobenzyl β,γ-unsaturated ketones 2 can readily occur under basic conditions to generate 2-bromobenzyl α,β-unsaturated ketones 3. The 2-bromobenzyl α,β-unsaturated ketones 3 can be transformed into 2-naphthols 4 via intramolecular Heck reaction in satisfactory to good yields.

The tetrabutylammonium complex with a 2:5 stoichiometry, (n-Bu₄N)₂(TCNQ)₅, has been prepared and structurally characterized by X-ray crystallography. Diagnostic bands in the Raman spectrum and signature features in the electrochemistry confirm that the TCNQ moieties are partially charged in the solid state. EPR, magnetic susceptibility, and electrical conductivity measurements are all consistent with (n-Bu₄N)₂(TCNQ)₅ behaving as a quasi-one-dimensional organic semiconductor.

Novel hybrid structures of 5′-deoxyuridine and glycine were conceived and synthesized. Such nucleosyl amino acids (NAAs) represent simplified analogues of the core structure of muraymycin nucleoside antibiotics, making them useful synthetic building blocks for structure–activity relationship (SAR) studies. The key step of the developed synthetic route was the efficient and highly diastereoselective asymmetric hydrogenation of didehydro amino acid precursors toward protected NAAs. It was anticipated that the synthesis of unprotected muraymycin derivatives via this route would require a suitable intermediate protecting group at the N-3 of the uracil base. After initial attempts using PMB- and BOM-N-3 protection, both of which resulted in problematic deprotection steps, an N-3 protecting group-free route was envisaged. In spite of the pronounced acidity of the uracil-3-NH, this route worked equally efficient and with identical stereoselectivities as the initial strategies involving N-3 protection. The obtained NAA building blocks were employed for the synthesis of truncated 5′-deoxymuraymycin analogues.

A general design is presented for a stimulus-responsive small molecule that is capable of responding to a specific applied chemical or physical signal by releasing two different types of pendant small molecules and a colorimetric indicator simultaneously. A key aspect of this design is the ease with which these reagents are prepared: typically, only four synthetic steps are required. Moreover, the modular construction strategy provides access to stimuli-responsive reagents that are capable of (i) responding to a variety of applied signals and (ii) releasing a number of different small molecules that contain primary alcohols, secondary alcohols, or phenols. These stimuli-responsive reagents are stable under physiological conditions (neither hydrolysis nor thermal degradation of the reagent occurs in significant quantity), and when they are exposed to the appropriate applied signal, they release both pendant small molecules and the colorimetric indicator completely within hours. Finally, unlike other functional groups, such as carbonates, that are used to connect alcohol-bearing molecules to controlled-release reagents, the linkage described in this article increases in hydrolytic stability (rather than decreases) as the pK_a of the pendant alcohol decreases.

A new class of macrobicyclic azacryptand containing dipyrrolylmethane subunits with nitrogen bridgeheads was synthesized by the Mannich reaction of the dipyrrolylmethane in the presence of aqueous ammonia. The azacryptand exhibits a staggered conformation in the solid state, but is in a dynamic equilibrium with the eclipsed conformation in solution studied by the variable-temperature ¹H NMR methods. The azacryptand has a specific size suitable only for fluoride ion; large anions such as NO₃^– bind in the clefts of the macrobicycle as shown by the X-ray structures of its fluoride ion inclusion and the nitrate anion complexes. The anion binding studies showed that it has high selectivity and affinity for fluoride ion in acetone over other anions studied, which was supported by ¹H and ¹⁹F NMR methods. The azacryptand has fast fluoride ion-mediated proton–deuterium exchanges with acetone-d₆ studied by the ¹⁹F NMR method.

A one-pot protocol involving Zn/CuI/TFA-catalyzed domino three-component and subsequent carbocyclization reactions is described. The reaction proceeds via formation of propargyl amines from biphenyl-2-carbaldehydes/terminal alkynes/piperidine followed by the elimination of piperidine and ring closure to furnish phenanthrene derivatives in good yields. The strategy involves C(sp)-H activation–CH functionalization with imine-alkyne activation–1,5 hydride shift−β-elimination of piperidine–allene formation–6π cycloaddition–isomerization domino sequence. Evidence for the involvement of allenes as an intermediate during carbocyclization is discussed.

The oxygenation of n-butyl and n-butoxy chains bonded to silica with methyl(trifluoromethyl)dioxirane (1) revealed the ability of the silica matrix to release electron density toward the reacting C₂–H σ-bond through the Si–C₁ and Si–O₁ σ-bonds connecting the alkyl chain to the surface (silicon β-effect). The silica surface impedes neither the alkyl chain adopting the conformation required for the silicon β-effect nor dioxirane 1 approaching the reactive C₂ methylene group. Reaction regioselectivity is insensitive to changes in the solvation of the reacting system, the location of organic ligands on the silica surface, and the H-bonding character of the silica surface. Reaction rates are faster for those organic ligands either within the silica pores or bonded to hydrophilic silica surfaces, which evidence the enhanced molecular dynamics of confined dioxirane 1 and the impact of surface phenomena on the reaction kinetics. The oxygenation of n-butyl and n-butoxy chains carrying trimethylsilyl, trimethoxysilyl, and tert-butyl groups with dioxirane 1 under homogeneous conditions confirms the electronic effects of the silyl substituents and the consequences of steric hindrance on the reaction rate and regioselectivity. Orthosilicic acid esters react preferentially at the methylene group adjacent to the oxygen atom in clear contrast with the reactivity of the carboxylic or sulfonic acid alkyl esters, which efficiently protect this position toward oxidation with 1.

An acetate anion bearing an imidazolium cation as its charge tag was reacted with M(OAc)₂ complexes (where M = Ni, Cu, and Pd; in situ reaction) to form members of a new class of charge-tagged metal complexes. The formation of these unprecedented precatalysts with potential for cross-coupling reactions was confirmed by electrospray ionization (and tandem) mass spectrometry. The catalytic performance of the palladium complex was tested in Heck and Suzuki cross-coupling reactions, often with superior activity and yields as compared with Pd(OAc)₂.

Oxidation of the fullerenediol C₆₀(OH)₂(O)(OAc)(OOtBu)₃ with PhI(OAc)₂ yields the open-cage fullerene derivative C₆₀(O)₂(O)(OAc)(OOtBu)₃2 with an 11-membered orifice. Compound 2 reacts with aniline to form a new open-cage derivative with a 14-membered orifice, which yields an 18-membered open-cage fullerene derivative upon addition of another molecule of aniline. Two different types of aniline derivatives with either electron-donating or electron-withdrawing substituents can be added sequentially, affording an unsymmetrical moiety in the open-cage structure. Reduction potentials of the 18-membered open-cage fullerene derivatives can be fine-tuned by changing the substituents on the aniline. The results provide new insights about the mechanism of open-cage reactions of fullerene-mixed peroxide.

An efficient synthesis toward highly diversified α-carboline derivatives via a three-component tandem reaction using acid chlorides, terminal alkynes, and 2-aminoindole hydrochlorides has been described. The salient feature of the one-pot strategy involves regioselective [3 + 3]-cyclocondensation and the presence of water in the reaction medium to facilitate cyclization. Nonaqueous conditions furnished products in poor yields.

The in situ preparation of chiral amido alkyl ate yttrium complexes from an array of chiral N-benzyl-like-substituted binaphthyldiamines is reported. These chiral heteroleptic complexes are shown to be efficient catalysts for the enantioselective intramolecular hydroamination of primary amines tethered to sterically demanding alkenes at high reaction temperatures. Fine tuning of their chiral environment allowed up to 77% ee to be reached for the cyclization of aminoalkenes bearing 1,2-dialkyl-substituted carbon–carbon double bonds. These chiral complexes also demonstrate the ability to promote the cyclization of amine-tethered trisubstituted alkenes in up to 55% ee, as the first report of the formation of enantioenriched quaternary centers by an hydroamination reaction.

A full account of the total synthesis of (±)-maistemonine, (±)-stemonamide, and (±)-isomaistemonine is presented. Two approaches have been developed to construct the basic pyrrolo[1,2-a]azepine core of the Stemona alkaloids, featuring a tandem semipinacol/Schmidt rearrangement of a secondary azide and a highly stereoselectively desymmetrizing intramolecular Schmidt reaction, respectively. To build the common spiro-γ-butyrolactone, a new protocol was carried out by utilizing an intramolecular ketone-ester condensation as the key transformation. The vicinal butyrolactone moiety of (±)-maistemonine was stereoselectively introduced via a one-pot procedure involving the epimerization at C-3 and carbonyl allylation/lactonization. Moreover, (±)-stemonamide was divergently synthesized from a common intermediate, and (±)-isomaistemonine was obtained via the epimerization of (±)-maistemonine at C-12.

Treatment of 1,6-anhydrosugars with commercially available bis(trimethylsilyl) sulfide in the presence of trimethylsilyl triflate led to the formation of α-glycosyl thiols. All the reactions were highly stereoselective and afforded the α-glycosyl thiols in good to excellent yields. By this procedure, a variety of 1,6-anhydrosugars, differing in their sugar units, glycosidic linkages, and protecting group pattern, were converted smoothly into the corresponding α-glycosyl thiols, which could be of great utility in thioglycoside chemistry. It is noteworthy that 1,6-anhydrosugars carrying the 2-O-acyl group and 1,6-anhydrosugar-containing oligosaccharides could also be ring-opened stereospecifically under the same conditions to give rise to the corresponding 1-thiosugars in high yields. Thus, a very concise and efficient access to α-glycosyl thiols of great value was established.

A highly efficient catalytic system for C–H activation has been worked out that involves inexpensive RuCl₃·xH₂O and a specific amount of PPh₃. This procedure has been successfully applied to a practical synthesis of angiotensin II receptor blockers (ARBs). The residual ruthenium that existed in the reaction mixture was thoroughly removed by treatment with properly selected metal scavengers. The new process permits ready access to the important class of drugs in a highly atom-economical and sustainable manner.

We report the synthesis of nine conjugated cruciform-shaped molecules based on the central benzo[1,2-d:4,5-d′]bisoxazole nucleus, at which two conjugated currents intersect at a ∼90° angle. Cruciforms’ substituents were varied pairwise among the electron-neutral phenyl groups, electron-rich 4-(N,N-dimethylamino)phenyl substituents, and electron-poor pyridines. Hybrid density functional theory calculations revealed that the highest occupied molecular orbitals (HOMOs) are localized (24–99%) in all cruciforms, in contrast to the lowest unoccupied molecular orbitals (LUMOs) which are strongly dependent on the substitution and less localized (6–64%). Localization of frontier molecular orbitals (FMOs) along different axes of these cruciforms makes them promising as sensing platforms, since analyte binding to the cruciform should mandate a change in the HOMO–LUMO gap and the resultant optical properties. This prediction was verified using UV/vis absorption and emission spectroscopy: cruciforms’ protonation results in hypsochromic and bathochromic shifts consistent with the preferential stabilization of HOMO and LUMO, respectively. In donor–acceptor-substituted systems, a two-step optical response to protonation was observed, wherein an initial bathochromic shift is followed by a hypsochromic one with continued acidification. X-ray diffraction studies of three selected cruciforms revealed the expected ∼90° angle between the cruciform’s substituents, and crystal packing patterns dominated by [π···π] stacking and edge-to-face [C–H···π] contacts.

We have developed a highly optimized methodology that allows for the oxidative acetoxylation of a sterically and electronically demanding library of analogues of benzo[h]quinoline. The optimal conditions for the insertion of an OAc group were identified after examining various reaction parameters (solvent, oxidant, catalyst, temperature, time). The conditions identified (Pd(OAc)₂, PhI(OAc)₂, MeCN, 150 °C, 16 h), combined with the hydrolysis of acetates, resulted in the formation of hydroxybenzoquinolines in 27–59% yield, whereas all previously published procedures were ineffective. This synthesis was compatible with diverse functionalities (ester, aldehyde, carbon–carbon triple bond) and, most importantly, worked for sterically hindered analogues as well as for compounds possessing electron-donating and electron-withdrawing substituents at various positions. All the obtained compounds demonstrated excited-state intramolecular proton transfer (ESIPT) manifesting as small fluorescence quantum yields and large Stokes shifts (8300–9660 cm^–1). The effect of structural variations in eight 10-hydroxybenzo[h]quinoline analogues on absorption and emission properties was studied in detail.

Regioselective iron-catalyzed cross-dehydrogenative coupling (CDC) of two aromatic compounds using tert-BuOOH as oxidant under mild conditions has been reported. The direct oxidative coupling reaction is selective toward creation of a carbon–carbon bond at the position ortho to the functional groups of the substrates, completely preventing the homocoupled products. The C–C bond-forming reaction makes the method versatile, leading to functionalized 2,2′ -disubstituted biaryls.

The conformational space of cyclooctene has been explored computationally in order to rationalize its high epoxidation selectivity. Four different conformations were identified. Each conformation is chiral and has two enantiomeric forms. The degeneracy is further increased by a ring-inversion process, yielding a total of 16 conformers. The potential energy surface for the interconversion of these conformers was characterized via intrinsic reaction coordinate analyses. Furthermore, an evaluation of the microcanonical partition functions allowed for a quantification of the entropy contributions and hence the calculation of the equilibrium composition at different temperatures. The results strongly suggest that the high epoxidation selectivity, typically observed for cyclooctene, is related to a poor σ_C−αH–π_C═C orbital overlap in the predominant conformation, disfavoring αH-abstraction by radical species and thus allylic byproduct formation via undesired homolytic side-reactions.

The efficient preparation of heterocycles with a range of substitutions ortho to heteroatoms remains as a challenge in organic synthesis, particularly relevant to the construction of druglike molecules due to the ubiquitous presence of such moieties in that chemical space. Modular installation of heterocyclic building blocks using Suzuki–Miyaura cross-coupling is a conceptually useful strategy to address this challenge, though this has historically been met with technical difficulty due to issues of inaccessibility and instability of the requisite heterocyclic boronates. Herein we report a mild and highly regioselective cycloaddition approach which affords convenient access to stable MIDA boronate-functionalized isoxazoles and triazoles and their subsequent efficient Suzuki–Miyaura cross-coupling. This methodology is then further applied to a set of druglike compounds in an efficient one-pot telescoped sequence in line with green chemistry principles.

A resin-bound nitroso compound sequestered a single unexpected component from crude plant seed extracts. Several plants, including Piper nigrum, Eugenia caryophyllata, and Pimenta dioica, were extracted with organic solvent in the presence of a nitroso-containing resin. The nitroso resin selectively sequestered a single compound, β-caryophyllene, via a chemo- and regioselective ene reaction. The ene product was released from the resin, and proper selection of the solid-phase linker and cleavage cocktail allowed concomitant further transformation of the primary ene product to a novel functionalized polycycle. Preliminary studies indicate that the new hydroxylamine-containing natural product derivatives have antibiotic activity.

A new method for the generation of dicationic species via ionization of diols is described. The method makes use of milder reagents at room temperatures, an advantage over use of Magic Acid at −78 °C. A series of mono- and dications were synthesized successfully, including previously unattainable species.

We describe a simple and novel protocol for the synthesis of tetrahydro-1,4-benzodiazepin-2-ones with three points of diversity, exploiting the acylating properties of the recently rediscovered Ugi-imide. The final compounds can be easily prepared in three synthetic steps using a multicomponent reaction, a Staudinger reduction, and an acylative protocol, with good to excellent yields for each synthetic step.

A palladium-catalyzed Negishi coupling reaction has been developed to synthesize fluorous 5-methylcytosines. These fluorous nucleosides are incorporated into the oligonucleotides that correspond to part of the promoter region of Oct4, a master gene that undergoes dynamic DNA demethylation during cellular reprogramming. The separation of the fluorous oligonucleotides from its nonfluorous analogues has been achieved through solid-phase extraction over fluorous silica, suggesting its potential use in probing DNA demethylation.

Treatment of N,N-dimethyl 2-[2-(2-ethynylphenyl)ethynyl]anilines (1) with 1.2 equiv of iodine in CH₂Cl₂ gave benzo[a]carbazoles (2) in good yields. Mechanistic studies showed this reaction must go through the haloindole (3) followed by iodonium ion catalyzed atom-transfer cyclization reaction to give the benzo[a]carbazoles.

The formation of highly stable inclusion complexes in aqueous solution between the organometallic cobaltocenium cation (Cob⁺) and the hosts cucurbit[7]uril (CB7) and cucurbit[8]uril (CB8) was used to develop a simple method, based on UV–vis titrations, to assay the purity of samples of these two hosts. The equilibrium association constant (K) of the Cob⁺@CB7 complex had been previously reported by our group as 5.7 × 10⁹ M^–1 at 25 °C in 50 mM sodium acetate medium. In this work, we determine a K value of 1.9 × 10⁸ M^–1 at 25 °C in the same medium for the Cob⁺@CB8 complex. The high stability of these complexes and their decreased molar absorptivity coefficients (at 261 nm), compared to that for free Cob⁺, lead to straightforward titration plots when graphing absorbance versus concentration of added CB7 (or CB8) host, at constant Cob⁺ concentration.

Isocyanoacetates are uniquely reactive compounds characterized by an ambivalent isocyano functional group and an enolizable α-carbon. It is widely believed that chiral α-substituted isocyanoacetates are configurationally unstable in some synthetically useful isocyanide-based multicomponent reactions. Herein, we demonstrate that chiral isocyanoacetates can be used with minimal to negligible epimerization in a variety of canonical Ugi four-component condensations as well as Joullié–Ugi three-component condensations, reactions that are particularly useful for constructing complex peptide structures in a single synthetic operation.

A dicyanovinyl-substituted benzofurazan derivative (C1) was prepared as an efficient ratiometric chemosensor for cyanide anion detection in aqueous acetonitrile solution. Mechanism studies suggested that the nucleophilic addition of cyanide to the α-position of the dicyanovinyl group blocked the ICT progress of C1 and induced remarkable emission and absorption shift.

A reliable, catalytic asymmetric vinylogous Mukaiyama–Mannich reaction of pyrrole-based silyl dienolates is introduced that is particularly apt for alkyl- and α-alkoxyalkyl-substituted aldehydes. The reaction course is effectively orchestrated by the Hoveyda–Snapper amino acid-based chiral ligand/silver(I) catalyst combination to produce valuable vicinal diamino carbonyl compounds in high yields, with virtually complete γ-site- and anti-selectivity and significant catalyst-to-product chirality transfer. The utility of the Mannich products can be seen in the synthesis of an unprecedented perhydrofuro[3,2-b]pyrrolone product, an aza-analogue of naturally occurring (+)-goniofufurone.

A double Sonogashira-type coupling reaction between aryl bromides and alkynes using a catalytic Pd/XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) system was introduced as an efficient method for the synthesis of shape-persistent macrocycles (SPMs). This approach is advantageous in the synthesis of SPMs with a single pyridine unit.

A novel four-component reaction between 2-formylbenzoic acids, malononitrile, isocyanides, and alcohols has been developed for a highly efficient preparation of alkyl-2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)benzoate derivatives. This high atom economy reaction led to the construction of two carbon–carbon bonds, one amide, and one ester group in a single synthetic step. Furthermore, a three-component reaction between 2-formylbenzoic acids, malononitrile, and isocyanides in dichloromethane for the preparation of isochromeno[3,4-b]pyrroles has been reported.

Kinetic resolution of sterically hindered racemic α-tert-alkyl-α-hydroxy esters is performed by enantiomer-selective carbamoylation with the t-Bu-Box–Cu(II) catalyst (Box = bis(oxazoline)). The reaction with 0.5 equiv of n-C₃H₇NCO is carried out with a substrate-to-catalyst molar ratio of 500–5000 at −20 to 25 °C. The high enantiomer-discrimination ability of the catalyst achieves an excellent stereoselectivity factor (s = k_fast/k_slow) of 261 in the best case. A catalytic cycle for this reaction is proposed.

The synthesis of an azide-bearing N-mustard S-adenosyl-l-methionine (SAM) analogue, 8-azido-5′-(diaminobutyric acid)-N-iodoethyl-5′-deoxyadenosine, has been accomplished in 10 steps from commercially available 2′,3′-isopropylidene adenosine. Critical to this success was executing C8 azidation prior to derivatizing the 5′-position of the ribose sugar and the late stage alkylation of the 5′ amino group with bromoethanol, which was necessitated by the reactivity of the aryl azide moiety. The azide-bearing N-mustard is envisioned as a useful biochemical tool by which to probe DNA and protein methylation patterns.

A general strategy is developed for the stereoselective synthesis of C-substituted morpholine derivatives using intramolecular reductive etherification reaction. The method is extended to the first stereoselective total synthesis of (±)-chelonin C.

The dipeptidyl peptidase-IV inhibitor saxagliptin (Onglyza) can undergo a thermodynamically favored cyclization to form the corresponding cyclic amidine. The kinetics and mechanism of this conversion were examined to develop a commercial synthesis that afforded saxagliptin with only trace levels of this key byproduct. Important findings of this work are the identification of a profound solvent effect and the determination of an autocatalytic pathway. Both of these phenomena result from transition structures involving proton transfer.

Treatment of β-monosubstituted enamines with phenyliodine bis(trifluoroacetate) (PIFA) was found to give a variety of 4,5-disubstituted 2-(trifluoromethyl)oxazoles. This approach allows the incorporation of the trifluoromethyl moiety in PIFA into the final products, which presumably takes place via the oxidative β-trifluoroacetoxylation of the enamine substrates followed by subsequent intramolecular cyclization.

We report a detailed kinetic and mechanistic study of the reaction of a widely used therapeutic agent, deferoxamine (DFO), which contains three nucleophilic hydroxamate groups, with the model phosphate diester bis-2,4-dinitrophenylphosphate BDNPP. We clarify the mechanism by detecting important phosphorylated intermediates in the model reaction and show that the mechanism can be extended to the reaction with DNA. The effectiveness of DFO in cleaving DNA was examined over a range of pH in the absence and presence of a biologically available metal (Zn²⁺). The results inform and complement ongoing studies involving DFO, which can act as a powerful nucleophile toward DNA and other targets susceptible to nucleophilic attack.