Visible-light mediated catalytic asymmetric radical deuteration at non-benzylic positions

Site- and enantioselective incorporation of deuterium into organic compounds is of broad interest in organic synthesis, especially within the pharmaceutical industry. While catalytic approaches relying on two-electron reaction manifolds have allowed for stereoselective delivery of a formal deuteride (D–) or deuteron (D+) at benzylic positions, complementary strategies that make use of one-electron deuterium atom transfer and target non-benzylic positions remain elusive. Here we report a photochemical approach for asymmetric radical deuteration by utilizing readily available peptide- or sugar-derived thiols as the catalyst and inexpensive deuterium oxide as the deuterium source. This metal-free platform enables four types of deuterofunctionalization reactions of exocyclic olefins and allows deuteration at non-benzylic positions with high levels of enantioselectivity and deuterium incorporation. Computational studies reveal that attractive non-covalent interactions are responsible for stereocontrol. We anticipate that our findings will open up new avenues for asymmetric deuteration.

Site-and enantioselective incorporation of deuterium into organic compounds is of broad interest in organic synthesis, especially within the pharmaceutical industry. While catalytic approaches relying on two-electron reaction manifolds have allowed for stereoselective delivery of a formal deuteride (D -) or deuteron (D + ) at benzylic positions, complementary strategies that make use of one-electron deuterium atom transfer and target nonbenzylic positions remain elusive. Here we report a photochemical approach for asymmetric radical deuteration by utilizing readily available peptide-or sugar-derived thiols as the catalyst and inexpensive deuterium oxide as the deuterium source. This metal-free platform enables four types of deuterofunctionalization reactions of exocyclic olefins and allows deuteration at nonbenzylic positions with high levels of enantioselectivity and deuterium incorporation. Computational studies reveal that attractive non-covalent interactions are responsible for stereocontrol. We anticipate that our findings will open up new avenues for asymmetric deuteration.
Deuterium is a stable and non-radioactive isotope of hydrogen and deuterium-labeled compounds are widely used in a broad range of disciplines [1][2][3][4][5][6] . While some applications need deuterated compounds with high overall deuterium content without considering site-and stereoselectivity, others require deuteration at a distinct position and/or in a stereoselective manner. In the pharmaceutical industry, for example, site-and enantioselective incorporation of deuterium into drug molecules can slow down drug metabolism and potential epimerization of stereocenters, among other benefits, thereby improving drug efficacy 6 . Approval of the first deuterated drug, deutetrabenazine, by the US Food and Drug Administration in 2017 has further spurred the development of novel deuteration methods. While considerable progress has been made on regioselective nonasymmetric deuteration [2][3][4] , asymmetric deuteration remains underexplored. In this regard, protocols employing enantioenriched starting materials have emerged, allowing for stereoretentive hydrogen isotope exchange [7][8][9][10][11] and highly diastereoselective deuteration 12,13 . In contrast, catalytic asymmetric deuteration approaches using prochiral or racemic substrates are still limited, mainly due to the challenges associated with identifying a chiral catalyst capable of binding with the commonly used deuterating reagents such as deuterium gas, deuterium oxide, and deuterated solvents. While the use of chiral transition metal complexes [14][15][16][17] , enzymes [18][19][20] , and small-molecule catalysts such as chiral phosphoric acids 21-23 have met with some success, deuterations are mostly restricted to benzylic positions in these studies. Moreover, from a mechanistic perspective, the deuteration event in the existing approaches typically proceeds through a two-electron manifold where the deuterium atom is introduced to stereocenters as a formal deuteride (D -) or deuteron (D + ) (Fig. 1a), with notable exceptions being disclosed recently in the deuterium labeling experiments of Hyster's 18,19 and Jiang's 23 work, where a radical deuteration pathway 24 is operative when a deuterated enzyme cofactor or deuterated Hantzsch ester is utilized as the deuterium source.
Motivated by the growing interest in merging asymmetric organocatalysis with photocatalysis [25][26][27][28][29][30][31][32] and in view of the paucity of practical methods for asymmetric radical deuterations, we recently questioned whether a photocatalytic radical deuteration could be achieved in a highly enantioselective and cost-effective fashion. In particular, we hypothesized that a combination of chiral thiols with deuterium oxide (D 2 O) might be a potential solution, given the widespread use of achiral thiols as a catalyst for non-asymmetric radical deuteration 4,33-36 and the encouraging stereocontrol that chiral thiol catalysts exerted in a handful of prior work [37][38][39][40] . Additionally, the following features make this strategy promising: 1) uncatalyzed background deuteration-a common issue when carbon anions are involved-would be inhibited as prochiral carbon radicals are virtually unreactive towards D 2 O due to the high bond dissociation energy (BDE) of the O-D bond (119 kcal/mol for HO-H bond) 24,41 , 2) deuterium atom would be covalently bonded to the chiral thiol catalyst through facile in-situ hydrogen/deuterium exchange 4 , thereby enhancing enantiofacial discrimination for the deuteration event. If successful, this strategy would not only introduce a complementary and mechanistically distinct approach to construct deuterated stereocenters, but also enable asymmetric deuteration in a metal-free manner, a feature that would be appealing to the pharmaceutical industry.
Herein, we report a photochemical approach for catalytic, asymmetric radical deuteration at non-benzylic positions in the context of deuteroboration, deuterosilylation, deuterophosphinoylation, and deuterodifluoroalkylation of exocyclic olefins using inexpensive D 2 O and readily available thiol catalysts derived from peptides or sugars (Fig. 1b).

Reaction development
During our investigations on photoinduced hydroalkylation of olefins under the joint catalysis of Lewis base-borane and thiol 42 , we serendipitously observed the addition of N-heterocyclic carbene (NHC)-BH 3 complex 43,44 1a onto olefins. While photoinduced hydroboration of olefins using NHC-BH 3 complexes have been disclosed recently by several groups [45][46][47][48][49] , asymmetric version of the reaction remains unexplored. We thus chose the reaction of 1a and exocyclic olefin 2a as a model reaction to evaluate our hypothesis using chiral thiols that are easily prepared from comercially available chiral sources such as sugars, amino acids, and peptides (Table 1). While Roberts have shown that sugar-derived thiols such as S1 are competent catalysts for radical hydrosilylation of olefins under thermal conditions, only a single product with high enantiomeric ratio (97.5:2.5 er) was obatained using a sterically very demanding substrate, with low to moderate enantioselectivity for all the other substrates 37 . We started our investigation by using S1 as the deuterium atom transfer (DAT) catalyst and readily available 4DPAIPN as the organophotocatalyst in a binary solvent mixture of toluene and D 2 O (3:1) at 10°C. While the desired product 3a was obatined in 56% yield with 96% D upon isolation, a very low er was observed (entry 1). Other chiral pool-derived thiols such as S2-S4 also provided the product in almost racemic form (entries 2-4). To our delight, when cysteine-derived β-turn-containing peptidic thiol S5, which was recently developed by Miller and Knowles for the deracemization of ureas 39 , was tested under our conditions, 3a was obatined in 67% yield with 93:7 er and high levels of deuterium incorporation (94% D) at the α-N position (entry 5). Thiol S6 with a leucine unit gave same er but lower yield of 3a while thiol S7 with a cyclopropane moiety provided slightly lower er (entries 6 and 7). We then examined the influence of D 2 O on the reactivity and enantioselectivity of the reaction. Increasing the amount of D 2 O (toluene:D 2 O = 1:1) significantly lowered the yield of 3a but increased the deuterium incorporation to 97% (entry 8). In contrast, decreasing the amount of D 2 O (toluene:D 2 O = 4:1) had negnigible influence on the reaction yield but diminished the deuterium incorporation to 90% (entry 9). Interestingly, the enantioselectivity reamined the same under these conditions. However, when the reaction was carried out in the absence of D 2 O, the er dropped to 88:12, although the reaction efficiency was maintained (entry 10). Extending the reaction time to 72 h further improved the yield of 3a to 73% (entry 11). Importantly, control experiments confirmed that the photocatalyst, visible light, and the thiol are essential for the reaction (entries [12][13][14].

Reaction scope
With the optimized conditions in hand, the scope and limitations of the deuteroboration reaction was explored (Fig. 2a). NHC boranes with various substituents on nitrogen and 1,2,4-triazol-5-ylidene borane all underwent the reaction smoothly, providing the desired products 3a-3h in good yields with high levels of deuterium incorporation and with er ranging from 89:11 to 94:6. Other Lewis baseborane complexes such as Ph 3 P-BH 3 and DMAP-BH 3 were evaluated but no reactivity was observed under the current conditions. In addition to 2-oxazolidinone-based olefins, exocyclic olefins on 2-piperidinones and 2-pyrrolidinones are also viable substrates, furnishing the corresponding products 3i-3p in 57-74% yield with er up to 97:3. Interestingly, high resolution mass spectra (HRMS) analysis indicated that the BH 2 moieties in all these products were also partially deuterated. We also briefly examined the deuterosilylation       37 . Under room temperature, the reaction of triphenylsilane with 2a in the presence of S5 afforded the desired product 4a in 85% yield with 89% D and 88:12 er (Fig. 2b). The er was improved to 92:8 upon using S7 as the thiol catalyst. To demonstrate the practicality of the reaction, we scaled up the reaction with lower catalyst loadings and 1.08 gram of 4a was obtained with comparable results as that of the small scale reaction. By comparison, the reaction using Roberts' optimal thiol S1 under otherwise identical conditions provided 4a in 70% yield with 96% D but with very low enantioselectivity (46:54 er). Replacing the phenyl group on nitrogen with nbutyl group produced 4b with a decreased er (82:18) while the use of 2-piperidinone-based olefins afforded 4c and 4d in moderate yields with good enantioselectivities. Other silanes such as diphenylmethylsilane, tris(trimethylsilyl)silane, and diphenylmethylsilane were also tolerated (4e-4g). γ-Lactone-based olefin afforded the product 4h in good yield with modest levels of enantioselectivity. 1,1-Disubstituted olefins in acyclic systems were tested but typically gave the corresponding products in racemic form ( Supplementary Fig. 1), in line with the long-standing challenge of controlling the stereoselectivity of acyclic radicals 50  S7 was used instead of S5. c Gram-scale reaction with 4DPAIPN (0.5 mol%) and S7 (10 mol%). d S1 was used instead of S5.
conditions for the synthesis of 4a, the deuterium content of 4a dropped from 90% to~80%, although the yield and enantioselectivity were similar to those of the standard conditions ( Supplementary  Fig. 2). These observations suggest that partial H/D exchange occurred for the D 2 O during the reaction, leading to a decreased deuterium content for the recycled D 2 O. Next, we turned our attention to explore the applicability of this deuteration strategy in other photocatalytic systems. Given the versatile utilities of organophosphorous compounds and the similar bond strength of P-H bond (BDE = 79 kcal/mol for diphenylphosphine oxide) 51 and B-H bond of NHC-boranes (BDE = 74-80 kcal/mol) 43 , we hypothesized that phosphorous-centered radicals might be formed in a similar fashion and engage in alkene deuterophosphinoylation. While inital trials with peptidic thiol catalysts proved fruitless, we were pleased to find that highly enantioselective deuterophosphinoylation could be achieved using a new β-mannose-derived thiol catalyst S8 (Fig. 3a). Using diarylphosphine oxides as the phosphinoyl radical precursor, various methylenelactams and methylenelactones were well tolerated to deliver the desired products 5a-5g in 44-75% yields with good levels of enantioselectivity (94:6->99:1 er). The structure and absolute configuration of 5a was determined to be R using singlecrystal X-ray diffraction. Interestingly, for products 5d and 5f, partial deuteration at the α-P position was also observed. Other phosphorouscentered radical precursors such as diphenylphosphine sulfide and diethyl thiophosphite are also compatible (5h and 5i). Of particular note is that diphenylphosphine borane complex is also a suitable substrate for this transformation, as exemplified by the synthesis of 5j. For deuterophosphinoylation and deuterodifluoroalkylation reactions, the substitutes at the allylic positions were found to be very important as much lower conversions and enantioselectivities were observed using an olefin devoid of such substituents ( Supplementary  Fig. 3

). The reason behind this observation remains unknown and is currently under investigation.
Having demonstrated the generality of this enantioselective deuterofunctionalization strategy for introducing heteroatoms to olefins, we sought to extend it to alkene deuteroalkylation. We chose α-bromodifluoroacetamides as alkyl radical precursors given their widespread applications in radical chemistry and the importance of difluoroalkylated compounds 52 . To our delight, using thiol S8 as the DAT catalyst and Hantzsch ester (HE) as an electron donor, photoreductive deuterodifluoroalkylation reactions ocurred smoothly to furnish gem-difluoroand deuterium-containing products 6a−6e in modest to good yields with high levels of enantioselectivity and deuterium incorporation (Fig. 3b).

Product derivatization
The deuterated products obtained in this study can be easily elaborated to provide versatile chiral building blocks without erosion of enantiopurity and deuterium content (Fig. 4). For example, NHCborane 3a was treated with 2M HCl and pinacol to provide

Mechanistic studies
Subsequently, preliminary mechanistic studies were carried out to shed some light on the mechanism of the reactions. We focused on the deuteroboration reaction of 1a and 2a catalyzed by thiol S5. First, addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) to the reaction mixture completely inhibited the reaction with radical adduct 13 being detected by HRMS (Fig. 5a) 49 , although reductive quenching by 1a is thermodynamically more favorable (Fig. 5b). Intrigued by these observations, we further investigated the influence of water on redox potentials and the quenching rate. While the oxidation potential of S5 and the reduction potential of 4DPAIPN were largely unchanged in the presence of water (Supplementary Figs. 13 and 14), the quenching rate of thiol increased significantly when D 2 O was present (blue line in Fig. 5b), suggesting that D 2 O is not merely a deuterium source in the reaction. As concerted proton−coupled electron transfer (PCET) with water being the the proton acceptor is a very common process in biological systems [56][57][58] , we attributed the increased quenching rate of thiol in the presence of D 2 O to a concerted oxidative PCET process where water is the proton acceptor. In line with this proposal, we observed that the reaction of 1a and 2a was much faster in the presence of D 2 O than in its absence (Supplementary Table 7). Finally, the quantum yield of the reaction of 1a and 2a was determined to be 0.76%, indicating that a radical chainbased mechanism is unlikely. While further mechanistic investigations for the other three types of reactions are currently underway in our laboratory, a plausible mechanism was proposed based on prior work 44,46,59 and our experimental observations (Fig. 5c). Photoexcitation of the photocatalyst (PC) with visible light would produce the excited stated PC * , which oxidizes a thiol catalyst to generate an electrophilic thiyl radical I via a PCET process. A polarity-matched hydrogen atom transfer (HAT) event then occurs between the thiyl radical and a hydridic R-H (R=B, Si or P) bond of the substrate 60,61 . Subsequent radical addition to the olefin furnishes a prochiral and nucleophilic carbon-centered radical III, which undergoes polarity-matched and stereoselective DAT with the in-situ generated deuterated chiral thiol (R * SD) to deliver the desired deuterated product and regenerate the thiyl radical. Finally, single-electron reduction of the thiyl radical by the reduced state of the photocatalyst (PC •-) would regenerate the groundstate photocatalyst and the deuterated thiol after protonation.

Computational studies
To elucidate the origin of enantioselectivity for the DAT step, we performed density functional theory (DFT) calculations at the CPCM(Toluene) PBE0/6-311++G(3d,2p)//ωB97xD/6-31+G(d,p) level of theory using thiol S6 as the catalyst for the reaction of 1a and 2a (Fig. 5d, see Supplementary Information for computational details). After conformation analysis of the peptide catalyst based on Miller's pioneering studies on β-turn-containing tetrapeptides 62,63 , it was found that the approach of the radical adduct in the transition state (TS) is dictated by the C=O···H-N interaction in the backbone (highlighted with blue dash lines). Moreover, the Si and Re faces of the carbon radical interact differently with the peptidic thiol in the transition states due to non-covalent dispersion interactions 64,65 , with TS-Si displaying strong C-H···π interactions between the proline and the phenyl ring of the radical adduct. In contrast, only weak C−H···π interactions are identified in TS-Re. As depicted in the NCI plot and quantified in the distortion/interaction analysis 66 , the interaction between the radical adduct and the thiol catalyst is stronger by 1.6 kcal/mol in TS-Si. In addition, the overall activation energy difference considering entropic contributions is calculated to be 1.3 kcal/mol (ΔΔG ≠ ), corresponding to a theoretical er of 91:9 at 10°C in favor of R enantiomer, which is in close agreement with the experimentally observed sense and magnitude of enantioinduction (93:7 er). In summary, by merging organocatalysis with photoredox catalysis, highly enantioselective radical deuteration at non-benzylic positions has been achieved using peptide-or sugar-derived thiol catalysts and D 2 O. This metal-free approach is uniformly effective for deuteroboration, deuterosilylation, deuterophosphinoylation, and deuterodifluoroalkylation of exocyclic olefins. We anticipate that this catalytic asymmetric deuteration strategy will be applicable to other radical reactions terminated with a hydrogen atom transfer event and will be of guiding significance and practical utility.

General procedure for the deuteroboration of olefins
To an oven-dried 16 × 60 mm vial containing a dry Teflon stir bar were charged with 4DPAIPN (0.8 mg, 0.001 mmol), thiol catalyst S5 (9.0 mg, 0.015 mmol), and NHC-BH 3 1a (22.2 mg, 0.2 mmol). After sequential addition of dry toluene (0.75 mL), D 2 O (0.25 mL), and olefin 2a (17.5 mg, 0.1 mmol), the reaction mixture was flushed with nitrogen gas for two minutes and then the vial was sealed with a cap and parafilm. The vial was placed in a cooling station and a 30 W blue LED (λ max = 441 nm) was then placed at the top of the cooling station, which is connected to a chiller to maintain the temperature of the cooling water at 10°C. The reaction mixture was stirred at 10°C under irradiation with a stirring rate of 400 r/min for 72 h. When the reaction is complete as monitored by thin layer chromatography and gas chromatography-mass spectrometry, CH 2 Cl 2 (10 mL) and H 2 O (5 mL) were added, the organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (10 mL ×3). The combined organic layer was washed with brine and dried over anhydrous Na 2 SO 4 . After filtration and evaporation, the residue was purified by chromatography on silica gel to afford the desired product.

Data availability
All data generated or analyzed during this study are included in this Article and the Supplementary Information and Supplementary Data files. Details about materials and methods, experimental procedures, mechanistic studies, characterization data, computational details, NMR and HPLC spectra are available in the Supplementary Information. Calculated coordinates are available in the Supplementary Data file. Crystallographic data for compounds 3c, 4a, and 5a are available free of charge from the Cambridge Crystallographic Data Centre (CCDC) under reference number 2143290, 2106905, and 2106903, respectively (https://www.ccdc.cam.ac.uk/ structures).