A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction

Abstract

The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon–carbon bonds. Use of prochiral, heteroatom-substituted radicals results in stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin–Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.

Recent advances in visible light-activated radical coupling reactions triggered by (i) ruthenium, (ii) iridium and (iii) organic photoredox agents

“…were achieved by the team of Phipps with an iridium complex by using a chiral Brønsted acid such as TRIP in their reactions (Scheme 144). [184][185][186] This was followed by an investigation to uncover the mechanism of the reaction and in particular, the steps that controlled the stereoselectivity. Reductive cleavage of the phthalimidoylcarboxylates 499, resulted in a carboxyl radical.…”

Identifying the true origins of selectivity in chiral phosphoric acid catalyzed N-acyl-azetidine desymmetrizations

“…18 As such, there has been significant effort deployed toward the computational study of asymmetric CPA-catalyzed reactions over the last decades. 19 Reactions involving imines and other sp 2 -hybridized carbon electrophiles are particularly well-studied experimentally and computationally (including multivariate analysis), 10,[20][21][22][23][24][25][26][27][28][29][30][31][32] yet few qualitative models have been proposed. Notably, Goodman and coworkers compiled an impressive breadth of quantitative computational data to develop their comprehensive qualitative model for imine additions, which focuses on the features making the TS leading to the major product favorable and explains why this arrangement is unfavorable for the minor enantiomer.…”

Hydrogen Atom Transfer-Driven Enantioselective Minisci Reaction of Amides

“…Computational modeling supported this hypothesis and revealed an unexpected internal mode of deprotonation (as shown). 50 In our original work, we utilized redox-active esters (RAEs) derived from N -acetyl amino acids as radical precursors, the reduction of which formed N -acyl, α-amino radicals ( Figure 1 b, upper box). 51 , 52 In addition to providing excellent control of enantioselectivity, the CPA catalyst was able to impart high regioselectivity for the C2 position of the heteroarenes, whereas typically mixtures of regioisomers would be expected in many cases.…”

“…These are unlikely to be conducive to selectivity in our protocol, as experimental and computational studies have firmly established that the N–H functionality plays a crucial role in interacting with the catalyst ( Figure 1 a). 50 Only a handful of HAT-driven Minisci reaction reports contain examples of successful HAT from the α-position of N -acylated primary amines, causing concern that this may be problematic. 61 , 62 We anticipated that a major challenge would be to achieve this in the presence of other abstractable hydrogen atoms.…”

“… 49 , 50 Computational studies demonstrated that deprotonation of the resulting radical cation 33 is the stereodetermining step and occurs through an internal deprotonation mode effected by the amide carbonyl. 50 This proton is rapidly transferred to a new molecule of starting material (not shown) so that the CPA cycle can continue. In accordance with Li and coworkers’ mechanistic evidence, we suspect that the resultant neutral radical 34 is then oxidized by ketyl radical 35 with an accompanied proton transfer, giving the Minisci product together with acetoin as the byproduct.…”