The full paper can be found in Organic Letters.¹

BMS-986142 - Investigational BTK inhibitor (leukemia treatment).

Atroposelective imidation strategy.

Following extensive catalyst optimization, we were able to obtain a selective and specific catalyst, featuring novel and unusual key elements. Here is a sketch of the transformation and the lead catalyst.

Click and drag to rotate, Ctrl+click/Mouse3 to move, scroll/right-click to zoom.

Catalyst conformational dynamism

Lead catalyst converting between its hairpin and folded conformations.

Moving on to the transformation, we devised a large reaction space to be characterized computationally, and we ended up modeling the two reaction steps (addition and elimination) through ten different activation modes across four substrate stereoisomers and two catalyst foldamers, for a total of ~400 transition states. After achieving a solid alignment with the experimental results, we started looking for the selectivity-defining factors. An initial, striking observation we made was that the four productive transition states leading to the two enantiomers of the product all featured topologically different transition states. Each enantiomer of the product is formed via a different diastereoisomer and features a unique activation mode for each of the two reaction steps. Moreover, each enantiomer of the product also has a different rate-determining step!

Productive potential energy surface of the reaction. Energetic data at the M06-2X/def2-QZVP/CPCM(PhCF₃)//R²SCAN-3c/CPCM(PhCF₃) level.

How can we tease apart individual effects in such a complex reaction landscape? By closely inspecting transition state structures, we noticed the importance of the conformation of the unusual difluoroacetyl moiety present in the catalyst. The close contacts between the strongly polarized C(F₂)-H bond and oxygen atoms hinted at the presence of CH-O non-classical hydrogen bonds (2.7-3.1 Å). This group showed the remarkable ability to selectively engage as a bidentate hydrogen bond donor only in the transition states leading to the major enantiomer (S_a), while only acting as monodentate in the disfavored pathway to the minor (R_a). Here you can find some interactive models of the transition states, where you can observe this behavior.

TS1 S_a (major, bidentate difluoroacetamide)

TS1 R_a (minor, monodentate difluoroacetamide)

In the second transition state (TS2, elimination) the situation is the same, and the major enantiomer (S_a) is formed via an activation mode that features bidentate coordination of the difluoroacetamide moiety. The minor enantiomer once again only features monodentate coordination in the transition state (TS2 R_a).

TS2 S_a (major, bidentate difluoroacetamide)

TS2 R_a (minor, monodentate difluoroacetamide)

Conclusions

All the structures in this post can be found in the GitHub repository of this work.

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1. The full paper is now published in Organic Letters. ↩