Total Syntheses of Amphidinolides B G and H

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 Speaker： Lu Yi-chih Date ： 2012/11/17

Structure of Amphidinolides B, G and H 26 25 25 2

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 L 1210 IC 50 = 1. 4 x 10 -4μg/ml IC 50 = 4. 8 x 10 -4μg/ml IC 50 = 5. 4 x 10 -3μg/ml KB IC 50 = 4. 2 x 10 -3μg/ml IC 50 = 5. 2 x 10 -4μg/ml IC 50 = 5. 9 x 10 -3μg/ml 3

Family structure of Amphidinolide G 4

Family structure of Amphidinolide B 5

Past synthesis of Amphidinolide H Angew. Chem. 2007, 119, 9425 -9430 6

Past synthesis of Amphidinolide B 1 and Amphidinolide B 2 J. AM. CHEM. SOC. 2008, 130, 7253 -7255 7

Retrosynthetic analysis of Amphidinolide B 8

Synthesis of alkyne 9 Corey-Fuchs alkyne synthesis alkyl 9

Construction of diene 14 through acetylide coupling Wittig olefination alkyl 10

Synthesis of aldehyde 6 by Dess-Martin oxidation 11

Synthesis of ketone 7 throuhgt Wittig olefination and Sharpless asymmetric dihydroxylation 12

Preparation of carboxylic acid 5 13

Combine aldehyde 6 and ketone 18 by aldol reaction 14

Synthesis of alcohol 19 15

To obtain epoxide alcohol 4 via Sharpless asymmetric epoxidation 16

Total synthesis of amphidinolide B Yamaguchi Ring-closing esterification metathesis alkyl 17

Preparation of ketone 25 18

Combine aldehyde 23 and ketone 24/25 via aldol reaction 19

To abtain alcohol 29 throught Yamaguchi reaction 20

Synthesis of allylic epoxide 30 vis Sharpless asymmetric epxidation and Wittig olefination 21

Total Synthesis of amphidinolide G (2) 22

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. 23

Summary Journal Natural product Angew. Chem. 2007, Amphidinolide H 119, 9425 -9430 Key steps Stille copuling aldol reaction RCM reaction esterification steps yield 21 0. 4% J. AM. CHEM. SOC. 2008, 130, 72537255 Amphidinolide B 1 aldol reaction esterification Amphidinolide B 2 Wadsworth-Emmons olefination 25 0. 3% 25 0. 9% Angew. Chem. Int. Ed. 2012, 51, 98779880 Amphidinolide B 21 6. 9% 23 3. 2% Amphidinolide G RCM reaction aldol reaction esterification Acetylide coupling 24

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