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Stereocontrolled Synthesis of the Portimine Skeleton via Organocatalyst-Mediated Asymmetric Stannylation and Stereoretentive C(sp3)–C(sp2) Stille Coupling
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Stereocontrolled Synthesis of the Portimine Skeleton via Organocatalyst-Mediated Asymmetric Stannylation and Stereoretentive C(sp3)–C(sp2) Stille Coupling
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Organic Letters

Cite this: Org. Lett. 2025, 27, 4, 942–947
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https://doi.org/10.1021/acs.orglett.4c04245
Published January 22, 2025

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Abstract

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Our efforts toward the synthesis of the marine natural product portimine are described. The key to the synthesis of the skeleton is a stereoretentive copper-catalyzed C(sp3)–C(sp2) Stille-type cross-coupling that enables the convergent assembly of functionalized fragments. The core skeleton of portimine was constructed via ring-closing metathesis and transannular acetal formation.

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Of the many known marine natural products, cyclic imine toxins from dinoflagellates have in particular attracted much interest due to their extremely diverse biological activities and unique chemical structures. (1) However, the strong neurotoxicity of these marine natural products complicates their use as lead compounds in the development of pharmaceuticals. Portimine (1) is a cyclic imine natural product isolated originally from a marine dinoflagellate Vulcanodinium rugosum in New Zealand, (2) and is of particular interest to our laboratory. Its relative and absolute configuration was determined by Tanaka and co-workers (Figure 1). (3) Portimine (1) exhibits potent anticancer, (2) antifouling, (4) and anti-HIV-1 activities. (5) Furthermore, portimine (1) was recently shown to selectively induce apoptosis in human cancer cell lines (6) yet shows low acute toxicity in mice. Given these potent biological activities and low toxicity, portimine (1) has significant potential as a pharmaceutical lead compound and/or reagent. Portimine (1) has a 5-membered cyclic imine structure, which is very rare in cyclic imine natural products. Other unique molecular features of portimine (1) include a cyclohexene ring containing a quaternary carbon center (C-3), a highly oxidized 14-membered macrocyclic core skeleton, and a medium-sized cyclic acetal. The remarkable biological activities and unique chemical structure of portimine (1) make it an attractive synthetic target. Synthetic studies of portimine (1) have been reported by the Fujiwara, (7) Brimble, (8) Harran, (9) and Zakarian groups, (10) and recently Baran and co-workers reported the first elegant total synthesis of portimine (1). (11)

Figure 1

Figure 1. Structure and our retrosynthetic analysis of portimine (1).

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Our group has been working on the total synthesis of marine natural products using powerful synthetic methodologies (i.e., transition-metal-catalyzed carbon–carbon bond-forming coupling chemistry). (12) In the course of this research, we began investigating the total synthesis of portimine (1). We describe herein our synthetic efforts toward the total synthesis of portimine (1) based on our original retrosynthesis approach.

This approach toward portimine (1) is illustrated in Figure 1. Our synthetic target was compound 2 containing a macrocyclic core skeleton which an intermediate toward (1) by cyclic imine formation and oxidation at C-13, C-14, and C-21 in a late stage of synthesis. We envisioned that macrocyclic compound 2 could be synthesized from compound 3 by ring-closing metathesis (RCM) (13) between C-13 and C-14, followed by transannular acetal formation. Bond disconnection at the α-alkoxyketone moiety (between C-4 and C-5) in compound 3 gives chiral α-alkoxyalkylstannane 4 and thioester 5, which would then be convergently coupled by copper-catalyzed C(sp3)-C(sp2) Stille-type cross-coupling. (14) The advantage of this key last step is that the coupling of chiral α-alkoxyalkylstannane would proceed with high stereochemical retention (specifically at the C-5 position for stannane 4), but there are no examples in the literature of the application of this coupling reaction to substrates with complex structures such as 4 and 5. In addition, the steric bulkiness of thioester 5 is likely to hinder efficient coupling. It was assumed that chiral α-alkoxyalkylstannane 4 could be easily synthesized from aldehyde 6 via organocatalyst-mediated asymmetric stannylation. (15) Our aim was to synthesize thioester 5 from readily available starting materials 7 and 8, controlling the configuration at C-3 and C-16 using the asymmetric Diels–Alder reaction developed by Evans. (16)

The synthesis of chiral α-alkoxyalkylstannane is illustrated in Scheme 1. The Evans syn-aldol reaction (17) of aldehyde 9 (18) and N-acyloxazolidinone 10 (19) proceeded smoothly to give alcohol 11 in 87% yield with excellent diastereoselectivity (dr >20:1). Reduction of 11 using LiBH4 and subsequent tosylation gave alcohol 12 in 90% yield over two steps. After protection of the secondary alcohol of 12 as a diisopropylsilyl (TIPS) ether, the cyano group was introduced by treatment with NaCN, and then reduced with diisobutylaluminum hydride (DIBALH) at −78 °C. Methylenation of the resulting aldehyde under Wittig olefination conditions provided compound 13 in 72% yield over four steps. Treatment of compound 13 with NaOH at 60 °C smoothly and selectively removed the tert-butyldimethylsilyl (TBS) group, and the corresponding primary alcohol was obtained in 99% yield. Parikh-Doering oxidation (SO3·pyridine, Et3N, CH2Cl2, DMSO) (20) of this alcohol provided aldehyde 14 in 94% yield. Various methods for the asymmetric synthesis of α-alkoxyalkylstannanes have been reported to date. (21) We chose a facile organocatalyst-mediated asymmetric stannylation requiring only mild reaction conditions. (15) Thus, in accordance with Falck’s report, treatment of aldehyde 14 with (R)- diphenylprolinol in the presence of n-butyltin hydride and diethylzinc led to asymmetric stannylation with excellent diastereoselectivity (dr 97:3). However, the obtained alcohol was unstable and thus was immediately converted to thiocarbamate 15 using a two-step protection sequence. The configuration of the newly created stereogenic center by organocatalyst-mediated asymmetric stannylation was established by a modified Mosher analysis approach (see Supporting Information). (22)

Scheme 1

Scheme 1. Synthesis of α-Alkoxyalkylstannane 15
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The synthesis of the thioester is shown in Scheme 2. Asymmetric Diels–Alder reaction of α-methylene γ-lactam 7 (23) and diene 16 (23) proceeded smoothly under Evans reaction conditions (16) in the presence of [Cu((S,S)-tert-Bu-box)](SbF6)2 to give spirocyclic cyclohexene 17 in 89% yield with excellent diastereo and enantioselectivity (dr >20:1 and er 98:2). (24) Evans conditions have been applied to the synthesis of δ-lactam (25) and ε-lactam, (26) but to our knowledge, the present report is the first example of its application for γ-lactam synthesis. Removal of the Cbz group using Et2AlCl and PhSMe (27) gave the corresponding N–H lactam in quantitative yield, and subsequent introduction of a 2-nitrobenzenesulfonyl (Ns) group by using n-BuLi and NsCl gave Ns lactam 18 in 90% yield. Thus, the Cbz group was converted to the Ns group. Ring-opening of the lactam was carried out using LiOH, and carboxylic acid 19 was obtained in 86% yield. Various methods to introduce thioesters were unsuccessful (i.e., when the carboxyl group in 19 was activated, lactam 18 was easily formed by the nucleophilic attack of Ns amide). This problem was addressed by masking the carboxyl group in situ by treating 19 with TMS-imidazole. Next, the Ns amide was protected with tert-butoxycarbonyl (Boc) under standard reaction conditions (Boc2O, Et3N, DMAP) to obtain carboxylic acid 20 in 80% yield in a one-pot operation. Finally, 20 was converted into the corresponding acid chloride, then treatment with 4-nitrothiophenol and pyridine completed the synthesis of thioester 21.

Scheme 2

Scheme 2. Synthesis of Thioester 21
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With the coupling substrates 15 and 21 in hand, we examined the key copper-catalyzed C(sp3)-C(sp2) Stille-type cross-coupling reaction (Scheme 3). (14) Investigation of the reaction conditions pointed to the use of copper(I) thiophene-2-carboxylate (CuTC) (14b) as a catalyst and heating in toluene. This removed the Boc group and thus we reintroduced the Boc group after the coupling reaction to afford the coupling product 22 in 61% overall yield with excellent diastereoselectivity (dr >20:1). However, the coupling reaction proceeded very slowly, taking 5 days to reach 48% yield. Further extension of reaction time or addition of catalysts resulted in lower yields. This was attributed to the byproduct Bu3SnS-p-NO2Ph produced during the reaction process, (14b) which was coordinated to the copper catalyst and inhibited cross-coupling. Therefore, the reaction was carried out in a short time, and the resulting Bu3SnS-p-NO2Ph was removed. Then the same reaction was repeated three times and the product was pooled to obtain the total yield. We confirmed the configuration of the stereogenic center at the C-5 position in compound 22 as follows. Exposure of 22 to m-CPBA resulted in the selective removal of thiocarbamate (28) to give formyl ester 23. Subsequent treatment of 23 with K2CO3 in MeOH provided alcohol 24 in 78% yield over two steps. Alcohol 24 was converted to (R)- and (S)-MTPA esters and their configurations were confirmed by a modified Mosher analysis, (22) as shown in Scheme 3 (see Supporting Information for details). The key coupling reaction proceeded with extremely high stereochemical retention, and the chirality of α-alkoxyalkylstannane 15 was completely transferred to the coupling product 22. Similar couplings have occasionally been applied to the synthesis of natural products. (29) However, to our knowledge, the present study is the first to apply stereoretentive copper-catalyzed C(sp3)-C(sp2) Stille-type cross-coupling between diversely functionalized compounds such as 15 and 21.

Scheme 3

Scheme 3. Key Coupling and Stereochemical Conformation of Alcohol 24 through Modified Mosher Analysis
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Having achieved efficient coupling, the next challenge was the formation of a 14-membered macrocycle by RCM (Scheme 4). The tert-butyldiphenylsilyl (TBDPS) group was selectively removed using a mixture of TBAF/AcOH to obtain primary alcohol 26 in 91% yield. Swern oxidation of alcohol 26 ((COCl)2, Et3N, DMSO) (30) proceeded smoothly, but the corresponding aldehyde was very unstable and decomposed during workup and purification. Therefore, the subsequent Grignard reaction was carried out immediately in a one-pot operation after the Swern oxidation step to obtain propargyl alcohol 27 in 98% overall yield with excellent diastereoselectivity (dr >20:1). The configuration of the newly generated stereogenic center at the C-15 position by Grignard reaction was established by a modified Mosher analysis (see Supporting Information). (22) We also attempted to introduce vinyl group but the reaction was surprisingly very sluggish, in contrast to the introduction of ethynyl group, and thus our attempts to introduce functional groups other than ethynyl were unsuccessful. Removal of the Ns group with PhSH, K2CO3, in DMF provided the corresponding amide in 91% yield. The terminal alkyne (at C-14) was partially hydrogenated by using Pd/CaCO3, 3,6-dithia-1,8-octanediol (A) (31) under a H2 atmosphere to afford the corresponding allylic alcohol in quantitative yield. Furthermore, PDC oxidation of allylic alcohol (at C-15) gave enone 28 in 88% yield. Having obtained substrate 28, we attempted the RCM reaction. RCM reaction using the second Hoveyda-Grubbs catalyst (HG-II, 21 mol %) (13) in toluene (1.0 mM) provided 14-membered macrocyclic compound 29 in excellent yield (82%, E/Z = 5.8/1).

Scheme 4

Scheme 4. Construction of 14-Membered Macrocycles by RCM
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The next challenge was to construct the portimine core skeleton by transannular acetal formation. We began our investigations using 29-(E) (Scheme 5, upper column). Luche reduction (NaBH4, CeCl3·7H2O, EtOH, – 78 to −60 °C) (32) of 29-(E) proceeded regioselectively at the C-15 ketone to give the desired allylic alcohol in 73% yield, along with its diastereomer in 18% yield. Removal of the TIPS group using HF·pyridine in THF/pyridine (1:1) gave diol 30 in 92% yield. We investigated many reaction conditions for transannular acetal formation using diol 30 but were unable to obtain the desired acetal 31, possibly because distortion of acetal 31 by E-olefin made the cyclization process unfavorable. We therefore examined transannular acetal formation starting from 29-(Z) (Scheme 5, lower column).

Scheme 5

Scheme 5. Challenges of Transannular Acetal Formation and Construction of the Macrocyclic Acetal Skeleton of Portimine
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Luche reduction (NaBH4, CeCl3·7H2O, EtOH, −78 to −60 °C) (32) of 29-(Z) proceeded with excellent regio and diastereoselectivity to give the allylic alcohol in 90% yield with excellent diastereoselectivity (dr >20:1). The configuration of the newly generated stereogenic center at C-15 from ketone 29-(Z) by Luche reduction was established by a modified Mosher analysis (see Supporting Information). (22) Subsequent deprotection of the TIPS group gave diol 32 in 90% yield. To our delight, transannular acetal formation of 32 proceeded smoothly by the action of TsOH·H2O in CH2Cl2 to afford acetal 33 in 91% yield. Selective removal of the thiocarbamate group (28) by exposure of 33 to m-CPBA provided formyl ester 34. Finally, alcohol 35, with the same core skeleton as portimine, was synthesized by removal of the formyl group in 63% yield over two steps. Thus, our next challenge will be oxidation at C-13 and C-14.

The highlights of our synthesis are organocatalyst-mediated asymmetric stannylation to synthesize chiral α-alkoxyalkylstannane 15, and subsequent stereoretentive copper-catalyzed C(sp3)-C(sp2) Stille-type cross-coupling to achieve convergent fragment assembly of 15 and 21. It is worth noting that this coupling proceeded with high stereochemical retention. Furthermore, RCM and transannular acetal formation allowed us to construct the core skeleton of portimine. Further studies are currently underway toward the total synthesis of the natural product portimine (1).

Data Availability

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The data underlying this study are available in the published article and its 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.orglett.4c04245.

  • Experimental procedures, characterization data, and NMR spectra of all newly synthesized compounds. (PDF)

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Author Information

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  • Corresponding Authors
  • Author
    • Daisuke Sato - Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, 980-8577 Aoba-ku, Sendai, Japan
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was financially supported by JSPS KAKENHI Grant Number JP23K14314. We thank Dr. Shota Nagasawa (Tohoku University) for FAB and ESI-TOF mass measurements.

References

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This article references 32 other publications.

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    Saito, T.; Fujiwara, K.; Kondo, Y.; Akiba, U.; Suzuki, T. Synthesis of the cyclohexene segment of portimine. Tetrahedron Lett. 2019, 60, 386– 389,  DOI: 10.1016/j.tetlet.2018.12.063
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    7
    Synthesis of the cyclohexene segment of portimine
    Saito, Takafumi; Fujiwara, Kenshu; Kondo, Yoshihiko; Akiba, Uichi; Suzuki, Takanori
    Tetrahedron Letters (2019), 60 (4), 386-389CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    The synthesis of the cyclohexene segment I of portimine, a marine cytotoxin from the dinoflagellate Vulcanodinium rugosum, was achieved. The route includes an acylation/aldol reaction from 3-ethoxycyclohex-2-enone to create the C3 center, the 1,4-addn. of a vinyl group at C16, the diastereoselective dihydroxylation of the vinyl group to generate the C15 center, a vinylation/dehydration sequence to set up the diene moiety, and stepwise installation of the amino-group-substituted C1 unit.
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  8. 8
    (a) Aitken, H. R. M.; Brimble, M. A.; Furkert, D. P. A catalytic asymmetric ene reaction for direct preparation of α-hydroxy 1, 4- diketones as intermediates in natural product synthesis. Synlett 2020, 31, 687– 690,  DOI: 10.1055/s-0037-1610748
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    There is no corresponding record for this reference.
    (b) Ding, X.; Aitken, H. R. M.; Pearl, E. S.; Furkert, D. P.; Brimble, M. A. Synthesis of the C4–C16 Polyketide Fragment of Portimines A and B. J. Org. Chem. 2021, 86, 12840– 12850,  DOI: 10.1021/acs.joc.1c01463
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    8b
    Synthesis of the C4-C16 Polyketide Fragment of Portimines A and B
    Ding, Xiao-Bo; Aitken, Harry R. M.; Pearl, Esperanza S.; Furkert, Daniel P.; Brimble, Margaret A.
    Journal of Organic Chemistry (2021), 86 (18), 12840-12850CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Stereoselective synthesis of the C4-C16 polyketide fragment I of portimines A and B is reported, enabled by our previously established method for the stereoselective synthesis of syn-α,α'-dihydroxyketones. The prepn. of this advanced fragment provides insights useful for the total synthesis of portimines A and B. An asym. Evans aldol reaction was used to install the C10-C11 adjacent stereogenic centers before incorporation of indantrione, followed by epoxidn. and epoxide opening to forge the challenging syn-α,α'-dihydroxyketone functionality.
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  9. 9
    Li, L.; El Khoury, A.; Clement, B. O.; Wu, C.; Harran, P. G. Asymmetric organocatalysis enables rapid assembly of portimine precursor chains. Org. Lett. 2022, 24, 2607– 2612,  DOI: 10.1021/acs.orglett.2c00556
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    9
    Asymmetric Organocatalysis Enables Rapid Assembly of Portimine Precursor Chains
    Li, Liubo; El Khoury, Anton; Clement, Brennan O'Neil; Wu, Carolyn; Harran, Patrick G.
    Organic Letters (2022), 24 (14), 2607-2612CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    Sequential organocatalytic addns. of 2-furanone and dihydroxyacetone derivs. to a crotonaldehyde lynchpin provide polyhydroxylated chains reminiscent of lactonized deoxo Kdn type sugars. Further homologation via Kulinkovich ring opening of the butyrolactone and acylation of the zinc homo-enolate derived from the incipient cyclopropanol allows assembly of functionalized chain precursors to portimine. Our expts. probe the stability and reactivity of monosubstituted methylidene pyrrolines and generate advanced intermediates useful for exploring the biosynthesis and de novo synthesis of portimine.
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  10. 10
    Lee, H. J.; Gladfelder, J. J.; Zakarian, A. Remoto Stereocontrol in the Ireland-Claisen Rearrangement by δ-Alkyl Group. J. Org. Chem. 2023, 88, 7560– 7563,  DOI: 10.1021/acs.joc.3c00535
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    10
    Remote Stereocontrol in the Ireland-Claisen Rearrangement by δ-Alkoxy Group
    Lee, Hye Joon; Gladfelder, Joshua J.; Zakarian, Armen
    Journal of Organic Chemistry (2023), 88 (11), 7560-7563CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Remote stereocontrol in the Ireland-Claisen rearrangement using a chiral acetonides e.g., I that serves as internal stereocontrol element is an effective and general method for chirality transfer from a δ-hydroxyl group in the allylic alc. unit. This strategy circumvents the need for redundant chirality at the α-position allylic alc., while simultaneously producing a terminal alkenes e.g., II that can streamline synthetic applications and complex mol. synthesis planning.
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  11. 11
    Tang, J.; Li, W.; Chiu, T. Y.; Martínes-Peña, F.; Luo, Z.; Chong, C. T.; Wei, Q.; Gazaniga, N.; West, T. J.; See, Y. Y.; Lairson, L. L.; Parker, C. G.; Baran, P. S. Synthesis of portimines reveals the basis of their anti-cancer activity. Nature 2023, 622, 507– 513,  DOI: 10.1038/s41586-023-06535-1
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    11
    Synthesis of portimines reveals the basis of their anti-cancer activity
    Tang, Junchen; Li, Weichao; Chiu, Tzu-Yuan; Martinez-Pena, Francisco; Luo, Zengwei; Chong, Christine T.; Wei, Qijia; Gazaniga, Nathalia; West, Thomas J.; See, Yi Yang; Lairson, Luke L.; Parker, Christopher G.; Baran, Phil S.
    Nature (London, United Kingdom) (2023), 622 (7983), 507-513CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio)
    Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chem. structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the mol. mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chem. through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumor-clearance models. Finally, practical access to the portimines and their analogs simplified the development of photoaffinity analogs, which were used in chem. proteomic expts. to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.
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  12. 12
    (a) Iwasaki, K.; Sasaki, S.; Kasai, Y.; Kawashima, Y.; Sasaki, S.; Ito, T.; Yotsu-Yamashita, M.; Sasaki, M. Total Synthesis of Polycavernosides A and B, Two Lethal Toxins from Red Alga. J. Org. Chem. 2017, 82, 13204– 13219,  DOI: 10.1021/acs.joc.7b02293
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    12a
    Total Synthesis of Polycavernosides A and B, Two Lethal Toxins from Red Alga
    Iwasaki, Kotaro; Sasaki, Satori; Kasai, Yusuke; Kawashima, Yuki; Sasaki, Shohei; Ito, Takanori; Yotsu-Yamashita, Mari; Sasaki, Makoto
    Journal of Organic Chemistry (2017), 82 (24), 13204-13219CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Polycavernosides A and B are glycosidic macrolide natural products isolated as the toxins causing fatal human poisoning by the edible red alga Gracilaria edulis (Polycavernosa tsudai). Total synthesis of polycavernosides A and B has been achieved via a convergent approach. The synthesis of the macrolactone core structure is highlighted by the catalytic asym. syntheses of the two key fragments using hetero-Diels-Alder reaction and Kiyooka aldol reaction as the key steps, their union through Suzuki-Miyaura coupling, and Keck macrolactonization. Finally, glycosylation with the L-fucosyl-D-xylose unit and construction of the polyene side chain through Stille coupling completed the total synthesis of polycavernosides A and B.
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    (b) Sasaki, M.; Iwasaki, K.; Arai, K.; Hamada, N.; Umehara, A. Convergent Synthesis of the HIJKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1 by a Late-Stage Reductive Olefin Coupling Approach. Bull. Chem. Soc. Jpn. 2022, 95, 819– 824,  DOI: 10.1246/bcsj.20220070
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    12b
    Convergent Synthesis of the HIJKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1 by a Late-Stage Reductive Olefin Coupling Approach
    Sasaki, Makoto; Iwasaki, Kotaro; Arai, Keisuke; Hamada, Naoya; Umehara, Atsushi
    Bulletin of the Chemical Society of Japan (2022), 95 (5), 819-824CODEN: BCSJA8; ISSN:0009-2673. (Chemical Society of Japan)
    The convergent synthesis of the HIJKLMN-ring fragment of Caribbean ciguatoxin C-CTX-1, the major causative toxin for ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic areas, is disclosed. The synthesis features a late-stage iron-catalyzed hydrogen atom transfer-initiated reductive olefin coupling to install the N-ring and a Suzuki-Miyaura coupling/thioacetalization strategy for the convergent assembly of the hexacyclic HIJKLM-ring skeleton I.
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    (c) Suwa, T.; Sasaki, M.; Umehara, A. Total Synthesis of (−)-Irijimaside A Enabled by Ni/Zr-Mediated Reductive Ketone Coupling. Org. Lett. 2024, 26, 4377– 4382,  DOI: 10.1021/acs.orglett.4c01367
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    (d) Sasaki, M.; Ohba, M.; Murakami, A.; Umehara, A. Convergent and Scalable Second-Generation Synthesis of the Fully Functionalized HIJKLMN-Ring Segment of Caribbean Ciguatoxin C-CTX-1. J. Org. Chem. 2024, 89, 18631– 18639,  DOI: 10.1021/acs.joc.4c02723
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    (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H. A Recyclable Ru-Based Metathesis Catalyst. J. Am. Chem. Soc. 1999, 121, 791– 799,  DOI: 10.1021/ja983222u
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    A Recyclable Ru-Based Metathesis Catalyst
    Kingsbury, Jason S.; Harrity, Joseph P. A.; Bonitatebus, Peter J. Jr.; Hoveyda, Amir H.
    Journal of the American Chemical Society (1999), 121 (4), 791-799CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A Ru carbene (I) that contains an internal metal-O chelate is an active metathesis catalyst and is readily obtained by the sequential treatment of Cl2Ru(PPh3)3 with (2-isopropoxyphenyl)diazomethane and PCy3. This Ru-carbene complex offers excellent stability to air and moisture and can be recycled in high yield by silica gel column chromatog. The structures of this and related complexes were unambiguously established by NMR and single-crystal x-ray diffraction studies.
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    (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. Efficient and Recyclable Monomeric and Dendritic Ru-Based Metathesis Catalysts. J. Am. Chem. Soc. 2000, 122, 8168– 8179,  DOI: 10.1021/ja001179g
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    Efficient and Recyclable Monomeric and Dendritic Ru-Based Metathesis Catalysts
    Garber, Steven B.; Kingsbury, Jason S.; Gray, Brian L.; Hoveyda, Amir H.
    Journal of the American Chemical Society (2000), 122 (34), 8168-8179CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Several highly active, recoverable and recyclable Ru-based metathesis catalysts are presented. The crystal structure of the Ru complex (I) bearing a 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene and styrenyl ether ligand is disclosed. The heterocyclic ligand significantly enhances the catalytic activity, and the styrenyl ether allows for the easy recovery of the Ru complex. Catalyst I promotes ring-closing metathesis (RCM) and the efficient formation of various trisubstituted olefins at ambient temp. in high yield within 2 h; the catalyst is obtained in >95% yield after silica gel chromatog. and can be used directly in subsequent reactions. Tetrasubstituted olefins can also be synthesized by RCM reactions catalyzed by I. In addn., the synthesis and catalytic activities of two dendritic and recyclable Ru-based complexes are disclosed. Examples involving catalytic ring-closing, ring-opening, and cross metatheses are presented where, unlike monomer I, the dendritic catalyst can be readily recovered.
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  14. 14
    (a) Falck, J. R.; Bhatt, R. K.; Ye, J. Tin-Copper Transmetalation: Cross-Coupling of alpha-Heteroatom-Substituted Alkyltributylstannanes with Organohalides. J. Am. Chem. Soc. 1995, 117, 5973– 5982,  DOI: 10.1021/ja00127a010
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    14a
    Tin-Copper Transmetalation: Cross-Coupling of α-Heteroatom-Substituted Alkyltributylstannanes with Organohalides
    Falck, J. R.; Bhatt, Rama K.; Ye, Jianhua
    Journal of the American Chemical Society (1995), 117 (22), 5973-82CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Copper(I), in the absence of other transition metals, catalyzes the cross-coupling of [α-(acyloxy)benzyl]tributylstannanes with allylic bromides in THF in fair to good yields and with aryl/vinyl halides less efficiently or not at all. Simple [α-(acyloxy)alkyl]tributylstannanes react sluggishly even with allyl bromide. However, proximal thiosubstituents on either reaction partner dramatically enhance yields, reaction rates, and the variety of suitable educts. (α-Phthalimidoylalkyl)tributylstannanes afford protected α-amino thio esters. In contrast with the Stille reaction, copper-mediated cross-couplings of α-heteroatom-substituted alkyltributylstannanes proceed with complete retention of configuration via a coordinatively stabilized organocopper intermediate that can be intercepted in good yield by 1,4-conjugate addn. to 2-cyclohexen-1-one.
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    (b) Li, H.; He, A.; Falck, J. R.; Liebeskind, L. S. Stereocontrolled Synthesis of α-Amino-α′-alkoxy Ketones by a Copper-Catalyzed Cross-Coupling of Peptidic Thiol Esters and α-Alkoxyalkylstannanes. Org. Lett. 2011, 13, 3682– 3685,  DOI: 10.1021/ol201330j
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    14b
    Stereocontrolled Synthesis of α-Amino-α'-alkoxy Ketones by a Copper-Catalyzed Cross-Coupling of Peptidic Thiol Esters and α-Alkoxyalkylstannanes
    Li, Hao; He, Anyu; Falck, John R.; Liebeskind, Lanny S.
    Organic Letters (2011), 13 (14), 3682-3685CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A stereocontrolled synthesis of α-amino-α'-alkoxy ketones is described. This pH-neutral copper(I) thiophene-2-carboxylate (CuTC)-catalyzed cross-coupling of amino acid thiol esters, e.g., I, and chiral nonracemic α-alkoxyalkylstannanes, e.g., II, gives α-amino-α'-alkoxy ketones, e.g., III, in good to excellent yields with complete retention of configuration at the α-amino- and α-alkoxy-substituted stereocenters.
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    (c) Cordovilla, C.; Bartolomé, C.; Martínez-Ilarduya, J. M.; Espinet, P. The Stille Reaction, 38 Years Later. ACS Catal. 2015, 5, 3040– 3053,  DOI: 10.1021/acscatal.5b00448
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    The Stille Reaction, 38 Years Later
    Cordovilla, Carlos; Bartolome, Camino; Martinez-Ilarduya, Jesus Ma; Espinet, Pablo
    ACS Catalysis (2015), 5 (5), 3040-3053CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    This review concs. on the mechanistic new knowledge and on important aspects such as the revolution with the use of bulky phosphines, the bimetallic alternative of the Stille reaction, the enantioselectivity in Stille and palladium-free Stille processes, the meaning of copper effect, or the possible approaches to make Stille coupling a greener process.
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  15. 15
    He, A.; Falck, J. R. Synthesis of Enantioenriched α-(Hydroxyalkyl)-tri-n-butylstannanes. Angew. Chem., Int. Ed. 2008, 47, 6586– 6589,  DOI: 10.1002/anie.200802313
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    (a) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. Chiral bis(oxazoline)copper(II) complexes as Lewis acid catalysts for the enantioselective Diels-Alder reaction. J. Am. Chem. Soc. 1999, 121, 7559– 7573,  DOI: 10.1021/ja991190k
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    16a
    Chiral Bis(oxazoline)copper(II) Complexes as Lewis Acid Catalysts for the Enantioselective Diels-Alder Reaction
    Evans, David A.; Miller, Scott J.; Lectka, Thomas; von Matt, Peter
    Journal of the American Chemical Society (1999), 121 (33), 7559-7573CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Bis(oxazoline)copper(II) complexes are highly enantioselective catalysts in Diels-Alder reactions involving bidentate dienophiles. Cationic [Cu((S,S)-t-Bu-box)]X2 complexes with different counterions have been used as catalysts, revealing a profound influence of the counterion on the rate and stereoselectivity of the catalyst. A square-planar catalyst-substrate complex is proposed to account for the high diastereo- and enantioselectivities obsd. Three bis(oxazoline)-Cu(II) X-ray structures have been obtained that support this model. Double-stereodifferentiating expts., performed employing chiral dienophiles, afforded results that are fully consistent with the proposed square-planar transition-state assemblage. In addn. to imide-based substrates, α,β-unsatd. thiazolidine-2-thiones have been introduced as a new class of dienophiles with enhanced reactivity. Kinetics expts. were performed to quantify the role that product inhibition plays in the course of the reaction. Rate and equil. binding consts. of various catalyst inhibitors were also derived from the kinetic anal. A comparative study was undertaken to elucidate the differences between the bis(oxazoline)-Cu(II) catalyst and the bis(oxazoline) catalysts derived from Fe(III), Mg(II), and Zn(II). Catalyst performance was found to be a function of a subtle relationship between bis(oxazoline) structure and transition metal.
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    (b) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. Bis(oxazoline) and Bis(oxazolinyl)pyridine Copper Complexes as Enantioselective Diels–Alder Catalysts: Reaction Scope and Synthetic Applications. J. Am. Chem. Soc. 1999, 121, 7582– 7594,  DOI: 10.1021/ja991191c
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    16b
    Bis(oxazoline) and Bis(oxazolinyl)pyridine Copper Complexes as Enantioselective Diels-Alder Catalysts: Reaction Scope and Synthetic Applications
    Evans, David A.; Barnes, David M.; Johnson, Jeffrey S.; Lectka, Thomas; von Matt, Peter; Miller, Scott J.; Murry, Jerry A.; Norcross, Roger D.; Shaughnessy, Eileen A.; Campos, Kevin R.
    Journal of the American Chemical Society (1999), 121 (33), 7582-7594CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The scope of the Diels-Alder reaction catalyzed by bis(oxazoline) copper complexes has been investigated. In particular, [Cu((S,S)-t-Bu-box)](SbF6)2 has been shown to catalyze the Diels-Alder reaction between 3-propenoyl-2-oxazolidinone and a range of substituted dienes with high enantioselectivity. This cationic complex has also been employed in the catalysis of analogous intramol. processes with good success. The total syntheses of ent-Δ1-tetrahydrocannabinol, ent-shikimic acid, and isopulo'upone, featuring the use of this chiral catalyst in more complex Diels-Alder processes, are described. Similarly, the cationic copper complex [Cu((S,S)-t-Bu-pybox)](SbF6)2 is effective in the Diels-Alder reactions of monodentate acrolein dienophiles while the closely related complex [Cu((S,S)-Bn-pybox)](SbF6)2 is the preferred Lewis acid catalyst for acrylate dienophiles in reactions with cyclopentadiene.
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  17. 17
    (a) Evans, D. A.; Bartroli, J.; Shih, T. L. Enantioselective Aldol Condensations. 2. Erythro-Selective Chiral Aldol Condensations via Boron Enolates. J. Am. Chem. Soc. 1981, 103, 2127– 2129,  DOI: 10.1021/ja00398a058
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    17a
    Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates
    Evans, D. A.; Bartroli, J.; Shih, T. L.
    Journal of the American Chemical Society (1981), 103 (8), 2127-09CODEN: JACSAT; ISSN:0002-7863.
    The bibutylboryl enolates derived from I and II (R = Me, SMe, CH2CO2Et) underwent highly stereoselective aldol condensations with R1CHO (R1 = Ph, Bu, Me2CH). Erythro diastereoselection was ≥99% and asym. induction within the erythro product manifold was »100:1. The resultant aldol adducts may be hydrolyzed with aq. base to the enantiomeric erythro β-hydroxy acids and the oxazolidone chiral auxiliaries recycled. In contrast, I and II (R = H) exhibited no enolate diastereoface selection in the condensation process; however, I and II (R1 = SMe) may be employed as chiral acetate enolate synthons.
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    (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. Stereoselective aldol condensations via boron enolates. J. Am. Chem. Soc. 1981, 103, 3099– 3111,  DOI: 10.1021/ja00401a031
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    Stereoselective aldol condensations via boron enolates
    Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R.
    Journal of the American Chemical Society (1981), 103 (11), 3099-111CODEN: JACSAT; ISSN:0002-7863.
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    Aldehyde 9 was readily synthesized from commercially available 1,4-cyclohexanedione monoethyleneketal in five steps. For details, see the Supporting Information.

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    For selected methods for synthesis of chiral α-alkoxyalkylstannanes, see:

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    The acyclic, sp3 organolithium reagents which are produced by BuLi exchange with diastereomerically or enantiomerically pure α-alkoxyorganostannanes, were configurationally stable for at least 15 mins. at -30°. The purified organostannanes were prepd. by the addn. of Bu3SnLi to aldehydes followed by hydroxyl protection and medium pressure liq. chromatog. on silica gel. Exchange was accomplished at -78° to give configurationally stable organolithium reagents which were treated with Me2CO, Me3SiCl, Me2SO4. The stereochem. of the addn. of Bu3SnLi to several aldehydes was studied to det. the extent of α-induction available with that reagent. While normal Cram's rule selectivity was comparable with unhindered Grignard reagents, β-oxygen substituted chiral aldehydes gave much more stereoselection for the chelation controlled product with the Sn anion.
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    A method for the synthesis of chiral cyclopentanes using tin-lithium exchange and cycloalkylation reactions is reported. The sec-butyllithium/(-)-sparteine-mediated deprotonation of an alkyl carbamate and subsequent substitution furnishes a highly enantioenriched stannane as a stable carbanion equiv. This was transformed into suitable cyclization precursors which underwent tin-lithium exchange and stereoselective cycloalkylation when reacted with butyllithium, giving highly enantioenriched cyclopentanes in very good yields. A kinetic resoln. was obsd. with a higher substituted stannane.
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  • Abstract

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    Figure 1

    Figure 1. Structure and our retrosynthetic analysis of portimine (1).

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    Scheme 1

    Scheme 1. Synthesis of α-Alkoxyalkylstannane 15
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    Scheme 2

    Scheme 2. Synthesis of Thioester 21
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    Scheme 3

    Scheme 3. Key Coupling and Stereochemical Conformation of Alcohol 24 through Modified Mosher Analysis
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    Scheme 4

    Scheme 4. Construction of 14-Membered Macrocycles by RCM
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    Scheme 5

    Scheme 5. Challenges of Transannular Acetal Formation and Construction of the Macrocyclic Acetal Skeleton of Portimine
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  • References

    This article references 32 other publications.

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      A review. From a small group of exotic compds. isolated only two decades ago, Cyclic Imine (CI) toxins have become a major class of marine toxins with global distribution. Their distinct chem. structure, biol. mechanism of action, and intricate chem. ensures that CI toxins will continue to be the subject of fascinating fundamental studies in the broad fields of chem., chem. biol., and toxicol. The worldwide occurrence of potent CI toxins in marine environments, their accumulation in shellfish, and chem. stability are important considerations in assessing risk factors for human health. This review article aims to provide an account of chem., biol., and toxicol. of CI toxins from their discovery to the present day.
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      Cyclic imine toxins from dinoflagellates: a growing family of potent antagonists of the nicotinic acetylcholine receptors
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      A review. The authors present an overview of the toxicol. profile of the fast-acting, lipophilic macrocyclic imine toxins, an emerging family of org. compds. assocd. with algal blooms, shellfish contamination and neurotoxicity. Worldwide, shellfish contamination incidents are expanding; therefore, the significance of these toxins for the shellfish food industry deserves further study. Emphasis is directed to the dinoflagellate species involved in their prodn., their chem. structures, and their specific mode of interaction with their principal natural mol. targets, the nicotinic acetylcholine receptors, or with the sol. acetylcholine-binding protein, used as a surrogate receptor model. The dinoflagellates Karenia selliformis and Alexandrium ostenfeldii / A. peruvianum have been implicated in the biosynthesis of gymnodimines and spirolides, while Vulcanodinium rugosum is the producer of pinnatoxins and portimine. The cyclic imine toxins are characterized by a macrocyclic skeleton comprising 14-27 carbon atoms, flanked by two conserved moieties, the cyclic imine and the spiroketal ring system. These phycotoxins generally display high affinity and broad specificity for the muscle type and neuronal nicotinic acetylcholine receptors, a feature consistent with their binding site at the receptor subunit interfaces, composed of residues highly conserved among all nAChRs, and explaining the diverse toxicity among animal species.
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      Selwood, A. I.; Wilkins, A. L.; Munday, R.; Shi, F.; Rhodes, L. L.; Holland, P. T. Portimine: a bioactive metabolite from the benthic dinoflagellate Vulcanodinium rugosum. Tetrahedron Lett. 2013, 54, 4705– 4707,  DOI: 10.1016/j.tetlet.2013.06.098
      2
      Portimine: a bioactive metabolite from the benthic dinoflagellate Vulcanodinium rugosum
      Selwood, Andrew I.; Wilkins, Alistair L.; Munday, Rex; Shi, Feng; Rhodes, Lesley L.; Holland, Patrick T.
      Tetrahedron Letters (2013), 54 (35), 4705-4707CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      Portimine, a new polycyclic ether toxin contg. a cyclic imine moiety, was isolated from the marine benthic dinoflagellate Vulcanodinium rugosum collected from Northland, New Zealand. The structure of portimine, including the relative configurations, was elucidated by spectroscopic analyses. The cyclic imine moiety consists of an unprecedented five-membered ring with a spiro-link to a cyclohexene ring. This is the only structural similarity to the pinnatoxin group of polycyclic ethers also produced by V. rugosum, which all contain a six-membered cyclic imine ring. The LD50 of portimine to mice by i.p. injection was 1570 μg/kg, indicating a much lower toxicity than many other cyclic imine shellfish toxins. In contrast, portimine was highly toxic to mammalian cells in vitro with an LC50 to P388 cells of 2.7 nM, and activation of caspases indicating apoptotic activity.
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    3. 3
      Hermawan, I.; Higa, M.; Hutabarat, P. U. B.; Fujiwara, T.; Akiyama, K.; Kanamoto, A.; Haruyama, T.; Kobayashi, N.; Higashi, M.; Suda, S.; Tanaka, J. Kabirimine, a New Cyclic Imine from an Okinawan Dinoflagellate. Mar. Drugs 2019, 17, 353– 361,  DOI: 10.3390/md17060353
      3
      Kabirimine, a new cyclic imine from an okinawan dinoflagellate
      Hermawan, Idam; Higa, Mikako; Hutabarat, Philipus Uli Basa; Fujiwara, Takeshi; Akiyama, Kiyotaka; Kanamoto, Akihiko; Haruyama, Takahiro; Kobayashi, Nobuyuki; Higashi, Masahiro; Suda, Shoichiro; Tanaka, Junichi
      Marine Drugs (2019), 17 (6), 353CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      On our quest for new bioactive mols. from marine sources, two cyclic imines (1, 2) were isolated from a dinoflagellate ext., inhibiting the growth of the respiratory syncytial virus (RSV). Compd. 1 was identified as a known mol. portimine, while 2 was elucidated to be a new cyclic imine, named kabirimine. The abs. stereochem. of 1 was detd. by crystallog. work and chiral derivatization, whereas the structure of 2 was elucidated by means of spectroscopic anal. and computational study on all the possible isomers. Compd. 1 showed potent cytotoxicity (CC50 < 0.097 μM) against HEp2 cells, while 2 exhibited moderate antiviral activity against RSV with IC50 = 4.20 μM (95% CI 3.31-5.33).
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    4. 4
      Brooke, D. G.; Cervin, G.; Champeau, O.; Harwood, D. T.; Pavia, H.; Selwood, A. I.; Svenson, J.; Tremblay, L. A.; Cahill, P. L. Antifouling activity of portimine, select semisynthetic analogues, and other microalga-derived spirocyclic imines. Biofouling 2018, 34, 950– 961,  DOI: 10.1080/08927014.2018.1514461
      4
      Antifouling activity of portimine, select semisynthetic analogues, and other microalga-derived spirocyclic imines
      Brooke, Darby G.; Cervin, Gunnar; Champeau, Olivier; Harwood, D. Tim; Pavia, Henrik; Selwood, Andrew I.; Svenson, Johan; Tremblay, Louis A.; Cahill, Patrick L.
      Biofouling (2018), 34 (8), 950-961CODEN: BFOUEC; ISSN:0892-7014. (Taylor & Francis Ltd.)
      A range of natural products from marine invertebrates, bacteria and fungi have been assessed as leads for nature-inspired antifouling (AF) biocides, but little attention has been paid to microalgal-derived compds. This study assessed the AF activity of the spirocyclic imine portimine (), which is produced by the benthic mat-forming dinoflagellate Vulcanodinium rugosum. Portimine displayed potent AF activity in a panel of four macrofouling bioassays (EC50 0.06-62.5 ng ml-1), and this activity was distinct from that of the related compds. gymnodimine-A (), 13-desmethyl spirolide C (), and pinnatoxin-F (). The proposed mechanism of action for portimine is induction of apoptosis, based on the observation that portimine inhibited macrofouling organisms at developmental stages known to involve apoptotic processes. Semisynthetic modification of select portions of the portimine mol. was subsequently undertaken. Obsd. changes in bioactivity of the resulting semisynthetic analogs of portimine were consistent with portimine's unprecedented 5-membered imine ring structure playing a central role in its AF activity.
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    5. 5
      Izumida, M.; Suga, K.; Ishibashi, F.; Kubo, Y. The Spirocyclic Imine from a Marine Benthic Dinoflagellate, Portimine, Is a Potent Anti-Human Immunodeficiency Virus Type 1 Therapeutic Lead Compound. Mar. Drugs 2019, 17, 495,  DOI: 10.3390/md17090495
      5
      The spirocyclic imine from a marine benthic dinoflagellate, portimine, is a potent anti-human immunodeficiency virus type 1 therapeutic lead compound
      Izumida, Mai; Suga, Koushirou; Ishibashi, Fumito; Kubo, Yoshinao
      Marine Drugs (2019), 17 (9), 495CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      In this study, we aimed to find chems. from lower sea animals with defensive effects against human immunodeficiency virus type 1 (HIV-1). A library of marine natural products consisting of 80 compds. was screened for activity against HIV-1 infection using a luciferase-encoding HIV-1 vector. We identified five compds. that decreased luciferase activity in the vector-inoculated cells. In particular, portimine, isolated from the benthic dinoflagellate Vulcanodinium rugosum, exhibited significant anti-HIV-1 activity. Portimine inhibited viral infection with an 50% inhibitory concn. (IC50) value of 4.1 nM and had no cytotoxic effect on the host cells at concns. less than 200 nM. Portimine also inhibited vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped HIV-1 vector infection. This result suggested that portimine mainly targeted HIV-1 Gag or Pol protein. To analyze which replication steps portimine affects, luciferase sequences were amplified by semi-quant. PCR in total DNA. This anal. revealed that portimine inhibits HIV-1 vector infection before or at the reverse transcription step. Portimine has also been shown to have a direct effect on reverse transcriptase using an in vitro reverse transcriptase assay. Portimine efficiently inhibited HIV-1 replication and is a potent lead compd. for developing novel therapeutic drugs against HIV-1-induced diseases.
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    6. 6
      Cuddihy, S. L.; Drake, S.; Harwood, D. T.; Selwood, A. I.; McNabb, P. S.; Hampton, M. B. The marine cytotoxin portimine is a potent and selective inducer of apoptosis. Apoptosis 2016, 21, 1447– 1452,  DOI: 10.1007/s10495-016-1302-x
      6
      The marine cytotoxin portimine is a potent and selective inducer of apoptosis
      Cuddihy, Sarah L.; Drake, Sarah; Harwood, D. Tim; Selwood, Andrew I.; McNabb, Paul S.; Hampton, Mark B.
      Apoptosis (2016), 21 (12), 1447-1452CODEN: APOPFN; ISSN:1360-8185. (Springer)
      Portimine is a recently discovered member of a class of marine micro-algal toxins called cyclic imines. In dramatic contrast to related compds. in this toxin class, portimine has very low acute toxicity to mice but is highly cytotoxic to cultured cells. In this study we show that portimine kills human Jurkat T-lymphoma cells and mouse embryonic fibroblasts (MEFs), with LC50 values of 6 and 2.5 nM resp. Treated cells displayed rapid caspase activation and phosphatidylserine exposure, indicative of apoptotic cell death. Jurkat cells overexpressing the anti-apoptotic protein Bcl-2 or Bax/Bak knockout MEFs were completely protected from portimine. This protection was apparent even at high concns. of portimine, with no evidence of necrotic cell death, indicating that portimine is a selective chem. inducer of apoptosis. Treatment of the Bcl-2-overexpressing cells with both portimine and the Bcl-2 inhibitor ABT-737 proved a powerful combination, causing >90 % death. We conclude that portimine is one of the most potent naturally derived inducers of apoptosis to be discovered, and it displays strong selectivity for the induction of apoptotic pathways.
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    7. 7
      Saito, T.; Fujiwara, K.; Kondo, Y.; Akiba, U.; Suzuki, T. Synthesis of the cyclohexene segment of portimine. Tetrahedron Lett. 2019, 60, 386– 389,  DOI: 10.1016/j.tetlet.2018.12.063
      7
      Synthesis of the cyclohexene segment of portimine
      Saito, Takafumi; Fujiwara, Kenshu; Kondo, Yoshihiko; Akiba, Uichi; Suzuki, Takanori
      Tetrahedron Letters (2019), 60 (4), 386-389CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      The synthesis of the cyclohexene segment I of portimine, a marine cytotoxin from the dinoflagellate Vulcanodinium rugosum, was achieved. The route includes an acylation/aldol reaction from 3-ethoxycyclohex-2-enone to create the C3 center, the 1,4-addn. of a vinyl group at C16, the diastereoselective dihydroxylation of the vinyl group to generate the C15 center, a vinylation/dehydration sequence to set up the diene moiety, and stepwise installation of the amino-group-substituted C1 unit.
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    8. 8
      (a) Aitken, H. R. M.; Brimble, M. A.; Furkert, D. P. A catalytic asymmetric ene reaction for direct preparation of α-hydroxy 1, 4- diketones as intermediates in natural product synthesis. Synlett 2020, 31, 687– 690,  DOI: 10.1055/s-0037-1610748
      There is no corresponding record for this reference.
      (b) Ding, X.; Aitken, H. R. M.; Pearl, E. S.; Furkert, D. P.; Brimble, M. A. Synthesis of the C4–C16 Polyketide Fragment of Portimines A and B. J. Org. Chem. 2021, 86, 12840– 12850,  DOI: 10.1021/acs.joc.1c01463
      8b
      Synthesis of the C4-C16 Polyketide Fragment of Portimines A and B
      Ding, Xiao-Bo; Aitken, Harry R. M.; Pearl, Esperanza S.; Furkert, Daniel P.; Brimble, Margaret A.
      Journal of Organic Chemistry (2021), 86 (18), 12840-12850CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Stereoselective synthesis of the C4-C16 polyketide fragment I of portimines A and B is reported, enabled by our previously established method for the stereoselective synthesis of syn-α,α'-dihydroxyketones. The prepn. of this advanced fragment provides insights useful for the total synthesis of portimines A and B. An asym. Evans aldol reaction was used to install the C10-C11 adjacent stereogenic centers before incorporation of indantrione, followed by epoxidn. and epoxide opening to forge the challenging syn-α,α'-dihydroxyketone functionality.
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    9. 9
      Li, L.; El Khoury, A.; Clement, B. O.; Wu, C.; Harran, P. G. Asymmetric organocatalysis enables rapid assembly of portimine precursor chains. Org. Lett. 2022, 24, 2607– 2612,  DOI: 10.1021/acs.orglett.2c00556
      9
      Asymmetric Organocatalysis Enables Rapid Assembly of Portimine Precursor Chains
      Li, Liubo; El Khoury, Anton; Clement, Brennan O'Neil; Wu, Carolyn; Harran, Patrick G.
      Organic Letters (2022), 24 (14), 2607-2612CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      Sequential organocatalytic addns. of 2-furanone and dihydroxyacetone derivs. to a crotonaldehyde lynchpin provide polyhydroxylated chains reminiscent of lactonized deoxo Kdn type sugars. Further homologation via Kulinkovich ring opening of the butyrolactone and acylation of the zinc homo-enolate derived from the incipient cyclopropanol allows assembly of functionalized chain precursors to portimine. Our expts. probe the stability and reactivity of monosubstituted methylidene pyrrolines and generate advanced intermediates useful for exploring the biosynthesis and de novo synthesis of portimine.
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    10. 10
      Lee, H. J.; Gladfelder, J. J.; Zakarian, A. Remoto Stereocontrol in the Ireland-Claisen Rearrangement by δ-Alkyl Group. J. Org. Chem. 2023, 88, 7560– 7563,  DOI: 10.1021/acs.joc.3c00535
      10
      Remote Stereocontrol in the Ireland-Claisen Rearrangement by δ-Alkoxy Group
      Lee, Hye Joon; Gladfelder, Joshua J.; Zakarian, Armen
      Journal of Organic Chemistry (2023), 88 (11), 7560-7563CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Remote stereocontrol in the Ireland-Claisen rearrangement using a chiral acetonides e.g., I that serves as internal stereocontrol element is an effective and general method for chirality transfer from a δ-hydroxyl group in the allylic alc. unit. This strategy circumvents the need for redundant chirality at the α-position allylic alc., while simultaneously producing a terminal alkenes e.g., II that can streamline synthetic applications and complex mol. synthesis planning.
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    11. 11
      Tang, J.; Li, W.; Chiu, T. Y.; Martínes-Peña, F.; Luo, Z.; Chong, C. T.; Wei, Q.; Gazaniga, N.; West, T. J.; See, Y. Y.; Lairson, L. L.; Parker, C. G.; Baran, P. S. Synthesis of portimines reveals the basis of their anti-cancer activity. Nature 2023, 622, 507– 513,  DOI: 10.1038/s41586-023-06535-1
      11
      Synthesis of portimines reveals the basis of their anti-cancer activity
      Tang, Junchen; Li, Weichao; Chiu, Tzu-Yuan; Martinez-Pena, Francisco; Luo, Zengwei; Chong, Christine T.; Wei, Qijia; Gazaniga, Nathalia; West, Thomas J.; See, Yi Yang; Lairson, Luke L.; Parker, Christopher G.; Baran, Phil S.
      Nature (London, United Kingdom) (2023), 622 (7983), 507-513CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio)
      Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chem. structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the mol. mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chem. through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumor-clearance models. Finally, practical access to the portimines and their analogs simplified the development of photoaffinity analogs, which were used in chem. proteomic expts. to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.
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    12. 12
      (a) Iwasaki, K.; Sasaki, S.; Kasai, Y.; Kawashima, Y.; Sasaki, S.; Ito, T.; Yotsu-Yamashita, M.; Sasaki, M. Total Synthesis of Polycavernosides A and B, Two Lethal Toxins from Red Alga. J. Org. Chem. 2017, 82, 13204– 13219,  DOI: 10.1021/acs.joc.7b02293
      12a
      Total Synthesis of Polycavernosides A and B, Two Lethal Toxins from Red Alga
      Iwasaki, Kotaro; Sasaki, Satori; Kasai, Yusuke; Kawashima, Yuki; Sasaki, Shohei; Ito, Takanori; Yotsu-Yamashita, Mari; Sasaki, Makoto
      Journal of Organic Chemistry (2017), 82 (24), 13204-13219CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Polycavernosides A and B are glycosidic macrolide natural products isolated as the toxins causing fatal human poisoning by the edible red alga Gracilaria edulis (Polycavernosa tsudai). Total synthesis of polycavernosides A and B has been achieved via a convergent approach. The synthesis of the macrolactone core structure is highlighted by the catalytic asym. syntheses of the two key fragments using hetero-Diels-Alder reaction and Kiyooka aldol reaction as the key steps, their union through Suzuki-Miyaura coupling, and Keck macrolactonization. Finally, glycosylation with the L-fucosyl-D-xylose unit and construction of the polyene side chain through Stille coupling completed the total synthesis of polycavernosides A and B.
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      (b) Sasaki, M.; Iwasaki, K.; Arai, K.; Hamada, N.; Umehara, A. Convergent Synthesis of the HIJKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1 by a Late-Stage Reductive Olefin Coupling Approach. Bull. Chem. Soc. Jpn. 2022, 95, 819– 824,  DOI: 10.1246/bcsj.20220070
      12b
      Convergent Synthesis of the HIJKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1 by a Late-Stage Reductive Olefin Coupling Approach
      Sasaki, Makoto; Iwasaki, Kotaro; Arai, Keisuke; Hamada, Naoya; Umehara, Atsushi
      Bulletin of the Chemical Society of Japan (2022), 95 (5), 819-824CODEN: BCSJA8; ISSN:0009-2673. (Chemical Society of Japan)
      The convergent synthesis of the HIJKLMN-ring fragment of Caribbean ciguatoxin C-CTX-1, the major causative toxin for ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic areas, is disclosed. The synthesis features a late-stage iron-catalyzed hydrogen atom transfer-initiated reductive olefin coupling to install the N-ring and a Suzuki-Miyaura coupling/thioacetalization strategy for the convergent assembly of the hexacyclic HIJKLM-ring skeleton I.
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      (c) Suwa, T.; Sasaki, M.; Umehara, A. Total Synthesis of (−)-Irijimaside A Enabled by Ni/Zr-Mediated Reductive Ketone Coupling. Org. Lett. 2024, 26, 4377– 4382,  DOI: 10.1021/acs.orglett.4c01367
      There is no corresponding record for this reference.
      (d) Sasaki, M.; Ohba, M.; Murakami, A.; Umehara, A. Convergent and Scalable Second-Generation Synthesis of the Fully Functionalized HIJKLMN-Ring Segment of Caribbean Ciguatoxin C-CTX-1. J. Org. Chem. 2024, 89, 18631– 18639,  DOI: 10.1021/acs.joc.4c02723
      There is no corresponding record for this reference.
    13. 13
      (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H. A Recyclable Ru-Based Metathesis Catalyst. J. Am. Chem. Soc. 1999, 121, 791– 799,  DOI: 10.1021/ja983222u
      13a
      A Recyclable Ru-Based Metathesis Catalyst
      Kingsbury, Jason S.; Harrity, Joseph P. A.; Bonitatebus, Peter J. Jr.; Hoveyda, Amir H.
      Journal of the American Chemical Society (1999), 121 (4), 791-799CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A Ru carbene (I) that contains an internal metal-O chelate is an active metathesis catalyst and is readily obtained by the sequential treatment of Cl2Ru(PPh3)3 with (2-isopropoxyphenyl)diazomethane and PCy3. This Ru-carbene complex offers excellent stability to air and moisture and can be recycled in high yield by silica gel column chromatog. The structures of this and related complexes were unambiguously established by NMR and single-crystal x-ray diffraction studies.
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      (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. Efficient and Recyclable Monomeric and Dendritic Ru-Based Metathesis Catalysts. J. Am. Chem. Soc. 2000, 122, 8168– 8179,  DOI: 10.1021/ja001179g
      13b
      Efficient and Recyclable Monomeric and Dendritic Ru-Based Metathesis Catalysts
      Garber, Steven B.; Kingsbury, Jason S.; Gray, Brian L.; Hoveyda, Amir H.
      Journal of the American Chemical Society (2000), 122 (34), 8168-8179CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Several highly active, recoverable and recyclable Ru-based metathesis catalysts are presented. The crystal structure of the Ru complex (I) bearing a 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene and styrenyl ether ligand is disclosed. The heterocyclic ligand significantly enhances the catalytic activity, and the styrenyl ether allows for the easy recovery of the Ru complex. Catalyst I promotes ring-closing metathesis (RCM) and the efficient formation of various trisubstituted olefins at ambient temp. in high yield within 2 h; the catalyst is obtained in >95% yield after silica gel chromatog. and can be used directly in subsequent reactions. Tetrasubstituted olefins can also be synthesized by RCM reactions catalyzed by I. In addn., the synthesis and catalytic activities of two dendritic and recyclable Ru-based complexes are disclosed. Examples involving catalytic ring-closing, ring-opening, and cross metatheses are presented where, unlike monomer I, the dendritic catalyst can be readily recovered.
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    14. 14
      (a) Falck, J. R.; Bhatt, R. K.; Ye, J. Tin-Copper Transmetalation: Cross-Coupling of alpha-Heteroatom-Substituted Alkyltributylstannanes with Organohalides. J. Am. Chem. Soc. 1995, 117, 5973– 5982,  DOI: 10.1021/ja00127a010
      14a
      Tin-Copper Transmetalation: Cross-Coupling of α-Heteroatom-Substituted Alkyltributylstannanes with Organohalides
      Falck, J. R.; Bhatt, Rama K.; Ye, Jianhua
      Journal of the American Chemical Society (1995), 117 (22), 5973-82CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Copper(I), in the absence of other transition metals, catalyzes the cross-coupling of [α-(acyloxy)benzyl]tributylstannanes with allylic bromides in THF in fair to good yields and with aryl/vinyl halides less efficiently or not at all. Simple [α-(acyloxy)alkyl]tributylstannanes react sluggishly even with allyl bromide. However, proximal thiosubstituents on either reaction partner dramatically enhance yields, reaction rates, and the variety of suitable educts. (α-Phthalimidoylalkyl)tributylstannanes afford protected α-amino thio esters. In contrast with the Stille reaction, copper-mediated cross-couplings of α-heteroatom-substituted alkyltributylstannanes proceed with complete retention of configuration via a coordinatively stabilized organocopper intermediate that can be intercepted in good yield by 1,4-conjugate addn. to 2-cyclohexen-1-one.
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      (b) Li, H.; He, A.; Falck, J. R.; Liebeskind, L. S. Stereocontrolled Synthesis of α-Amino-α′-alkoxy Ketones by a Copper-Catalyzed Cross-Coupling of Peptidic Thiol Esters and α-Alkoxyalkylstannanes. Org. Lett. 2011, 13, 3682– 3685,  DOI: 10.1021/ol201330j
      14b
      Stereocontrolled Synthesis of α-Amino-α'-alkoxy Ketones by a Copper-Catalyzed Cross-Coupling of Peptidic Thiol Esters and α-Alkoxyalkylstannanes
      Li, Hao; He, Anyu; Falck, John R.; Liebeskind, Lanny S.
      Organic Letters (2011), 13 (14), 3682-3685CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A stereocontrolled synthesis of α-amino-α'-alkoxy ketones is described. This pH-neutral copper(I) thiophene-2-carboxylate (CuTC)-catalyzed cross-coupling of amino acid thiol esters, e.g., I, and chiral nonracemic α-alkoxyalkylstannanes, e.g., II, gives α-amino-α'-alkoxy ketones, e.g., III, in good to excellent yields with complete retention of configuration at the α-amino- and α-alkoxy-substituted stereocenters.
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      (c) Cordovilla, C.; Bartolomé, C.; Martínez-Ilarduya, J. M.; Espinet, P. The Stille Reaction, 38 Years Later. ACS Catal. 2015, 5, 3040– 3053,  DOI: 10.1021/acscatal.5b00448
      14c
      The Stille Reaction, 38 Years Later
      Cordovilla, Carlos; Bartolome, Camino; Martinez-Ilarduya, Jesus Ma; Espinet, Pablo
      ACS Catalysis (2015), 5 (5), 3040-3053CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      This review concs. on the mechanistic new knowledge and on important aspects such as the revolution with the use of bulky phosphines, the bimetallic alternative of the Stille reaction, the enantioselectivity in Stille and palladium-free Stille processes, the meaning of copper effect, or the possible approaches to make Stille coupling a greener process.
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    15. 15
      He, A.; Falck, J. R. Synthesis of Enantioenriched α-(Hydroxyalkyl)-tri-n-butylstannanes. Angew. Chem., Int. Ed. 2008, 47, 6586– 6589,  DOI: 10.1002/anie.200802313
      There is no corresponding record for this reference.
    16. 16
      (a) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. Chiral bis(oxazoline)copper(II) complexes as Lewis acid catalysts for the enantioselective Diels-Alder reaction. J. Am. Chem. Soc. 1999, 121, 7559– 7573,  DOI: 10.1021/ja991190k
      16a
      Chiral Bis(oxazoline)copper(II) Complexes as Lewis Acid Catalysts for the Enantioselective Diels-Alder Reaction
      Evans, David A.; Miller, Scott J.; Lectka, Thomas; von Matt, Peter
      Journal of the American Chemical Society (1999), 121 (33), 7559-7573CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Bis(oxazoline)copper(II) complexes are highly enantioselective catalysts in Diels-Alder reactions involving bidentate dienophiles. Cationic [Cu((S,S)-t-Bu-box)]X2 complexes with different counterions have been used as catalysts, revealing a profound influence of the counterion on the rate and stereoselectivity of the catalyst. A square-planar catalyst-substrate complex is proposed to account for the high diastereo- and enantioselectivities obsd. Three bis(oxazoline)-Cu(II) X-ray structures have been obtained that support this model. Double-stereodifferentiating expts., performed employing chiral dienophiles, afforded results that are fully consistent with the proposed square-planar transition-state assemblage. In addn. to imide-based substrates, α,β-unsatd. thiazolidine-2-thiones have been introduced as a new class of dienophiles with enhanced reactivity. Kinetics expts. were performed to quantify the role that product inhibition plays in the course of the reaction. Rate and equil. binding consts. of various catalyst inhibitors were also derived from the kinetic anal. A comparative study was undertaken to elucidate the differences between the bis(oxazoline)-Cu(II) catalyst and the bis(oxazoline) catalysts derived from Fe(III), Mg(II), and Zn(II). Catalyst performance was found to be a function of a subtle relationship between bis(oxazoline) structure and transition metal.
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      (b) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. Bis(oxazoline) and Bis(oxazolinyl)pyridine Copper Complexes as Enantioselective Diels–Alder Catalysts: Reaction Scope and Synthetic Applications. J. Am. Chem. Soc. 1999, 121, 7582– 7594,  DOI: 10.1021/ja991191c
      16b
      Bis(oxazoline) and Bis(oxazolinyl)pyridine Copper Complexes as Enantioselective Diels-Alder Catalysts: Reaction Scope and Synthetic Applications
      Evans, David A.; Barnes, David M.; Johnson, Jeffrey S.; Lectka, Thomas; von Matt, Peter; Miller, Scott J.; Murry, Jerry A.; Norcross, Roger D.; Shaughnessy, Eileen A.; Campos, Kevin R.
      Journal of the American Chemical Society (1999), 121 (33), 7582-7594CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The scope of the Diels-Alder reaction catalyzed by bis(oxazoline) copper complexes has been investigated. In particular, [Cu((S,S)-t-Bu-box)](SbF6)2 has been shown to catalyze the Diels-Alder reaction between 3-propenoyl-2-oxazolidinone and a range of substituted dienes with high enantioselectivity. This cationic complex has also been employed in the catalysis of analogous intramol. processes with good success. The total syntheses of ent-Δ1-tetrahydrocannabinol, ent-shikimic acid, and isopulo'upone, featuring the use of this chiral catalyst in more complex Diels-Alder processes, are described. Similarly, the cationic copper complex [Cu((S,S)-t-Bu-pybox)](SbF6)2 is effective in the Diels-Alder reactions of monodentate acrolein dienophiles while the closely related complex [Cu((S,S)-Bn-pybox)](SbF6)2 is the preferred Lewis acid catalyst for acrylate dienophiles in reactions with cyclopentadiene.
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    17. 17
      (a) Evans, D. A.; Bartroli, J.; Shih, T. L. Enantioselective Aldol Condensations. 2. Erythro-Selective Chiral Aldol Condensations via Boron Enolates. J. Am. Chem. Soc. 1981, 103, 2127– 2129,  DOI: 10.1021/ja00398a058
      17a
      Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates
      Evans, D. A.; Bartroli, J.; Shih, T. L.
      Journal of the American Chemical Society (1981), 103 (8), 2127-09CODEN: JACSAT; ISSN:0002-7863.
      The bibutylboryl enolates derived from I and II (R = Me, SMe, CH2CO2Et) underwent highly stereoselective aldol condensations with R1CHO (R1 = Ph, Bu, Me2CH). Erythro diastereoselection was ≥99% and asym. induction within the erythro product manifold was »100:1. The resultant aldol adducts may be hydrolyzed with aq. base to the enantiomeric erythro β-hydroxy acids and the oxazolidone chiral auxiliaries recycled. In contrast, I and II (R = H) exhibited no enolate diastereoface selection in the condensation process; however, I and II (R1 = SMe) may be employed as chiral acetate enolate synthons.
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      (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. Stereoselective aldol condensations via boron enolates. J. Am. Chem. Soc. 1981, 103, 3099– 3111,  DOI: 10.1021/ja00401a031
      17b
      Stereoselective aldol condensations via boron enolates
      Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R.
      Journal of the American Chemical Society (1981), 103 (11), 3099-111CODEN: JACSAT; ISSN:0002-7863.
      A variety of ketones and carboxylic acid derivs. were enolized with dialkylboryl triflates in the presence of a tertiary amine, and aldol condensations of the boron enolates were carried out. The stereochem. of the enolates formed from acyclic ketones depended on the structure of the ketone, the dialkylboryl triflate, and the tertiary amine. A mechanism for the enolization involving initial coordination of the boryl triflate to the ketone carbonyl with subsequent deprotonation by the amine is proposed to explain the results. Consistently good correlation was obsd. between the enolate geometry and the product aldol stereochem. for these acyclic ketones, regardless of the structure of the ketone or the B ligands. For the B enolate derived from cyclohexanone, use of cyclopentylthexylboron enolate in THF resulted in complete stereocontrol in the condensation. Although simple esters and amides cannot be enolized with the triflate reagents, EtC(O)SCMe3 was readily converted to the trans enolate. The stereoselectivity of the aldol condensations of this enolate also depended on the B ligands and the solvent. Carboxylic acids could be converted to the dialkylboryl enediolates, and the aldol condensations of these species were used to probe the relative reactivity of cis and trans enolates. Chiral B enolates were studied for possible asym. induction in the aldol condensation. Me ketone enolates exhibited moderate levels of chirality transfer, while cis enolates gave only 1 detectable diastereoisomer. The sense of chirality transfer was proven by detg. the abs. configurations of newly created centers of asymmetry. A transition-state model based on steric interactions is proposed for chirality transfer.
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    18. 18

      Aldehyde 9 was readily synthesized from commercially available 1,4-cyclohexanedione monoethyleneketal in five steps. For details, see the Supporting Information.

      There is no corresponding record for this reference.
    19. 19
      N-Acyloxazolidinone 10 was readily synthesized by DMAPO/Boc2O-madiated direct N-acylation method of oxazolidinone. For details, see the Supporting Information. Also see:Umehara, A.; Shimizu, S.; Sasaki, M. DMAPO/Boc2O-Mediated One-Pot Direct N-Acylation of Less Nucleophilic N-Heterocycles with Carboxylic Acids. ChemCatChem. 2023, 15, e202201596  DOI: 10.1002/cctc.202201596
      There is no corresponding record for this reference.
    20. 20
      Parikh, J. R.; Doering, W. v. E. Sulfur Trioxide in the Oxidation of Alcohols by Dimethyl Sulfoxide. J. Am. Chem. Soc. 1967, 89, 5505– 5507,  DOI: 10.1021/ja00997a067
      20
      Sulfur trioxide in the oxidation of alcohols by dimethyl sulfoxide
      Parikh, Jekishan R.; Doering, William v. E.
      Journal of the American Chemical Society (1967), 89 (21), 5505-7CODEN: JACSAT; ISSN:0002-7863.
      A soln. of pyridine-SO3 complex in Me2SO is used to oxidize p-nitrobenzyl alc., l-menthol, and many steroidal alcs. to the corresponding aldehydes and ketones.
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    21. 21

      For selected methods for synthesis of chiral α-alkoxyalkylstannanes, see:

      (a) Still, W. C.; Sreekumar, C. α-alkoxyorganolithium reagents. A new class of configurationally stable carbanions for organic synthesis. J. Am. Chem. Soc. 1980, 102, 1201– 1202,  DOI: 10.1021/ja00523a066
      21a
      α-Alkoxyorganolithium reagents. A new class of configurationally stable carbanions for organic synthesis
      Still, W. Clark; Sreekumar, C.
      Journal of the American Chemical Society (1980), 102 (3), 1201-2CODEN: JACSAT; ISSN:0002-7863.
      The acyclic, sp3 organolithium reagents which are produced by BuLi exchange with diastereomerically or enantiomerically pure α-alkoxyorganostannanes, were configurationally stable for at least 15 mins. at -30°. The purified organostannanes were prepd. by the addn. of Bu3SnLi to aldehydes followed by hydroxyl protection and medium pressure liq. chromatog. on silica gel. Exchange was accomplished at -78° to give configurationally stable organolithium reagents which were treated with Me2CO, Me3SiCl, Me2SO4. The stereochem. of the addn. of Bu3SnLi to several aldehydes was studied to det. the extent of α-induction available with that reagent. While normal Cram's rule selectivity was comparable with unhindered Grignard reagents, β-oxygen substituted chiral aldehydes gave much more stereoselection for the chelation controlled product with the Sn anion.
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      (b) Chan, P. C. M.; Chong, J. M. Asymmetric Reduction of Acylstannanes. Preparation of Enantiomerically Enriched α-Alkoxystannanes. J. Org. Chem. 1988, 53, 5584– 5586,  DOI: 10.1021/jo00258a048
      There is no corresponding record for this reference.
      (c) Christoph, G.; Hoppe, D. Asymmetric Synthesis of 2-Alkenyl-1-cyclopentanols via Tin–Lithium Exchange and Intramolecular Cycloalkylation. Org. Lett. 2002, 4, 2189– 2192,  DOI: 10.1021/ol026068w
      21c
      Asymmetric Synthesis of 2-Alkenyl-1-cyclopentanols via Tin-Lithium Exchange and Intramolecular Cycloalkylation
      Christoph, Guido; Hoppe, Dieter
      Organic Letters (2002), 4 (13), 2189-2192CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      A method for the synthesis of chiral cyclopentanes using tin-lithium exchange and cycloalkylation reactions is reported. The sec-butyllithium/(-)-sparteine-mediated deprotonation of an alkyl carbamate and subsequent substitution furnishes a highly enantioenriched stannane as a stable carbanion equiv. This was transformed into suitable cyclization precursors which underwent tin-lithium exchange and stereoselective cycloalkylation when reacted with butyllithium, giving highly enantioenriched cyclopentanes in very good yields. A kinetic resoln. was obsd. with a higher substituted stannane.
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    22. 22
      Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. High-Field FT NMR Application of Mosher’s Method. The Absolute Configurations of Marine Terpenoids. J. Am. Chem. Soc. 1991, 113, 4092– 4096,  DOI: 10.1021/ja00011a006
      22
      High-field FT NMR application of Mosher's method. The absolute configurations of marine terpenoids
      Ohtani, Ikuko; Kusumi, Takenori; Kashman, Yoel; Kakisawa, Hiroshi
      Journal of the American Chemical Society (1991), 113 (11), 4092-6CODEN: JACSAT; ISSN:0002-7863.
      Mosher's (1H) method to elucidate the abs. configuration of marine secondary alcs. was reexamd. by high-field FT NMR spectroscopy, which enables assignment of most of the protons of complex mols. There is a systematic arrangement of Δδ (δS- δR) values obtained for the (R)- and (S)-MTPA (3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid) esters of (-)-methanol, (-)-borneol, cholesterol, and ergosterol, whose abs. configurations are known. Anal. of the Δδ values of these compds. led to a rule which could predict the abs. configurations of natural products. When this rule was applied to marine terpenoids including cembranolides and xenicanes, their abs. configurations were assigned and a part of the results were confirmed by x-ray analyses. In the case of sipholenol A, which has a sterically hindered OH group, this rule is inapplicable. The problem is overcome by inverting the OH group to a less sterically hindered position; the resulting epimer gives systematically arranged Δδ values, which enabled the elucidation of the abs. configuration. Comparison of the present method with Mosher's 19F method indicates that the latter using 19F NMR lacks reliability, and that the abs. configurations of the natural products in the literature detd. by 19F NMR spectra of MTPA esters should all be reexamd.
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    23. 23

      γ-Lactam 7 and diene 16 were readily synthesized using a known procedure. For details, see the Supporting Information.

      There is no corresponding record for this reference.
    24. 24

      The absolute configuration of the C16 stereogenic center was determined by the phenylglycine methyl ester (PGME) method, and the relative stereochemistry of the C16/C3 stereogenic centers was determined by NOE correlations. See Supporting Information for details.

      There is no corresponding record for this reference.
    25. 25
      (a) Tsujimoto, T.; Ishihara, J.; Horie, M.; Murai, A. Asymmetric construction of the azaspiro[5.5]undec-8-ene system towards gymnodimine synthesis. Synlett 2002, 2002, 399– 402,  DOI: 10.1055/s-2002-20450
      There is no corresponding record for this reference.
      (b) Kong, K.; Moussa, Z.; Lee, C.; Romo, D. Total Synthesis of the Spirocyclic Imine Marine Toxin (−)-Gymnodimine and an Unnatural C4-Epimer. J. Am. Chem. Soc. 2011, 133, 19844– 19856,  DOI: 10.1021/ja207385y
      25b
      Total Synthesis of the Spirocyclic Imine Marine Toxin (-)-Gymnodimine and an Unnatural C4-Epimer
      Kong, Ke; Moussa, Ziad; Lee, Changsuk; Romo, Daniel
      Journal of the American Chemical Society (2011), 133 (49), 19844-19856CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The first total synthesis of the marine toxin (-)-gymnodimine (I) was accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels-Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The prepn. of the THF fragment utilized a chiral auxiliary based anti-aldol reaction. Two major spirolactam fragments were then coupled through an efficient Nozaki-Hiyama-Kishi reaction. An unconventional, ambient temp. t-BuLi-initiated intramol. Barbier reaction of an alkyl iodide was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addn. of a silyloxyfuran to a complex cyclohexanone appended the butenolide, and a few addnl. steps provided (-)-gymnodimine. A diastereomer of the natural product was also synthesized, 4-epi-gymnodimine, derived from the vinylogous Mukaiyama aldol addn.
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    26. 26
      (a) Ishihara, J.; Horie, M.; Shimada, Y.; Tojo, S.; Murai, A. Asymmetric construction of the azaspiro[5.6]dodec-9-ene system in marine natural toxins. Synlett 2002, 2002, 403– 406,  DOI: 10.1055/s-2002-20451
      There is no corresponding record for this reference.
      (b) Tsuchikawa, H.; Minamino, K.; Hayashi, S.; Murata, M. Efficient Access to the Functionalized Bicyclic Pharmacophore of Spirolide C by Using a Selective Diels–Alder Reaction. Asian J. Org. Chem. 2017, 6, 1322– 1327,  DOI: 10.1002/ajoc.201700164
      26b
      Efficient Access to the Functionalized Bicyclic Pharmacophore of Spirolide C by Using a Selective Diels-Alder Reaction
      Tsuchikawa, Hiroshi; Minamino, Kou; Hayashi, Sho; Murata, Michio
      Asian Journal of Organic Chemistry (2017), 6 (9), 1322-1327CODEN: AJOCC7; ISSN:2193-5807. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A functionalized bicyclic lactam such as (5S,6R)-5,6-dimethyl-3-methylene-2-oxo-azepane-1-carboxylic acid benzyl ester, was used as a key intermediate in an efficient synthesis of the pharmacophore of potent marine toxin spirolide C I and II (X = OSi(CH3)2C(CH3)3, 2,8,9-trioxa-5-aza-1-silabicyclo[3.3.3]undecan-1-yl), which was synthesized by using a highly selective Diels-Alder reaction. To improve the reactivity of this transformation without loss of selectivity, substrates that contain a silyl ether or silatrane moiety XC(=CH2)C(CH3)=CHCCCH3 were elaborately designed and converted into the spirobicyclic core structure with stereochem. control over the two asym. centers at the C7 and C29 positions I and II. Moreover, a further C-C bond formation by using a Hiyama cross-coupling reaction of the vinyl silatrane deriv. II (X = 2,8,9-trioxa-5-aza-1-silabicyclo[3.3.3]undecan-1-yl) facilitated versatile modification at the C5 position with an aryl or alkenyl substituent.
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    27. 27
      Tsujimoto, T.; Murai, A. Efficient Detachment of N-Benzyl Carbamate Group. Synlett 2002, 2002, 1283,  DOI: 10.1055/s-2002-32986
      There is no corresponding record for this reference.
    28. 28
      (a) Barma, D. K.; Bandyopadhyay, A.; Capdevila, J. H.; Falck, J. R. Dimethylthiocarbamate (DMTC): An Alcohol Protecting Group. Org. Lett. 2003, 5, 4755– 4757,  DOI: 10.1021/ol0354573
      28a
      Dimethylthiocarbamate (DMTC): An Alcohol Protecting Group
      Barma, D. K.; Bandyopadhyay, A.; Capdevila, Jorge H.; Falck, J. R.
      Organic Letters (2003), 5 (25), 4755-4757CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      Dimethylthiocarbamates (DMTCs), prepd. from the corresponding alcs. using com. dimethylthiocarbamoyl chloride, are spectrally simple, achiral, and nonpolar. DMTCs are moderately to highly stable to a wide range of reagents and conditions including metal hydrides, hydroboration, ylides, NaOH, HCl, organolithiums, Grignards, DDQ, PCC, Swern, n-Bu4NF, CrCl2, heat, and Lewis acids. They are readily removed by NaIO4 or H2O2 in the presence of other common alc. protecting groups.
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      (b) Kojima, M.; Nakamura, Y.; Ishikawa, T.; Takeuchi, S. Fluorous dimethylthiocarbamate (FDMTC) protecting groups for alcohols. Tetrahedron Lett. 2006, 47, 6309– 6314,  DOI: 10.1016/j.tetlet.2006.05.142
      There is no corresponding record for this reference.
    29. 29
      (a) Ye, J.; Bhatt, R. K.; Falck, J. R. Stereospecific α-alkoxystannane couplings with acyl chlorides: Total synthesis of (+)-goniofufurone. Tetrahedron Lett. 1993, 34, 8007– 8010,  DOI: 10.1016/S0040-4039(00)61436-3
      There is no corresponding record for this reference.
      (b) Wang, R.; Falck, J. R. Studies towards asymmetric synthesis of 4(S)-11-dihydroxydocosahexaenoic acid (diHDHA) featuring cross-coupling of chiral stannane under mild conditions. Org. Biomol. Chem. 2015, 13, 1624– 1628,  DOI: 10.1039/C4OB02324B
      There is no corresponding record for this reference.
    30. 30
      Huang, S. L.; Omura, K.; Swern, D. Oxidation of Sterically Hindered Alcohols to Carbonyls with Dimethyl Sulfoxide-Trifluor-acetic Anhydride. J. Org. Chem. 1976, 41, 3329– 3331,  DOI: 10.1021/jo00882a030
      There is no corresponding record for this reference.
    31. 31
      Lindlar, H.; Dubuis, R. Palladium Catalyst for Partial Reduction of Acetylenes. Org. Synth. 1966, 46, 89– 92,  DOI: 10.1002/0471264180.os046.27
      31
      Palladium catalyst for partial reduction of acetylenes
      Lindlar, Herbert; Dubuis, R.
      Organic Syntheses (1966), 46 (), 89-92CODEN: ORSYAT; ISSN:0078-6209.
      H2O (45 ml.) was added to a soln. of PdCl2 (1.48 g.) in 3.6 ml. 37% HCl soln. and the pH adjusted to 4.0-4.5 with 3N NaOH. The soln. was dild. to 100 ml. 18 g. CaCO3 added and the suspension heated to 75-85° with stirring until all the Pd had pptd. HCO2Na soln. (6.0 ml. 0.7N) was added with stirring and the catalyst color changed from brown to gray. A further 4.5 ml. HCO2Na soln. was added and the redn. completed by stirring the mixt. 40 min. at 75-85°. The black catalyst was filtered off and washed 8 times with 65 ml. H2O. A slurry of the moist catalyst, 60 ml. H2O, and 18 ml. 7.7% (AcO)2Pb soln. was stirred 45 min. at 75-85°, filtered, washed 4 times with 50 ml. H2O and oven-dried at 60-70°. Yield 19-19.5 g. A hydrogenation app. contg. 0.02 mole phenylacetylene, 0.10 g. Pd catalyst, 1.0 ml. quinoline and 15 ml. olefin-free petroleum ether was evacuated, stirring commenced, H2 admitted and the pressure maintained at 1 atm. Absorption slowed down when 0.02 mole H was absorbed (10-90 min.). This form of Pd can be used for hydrogenation of most triple bonds to double bonds. Redn. of doubly substituted acetylenes gives cis olefins.
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    32. 32
      (a) Luche, J.-L. Lanthanides in Organic Synthesis. 1. Selective 1,2 Reduction of Conjugated Ketones. J. Am. Chem. Soc. 1978, 100, 2226– 2227,  DOI: 10.1021/ja00475a040
      32a
      Lanthanides in organic chemistry. 1. Selective 1,2 reductions of conjugated ketones
      Luche, Jean Louis
      Journal of the American Chemical Society (1978), 100 (7), 2226-7CODEN: JACSAT; ISSN:0002-7863.
      Redns. of α,β-unsatd. ketones in MeOH soln. in the presence of a stoichiometric quantity of a lanthanide chloride yield the corresponding allylic alcs. in high yield. The reaction was proven by redn. of 3-penten-2-one and several 2-cycloalken-1-ones.
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      (b) Gemal, A. L.; Luche, J.-L. Lanthanoids in Organic Synthesis. 6. The reduction of α-enones by Sodium Borohydride in the Presence of Lanthanoid Chlorides: Mechanistic Aspects. J. Am. Chem. Soc. 1981, 103, 5454– 5459,  DOI: 10.1021/ja00408a029
      32b
      Lanthanoids in organic synthesis. 6. Reduction of α-enones by sodium borohydride in the presence of lanthanoid chlorides: synthetic and mechanistic aspects
      Gemal, Andre L.; Luche, Jean Louis
      Journal of the American Chemical Society (1981), 103 (18), 5454-9CODEN: JACSAT; ISSN:0002-7863.
      Lanthanoid chlorides (LnCl3) are efficient catalysts for the regioselective 1,2 redn. of α-enones by NaBH4 in MeOH. Optimal conditions of this reaction were detd. The major effect of Ln3+ is the catalysis of BH4- decompn. by the hydroxylic solvent to afford alkoxyborohydrides, which may be responsible for the obsd. regioselectivity. The stereoselectivity of the process is also modified by the presence of the Ln3+ ions, in that axial attack of cyclohexanone systems is enhanced.
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