Total Syntheses of Amphidinolides B, G, and H Akihiro Hara, Ryo Morimoto, Yuki Iwasaki, Tsuyoshi Saitoh, Yuichi Ishikawa, and Shigeru Nishiyama* Angew. Chem. Int. Ed. 2012, 51, 9877-9880 Professor, post doctor and juniors good morning. I am Lu Yi Chih. Today I will introduce the topic is Total synthesis of amphidinolides B,G and H. And the paper was published in Angewandte Chemie International Edition on 2012, volume 51, page 9877 to 9880 which had completed by Nishiyama and his co-workers. The two pictures are amphidinolides B, G, and H. I will introduce the natural product’s property and the author’s synthesis plan. Speaker： Lu Yi-chih Date ：2012/11/17

Structure of Amphidinolides B, G and H 26 25 In this page I will introduce the amphidinolide’s structure. We can see the picture. The same moiety of natrual product are macrolide and epoxide. But the different moiety of amphidinolides is carbon number . The amphidinolide B , H and G’s carbon number is 25, 25 and 26. Another the amphidinolide B and the amphidinolide H’s C16 and C26 is different. The amphidinolide B’s C16 and C26 is hydroxide group and hydride group. The amphidinolide H’s is hydride group and hydroxide group. 25

Isolation and Bioactivity of Amphidinolides In 1986 , Amphidinolide are series of unique cyotoxic macrolides isolation from dinoflagellates Amphidinium sp., which were separated from marine acoel flatworms Amphiscolops sp. by Kobayashi and co-workers. Amphidinolides were foud to biological effects on tumor cell lines. Amphidinolide B Amphidinolide H Amphidinolide G L1210 IC50 = 1.4x10-4μg/ml IC50 = 4.8x10-4μg/ml IC50 = 5.4x10-3μg/ml KB IC50 = 4.2x10-3μg/ml IC50 = 5.2x10-4μg/ml IC50 = 5.9x10-3μg/ml

Family structure of Amphidinolide G

Family structure of Amphidinolide B

Past synthesis of Amphidinolide H Angew. Chem. 2007, 119, 9425-9430

Past synthesis of Amphidinolide B1and Amphidinolide B2 J. AM. CHEM. SOC. 2008, 130, 7253-7255

Retrosynthetic analysis of Amphidinolide B

Corey-Fuchs alkyne synthesis Synthesis of alkyne 9 alkyl Corey-Fuchs alkyne synthesis First, we have to synthesis of alkyne 9 from diol 10, and prepared the diol from protection of 3-en-1-propatol by methoxylphenane and sharpless astmmetric dihydroxylation of compound to afford the diol 10. Than we protect of diol under the conditions, pivaloyl chloride in pyridine and t-butyl dimethylsilyl trifluoromethanesulfonate, and reductive removal of pivalate ester by DIBAL-H provided the alcohol 11. Parikh-Doering oxidation of 11 to got aldehyde intermedium, and subsequent reaction with PPh3 and CBr4 gave the corresponding 1,1-dibromoalkene, I introduce the mechanism, we success to get the dibromoalkene, was treated with EtMgBr to afford the alkyne. Removal of methoxyphenyl group in 12 using CAN gave the alcohohol, which upon protection as a TES ether afforded the desiered alkyne 9.

Construction of diene 14 through acetylide coupling Wittig olefination Success get the alkyne 9, we have to prepare the aldehyde 8 that to do acetylide coupling reaction. Synthesis of the aldehyde segment 8 was initiated by employing Evans alkylation of the acylated oxazolidinone with allyl iodide.This process formed adduct. Reductive removal of the chiral auxiliary in this substance followed by the tosylation of the resulting alcohol and cyanide substitution gave nitrile 11, which upon DIBAL reduction at 78 C furnished aldehyde 8. treatment of 9 with n-Buli, was reacted with 8 to furnish an alcohol which was then subjected to TPAP oxidation to producethe ketone 13. treatment of 13 with the Gilman reagent led to formation of the desired diene 14 by wittig olefination . alkyl

Synthesis of aldehyde 6 by Dess-Martin oxidation Removal of the TES group in 14 and subsequent Dess-Martin oxidation afforded the key intermediate 6.

Synthesis of ketone 7 throuhgt Wittig olefination and Sharpless asymmetric dihydroxylation We also prepared two  fragment ,ketone 7 and acid 5, to do aldol reaction and esterification, now I wanna show you how to synthesis the strar. DIBAL-H reduction of the nitrile produced the aldehyde, which was transformed into the unsaturated ester 16 by using a Wittig olefination. Sharpless asymmetric dihydroxylation of unsaturated ester 16 proceeded to afford the diol as a single diastereomer. Protect of diol ester S-6 using TBSOTf and 2,6-lutidine. The DIBAL-H reduction of ester 17 afforded alcohol compound. Followed by oxidation and addition of MeLi furnished the transformed into the ketone 7.

Preparation of carboxylic acid 5 The carboxylic acid 5, the final component needed in the convergent approach, was prepared from 4-penten-1-ol by a PCC oxidation, Wittig olefination, and hydrolysis sequence.

Combine aldehyde 6 and ketone 18 by aldol reaction

Synthesis of alcohol 19 The aldol product (S)-18 was converted into the TBS ester, from which the TBDPS group was selectively removed usingTBAF/AcOH/H2O in THF and DMF to afford the alcohol 19

To obtain epoxide alcohol 4 via Sharpless asymmetric epoxidation Sharpless asymmetric epoxidation to afford the epoxy alcohol as single diastereomer. A Dess-martin oxidation and Wittig olefination sequence efficiently provided the allylic epoxide 20 which was subjected to selective removal of the PMB group using DDQ and phosphate buffer ph 7.0 in DCM to affrod alcohol 4.

Total synthesis of amphidinolide B Yamaguchi esterification Ring-closing metathesis To finished the residue 4 successfully. Next step we made a usage the acid 5 / 2,4,6-trichlorobenzoyl chloride /DMAP in Et3N to couple with alcohol 4. RCM utilizing Grubbs’second-generation catalyst trans-formed 21 into the target 26-membered 22 withot producing the undesired Z isomer. Finally, cleavage of the TBS group in 22 produced 1 alkyl alkyl

Preparation of ketone 25

Combine aldehyde 23 and ketone 24/25 via aldol reaction The intermediate 26 could be generated by an aldol reaction between the aldehyde 23 and ketone 24/25, and the aldol product 27 could be produced in a higher yield. After protection of 27 as a TBS ether, selective deprotection with PPTS affroded the alcohol 28.

To abtain alcohol 29 throught Yamaguchi reaction Esterification of 28 with 5 by using the Yamaguchi olefination to affrod ester S-13, then treated ester S-13 with TBAF/AcOH/H2O to afford the alcohol 29.

Synthesis of allylic epoxide 30 vis Sharpless asymmetric epxidation and Wittig olefination Sharpless asymmetric epoxidation to afford the epoxy alcohol. A Des-martin oxidation and Wittig olefination sequence efficiently provided the allylic epoxide 30

Total Synthesis of amphidinolide G (2) RCM utilizing Grubbs’second-generation catalyst trans-formed 30 into the target 26-membered S-15 withot producing the undesired Z isomer. Finally, cleavage of the TBS group using TASF/DMF/H2O in THF in S-15 produced 2

Conclusion Total synthesis of amphidinolide B and amphidinolide H. The synthesis proceeds 21 steps and gave 6.9% yield , 23 steps and gave 3.2% yield.

Summary Journal Natural product Key steps steps yield Angew. Chem. 2007, 119, 9425-9430 Amphidinolide H Stille copuling aldol reaction RCM reaction esterification 21 0.4% J. AM. CHEM. SOC. 2008, 130, 7253-7255 Amphidinolide B1 Wadsworth-Emmons olefination 25 0.3% Amphidinolide B2 0.9% Angew. Chem. Int. Ed. 2012, 51, 9877-9880 Amphidinolide B Acetylide coupling 6.9% Amphidinolide G 23 3.2%

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