A Practical Synthesis of Trans-3-Substituted Proline Derivatives through 1,4-Addition

Abstract

A practical four-step synthesis of 3-alkyl-, vinyl-, and aryl-substituted proline derivatives, which are important building blocks for conformationally restrained peptide analogs, was developed. The method relies on a Cu-catalyzed 1,4-addition of Grignard reagents to N-protected 2,3-dehydroproline esters, efficiently prepared in a new one-pot protocol. The 1,4-addition products are obtained with good trans-selectivity (dr 5:1 to 25:1). A nonracemic sample of N-Cbz-3-vinylproline (74% ee) was obtained using Evans oxazolidinone as a chiral auxiliary.

Organocatalytic Michael Addition of Nitro Esters to α,β‐Unsaturated Aldehydes: Towards the Enantioselective Synthesis of trans‐3‐Substituted Proline Derivatives

“…Over the past decades, progress has been made in synthesizing chiral 3‐substituted proline derivatives4 by using an organometallic reagent or a chiral precursor/auxiliary. For example, Schmalz and co‐workers4a recently developed a Cu‐catalyzed 1,4‐addition strategy to synthesize the racemic trans ‐3‐substituted proline derivatives in four steps. The chiral trans ‐3‐vinylproline could, accordingly, be obtained with 74% ee in six steps via the Evans auxiliary approach.…”

“…Remarkably, we succeeded next in constructing the N ‐Cbz‐protected pyrrolidine 7a through the one‐pot operation, including intramolecular cyclization,17 hydrogenation,18 and N ‐Cbz protection 19. Finally, in order to further improve the low diastereoselectivity,4a the product 7a was treated with 0.98 equiv. of LiOH in H 2 O/MeOH/THF.…”

Synthesis of Racemic δ,δ‐Dimethylproline Derivatives

“…Specifically, vinyl triflate 6 and Δ 2 -pyrroline 8 should be suitable substrates to carry out cross-coupling reactions and 1,4-conjugate additions, respectively. In fact, analogous compounds derived from proline have been successfully employed, by us [17] and other authors, [27] in the synthesis of β-substituted prolines following these strategies. The β-functionalization of δ,δ-dimethylproline is expected to render analogues able to combine the propensity of the parent amino acid to lock the prolyl amide bond in the cis geometry with the presence of new side-chains.…”

“…would most probably render 10 as cis/trans mixture of isomers, as observed in the case of the Δ 2 -pyrroline derived from proline. [27] a 64% N CO 2 Me Accordingly, 6 (and 8) could be seen as suitable precursors to generate proline analogues that stabilize the cis geometry of the prolyl amide bond while incorporating additional functionality at C β . [31]…”

3-Substituted Prolines: From Synthesis to Structural Applications, from Peptides to Foldamers

“…A similar approach, but with improved yields regarding both the synthesis of the starting material and the 1,4 Michael addition on the enone, has been recently reported by Huy and co-workers [ 16 ]. Moreover, Huy succeeded elegantly in the synthesis of non racemic compounds ( Scheme 2 b) by introducing Evans chiral auxiliary on the dehydroproline derivative.…”