Origin of Stereodivergence in Cooperative Asymmetric Catalysis with Simultaneous Involvement of Two Chiral Catalysts

Abstract

Accomplishing high diastereo- and enantioselectivities simultaneously is a persistent challenge in asymmetric catalysis. The use of two chiral catalysts in one-pot conditions might offer new avenues to this end. Chirality transfer from a catalyst to product gets increasingly complex due to potential chiral match-mismatch issues. The origin of high enantio- and diastereoselectivities in the reaction between a racemic aldehyde and an allyl alcohol, catalyzed by using axially chiral iridium phosphoramidites PR/S-Ir and cinchona amine is established through transition-state modeling. The multipoint contact analysis of the stereocontrolling transition state revealed how the stereodivergence could be achieved by inverting the configuration of the chiral catalysts that are involved in the activation of the reacting partners. While the enantiocontrol is identified as being decided in the generation of PR/S-Ir-π-allyl intermediate from the allyl alcohol, the diastereocontrol arises due to the differential stabilizations in the C-C bond formation transition states. The analysis of the weak interactions in the transition states responsible for chiral induction revealed that the geometric disposition of the quinoline ring at the C8 chiral carbon of cinchona-enamine plays an anchoring role. The quinolone ring is noted as participating in a π-stacking interaction with the phenyl ring of the Ir-π-allyl moiety in the case of PR with the (8R,9R)-cinchona catalyst combination, whereas a series of C-H···π interactions is identified as vital to the relative stabilization of the stereocontrolling transition states when PR is used with (8S,9S)-cinchona.

Perspective: Found in translation: Quantum chemical tools for grasping non-covalent interactions

“…The relevance of NCI for studying large systems has been demonstrated on DNA, proteins, as well as nanotubes, 205,206 polymers, 207 and crystals under high pressure. 208 Moreover, this tool has also been used to explore reactivity, 114,184,209,210 dynamics, 191 and solvation 211 effects. Likewise, DORI has been used to explain the mechanisms of alkylperoxyl radical termination, 212 to investigate the conformational behavior of peptides in different media, 213,214 to design new materials, 215 and has also served as a component of new density functionals.…”

Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Benzyl Acrylates

“…With the hypothesis that these two NCIs contribute to the origin of the stereodiscrimination, we turned to computational analysis of the TS to provide further evidence for these hypotheses. 15b,15c,15e,15f,15h,17,21 …”

Iridium‐Catalyzed Enantioselective Intermolecular Indole C2‐Allylation

“…(1) the C3-methyl substituent causes unfavorable steric congestion due to the close non-bonding hydrogen atom pairs in TS-3 [B(H2···H5) = 2.15 and B(H2···H3) = 2.29 ]a nd (2) TS-2 enables superior p-p stacking between the electron-rich indole ring and the phenyl group of the electrophilic cinnamyl moiety,b oth of which contribute to the lower barrier of the direct C2-allylation pathway (see the Supporting Information for more details). [26] Finally,toexamine how p-stacking,identified in the above DFT studies (illustrated in Figure 1a,c), influences the regioselectivity of the reaction experimentally,a lkyl allylic alcohol 1p,w hich is unable to undergo aryl p-stacking,w as reacted under the standard conditions.T he reaction afforded an ear equal mixture of the C2-product 12 a and N1-product 12 a' ' (42 %and 41 %yield, respectively,Scheme 5) suggesting that the aryl p-stacking plays akey role in controlling the C2regioselectivity when reacting aryl allylic alcohols.B oth products were formed with high enantioselectivity. [27] Thus, at present we are only able to achieve high levels of C2regioselectivity using aryl substituted allylic alcohols.N onetheless,wewere pleased to observe that allylic substitution is still possible under our usual reaction conditions with aliphatic allylic alcohol 1p,g iven that p-allyl complex formation is known to be more challenging for such alcohols compared with the more activated benzylic systems that are the main focus of this study.…”