Science, 369, 1113
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RESEARCH ORGANIC CHEMISTRY Photoredox catalysis has emerged as an enabling platform for regioselective C–Hfunc- Static to inducibly dynamic stereocontrol: tionalization through the generation and har- nessing of reactive carbon-centered radical The convergent use of racemic intermediates toward a variety of syntheti- cally useful bond-forming reactions (15–17). b-substituted ketones The power of photoredox catalysis is high- lighted by its activation of conventionally Jacob S. DeHovitz*, Yong Yao Loh*, Jacob A. Kautzky, Kazunori Nagao, Andrew J. Meichan, inert, remote C–H bonds, enabling the func- Motoshi Yamauchi, David W. C. MacMillan†, Todd K. Hyster† tionalization of C–Hbondsatb-carbonyl (18), b-amino (19), and other unactivated aliphatic The synthesis of stereochemically complex molecules in the pharmaceutical and agrochemical industries C–Hmoieties(20) (Fig. 1B, left). On this basis, requires precise control over each distinct stereocenter, a feat that can be challenging and time we questioned whether we could leverage consuming using traditional asymmetric synthesis. Although stereoconvergent processes have the the photoredox-catalyzed generation of these potential to streamline and simplify synthetic routes, they are currently limited by a narrow scope of planar, prochiral radicals as a stereoablative inducibly dynamic stereocenters that can be readily epimerized. Here, we report the use of photoredox tool for traditionally static stereocenters. catalysis to enable the racemization of traditionally static, unreactive stereocenters through the Subsequent nonstereospecific trapping of intermediacy of prochiral radical species. This technology was applied in conjunction with biocatalysts these carbon-centered radical species by a such as ketoreductases and aminotransferases to realize stereoconvergent syntheses of stereodefined suitable hydrogen atom transfer (HAT) cat- g-substituted alcohols and amines from b-substituted ketones. alyst could then enable the racemization of Downloaded from static stereocenters via the reversible cleav- age and formation of C–H bonds, allowing he concept of static stereocenters is a a number of well-established strategies that the use of substrates with remote, unactivated, fundamental principle that underpins elegantly exploit the capacity for stereogenic static C–H stereocenters in stereoconvergent the induction, application, and teaching racemization or epimerization (Fig. 1A, right). processes. of stereochemistry. The vast majority of In particular, out-of-equilibrium processes, Specifically, we postulated that the direct T http://science.sciencemag.org/ stereocenters are considered to be inher- such as the uphill olefin isomerization shown b-functionalization of saturated cyclic ketones ently static (i.e., once formed, they are stable by Weaver and colleagues (8) and the dera- via the merger of photoredox and organocatalysis toward racemization or epimerization) (Fig. 1A, cemizations detailed by Turner and colleagues could serve as a framework for a method toward left). As a result, the configuration of a stereo- (9) and Knowles, Miller, and colleagues (10), the racemization of b-keto stereocenters through center is generally thought to be intrinsically as well as a litany of dynamic kinetic resolu- the intermediacy of a key 5p e– b-enaminyl coupled to the step in which it was forged, tions (DKRs) have successfully used dynamic radical species (Fig. 1C) (18). In contrast to the requiring each bond-forming step to also bear stereocontrol over the past two decades (11–13). well-precedented DKRs of a-substituted ketones the burden of possessing high levels of kinetic Among these strategies, DKRs rely on the rapid (11), DKRs of b-substituted ketones have re- stereocontrol. This approach to structural interconversion of substrate enantiomers, in mained underdeveloped owing to a lack of complexity has been adopted universally (1–6); combination with stereoselective bond for- general methods for the racemization of static however, alternative strategies wherein bond mation, to transform racemic substrates into b-keto stereocenters. By applying the proposed on October 13, 2020 formation and stereochemical induction are enantio- and diastereomerically pure products photoredox racemization protocol in conjunc- decoupled could prove to be both powerful and (Fig. 1A, right). Such a stereoconvergent ap- tion with a ketoreductase-catalyzed kinetic complementary. proach can substantially simplify the steps resolution, we aimed to achieve a broadly ap- Whereas most of the stereocenters in organic required for complex molecule synthesis by plicable dynamic reductive kinetic resolution chemistry are classified as static, a small cadre effectively decoupling bond formation from of b-substituted ketones to furnish stereode- of structural motifs are amenable to stereo- stereoinduction, as racemic intermediates can fined g-substituted alcohols as products. A chemical interconversion (or stereoablation) be converted to stereochemically pure final crucial design element of this DKR strategy under prescribed reaction conditions. These products. is the inability of alcohol products to form the inducibly dynamic centers typically incorpo- Dynamic kinetic resolutions are nonetheless key b-enaminyl radical intermediate, thereby rate (i) acidic C–H bonds that can undergo currently restricted to substrates that incorpo- precluding the product from undergoing race- reversible deprotonation in the presence of rate traditionally inducibly dynamic stereo- mization after its formation. an appropriate base (e.g., a-carbonyl C–H centers, which constitutes a serious limitation A proposed mechanism for this photoredox- bonds); (ii) a-heteroatom C–H bonds (such given that most stereogenic centers in organic and enzyme-catalyzed DKR of b-substituted as a-hydroxy or a-amino) that can readily chemistry are static. With this in mind, we ketones is outlined in Fig. 2A. For demonstration participate in hydrogen atom transfer (Fig. sought to determine whether it might be feasi- purposes, we have depicted the racemization 1A, right); and (iii) C–heteroatom bonds ble to develop catalytic approaches that would process as the conversion of (S)-1 to the faster that can undergo reversible formation via render traditionally static stereocenters dy- reacting active enantiomer (R)-1.Thisbegins 1,2- or 1,4-addition (e.g., acetals or b-amino namic under mild conditions. In particular, we through the condensation of (S)-1 with amine carbonyls) (7). were interested in combining such racemization catalyst 2 to form stereodefined enamine (S)-3 Although dynamic stereochemistry might protocols with the exquisite stereoselectivity in situ. At the same time, photoexcitation of seem antithetical to the objective of a multi- of enzymes toward molecules with static distal photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)](PF6)(4) step stereoselective synthesis, there have been stereocenters (14) (Fig. 1B, right). Here, we would generate the highly oxidizing excited describe such an advance, wherein we apply state *Ir(III) (5) (half-wave reduction potential red III II Merck Center for Catalysis, Princeton University, Princeton, photoredox catalysis to racemize traditionally E1/2 [*Ir /Ir ]=+1.21Vversusthesatu- NJ 08544, USA. static b-keto stereocenters while successfully rated calomel electrode (SCE) in MeCN) (21). *These authors contributed equally to this work. S 3 †Corresponding author. Email: [email protected] merging this protocol with biocatalysis to This species can then oxidize enamine ( )- •+ (D.W.C.M.); [email protected] (T.K.H.) achieve a dynamic kinetic resolution. (half-peak potential Ep [3/3 ]=+0.36Vversus DeHovitz et al., Science 369, 1113–1118 (2020) 28 August 2020 1of6 RESEARCH | REPORT Downloaded from http://science.sciencemag.org/ on October 13, 2020 Fig. 1. Inducing dynamic stereochemistry for asymmetric synthesis. reactions. R and S indicate the stereochemistry of compounds. (B) Combination (A) Static stereocenters versus inducibly dynamic stereocenters. Red circles of photoredox catalysis and biocatalysis for stereoconvergent reactions. (C) (filled and unfilled) indicate substrates containing static stereocenters. Blue Proposed photoredox- and enzyme-catalyzed dynamic kinetic resolution. Me, circles (filled and unfilled) indicate substrates containing inducibly dynamic methyl; Et, ethyl; iPr, isopropyl; Bn, benzyl; En, enamine; H•, hydrogen atom stereocenters. Blue diamonds indicate products formed from stereoconvergent transfer. SCE in MeCN) (22) to give reduced Ir(II) spe- 76.9 kcal mol−1 (25)]. We expect this HAT PhS–]=–0.06 V versus SCE in MeCN] (26). cies (6) and enaminyl radical cation 7. Sub- event to be nonstereoselective, resulting in the Finally, enamine (R)-3 undergoes hydrolysis sequent allylic deprotonation of 7, due to an gradual racemization of the stereocenter, with to furnish the active enantiomer of the ketone increase in acidity of the allylic C–Hbond,can the formation of the opposite enantiomer of (R)-1. Concurrent with this racemization pro- then provide the nucleophilic 5p e– b-enaminyl the enamine [(R)-3] occurring only 50% of the cess, the ketoreductase-catalyzed stereoselec- radical 8 (23). The formation of this key pro- time. The photoredox and HAT catalytic cycles tive reduction of (R)-1 is constantly occurring chiral radical intermediate ablates the stereo- canthenconvergeinasingle-electrontransfer to furnish enantiopure alcohol 12 as product, chemistry at the b-carbon, and subsequent (SET) event between