Chemical Biology of Epothilone.pdfVIP

Me OMe O O MeO OMe MeO O HO O O O HN O Me Me O R N Me OMe colchicine R Ac rhizoxin colcemide R Me HO OH N O H O N O N O H MeOOC MeO N OAc MeO OMe R MeOOC OH OMe vinblastine R Me vincristine R CHO podophyllotoxine O R AcO O O OH S Ph NH O HO N Ph OH O O H O HO BzO AcO O OH O taxol epothilone A R H epothilone B R Me O O OH OH O O OH OH NH2 discodermolid O O Me O N Me O N H Me H Me N N O Me O Me H OH H OMe Me Me COOMe Me Me O OAc sarcodictyin A eleutherobin OH O OH R O O S S OH HO N HO N O O O OH O O OH O 1: R H : epothilone A 5: epothilone E 2: R Me : epothilone B R S HO N O 3: R H : epothilone C O OH O 4: R Me : epothilone D OH OTPS 6 EDC OTPS 4-DMAP O 86% COOH O O O 7 8 LDA O –78 °C epoxidation 9 75% O 19 S 12 20 13 21 HO OTPS + HO OTPS HO 7 15 N 17 O ca. 1.5:1 O 3 1 O 6 O O O O O OH O 10 11 1: epothilone A PCy3 CH2Cl2 Cl Ph CH2Cl2 25 °C Ru 25 °C 85% Cl 79% olefin metathesis PCy3 Wittig HO 12 HO 12 12 S reaction 20 13 O 15 O 15 HO 7 15 N 21 OR OR O O 3 1 O 6 aldol O O O OH O esterification condensation TBAF 12: R TPS TBAF 14: R TPS 3: epothilone C 92% 13: R H 95% 15: R H O 9 LDA HO 7 HO 7 + –78 °C COOH 6 COOH 6 COOH O O O 7 16 ca. 2:3 17 S EDC N 4-DMAP OH 18 73% S S HO HO N N O ca. 2:3 O O O O O 20 19 PCy3 CH2Cl2 Cl Ru Ph CH2Cl2 25 °C 25 °C 86% Cl PCy3 66% HO S HO S O O N N O O 23 O O 21 O O mCPBA or CF3 0 °C O NaHMDS, HMPA O N O O N n-C H I HO S HO S SO2 5 9 SO2 O O 25 26 N N O O LiAlH4 60% over two steps 24 O O 22 TPAP, NMO O HO 95% 9 27 1. + -Ipc2B allyl H O O 2. TBSOTf, 2,6-lutidine O OTBS 28 73% over two steps 29 O3 Ph P 90% 3 NaClO2 2-methyl-2-butene COOH CHO NaH PO tBuOH:H O O OTBS 2 4, 2 O OTBS 31 93% 30 S S DIBAL-H EtOOC N 90% OHC N 32 33 Ph P C CH CHO 98% 3 3 S + -Ipc2B allyl S N 96% O N OH 35 34 1. I , Ph P, 2 3 OHC 1,4-butanediol, imidazole Cl O O NaH, nBu NI OH PPh3 I 9 LDA HO HO 4 2