title: Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin.
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 (1)H 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).
authors.affiliation: Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Heintzelman
authors.forename: Wen-Kui
authors.initials: WK
authors.lastname: Fang
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Keen
authors.forename: Grier A
authors.initials: GA
authors.lastname: Wallace
authors.forename: Steven M
authors.initials: SM
authors.lastname: Weinreb
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D001427:Bacterial Toxins; D018360:Crystallography, X-Ray; D000458:Cyanobacteria / Q000737:chemistry / Q000378:metabolism; D000087522:Cyanobacteria Toxins; D006801:Humans; D008099:Liver / Q000187:drug effects; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
chemical_list: D000470:Alkaloids; D001427:Bacterial Toxins; D000087522:Cyanobacteria Toxins; C089595:cylindrospermopsin; D014498:Uracil