title: Asymmetric synthesis of the highly potent anti-metastatic prostacyclin analogue cicaprost and its isomer isocicaprost.
abstract: 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 omega-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 alpha-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 alpha-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 omega-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.
authors.affiliation: Institut für Organische Chemie der Rheinisch-Westfälischen Technischen Hochschule (RWTH) Aachen, Prof.-Pirlet-Str. 1, D-52056 Aachen, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Lerm
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gais
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Cornelia
authors.initials: C
authors.lastname: Vermeeren
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D007536:Isomerism; D008958:Models, Molecular; D015394:Molecular Structure; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis*
chemical_list: D000970:Antineoplastic Agents; D011465:Prostaglandins, Synthetic; D011464:Epoprostenol; C043867:cicaprost