Asymmetrische Totalsynthese des hochwirksamen Prostacyclin-Analogons Cicaprost
type: CreativeWork
description: An asymmetric synthesis of cicaprost and a formal asymmetric synthesis of isocicaprost by a new strategy are described. The key steps of theses syntheses are the coupling of chiral bicyclic C6-C14 alkyne building blocks with a chiral C15-C20 omega-side chain Weinreb-amide building block at the C14-C15 bond with formation of bicyclic ketones, whose omega-side chain carbonyl group at C15 was reduced with high diastereoselectivity with catecholborane in the presence of a chiral oxazaborolidine catalyst. The alpha-side chain was established by a stereoselective olefination of the bicyclic ketone, containing the complete omega-side chain, with a chiral phosphono acetate derived from (1S,2R)-nor-8-phenylmenthol. Asymmetric syntheses of the key intermediates, the bicyclic C6-C14 alkynes, was accomplished starting from achiral bicylic C6-C12 ketones by using enantioselective deprotonation methodology. In the course of the syntheses of these alkynes a new method for the alpha-ethynylation of ketones was developed, which features an aldol reaction of the corresponding silyl enol ether with chloral in the presence of TiCl4 and the elimination of the trichlorocarbinol derivative with nBuLi. In addition a new aldehyde to terminal alkyne transformation by using the elimination of an alkenyl aminooxosulfonium salt as key step has been realized. Asymmetric synthesis of the C15-C20 omega-side chain building block was accomplished by the oxazolidinone method by using (4R)-benzyl-oxazolidin-2-one as chiral auxiliary. An alternative synthesis of the C15-C20 building block was developed based on malonate synthesis of the racemate and its preparative scale separation by HPLC on a chiral stationary phase containing column, which gave both enantiomers with >=99% ee in high yields.
abstract: An asymmetric synthesis of cicaprost and a formal asymmetric synthesis of isocicaprost by a new strategy are described. The key steps of theses syntheses are the coupling of chiral bicyclic C6-C14 alkyne building blocks with a chiral C15-C20 omega-side chain Weinreb-amide building block at the C14-C15 bond with formation of bicyclic ketones, whose omega-side chain carbonyl group at C15 was reduced with high diastereoselectivity with catecholborane in the presence of a chiral oxazaborolidine catalyst. The alpha-side chain was established by a stereoselective olefination of the bicyclic ketone, containing the complete omega-side chain, with a chiral phosphono acetate derived from (1S,2R)-nor-8-phenylmenthol. Asymmetric syntheses of the key intermediates, the bicyclic C6-C14 alkynes, was accomplished starting from achiral bicylic C6-C12 ketones by using enantioselective deprotonation methodology. In the course of the syntheses of these alkynes a new method for the alpha-ethynylation of ketones was developed, which features an aldol reaction of the corresponding silyl enol ether with chloral in the presence of TiCl4 and the elimination of the trichlorocarbinol derivative with nBuLi. In addition a new aldehyde to terminal alkyne transformation by using the elimination of an alkenyl aminooxosulfonium salt as key step has been realized. Asymmetric synthesis of the C15-C20 omega-side chain building block was accomplished by the oxazolidinone method by using (4R)-benzyl-oxazolidin-2-one as chiral auxiliary. An alternative synthesis of the C15-C20 building block was developed based on malonate synthesis of the racemate and its preparative scale separation by HPLC on a chiral stationary phase containing column, which gave both enantiomers with >=99% ee in high yields.
author: Lerm, Marco
language: ger
keywords: info:eu-repo/classification/ddc/540, Chemie, Totalsynthese, Prostacyclin, Cicaprost
date published: 2003
date modified: 2026-07-30T19:43:10Z
provider: RWTH Aachen University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Publikationsserver der RWTH Aachen University