Complementary and stereodivergent approaches to the synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids from enantiopure hydroxylated lactams

Abstract

We describe two complementary and stereodivergent routes, from commercially available and inexpensive starting materials, for the synthesis of 4,5-dihydroxy- and 5-hydroxypipecolic acids based on the chemistry of lactam-derived enol phosphates. The synthesis of the 4,5-cis-4,5- dihydroxypipecolic acids required the preparation from 2-deoxy-D- and -L-ribose of the enantiopure cis-(4S,5R)- and -(4R,5S)-4,5-dihydroxy-δ-valerolactam, respectively. These new chiral synthons are potentially useful for the synthesis of other natural products. The key step is the Pd-catalyzed methoxycarbonylation reaction of the enol phosphates generated from these lactams. This reaction provided enecarbamate esters that were easily converted by stereoselective reduction to the target compounds. The synthesis of the 4,5-trans-4,5-dihydroxypipecolic acid, as well as of 5-hydroxypipecolic acids, was realized from a known (S)-5-hydroxy-δ-valerolactam derivative and, for the dihydroxylated compound, required a highly stereoselective allylic bromination reaction of the enecarbamate ester obtained by methoxycarbonylation of the enol phosphate. The preparation of the (4R,5S) enantiomer of the cis-4,5-dihydroxy-δ-valerolactam from 2-deoxy-L-ribose, alongside the fact that (R)-5-hydroxy-δ-valerolactam can be prepared from (R)-(-)-γ-hydroxymethyl-γ-butyrolactone, means our approach allows for the synthesis of all stereoisomers of these compounds, which can be employed as conformationally constrained scaffolds in drug discovery. The stereoselective synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids was accomplished by sequential Pd-catalysed methoxycarbonylation and stereoselective reduction of enantiopure hydroxylated lactam-derived enol phosphates obtained from both enantiomers of commercially available γ-hydroxymethyl-γ- butyrolactone and 2-deoxyribose. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.