Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles

Abstract

We recently reported a chiral phosphoric acid (CPA) catalyzed enantioselective photomediated ring contraction of piperidines and other saturated heterocycles. By extruding a single heteroatom from a ring, this transformation builds desirable C(sp³)-C(sp³) bonds in the ring contracted products; however, the origins of enantioselectivity remain poorly understood. In this work, enantioselectivity of the ring contraction has been explored across an expanded structurally diverse substrate scope, revealing a wide range of enantioselectivities (0-99%) using two distinct CPA catalysts. Mechanistic investigations support rate-determining excitation that generates short-lived achiral intermediates that are intercepted by the CPA in an enantiodetermining ring closure. The effects of competitive uncatalyzed reactivity and light-driven reversibility of the enantiodetermining ring closure on enantioselectivity have been elucidated. Statistical models were built by regressing the range of enantioselectivities from the substrate scope against key structural features of the products for both CPA catalysts. The resultant models suggested distinct factors that influence the enantioselectivity response for each catalyst and enabled rational modification of a pharmaceutically relevant target molecule to improve enantioselectivity. Finally, density functional theory (DFT)-based transition state analysis identified distinct noncovalent interactions with each catalyst that correlated with the unique selectivity-relevant features uncovered through statistical modeling. Our findings not only offer comprehensive insight into the origins of enantioselectivity in this system but should also aid future development of related photomediated CPA-catalyzed reactions.

Figure 1.

(a) Schematic for the photomediated ring contraction of saturated heterocycles. (b) Proposed mechanism. (c) Conceptual outline of this work.

Figure 2.

Scope of enantioselective photomediated ring contractions with (R)-TRIP and (R)-XYL SPA. *Data reported in Science 2021, 373, 1004. ^†Data reported in JACS 2024, 146, 5580. Reactions were performed on 0.05 mmol scale. Isolated yields reported for uncatalyzed reactions. ¹H NMR yields for catalyzed reactions are reported against Ph₃CH internal standard. Diastereomeric ratios were determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. Enantiomeric excess was measured by chiral HPLC or SFC analysis. Reported enantioselectivities are relative to the absolute stereochemistry as drawn for each structure.

Figure 3.

Mechanistic experiments. (a) Reaction order in substrate was obtained by the method of initial rates and determined to be first order. (b) Effect of catalyst loading on initial rates was determined to be negative. (c) Decreasing catalyst loading leads to reduced product enantioselectivity due to competing background reactivity. (d) Linear enantioselectivity response to catalyst enantiopurity. (e) Control experiments with cyclic thiane demonstrating catalyst saturation at 10 mol %.

Figure 4.

Proposed photomediated retro-Mannich pathway for enantiomerization or enantioenrichment of products.

Figure 5.

Statistical models for selectivity trends with (a) (R)-TRIP (PA1) and (b) (R)-XYL SPA (PA2).

Figure 6.

(a) Rational modification of a Rimiterol derivative. Major enantiomeric product with PA1 shown; catalysts give opposite absolute selectivities. (b) Coefficient contributions to predicted ΔΔG^‡ shown for 23.

Figure 7.

Representative reaction energy profile for the enantiodetermining Mannich ring closure affording 1 with PA1 (left, blue) and PA2 (right, green), M06–2X(D3)/6–311+G(d,p)/SMD(benzene)//B3LYP/Def2SVP/SMD(benzene, SAS).

Figure 8.

(a) Major transition state for PA1 with 1 (left); NCIPLOT of key transition state interactions (right). (b) Minor transition state for PA1 with 1 (left); NCIPLOT of key transition state interactions (right). Only intermolecular interactions plotted. Green = weakly attractive, blue = strongly attractive, red = repulsive.

Figure 9.

(a) Major transition state for PA2 with 1 (left); NCIPLOT of key transition state interactions (right). (b) Minor transition state for PA2 with 1 (left); NCIPLOT of key transition state interactions (right). Only intermolecular interactions plotted. Green = weakly attractive, blue = strongly attractive, red = repulsive.

Figure 10.

Stereochemical models for PA1 and PA2. (a) Model for PA1 with model product 1. (b) Model for PA2 with model product 1.