Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy

Pu Sun, Cuixiang Sun, Steven M. Weinreb

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (±)-lepadiformine (6). The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R),5(S),10(S),13(S).

Original languageEnglish (US)
Pages (from-to)4337-4345
Number of pages9
JournalJournal of Organic Chemistry
Volume67
Issue number12
DOIs
StatePublished - Jun 14 2002

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Enantiomers
Alkaloids
Ions
Pyrrolidonecarboxylic Acid
Amino Alcohols
Hydroformylation
Silanes
Acetals
Nitriles
Bromides
Aldehydes
Copper
Hydrolysis
Salts
Oxidation
Acids
lepadiformine
allylsilane

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

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title = "Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy",
abstract = "Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (±)-lepadiformine (6). The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R),5(S),10(S),13(S).",
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Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy. / Sun, Pu; Sun, Cuixiang; Weinreb, Steven M.

In: Journal of Organic Chemistry, Vol. 67, No. 12, 14.06.2002, p. 4337-4345.

Research output: Contribution to journalArticle

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T1 - Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy

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