Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design, Synthesis, and Application in Asymmetric Steglich Rearrangement

Abstract

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design, Synthesis, and Application in Asymmetric Steglich Rearrangement

“…It should be noted that it was the first asymmetric rearrangement of C(4)-tBu-substituted oxazolyl carbonate.C(4)-phenyl substitution resulted in poor enantioselectivity (entry 13). Them igrating group had been proven to play ap ivotal role in different catalytic systems (entries 1, [14][15][16]. The-CO 2 Bn group could afford ab etter result (entry 1), consistent with the work of Fu et al [17a] The-CO 2 Ph group only afforded am oderate result, for which excellent results were obtained in the work of Smith et al [17h] and in the Chen and Yu group.…”

“…The-CO 2 Bn group could afford ab etter result (entry 1), consistent with the work of Fu et al [17a] The-CO 2 Ph group only afforded am oderate result, for which excellent results were obtained in the work of Smith et al [17h] and in the Chen and Yu group. [17r] Considering the sterically hindered -CO 2 C(Me) 2 CCl 3 or -CO 2 CH 2 CCl 3 group has been achieved with excellent results by Smith et al [17h] and Ooi et al, [17j] respectively,t he rearrangement of -CO 2 C(Me) 2 CCl 3 derivatives 15 o,p were examined, and the C-carboxylated products 16 o,p were obtained with excellent results (entries [15][16].…”

“…Thec atalysts were synthesized from l-prolinamides and 3-bromo-4-nitropyridine N-oxide follow the synthetic route depicted in Scheme 2. [15] Then, chiral DMAP-N-oxides 13 were applied in the asymmetric Steglich rearrangement [16,17] of O-acylated azlactones to their C-acylatedi somers containing aq uaternary stereocenter,w hich served as am odel system for evaluating the efficiencyofchiral acyl transfer catalysts (Table 1). When chiral DMAP-N-oxide 13 a bearing abulky isopropyl group at the ortho positions of the aniline was used, the C-carboxylated product 16 a was generated in 55 %y ield with 77 % ee.…”

Recent Advances in Azlactone Transformations

“…In 2019, aiming to carrying out an asymmetric acyloxy transfer between O ‐substituted azlactones ( 178 ) and their C ‐substituted isomer ( 180 ), Guo and co‐workers synthesized chiral DMAP N ‐oxide catalysts ( 179 ), in which the oxygen atom acts as the nucleophilic site (Scheme A) . It is worth mentioning that the amide group on the catalyst side‐chain was crucial for the stereoinduction, making these DMAP N ‐oxides more effective than the most classical DMAP catalyst employed in the Steglich rearrangement.…”

The Steglich Rearrangement of 2‐Oxindole Derivatives Promoted by Anion‐based Nucleophilic Catalysis

“…The Lewis base‐catalysed Steglich rearrangement involving O ‐ to C ‐acyl transfer in oxazolyl carbonates (and related O ‐acylated benzofuran‐ and ‐oxindole derivatives) has been used as an effective method for generating chiral all‐carbon quaternary stereocentres and as a platform to both demonstrate and evaluate the ability of chiral catalysts to bring about enantioselective acylation . A wide variety of neutral chiral nucleophilic catalysts have been reported to promote the rearrangement, including ( inter alia ) derivatives of 4‐pyrrolidinopyridine (PPY), N,N ‐dimethylaminopyridine (DMAP), chiral phosphines, amidines, isothioureas, N ‐heterocyclic carbenes, chiral thioureas (in conjunction with DMAP), helical poly(quinoxaline‐2,3‐diyl)s bearing achiral aminopyridines, and most recently ‐ a modified DMAP‐ N ‐oxides …”