Enantiodivergent Synthesis of (R)- and (S)-Rolipram.docVIP

Molecules 1998, 3, 107–119 molecules ISSN 1420-3049 Enantiodivergent Synthesis of (R)- and (S)-Rolipram Joachim Demnitz, Luigi LaVecchia, Edmond Bacher, Thomas H. Keller, Thomas Müller, Friedrich Schürch, Hans-Peter Weber and Esteban Pombo-Villar* Preclinical Research, Novartis Pharma Ltd, CH-4002 Basel, Switzerland, phone +41 61 324 9865, fax +41 61 324 9794, e-mail esteban.pombo@ Received: 2 November1997 / Accepted: 23 February1998 / Published: 10 March 1998 Abstract: Both enantiomers of rolipram (1) have been prepared in large quantity from a common intermediate rac-3-(3’-cyclopentyloxy-4’-methoxy)phenyl-4-nitro butyric acid (6), which was resolved by way of the two readily separable diastereoisomeric amides obtained with (S)-(- )-phenylethylamine. Reduction of the nitro group and intramolecular transamidation gave (R)-(- )-1 and (S)-(+)-1, respectively. CD spectra of both enantiomers of rolipram are reported and discussed. Both enantiomers of rolipram presented the same potency of inhibitory activity against recombinant cyclic-AMP-selective phosphodiesterase (PDE4) subtypes. Keywords: Rolipram, phosphodiesterase, circular dichroism (CD) spectra, enantiodivergent synthesis. Introduction quantities of both enantiomers. In this paper we report a new synthesis of the enantiomers of 1, and the Rolipram (1) is a compound with varied biological characterisation of these compounds as inhibitors of PDE4 enzyme subtypes. activity. In particular, attention has been drawn to the emetic [1], antiinflammatory [2], immunosupressant [3], antidepressive [4,5], putative antiparkinsonian [6], and The industrial synthesis of rac-(1) and resolution of the enantiomers either chromatographically [13-15] or by classical (enzymatic) resolution of an intermediate in the synthesis [16] has been reported. Asymmetric syntheses of 1 have been recently reviewed [17]. Addi