- Dolastatins 23: Stereospecific synthesis of dolaisoleuine
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The remarkable antineoplastic peptide dolastatin 10, isolated from the opisthobranchia mollusc Dolabella auricularia, is currently in clinical development and further improvements in its total synthesis have been undertaken. Major effort has been directed at devising more stereoselective routes to the dolastatin 10 amino acid units dolaisoleuine 2 and dolaproine 3, each bearing three chiral centres. We report herein highly stereoselective routes to both natural (3R,4S,5S)-dolaisoleuine 2 and its 3S,4S,5S-isomer 14 (Z replaces H) using an asymmetric aldol methodology. Key reaction steps are condensation of chiral α-(methylsulfanyl)acetyloxazolidinone 4d with (S)-N-Z-N-Me-isoleucinal 6 using dibutylboron triflate followed by reductive desulfurization, O-methylation and cleavage of the oxazolidinone auxiliary to complete a simple route to N-benzyloxycarbonyldolaisoleuine 10. By substituting chiral oxazolidinone 5d for 4d the 3S-isomer of N-benzyloxycarbonyldolaisoleuine 14 was selectively obtained.
- Pettit, George R.,Burkett, Douglas D.,Williams, Michael D.
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p. 853 - 858
(2007/10/03)
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- Synthesis and antitumor activity of novel dolastatin 10 analogs
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Dolastatin 10 (1) is a potent antineoplastic pentapeptide. Novel dolastatin 10 analogs each modified at one of the constituent amino acid derivatives, were synthesized and their antitumor activity was evaluated against P388 leukemia in mice. The structural requirements for antitumor activity are discussed. Some of the analogs, 31c, 35c, 38b, and 50c showed excellent activity in vivo. Highly active 50c, which lacks the thiazole group of 1, was selected for further development as an antitumor agent.
- Miyazaki,Kobayashi,Natsume,Gondo,Mikami,Sakakibara,Tsukagoshi
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p. 1706 - 1718
(2007/10/03)
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- An expeditious synthesis of dolastatin 10
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Total synthesis of dolastatin 10 (1) was completed by developing an efficient synthesis of two key amino acid components, Dil (6) and Dap (11), and subsequent stepwise coupling of five amino acid components from C-terminal Doe.
- Tomioka, Kiyoshi,Kanai, Motomu,Koga, Kenji
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p. 2395 - 2398
(2007/10/02)
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