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. 2020 Dec 16;142(50):21091-21101.
doi: 10.1021/jacs.0c09668. Epub 2020 Nov 30.

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

Kristaps Ermanis  1 , Avene C Colgan  1 , Rupert S J Proctor  1 , Barbara W Hadrys  1 , Robert J Phipps  1 , Jonathan M Goodman  1
Affiliations

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

Kristaps Ermanis et al. J Am Chem Soc. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Overview of the enantioselective Minisci reaction, general mechanistic hypothesis, and key questions at the outset of this work.
Scheme 1
Scheme 1. Competition Experiments To Determine Primary KIE Values
Figure 2
Figure 2
Nonlinear effect studies with the RAE derived from valine, carried out with either 1 mol % or 5 mol % loading of TRIP. Data points are average of two runs. See SI for full details.
Figure 3
Figure 3
(a) Initial mechanistic hypothesis and four computationally identified deprotonation activation modes: QH, BH, AH, and IH. (b) Full reaction pathway energy diagram via the IH activation mode displaying all four diastereomeric addition transition states (I–II TS) and all four diastereomeric deprotonation transition states (II–III TS). All energies relative to the QuinTRIP/radical complex I; M06-2X/def2-TZVPD/SMD(1,4-dioxane)//B3LYP/6-31G**/SMD(1,4-dioxane).
Figure 4
Figure 4
Revised full reaction pathway energy diagram via the computationally identified novel deprotonation mode INT displaying all four diastereomeric addition transition states (I–II TS) and all four diastereomeric deprotonation transition states (II–IV TS). All energies relative to the QuinTRIP/radical complex I; M06-2X/def2-TZVPD/SMD(1,4-dioxane)//B3LYP/6-31G**/SMD(1,4-dioxane).
Figure 5
Figure 5
Rationalizing the stereoselectivity in the INT deprotonation mode. (a) Diastereoselectivity model, (b) enantioselectivity models (front view), and (c) enantioselectivity models (top view).
Figure 6
Figure 6
Comparing the conformational equilibria outside (a) and inside (b) the catalyst pocket. All energies are free energies relative to the lowest energy intermediate conformation; M06-2X/def2-TZVPD/SMD(1,4-dioxane)//B3LYP/6-31G**/SMD(1,4-dioxane).
Figure 7
Figure 7
Additional substrates explored computationally with experimentally observed enantioselectivities, and the computationally located lowest energy deprotonation transition states. The energies quoted are the difference between the lowest energy S and R producing INT transition states, M06-2X/def2-TZVP/SMD(1,4-dioxane)// B3LYP/6-31G**. The enantioselectivity predictions take into account both INT and IH deprotonation modes.
Figure 8
Figure 8
Rationalization of prior experimental observations relating to scope, in the context of the new computational model.
Figure 9
Figure 9
Overview of selectivity control in the CPA-catalyzed Minisci reaction.
See this image and copyright information in PMC

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