Dolastatins 23

Stereospecific synthesis of dolaisoleuine

George Pettit, Douglas D. Burkett, Michael D. Williams

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)853-858
Number of pages6
JournalJournal of the Chemical Society - Perkin Transactions 1
Issue number8
StatePublished - Apr 21 1996

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dolastatin 10
Oxazolidinones
Isomers
Bearings (structural)
Molluscs
Methylation
Desulfurization
Antineoplastic Agents
Condensation
Amino Acids
Peptides

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Dolastatins 23 : Stereospecific synthesis of dolaisoleuine. / Pettit, George; Burkett, Douglas D.; Williams, Michael D.

In: Journal of the Chemical Society - Perkin Transactions 1, No. 8, 21.04.1996, p. 853-858.

Research output: Contribution to journalArticle

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abstract = "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.",
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