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.

Monomethyl ethers of 4,5-dihydroxypipecolic acid from Petaladenium urceoliferum : Enigmatic chemistry of an enigmatic legume

“…Compound 2 is therefore (2S,4S,5R)-5-hydroxy-4-methoxypipecolic acid ( = L-cis-4-methoxy-cis-5-hydroxypipecolic acid). The coupling constants for this molecule were similar to those recorded for (2S,4S,5R)-4,5-dihydroxypipecolic acid (Scarpi et al, 2013). In the case of 3, coupling constant data were similar to those of (2S,4R,5S)-4,5-dihydroxypipecolic acid (Scarpi et al, 2013) indicating an assignment of (2S,4R,5S)-5-hydroxy-4-methoxypipecolic acid ( = L-trans-4-methoxy-cis-5-hydroxypipecolic acid).…”

“…The coupling constants for this molecule were similar to those recorded for (2S,4S,5R)-4,5-dihydroxypipecolic acid (Scarpi et al, 2013). In the case of 3, coupling constant data were similar to those of (2S,4R,5S)-4,5-dihydroxypipecolic acid (Scarpi et al, 2013) indicating an assignment of (2S,4R,5S)-5-hydroxy-4-methoxypipecolic acid ( = L-trans-4-methoxy-cis-5-hydroxypipecolic acid). For compound 1, both H-4 and H-5 had no diaxial couplings indicating that these protons must adopt equatorial positions.…”

From synthetic control to natural products: a focus on N‐heterocycles

“…Conversion of 22 to enecarbamate ester 25 (Scheme ) was carried out as usual after N protection ( 23 ), vinyl phosphate formation ( 24 ) and Pd‐catalysed methoxycarbonylation of the latter. Hydrogenation of 25 proceeded with good stereoselectively (diasteromeric excess 8:1), and provided target cis ‐5‐hydroxypipecolic acid 28 in quantitative yield after exhaustive hydrolysis …”

α-Chymotrypsin andl-acylase aided synthesis of 5-hydroxypipecolic acid via Jacobsen's hydrolytic kinetic resolution of epoxy amino acids

“…9 Due to its above mentioned biological relevance and ability to induce rigidity owing to its cyclic structure, several groups have attempted the synthesis of 5-hydroxypipecolic acid. 7,[10][11][12][13][14] In this context glycine amino acid residues functionalized with epoxide side chains are synthetically valuable precursors for generation of cyclic amino acids. We recently synthesized 4-hydroxyproline isomers from epoxide derived from 2-amino-4-pentenoic acid (allyl glycine), by selective intramolecular reaction of amine on C 5 carbon.…”