Enantioselective and Chemoselective Phosphine Oxide‐catalyzed Aldol Reactions of N‐Unprotected Cyclic Carboxyimides

Abstract

Asymmetric catalytic transformations of N-unprotected cyclic carboxyimides such as succinimides, hydantoins, oxazolidinediones, and glitazones, is a powerful way of directly accessing variety of biologically valuable chiral compounds. Herein, a bis(trichlorosilyl) nucleophilic intermediate formed from cyclic carboxyimides was reacted with aldehydes via (S)-SEGPHOS dioxide (SEGPHOSO), proceeding the aldol reaction in highly enantioselective fashion through a cyclic transition state. Furthermore, N-unprotected carboxyimides were chemoselectively activated, even in the presence of N-alkylated carboxyimides, to undergo stereoselective and chemoselective aldol reactions via in situ silicon tetrachloride activation. The functionalized cyclic carboxyimides is readily derived to the several synthetic units derivatization to various chiral building blocks without unnecessary protection/deprotection steps.

Catalytic Asymmetric Synthesis of α-Mono and α,α-Disubstituted 5- and 6-Membered α-Aza-lactams

“…In 2023, Kotani and Nakajima 23 documented the direct nucleophilic activation of N -unprotected cyclic carboxyimides 89 , including succinimides, oxazolidinediones, thiazolidinediones (glitazones), and hydantoins, via in situ NH protection and generation of trichlorosilyl enol ethers upon reaction with SiCl 4 and subsequent enantioselective aldol reactions catalyzed by a chiral phosphine oxide (Scheme 16 ). Control experiments proved that this method presented high chemoselectivity for the activation of N -unprotected cyclic carboxyimides as the corresponding N -methyl analogues did not react under similar conditions.…”

“…Scheme23 Chiral organophosphoric acid catalyzed sequential coupling/rearrangement involving 1,2-diketo ester hydrates 124 and 1,2diamines that leads to piperazinones 126…”

Chiral Quaternary Ammonium Salt‐Catalyzed Enantioselective Addition Reactions of Hydantoins

“…Nevertheless, it is fair to say that enantioselective variants are still rare, especially those where the configuration of the tetra-substituted stereogenic center is controlled in the CÀ C bond forming step. [25] Very recently, Keenan, Jean, and Arseniyadis reported the alkylation of hydantoins 1 under mild biphasic conditions using quaternary ammonium salt (Q + X À ) phase-transfer catalysts (PTCs). [24] Besides developing a highly efficient racemic protocol for reactions of compounds 1 with various alkyl halides and Michael acceptors, first attempts towards an asymmetric variant by using chiral Q + X À derivatives were carried out too.…”

“…Considering the general value of (chiral) hydantoins, it comes as no surprise that the development of (asymmetric) reaction protocols to access (enantioenriched) hydantoins 1 or 2 emerged as an important task. [4,5.9–26] Besides valuable strategies to construct the heterocyclic motive itself, like the Biltz, [9,26] the Bucherer‐Bergs, [10] the Urech, [11] or the Read synthesis, [12] also classical α‐functionalizations of preformed non‐ or mono‐substituted hydantoins have been established to access structurally diverse α‐(di)substituted hydantoins ( Scheme 1 A ) [13–25] . Various types of C‐electrophiles have been successfully utilized to access hydantoins 2 .…”

“…Various types of C‐electrophiles have been successfully utilized to access hydantoins 2 . Nevertheless, it is fair to say that enantioselective variants are still rare, especially those where the configuration of the tetra‐substituted stereogenic center is controlled in the C−C bond forming step [25] …”