Total Synthesis of the 7,10‐Epimer of the Proposed Structure of Amphidinolide N,Part I: Synthesis of the C1–C13 Subunit

Amphidinolide N, the structure of which has been recently revised, is a 26‐membered macrolide featuring allyl epoxide and tetrahydropyran moieties with 13 chiral centers. Due to its challenging structure and extraordinary potent cytotoxicity, amphidinolide N is a highly attractive target of total synthesis. During our total synthesis studies of the 7,10‐epimer of the proposed structure of amphidinolide N, we have synthesized the C1–C13 subunit enantio‐ and diastereoselectively. Key reactions include an l ‐proline catalyzed enantioselective intramolecular aldol reaction, Evans aldol reaction, Sharpless asymmetric epoxidation and Tamao–Fleming oxidation. To aid late‐stage manipulations, we also developed the 4‐(N‐benzyloxycarbonyl‐N‐methylamino)butyryl group as a novel ester protective group for the C9 alcohol.     

Synthesis,Isolation and Structures of Trifluoromethylated Fullerenes D2‐C76, C76(1)(CF3)10–18

High‐temperature trifluoromethylation of fullerene C₇₆ chlorination products followed by HPLC separation of C₇₆(CF₃)_n derivatives resulted in the isolation and X‐ray structural characterization of thirteen C₇₆(1)(CF₃)_n compounds including nine new isomers such as one isomer of C₇₆(1)(CF₃)₁₀, two C₇₆(1)(CF₃)₁₂, three C₇₆(1)(CF₃)₁₄, one C₇₆(1)(CF₃)₁₆, and two isomers of C₇₆(1)(CF₃)₁₈. Depending on their addition patterns, C₇₆(1)(CF₃)_n isomers are divided into three subgroups and discussed in terms of trifluoromethylation pathways and relative formation energies.     

Stereoselective Synthesis of the Proposed C79–C104 Fragment of Symbiodinolide

Stereoselective and streamlined synthesis of the proposed C79–C104 fragment 2 of symbiodinolide ( 1 ), a polyol marine natural product with a molecular weight of 2860, was achieved. In the synthetic route, the proposed C79–C104 fragment 2 was synthesized by utilizing a Julia–Kocienski olefination and subsequent Sharpless asymmetric dihydroxylation as key transformations in a convergent manner. Detailed comparison of the ¹³C NMR chemical shifts between the natural product and the synthetic C79–C104 fragment 2 revealed that the stereostructure at the C91–C99 carbon chain moiety of symbiodinolide ( 1 ) should be reinvestigated.     

群柱虫内酯官能团化的C2-C10片段的立体选择性合成

本文以廉价的消旋甲基戊二酸酐为起始原料,完成了具有抗肿瘤活性的海洋天然产物群柱虫内酯（Clavulactone）官能团化的C2-C10片段的立体选择性合成。使用的关键方法包括不对称去对称化获得光学纯手性孤立甲基,和RCM方法构建顺式烯烃。该片段的获得为群柱虫内酯的全合成提供了基础。     

Stereoselective Synthesis of the C(1) – C(28) Fragment of Amphidinol 3

A stereoselective synthesis of the polyol side chain (C(1) – C(28)) of amphidinol 3 has been accomplished following Sharpless epoxidation, Crimmins aldol reaction, Jacobsen kinetic resolution, Sharpless asymmetric dihydroxylation, and our own reaction for the synthesis of a chiral allylic alcohol from an epoxy alcohol. The olefin functionality was introduced by a cross metathesis and Julia–Kocienski olefination.     

Stereodivergent Synthesis and Stereochemical Reassignment of the C79–C104 Fragment of Symbiodinolide

We have synthesized eight possible diastereoisomers 3 a – h of the C79–C97 fragment of symbiodinolide ( 1 ) in a stereodivergent manner by utilizing a dithiane addition to the aldehyde as a key step. Comparison of the ¹³C NMR chemical shifts of the natural product 1 and the synthetic products 3 a – h indicated that the relative stereostructure of this fragment in symbiodinolide ( 1 ) is that represented in 3 a or f . We have stereodivergently synthesized eight possible diastereoisomers of the C94–C104 fragment 4 a – h , and we have compared their ¹³C NMR chemical shifts with those of the natural product, which established the relative stereochemistry of this fragment to be that described in diastereoisomers 4 a or e . By combining the stereostructural outcomes of the C79–C97 and C94–C104 fragments, we have proposed four candidate compounds of the C79–C104 fragment 2 a – d . We also synthesized diastereoisomers 2 a and b ( 2 a in the preceding article; Chem. Eur. J. 2015 , DOI: 10.1002/chem.201503880) by a Julia–Kocienski olefination and diastereoisomers 2 c and d by a Wittig reaction. By comparing the ¹³C NMR chemical shifts of natural symbiodinolide ( 1 ) with those of the synthetic products 2 a – d , we have reassigned the stereostructure of the C79–C104 fragment of natural product 1 to be that depicted in diastereoisomer 2 b .     

Synthesis of the C1‐C10 Fragment of Muamvatin

This report delineates our efforts towards the synthesis of a stereochemically well‐defined ketone, the C₁?C₁₀ fragment of muamvatin, the first example of a 2, 4, 6‐trioxaadamantane ring skeletal polypropionate marine natural product, using two non‐aldol variants. i) The Shimizu reaction, a Pd(0) mediated stereoselective epoxy‐ring opening of alkenyl oxiranes, was employed for the stereoselective installation of methyl groups in syn‐fashion and ii) Bode's protocol, a NHC‐mediated reaction on β‐epoxy aldehydes, was utilized for stereoselective construction of methyl and hydroxyl groups in anti‐fashion.     

Synthesis and Stereochemical Revision of the C31–C67 Fragment of Amphidinol 3

Amphidinol 3 (AM3) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. Although the absolute configuration of AM3 was determined in 1999 by extensive NMR analysis and degradation of the natural product, it was a daunting task because of the presence of numerous stereogenic centers on the acyclic carbon chain and the limited availability from natural sources. Thereafter, revisions of the absolute configurations at C2 and C51 were reported in 2008 and 2013, respectively. Reported herein is the revised absolute configuration of AM3: 32S, 33R, 34S, 35S, 36S, and 38S based on the chemical synthesis of partial structures corresponding to the C31–C67 fragment of AM3 in combination with degradation of the natural product. The revised structure is unique in that both antipodal tetrahydropyran counterparts exist on a single carbon chain. The structural revision of AM3 may affect proposed structures of congeners related to the amphidinols.     

Total Synthesis of the 7,10‐Epimer of the Proposed Structure of Amphidinolide N,Part II: Synthesis of C17–C29 Subunit and Completion of the Synthesis

The total synthesis of 7,10‐epimer of the proposed structure of amphidinolide N was accomplished. The requisite chiral C17–C29 subunit was assembled stereoselectively via Keck allylation, Shi epoxidation, diastereoselective 1,3‐reduction, and a later oxidative synthesis of the THF framework. The C1–C13 and C17–C29 subunits were successfully coupled using a Enders RAMP “linchpin” as the C14–C16 three carbon unit, thereby controlling the chirality at C14 and C16. The labile allyl epoxy moiety was successfully constructed by Grieco–Nishizawa olefination at a final stage of the synthesis.