The preparation of (S)-3,4-dehydroproline from (2S,4R)-4-hydroxyproline

Abstract

(2S,4R)-N-Benzyloxycarbonyl-4-tosyloxyproline methyl ester, readily prepared from commercially available (2S,4R)-N-benzyl-oxycarbonyl-4-hydroxyproline, was converted to (S)-3,4-dehydroproline of high enantiomeric purity by a process which involved a highly regioselective phenylselenoxide elimination to introduce the olefinic function.

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

“…Therefore, as proof of principle, we investigated the synthesis of the 4 R -thiophenyl proline-containing peptide ( 16 ) via direct conversion of Hyp to 4 S -bromoproline ( 25 ), followed by S N 2 reaction with the thiophenolate (Scheme 9). 31d, 34 Both reactions proceeded with good overall conversion, providing simpler two-step access to 4 R -substituted prolines via S N 2 reaction.…”

“…17o, p, 21f, 32 In addition, the azidoproline-containing peptides were converted to the ionizable aminoprolines ( 19 , 22 ) and guanidinoprolines ( 20 , 23 ) via reduction of the azide to the amine and guanylation. 21l, 31d, 33 In general, the proline mesylates ( 5 , 6 ) and para -nosylates ( 9 , 10 ) were similarly effective for S N 2 reactions on solid phase (see HPLC chromatograms in the Supporting Information), whereas the tosylates ( 7 , 8 ) were less effective, resulting in poorer conversion and/or more side products. 21j, k …”

“…19a, 21b, 21e, 21j, k, 31 Hydroxyproline residues were readily converted to include leaving groups including mesylates, tosylates, para -nosylates, and ortho -nosylates. These derivatives were stable to standard TFA cleavage conditions and isolable as the sulfonates (see below for structural analysis of the sulfonates and all derivatives).…”

“…Mitsunobu reactions on solid phase with Hyp and hyp proceeded readily for 4-nitrothiophenol and selenophenol (derived from in situ reduction of diphenyl diselenide with sodium borohydride) (Scheme 11, 39 - 42 ). 31b In contrast, Mitsunobu reaction with thiophenol only proceeded to high conversion for hyp, to generate the 4 R phenyl thioether ( 16 ). The 4 S phenyl thioether ( 17 ) was instead synthesized by S N 2 reaction (Scheme 8), which was also alternatively used to synthesize the 4 R phenyl thioether (Scheme 8 and Scheme 9).…”

Synthesis of Novel Pyrrolo[3,4‐d]pyrazole‐dicarboxylic Acids and Evaluation of Their Interaction with Glutamate Receptors

“…-The synthetic route to the N(1)-substituted amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b is depicted in the Scheme. The key step is represented by the 1,3-dipolar cycloaddition of the two nitrilimines [10], derived by dehydrohalogenation of chloro hydrazono esters 6a and 6b, to methyl N-Boc-3,4-didehydro-(S)-prolinate (S)-7 [11] (Scheme). The N(1)-substituted chloro hydrazono esters 6a and 6b were, in turn, synthesized from the hydrazines 3a and 3b, respectively, according to a known procedure [12].…”