Concerted Amidation of Activated Esters: Reaction Path and Origins of Selectivity in the Kinetic Resolution of Cyclic Amines via N-Heterocyclic Carbenes and Hydroxamic Acid Cocatalyzed Acyl Transfer

Abstract

The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…The biological relevance of chiralalcohols hasdriven the development of many methods for their kinetic resolution (KR), which have been subjected to numerous experimental and theoretical studies. [1][2][3][4][5][6][7][8][9][10][11][12][13] Amonga vailables trategies for the KR of alcohols, chiral 4-dimethylaminopyridine (DMAP) catalyzed KRs are particularly appealingd ue to their operational simplicity,h igh turnover,a nd environmental friendliness. [14][15][16][17][18][19] Studying such reactions computationally not only enriches our understanding of thesep rocesses but also creates opportunities to improvetheir efficiency.…”

Chemoselective Intramolecular Formal Insertion Reaction of Rh–Nitrenes into an Amide Bond Over C−H Insertion

“…The generation of Rh-nitreneh as already been analyzed theoretically, [7a] and we therefore startedo ur calculations from Rh-nitrene (RT). The N + ÀN À ylide intermediate IM cis-C-N possessing a cis-fused diazabicyclic ring system was generated with the lowest activation energy of + 6.9 kcal mol À1 ,c omparedw ith the other possible reactions startingf rom RT,v ia the NÀNb ond-formingt ransition state TS1 cis-C-N .T he following[ 1,2] acyl transfer, [39] which consists of CÀNb ond cleavage, proceeded with ar easonable activation energy (IM cis-C-N !TS2 cis-C-N , + 12.5 kcal mol À1 )t of urnish the amide insertion product PD C-N after dissociation of [Rh 2 (esp-OMe) 2 ]. [40] The bond distances andd ihedrala ngles of PD C-N are consistentw ith the X-ray diffraction data of 2a.A lthought he formation of the trans-fused N + ÀN À ylide species IM trans-C-N and the sequential acyl migration also reached PD C-N , the activation energy of the former step was + 18.5 kcal mol À1 (RT!TS1 trans-C-N ), whichi ndicates that the trans-fused N + ÀN À ylide intermediate is unfavorable.…”

Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights

“…12 These studies concluded that acylation occurred via a concerted 7-membered transition state with concomitant proton transfer guided by the hydroxamic acid and with the α-substituent placed in the axial position. In contrast, other work from our group on the resolution of morpholines with stoichiometric chiral acyl donors and achiral hydroxamic acids was most consistent with a stereochemical model featuring an equatorial substituent of a morpholine.…”