Light - driven deracemization enabled by excited - state electron transfer

Abstract

Deracemization is an attractive strategy for asymmetric synthesis, but intrinsic energetic challenges have limited its development. Here, we report a deracemization method in which amine derivatives undergo spontaneous optical enrichment upon exposure to visible light in the presence of three distinct molecular catalysts. Initiated by an excited-state iridium chromophore, this reaction proceeds through a sequence of favorable electron, proton, and hydrogen-atom transfer steps that serve to break and reform a stereogenic C-H bond. The enantioselectivity in these reactions is jointly determined by two independent stereoselective steps that occur in sequence within the catalytic cycle, giving rise to a composite selectivity that is higher than that of either step individually. These reactions represent a distinct approach to creating out-of-equilibrium product distributions between substrate enantiomers using excited-state redox events.

Fig. 1.. Reaction development.

(A) Thermodynamic and kinetic challenges in developing methods for selective deracemization. (B) General, light-driven strategies for achieving out-of-equilibrium deracemization through excited-state redox events. (C) Bach’s report on light-driven deracemization via selective energy transfer. (D) Light-driven deracemization of cyclic ureas by excited-state electron transfer.

Fig. 2.. Discovery of light-driven deracemization

(A) Initial observations. Ir is racemic in all experiments. (B) Postulated mechanism.

Fig. 3.. Reaction optimization and scope studies.

(A) Optimization of reaction conditions. Reactions were performed on 0.025 mmol scale. Yields were determined by ¹H NMR analysis of crude reaction mixtures relative to an internal standard. The er was determined by HPLC analysis on a chiral stationary phase. *10 %m/v of molecular sieves (MS) †5 mol% of disulfide ‡5 %m/v of MS. (B) Reaction scope. Reactions were run at 0.25 mmol scale unless otherwise noted. Yields and er values are for isolated material after purification and are the average of two experiments. In parentheses are yields and er’s obtained on 0.025 mmol scale analyzed by ¹H NMR and HPLC analysis, in which the internal reaction temperature was measured to be 25 °C. §Reaction scale = 0.10 mmol. ¶Reaction time = 12 h. #Reaction scale = 0.025 mmol, NMR yield.

Fig. 4.. Preliminary mechanistic studies.

(A) Free energy profile of light-driven deracemization from rac-2a to (R)-2a. Details included in supplementary materials. (Fig. S3) (B) Time-course studies for deracemization of rac-2a to (R)-2a. (C) Selective stereoinversion of (S)-2a to (R)-2a.