American Chemical Society
Browse
ja030200l_si_002.pdf (1.16 MB)

Asymmetric Synthesis of the Highly Potent Anti-Metastatic Prostacyclin Analogue Cicaprost and Its Isomer Isocicaprost

Download (1.16 MB)
journal contribution
posted on 2003-07-19, 00:00 authored by Marco Lerm, Hans-Joachim Gais, Kejun Cheng, Cornelia Vermeeren
An asymmetric synthesis of the anti-metastatic prostacyclin analogue cicaprost and a formal one of its isomer isocicaprost by a new route are described. A key step of these syntheses is the coupling of a chiral bicyclic C6−C14 ethynyl building block with a chiral C15−C21 ω-side chain amide building block with formation of the C14−C15 bond of the target molecules. A highly stereoselective reduction of the thereby obtained C6−C21 intermediate carrying a carbonyl group at C15 of the side chain was accomplished by the chiral oxazaborolidine method. The chiral phosphono acetate method was used for the highly stereoselective attachment of the α-side chain to the bicyclic C6−C21 intermediate carrying a carbonyl group at C6. Asymmetric syntheses of the bicyclic C6−C14 ethynyl building blocks were carried out starting from achiral bicyclic C6−C12 ketones by using the chiral lithium amide method. In the course of these syntheses, a new method for the introduction of an ethynyl group at the α-position of the carbonyl group of a ketone with formation of the corresponding homopropargylic alcohol was devised. Its key steps are an aldol reaction of the corresponding silyl enol ether with chloral and the elimination of a trichlorocarbinol derivative with formation of the ethynyl group. In addition, a new aldehyde to terminal alkyne transformation has been realized. Its key steps are the conversion of an aldehyde to the corresponding 1-alkenyl dimethylaminosulfoxonium salt and the elimination of the latter with a strong base. Two basically different routes have been followed for the synthesis of the enantiomerically pure C15−C21 ω-side chain amide building block. The first is based on the chiral oxazolidinone method and features a highly stereoselective alkylation of (4R)-N-acetyl-4-benzyloxazolidin-2-one, and the second encompasses a malonate synthesis of the racemic amide and its efficient preparative scale resolution by HPLC on a chiral stationary phase containing column.

History