Studies on a total synthesis of the microbial immunosuppresive agent FR901483

Jeffrey E. Kropf, Ivona C. Meigh, Magnus W.P. Bebbington, Steven M. Weinreb

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

A strategy is outlined for construction of the fungal immunosuppressant FR901483 (1). It was possible to convert 1,4-cyclohexanedione monoethylene ketal in five simple steps to iodoacetamide ketone 10, which was cyclized in good yield to the key bridged keto lactam 11 containing the A/B 2-azabicyclo-[3.3.1] nonane ring system of the natural product. This intermediate could be transformed to N-Boc lactam 16, whose derived enolate underwent stereoselective hydroxylation with the Davis oxaziridine to produce alcohol 17 having the desired C-2 configuration. Compound 17 was then converted in three steps to alkoxy carbamate 20. The N-acyliminium ion derived from intermediate 20 could be alkylated in good overall yield with p-methoxybenzylmagnesium chloride to afford a 5:4 mixure of the desired PMB product 21 and the epimer 23. In an attempt to improve the stereoselectivity in this alkylation, the inverted C-4 protected alcohol N-Boc lactam 33 was prepared and its enolate was hydroxylated. Inexplicably, the product of this reaction was the undesired equatorial alcohol 34. Some model systems were investigated toward annulation of the C-ring of the natural product. It was found that homoallylic amine 40 could be cyclized with PhSCl in the presence of silica gel to generate the desired 5-endo tetracyclic product 42 in moderate yield. This cyclization protocol was also successfully applied to the actual FR901483 system 22, leading to the requisite tricycle 43.

Original languageEnglish (US)
Pages (from-to)2046-2055
Number of pages10
JournalJournal of Organic Chemistry
Volume71
Issue number5
DOIs
StatePublished - Mar 5 2006

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Lactams
Alcohols
Biological Products
Azabicyclo Compounds
Iodoacetamide
Stereoselectivity
Hydroxylation
Carbamates
Cyclization
Silica Gel
Alkylation
Immunosuppressive Agents
Ketones
Amines
Chlorides
Ions
FR 901483

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Kropf, J. E., Meigh, I. C., Bebbington, M. W. P., & Weinreb, S. M. (2006). Studies on a total synthesis of the microbial immunosuppresive agent FR901483. Journal of Organic Chemistry, 71(5), 2046-2055. https://doi.org/10.1021/jo052466b
Kropf, Jeffrey E. ; Meigh, Ivona C. ; Bebbington, Magnus W.P. ; Weinreb, Steven M. / Studies on a total synthesis of the microbial immunosuppresive agent FR901483. In: Journal of Organic Chemistry. 2006 ; Vol. 71, No. 5. pp. 2046-2055.
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Kropf, JE, Meigh, IC, Bebbington, MWP & Weinreb, SM 2006, 'Studies on a total synthesis of the microbial immunosuppresive agent FR901483', Journal of Organic Chemistry, vol. 71, no. 5, pp. 2046-2055. https://doi.org/10.1021/jo052466b

Studies on a total synthesis of the microbial immunosuppresive agent FR901483. / Kropf, Jeffrey E.; Meigh, Ivona C.; Bebbington, Magnus W.P.; Weinreb, Steven M.

In: Journal of Organic Chemistry, Vol. 71, No. 5, 05.03.2006, p. 2046-2055.

Research output: Contribution to journalArticle

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T1 - Studies on a total synthesis of the microbial immunosuppresive agent FR901483

AU - Kropf, Jeffrey E.

AU - Meigh, Ivona C.

AU - Bebbington, Magnus W.P.

AU - Weinreb, Steven M.

PY - 2006/3/5

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