Construction of an advanced tetracyclic intermediate for total synthesis of the marine alkaloid sarain A

Sungwoo Hong, Jinhai Yang, Steven M. Weinreb

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

In work directed toward a total synthesis of the marine alkaloid sarain A (1), the advanced intermediate 54, containing all the key elements and the seven stereogenic centers of sarain A, has been successfully synthesized from bicyclic lactam 4, previously prepared via an intramolecular stereospecific [3 + 2]-azomethine ylide dipolar cycloaddition. Intermediate lactam 4 could be efficiently converted to N-Boc derivative 12. Introduction of a two-carbon fragment into lactam 12 which eventually becomes the C-7′,8′ syn diol of the "eastern" ring was then achieved by C-acylation of the corresponding enolate with methoxyacetyl chloride followed by a highly stereoselective ketone reduction with Zn(BH4)2 to afford alcohol 16. Intermediate 16 has the incorrect C-7′ relative stereochemistry for sarain A, but this problem was conveniently remedied by inverting the C-7′ center via an intramolecular Ohfune-type cyclization of the silyl carbamate derived from Boc mesylate 27 to produce the key cyclic carbamate 28. It was then possible to convert acetal 28 to allylsilane 32 followed by cyclization to the alkaloid tricyclic core 33 via an allylsilane/N-sulfonyliminium ion cyclization. Formation of the "western" macrocyclic ring has been successfully addressed using functional group handles at C-3′ and N-1′ on the tricyclic core via a ring-closing olefin metathesis (RCM) strategy with the second-generation Grubbs ruthenium catalyst to produce intermediate macrolactam 47. A chelation-controlled addition of ethynylmagnesium bromide to advanced aldehyde 51 afforded a single diastereomeric adduct 53 which is tentatively assigned to have the correct C-7′,8′ syn-diol stereochemistry. This adduct could be rearranged to the conveniently protected amino carbonate 54 which is set up for construction of the remainder of the eastern ring of sarain A.

Original languageEnglish (US)
Pages (from-to)2078-2089
Number of pages12
JournalJournal of Organic Chemistry
Volume71
Issue number5
DOIs
StatePublished - Mar 5 2006

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Alkaloids
Lactams
Cyclization
Stereochemistry
Carbamates
Acylation
Acetals
Mesylates
Ruthenium
Cycloaddition
Carbonates
Alkenes
Chelation
Ketones
Bromides
Aldehydes
Functional groups
Chlorides
Carbon
Alcohols

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Hong, Sungwoo ; Yang, Jinhai ; Weinreb, Steven M. / Construction of an advanced tetracyclic intermediate for total synthesis of the marine alkaloid sarain A. In: Journal of Organic Chemistry. 2006 ; Vol. 71, No. 5. pp. 2078-2089.
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abstract = "In work directed toward a total synthesis of the marine alkaloid sarain A (1), the advanced intermediate 54, containing all the key elements and the seven stereogenic centers of sarain A, has been successfully synthesized from bicyclic lactam 4, previously prepared via an intramolecular stereospecific [3 + 2]-azomethine ylide dipolar cycloaddition. Intermediate lactam 4 could be efficiently converted to N-Boc derivative 12. Introduction of a two-carbon fragment into lactam 12 which eventually becomes the C-7′,8′ syn diol of the {"}eastern{"} ring was then achieved by C-acylation of the corresponding enolate with methoxyacetyl chloride followed by a highly stereoselective ketone reduction with Zn(BH4)2 to afford alcohol 16. Intermediate 16 has the incorrect C-7′ relative stereochemistry for sarain A, but this problem was conveniently remedied by inverting the C-7′ center via an intramolecular Ohfune-type cyclization of the silyl carbamate derived from Boc mesylate 27 to produce the key cyclic carbamate 28. It was then possible to convert acetal 28 to allylsilane 32 followed by cyclization to the alkaloid tricyclic core 33 via an allylsilane/N-sulfonyliminium ion cyclization. Formation of the {"}western{"} macrocyclic ring has been successfully addressed using functional group handles at C-3′ and N-1′ on the tricyclic core via a ring-closing olefin metathesis (RCM) strategy with the second-generation Grubbs ruthenium catalyst to produce intermediate macrolactam 47. A chelation-controlled addition of ethynylmagnesium bromide to advanced aldehyde 51 afforded a single diastereomeric adduct 53 which is tentatively assigned to have the correct C-7′,8′ syn-diol stereochemistry. This adduct could be rearranged to the conveniently protected amino carbonate 54 which is set up for construction of the remainder of the eastern ring of sarain A.",
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Construction of an advanced tetracyclic intermediate for total synthesis of the marine alkaloid sarain A. / Hong, Sungwoo; Yang, Jinhai; Weinreb, Steven M.

In: Journal of Organic Chemistry, Vol. 71, No. 5, 05.03.2006, p. 2078-2089.

Research output: Contribution to journalArticle

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AB - In work directed toward a total synthesis of the marine alkaloid sarain A (1), the advanced intermediate 54, containing all the key elements and the seven stereogenic centers of sarain A, has been successfully synthesized from bicyclic lactam 4, previously prepared via an intramolecular stereospecific [3 + 2]-azomethine ylide dipolar cycloaddition. Intermediate lactam 4 could be efficiently converted to N-Boc derivative 12. Introduction of a two-carbon fragment into lactam 12 which eventually becomes the C-7′,8′ syn diol of the "eastern" ring was then achieved by C-acylation of the corresponding enolate with methoxyacetyl chloride followed by a highly stereoselective ketone reduction with Zn(BH4)2 to afford alcohol 16. Intermediate 16 has the incorrect C-7′ relative stereochemistry for sarain A, but this problem was conveniently remedied by inverting the C-7′ center via an intramolecular Ohfune-type cyclization of the silyl carbamate derived from Boc mesylate 27 to produce the key cyclic carbamate 28. It was then possible to convert acetal 28 to allylsilane 32 followed by cyclization to the alkaloid tricyclic core 33 via an allylsilane/N-sulfonyliminium ion cyclization. Formation of the "western" macrocyclic ring has been successfully addressed using functional group handles at C-3′ and N-1′ on the tricyclic core via a ring-closing olefin metathesis (RCM) strategy with the second-generation Grubbs ruthenium catalyst to produce intermediate macrolactam 47. A chelation-controlled addition of ethynylmagnesium bromide to advanced aldehyde 51 afforded a single diastereomeric adduct 53 which is tentatively assigned to have the correct C-7′,8′ syn-diol stereochemistry. This adduct could be rearranged to the conveniently protected amino carbonate 54 which is set up for construction of the remainder of the eastern ring of sarain A.

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