Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin

Geoffrey R. Heintzelman, Wen Kui Fang, Stephen P. Keen, Grier A. Wallace, Steven M. Weinreb

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/ Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the 1H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).

Original languageEnglish (US)
Pages (from-to)3939-3945
Number of pages7
JournalJournal of the American Chemical Society
Volume124
Issue number15
DOIs
StatePublished - Apr 17 2002

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Stereochemistry
Fresh Water
Alcohols
Cyclization
Metabolites
Biological Products
Crystal structure
Nuclear magnetic resonance
sulfoxide
Derivatives
X rays
Uracil
Poisons
Guanidine
cylindrospermopsin
X-Rays

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Heintzelman, Geoffrey R. ; Fang, Wen Kui ; Keen, Stephen P. ; Wallace, Grier A. ; Weinreb, Steven M. / Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin. In: Journal of the American Chemical Society. 2002 ; Vol. 124, No. 15. pp. 3939-3945.
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abstract = "A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/ Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the 1H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).",
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Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin. / Heintzelman, Geoffrey R.; Fang, Wen Kui; Keen, Stephen P.; Wallace, Grier A.; Weinreb, Steven M.

In: Journal of the American Chemical Society, Vol. 124, No. 15, 17.04.2002, p. 3939-3945.

Research output: Contribution to journalArticle

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AU - Heintzelman, Geoffrey R.

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N2 - A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/ Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the 1H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).

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