Static to inducibly dynamic stereocontrol: The convergent use of racemic β-substituted ketones

Abstract

The synthesis of stereochemically complex molecules in the pharmaceutical and agrochemical industries requires precise control over each distinct stereocenter, a feat that can be challenging and time consuming using traditional asymmetric synthesis. Although stereoconvergent processes have the potential to streamline and simplify synthetic routes, they are currently limited by a narrow scope of inducibly dynamic stereocenters that can be readily epimerized. Here, we report the use of photoredox catalysis to enable the racemization of traditionally static, unreactive stereocenters through the intermediacy of prochiral radical species. This technology was applied in conjunction with biocatalysts such as ketoreductases and aminotransferases to realize stereoconvergent syntheses of stereodefined γ-substituted alcohols and amines from β-substituted ketones.

Biocatalysis

“…However, the range of reactions compared with those used in organic synthesis is still small and there are some obvious gaps in the repertoire of biocatalytic reactions that are currently being identified, including halogenation, amidebond formation, C-C bond formation and cleavage, ether formation, carbonylation, C=C bond functionalization, isomerization and reduction of isolated C=C bonds 140 . Some of these issues are being addressed by combining chemical and enzymatic reactions 185 . Biocatalysis also offers opportunities to develop reactions that are chemically difficult, such as remote and selective C-H activation, which is often observed in nature 148,178 , but the scale and substrate scope remain limitations for biocatalytic C-H activation 186 .…”

Advances in photo-enzymatic-coupling catalysis system

“…d proposed intermolecular radical hydroalkylation to the synthesis of remote chiral carbonyls enabled by photoinduced catalytic promiscuity of ER catalysis proposed by Huang et al [81] (Copyright Springer Nature). e The method presented by DeHovitz et al for photoinduced promiscuity catalyzing dynamic kinetic resolution reactions of remote static stereocenters [82] (Copyright The American Association for the Advancement of Science) [82] (Copyright The American Association for the Advancement of Science) combination of photo-catalyzed regeneration and enzymatic reaction could have a "1 + 1 < 2" effect because of the catalytic condition mismatch of two processes. In nature, thylakoid offered a blueprint for cascading and regionalization, and a better understanding of natural photosynthesis component integration could be valuable for better design and precise control of this coupled system.…”

“…Biegasiewicz et al changed the catalytic performance of flavin-dependent ene-reductase with the help of light excitation strategy, and the asymmetric free radical cyclization reaction of α-chloroamide catalyzed by the enzyme was realized. Compared with the previously developed asymmetric free [82] radical reaction catalyzed by enzymes, this method unprecedentedly completed the construction of stereoselective C-C bonds, which can be used to stereoselectively synthesize five-to eight-membered β-chiral lactam products [80] ( Fig. 7c, Table 2, entry 3).…”

“…Dynamic kinetic resolution is currently limited to substrates containing traditionally inducible dynamic stereocenters, while most stereocenters in organic chemistry are static. Using similar photoinduced enzyme catalytic promiscuity strategy, DeHovitz et al reported that under the action of photo-redox catalysis, the traditional static and inactive stereocenter (β-substituted ketone) is mediated by prochiral free radical species to achieve racemization [82] (Fig. 7e, Table 2, entry 5).…”

Photo‐biocatalytic Cascades: Combining Chemical and Enzymatic Transformations Fueled by Light

“…More recently, MacMillan, Hyster and co‐workers reported a novel DKR approach based on the photoredox catalyzed racemization of static stereocenters of β‐substituted carbonyl compounds [110] . As indicated by the authors, this strategy could be successfully applied for the DKR of various β‐substituted ketones into corresponding chiral alcohols by combining organo‐ and photoredox catalysis, followed by a final stereoselective enzymatic reduction.…”