1. Introduction

Developing a reaction that tolerates different types of substituents is a long-standing target in organic synthesis, especially when the products are important building blocks and/or ubiquitous motifs in bioactive substances. For instance, enantioenriched vinyl-substituted syn-1,2-diols are valuable synthons in synthetic chemistry^[1-5], and widely exist in a range of naturally occurring products and artificial compounds such as paraconiothin J^[6], fuzanin C^[7], xestospongiene R^[8], diasearolide C^[9], and others (Scheme 1a). However, asymmetric catalytic methods for making such units are still underdeveloped. Sharpless asymmetric dihydroxylation (AD) of 1,3-butedienes is the most used approach to achieve the purpose, but the regioselectivity is hard to control when the two substituents are with similar properties (Scheme 1b, eq 1)^[10]. Asymmetric transfer hydrogenation (ATH)^[11-19] has been widely applied to obtain enantioenriched alcohols, and recently we reported that through the ATH of alkyl-substituted vinyl 1,2-diketones and the following diastereoselective reduction, vinyl 1,2-diols could be obtained (Scheme 1b, eq 2)^[20]; the reaction is compatible with only alkyl diketones and two steps are needed. Therefore, a general method that affords chiral vinyl 1,2-diols is still highly desirable. As our continued interest in the exploration of the creative application of 1,2-diketone compounds^[21-26], we report here the CuH-catalyzed asymmetric reduction of vinyl 1,2-diketones that allows access to a variety of vinyl 1,2-diols with high regioselectivity and stereoselectivity^[27-36]. It is noteworthy that although CuH-catalyzed reduction of ketones has been widely studied^[37-46], the reduction of vinyl-substituted 1,2-diketones using Cu-H catalysis has not been previously investigated. More importantly, the method tolerates both aryl and alkyl groups including those with similar steric and electronic properties (Scheme 1c).

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Scheme 1. The importance of vinyl syn-1,2-diols and the related synthetic methods.

2. Experimental Section

General Considerations: Commercially available materials were used as received. Unless otherwise noted, all reactions and manipulations involving air- or moisture-sensitive compounds were performed using standard Schlenk technique. All solvents were purified and dried using typical procedures. Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on a Bruker AVANCE III HD400 (400 MHz) spectrometer, a JEOL ECZ600S (600 MHz) and a JEOL ECZ400S (400 MHz). Chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethylsilane (δ = 0.00 ppm), and chloroform (δ = 7.26 ppm). ¹H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets), m (multiplet), etc. All first-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted are designated as multiplet (m) or broad (br). Carbon nuclear magnetic resonance (¹³C NMR) spectra were recorded on a Bruker AVANCE III HD400 (101 MHz) spectrometer, JEOL ECZ600S (151 MHz) and a JEOL ECZ400S (101 MHz). High resolution mass spectral analysis (HRMS) was performed on a Thermo Fisher Scientific Q Exactive Plus Hybrid Quadrupole-Orbitrap Mass Spectrometer. X-ray crystallography analysis was performed on an Agilent Super Nova X-ray diffractometer. Analytical thin-layer chromatography (TLC) was carried out on a WFH-203 F254 pre-coated silica gel plate (0.2 mm thickness). Visualization was performed using an ultraviolet (UV) lamp alongside staining reagents including 2,4-dinitrophenylhydrazine, potassium permanganate, and phosphomolybdic acid.

2.1 Copper-catalyzed asymmetric hydrosilylation

Copper-Catalyzed Asymmetric Hydrosilylation of (E)-1,4-diphenylbut-3-ene-1,2-dione 1a. An oven-dried screw-cap reaction tube equipped with a magnetic stir bar was charged with Cu(OAc)₂•H₂O (2.0 mg, 0.01 mmol) and ligand L4 (6.7 mg, 0.011 mmol) in a glove box. Anhydrous Et₂O (0.2 mL) and anhydrous MTBE (0.05 mL) were added via syringe. The mixture was stirred at room temperature for 15 min, and (EtO)₂MeSiH (44 μL, 0.275 mmol) was added via syringe. The mixture was stirred at room temperature for 10 min until the color changed from blue to green. Meanwhile, a second oven-dried screw-cap reaction tube equipped with a magnetic stir bar was charged with substrate 1a (23.6 mg, 0.1 mmol), CeCl₃ (12.3 mg, 0.05 mmol), anhydrous Et₂O (0.2 mL), and anhydrous MTBE (0.05 mL). The mixture was stirred at room temperature for 30 min. After this period, the catalyst solution from the first reaction tube was added slowly to the stirred mixture via syringe, and the resulting mixture was stirred at 0 °C for 8 h. Then, a saturated solution of NH₄F in MeOH (1 mL) was added and the mixture was stirred at room temperature for 10 min until the reaction was complete. The reaction mixture was then extracted with CH₂Cl₂ (3 × 15 mL). The combined organic extracts were washed with saturated brine (3 × 20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, v:v = 3:1) to afford the product 2a (colorless oil, 19.7 mg, 82% yield, 7:1 dr, 92% ee). Compound Data: R_f = 0.45 (petroleum ether/ethyl acetate, v:v = 3:1), 92% ee, [α]_D²⁰: -53.0 (c 0.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.34 (m, 4H), 7.33-7.27 (m, 5H), 7.25-7.20 (m, 1H), 6.57 (dd, J = 16.0, 1.3 Hz, 1H), 6.07 (dd, J = 16.0, 5.9 Hz, 1H), 4.60 (d, J = 7.0 Hz, 1H), 4.40 (ddd, J = 7.1, 6.0, 1.4 Hz, 1H), 2.69 (br, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 140.3, 136.6, 132.3, 128.7, 128.6, 128.3, 127.9, 127.6, 127.1, 126.6, 78.0, 76.9. HRMS (ESI-Quadrupole-Orbitrap) m/z: [M + Na]⁺ Calcd for C₁₆H₁₆O₂Na 263.1043; Found 263.1044. High-performance liquid chromatography (HPLC) analysis: 92% ee (Chiralcel IA, 3:97 ⁱPrOH/hexanes, 1 mL/min, 254 nm), R_t (major) = 32.2 min, R_t (minor) = 37.9 min. IR (KBr thin film, cm^-1): ν 3,368, 3,053, 1,494, 1,450, 1,265, 1,195, 1,051, 968, 735, 701, 546.

2.2 Esterification reaction of 2a

Esterification reaction of (1S,2S,E)-1,4-diphenylbut-3-ene-1,2-diol 2a. A 10 mL reaction tube was charged with 2a (24 mg, 0.1 mmol) and DMAP (2.4 mg, 0.02 mmol) at room temperature. CH₂Cl₂ (1 mL) was added via a syringe. Then, Et₃N (42 μL, 0.3 mmol) and 4-chlorobenzoyl chloride (38.5 μL, 0.3 mmol) were added to this tube. The reaction was stirred for 5 h at room temperature. Upon completion, the reaction was quenched with H₂O (1 mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3 × 10 mL) and saturated brine (3 × 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by chromatography (petroleum ether/ethyl acetate, v:v = 2:1) to afford product 3a (white solid, 51.2 mg, 99% yield, 90% ee). Compound Data: R_f = 0.5 (petroleum ether/ethyl acetate, v:v = 2:1), 90% ee, [α]_D²⁰: -120.0 (c 0.05, CHCl₃). ¹H NMR (600 MHz, CDCl₃) δ 7.96 (dd, J = 8.6, 2.4 Hz, 4H), 7.50 (d, J = 7.3 Hz, 2H), 7.39-7.36 (m, 6H), 7.34-7.32 (m, 1H), 7.28-7.25 (m, 4H), 7.24-7.21 (m, 1H), 6.64 (d, J = 15.8 Hz, 1H), 6.29 (d, J = 7.8 Hz, 1H), 6.17 (dd, J = 7.2, 7.2 Hz, 1H), 6.07 (dd, J = 15.9, 7.1 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 164.8, 164.7, 139.9, 136.0, 135.9, 135.4, 131.2, 129.1, 128.9, 128.8, 128.7, 128.5, 128.33, 128.27, 127.8, 126.8, 122.6, 77.3, 76.3. HRMS (ESI-Quadrupole-Orbitrap) m/z: [M + Na]⁺ Calcd for C₃₀H₂₂O₄Cl₂Na 539.0787; Found 539.0782. HPLC analysis: 90% ee (Chiralpak IA, 3:97 ⁱPrOH/hexanes, 1 mL/min, 254 nm), R_t (major) = 26.9 min, R_t (minor) = 31.9 min. IR (KBr thin film, cm^-1): ν 3,368, 2,961, 2,924, 2,312, 1,721, 1,594, 1,488, 1,455, 1,400, 1,258, 1,090, 1,014, 797, 756, 697.

2.3 N-iodosuccinimide (NIS)-mediated annulation of 2b

N-iodosuccinimide (NIS)-mediated annulation of (1S,2S,E)-1-(4-methoxyphenyl)-4-phenylbut-3-ene-1,2-diol 2b. A 10 mL reaction tube was charged with 2b (27 mg, 0.1 mmol, 92% ee) and NIS (24.7 mg, 0.11 mmol) at room temperature under an argon atmosphere. MeCN (0.7 mL) and H₂O (0.7 mL) were added via a syringe. The reaction was stirred for 3 h at room temperature. Upon completion, the reaction was quenched with saturated aqueous Na₂S₂O₃ (1 mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3 × 10 mL) and saturated brine (3 × 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by chromatography (petroleum ether/ethyl acetate, v:v = 2:1) to afford product 3b (white solid, 24.2 mg, 61% yield, 2:1 dr, 99% ee). Compound Data: R_f = 0.25 (petroleum ether/ethyl acetate, v:v = 2:1), 99% ee, [α]_D²⁰: -78.3 (c 0.08, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.50 (m, 2H), 7.43-7.33 (m, 5H), 6.98‒6.90 (m, 2H), 5.53 (d, J = 3.0 Hz, 1H), 5.47 (d, J = 10.2 Hz, 1H), 4.40-4.35 (m, 1H), 4.26 (dd, J = 10.2, 3.4 Hz, 1H), 3.82 (s, 3H), 1.86 (d, J = 1.8 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 159.8, 139.1, 128.69, 128.65, 128.5, 128.1, 126.8, 114.1, 86.8, 83.0, 75.6, 55.4, 36.1. HRMS (ESI-Quadrupole-Orbitrap) m/z: [M + Na]⁺ Calcd for C₁₇H₁₇O₃INa 419.0115; Found 419.0114. HPLC analysis: 99% ee (Chiralpak IA, 3:97 ⁱPrOH/hexanes, 1 mL/min, 254 nm), R_t (major) = 12.2 min, R_t (minor) = 16.6 min. IR (KBr thin film, cm^-1): ν 3,458, 2,957, 2,923, 2,853, 1,613, 1,514, 1,456, 1,259, 1,240, 1,071, 1,014, 843, 795, 703.

2.4 CuH-catalyzed stereoselective hydroamination of 2b

CuH-catalyzed stereoselective hydroamination of (1S,2S,E)-1-(4-methoxyphenyl)-4-phenylbut-3-ene-1,2-diol 2b. An oven-dried screw-cap reaction tube equipped with a magnetic stir bar was charged with Cu(OAc)₂ (1.8 mg, 0.005 mmol) and ligand ent-L2 (6.5 mg, 0.0055 mmol) in a glove box. Anhydrous THF (0.2 mL) was added via syringe. The mixture was stirred at room temperature for 15 min, and methyldimethoxysilane (DMMS, 61.5 μL, 1 mmol) was added via syringe. The mixture was stirred at room temperature for 10 min until the color changed from blue to yellow. Then, 2b (27 mg, 0.1 mmol, 92% ee) was added to the reaction. The mixture was stirred at room temperature for 48 h. Then, a saturated solution of NH₄F in MeOH (1 mL) was added and the mixture was stirred at room temperature for 10 min until the reaction was complete. The reaction mixture was then extracted with CH₂Cl₂ (3 × 15 mL). The combined organic extracts were washed with saturated brine (3 × 20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate, v:v = 2:1) to afford the product 4b (colorless oil, 42 mg, 90% yield, > 20:1 dr). Compound Data: R_f = 0.4 (petroleum ether/ethyl acetate, v:v = 2:1). ¹H NMR (600 MHz, CDCl₃) δ 7.43-7.34 (m, 11H), 7.30-7.28 (m, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 7.0 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 4.44 (d, J = 6.7 Hz, 1H), 4.02 (d, J = 13.0 Hz, 3H), 3.82-3.72 (m, 4H), 3.32 (s, 1H), 2.94 (d, J = 13.0 Hz, 2H), 2.49-2.31 (m, 1H), 1.37 (d, J = 14.0 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 159.3, 138.2, 135.8, 133.0, 129.5, 129.4, 128.9, 128.4, 128.3, 127.9, 127.6, 113.9, 78.1, 77.4, 62.4, 55.3, 54.0, 32.8. HRMS (ESI-Quadrupole-Orbitrap) m/z: [M + H]⁺ Calcd for C₃₁H₃₄O₃N 468.2533; Found 468.2530. [α]_D²⁰: +22.3 (c 0.4, CHCl₃). IR (KBr thin film, cm^-1): ν 3,304, 3,061, 3,026, 2,835, 1,970, 1,610, 1,512, 1,494, 1,452, 1,247, 1,105, 1,028, 831, 746, 697.

3. Results and Discussion

In the reaction optimization section, we selected diphenyl-substituted diketone 1a as the model substrate to evaluate its reactivity under CuH catalysis. As shown in Table 1, the semi-reduction acyloin-type products 3a and 4a are not desired, thus proposing additional challenges. Nevertheless, we employed Cu(OAc)₂, ligand L1, and diethoxymethylsilane (DEMS) to reduce 1a and found that diol 2a was obtained in 46% yield with 5:1 dr and 79% ee, together with a 39% total yield of 3a and 4a (Table 1, entry 1). When copper(I) thiophene-2-carboxylate (CuTc) was used as the catalyst, slightly higher dr and ee of 2a were observed (Table 1, entry 2). Then, we found that Cu(OAc)₂•H₂O was a good precursor to generate an active species in combination with chiral ligand BINAP (L1), which was able to reach high enantioselectivity control (Table 1, entry 3). The solvent screening showed that THF, ⁿhexane, and Et₂O are comparable with toluene (Table 1, entries 4-6), with Et₂O giving the highest ee of 2a (Table 1, entry 6). To further improve the regio- and stereoselectivities, we checked more ligands such as L2-L5 (Table 1, entries 7-10), and L4 stood out with respect to both the yield and ee of the product (Table 1, entry 9). Using L4 as the ligand, we evaluated more solvents such as 1,4-dioxane, CH₂Cl₂, and toluene, but failed to obtain better results (Table 1, entries 11-13). To our delight, using the mixture of Et₂O and methyl tert-butyl ether (MTBE), 2a was formed in high yield with 87% ee, although the dr was 4:1 (Table 1, entry 14). To enhance the dr value, we introduced a Lewis acid. MgF₂ was observed to improve both dr and ee of 2a (Table 1, entry 15), and CeCl₃ was found to deliver 2a with higher 6:1 dr and 90% ee (Table 1, entry 16). The role of CeCl₃ as a Lewis acid to chelate with a dicarbonyl substrate and promote the stereoselectivities of reduction/hydrogenation reactions has been demonstrated in known reports^[47-48]. Adjusting the amount of catalyst/ligand (Table 1, entry 17), the amount of CeCl₃ (Table 1, entry 18), and the ratio of Et₂O/MTBE and the temperature (Table 1, entry 19) led to slightly different results, and finally we identified the optimal conditions by using Cu(OAc)₂•H₂O (10 mol%), CeCl₃ (0.5 equiv), L4 (11 mol%), and 4:1 Et₂O/MTBE at 0 °C, and the vinyl diol 2a was obtained in 82% yield with 7:1 dr and 92% ee (Table 1, entry 20).

Table 1. Optimization of reaction conditions^a.

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entry	cat (mol%)	additive (equiv)	ligand (mol%)	solvent (mL)	temp. (°C)	2a yield (%) dr ee (%)			3a+4a yield (%)
1	Cu(OAc)2 (10)	–	L1 (11)	toluene (0.5)	25	46	5:1	79	39
2	CuTc (10)	–	L1 (11)	toluene (0.5)	25	50	7:1	81	35
3	Cu(OAc)2•H2O (10)	–	L1 (11)	toluene (0.5)	25	48	6:1	82	31
4	Cu(OAc)2•H2O (10)		L1 (11)	THF (0.5)	25	47	6:1	81	39
5	Cu(OAc)2•H2O (10)		L1 (11)	nhexane (0.2)	25	57	5:1	80	33
6	Cu(OAc)2•H2O (10)	–	L1 (11)	Et2O (0.5)	25	49	7:1	83	42
7	Cu(OAc)2•H2O (10)	–	L2 (11)	Et2O (0.5)	25	62	3:1	72	23
8	Cu(OAc)2•H2O (10)	–	L3 (11)	Et2O (0.5)	25	54	6:1	86	30
9	Cu(OAc)2•H2O (10)	–	L4 (11)	Et2O (0.5)	25	85	4:1	86	–
10	Cu(OAc)2•H2O (10)	–	L5 (11)	Et2O (0.5)	25	–	–	–	33
11	Cu(OAc)2•H2O (10)	–	L4 (11)	1,4-dioxane (0.5)	25	40	4:1	86	26
12	Cu(OAc)2•H2O (10)	–	L4 (11)	CH2Cl2 (0.5)	25	42	2:1	70	< 5
13	Cu(OAc)2•H2O (10)	–	L4 (11)	toluene (0.5)	25	67	3:1	83	< 5
14	Cu(OAc)2•H2O (10)	–	L4 (11)	Et2O/MTBE (0.45/0.15)	25	87	4:1	87	< 5
15	Cu(OAc)2•H2O (10)	MgF2 (1)	L4 (11)	Et2O/MTBE (0.45/0.15)	25	77	5:1	89	–
16	Cu(OAc)2•H2O (10)	CeCl3 (1)	L4 (11)	Et2O/MTBE (0.5/0.1)	15	74	6:1	90	<5
17	Cu(OAc)2•H2O (15)	CeCl3 (1)	L4 (16)	Et2O/MTBE (0.5/0.1)	15	58	7:1	91	39
18	Cu(OAc)2•H2O (10)	CeCl3 (0.5)	L4 (11)	Et2O/MTBE (0.5/0.1)	15	73	7:1	90	< 5
19	Cu(OAc)2•H2O (10)	CeCl3 (1)	L4 (11)	Et2O/MTBE (0.8/0.2)	0	63	6:1	90	9
20	Cu(OAc)2•H2O (10)	CeCl3 (0.5)	L4 (11)	Et2O/MTBE (0.4/0.1)	0	82	7:1	92	< 5
21	Cu(OAc)2•H2O (10)	CeCl3 (0.5)	L4 (11)	MTBE (0.5)	0	86	5:1	88	–

^a:All reactions were run on a 0.1 mmol scale under argon atmosphere for 2-8 h; DEMS (2.75 equiv). The diastereomeric ratio was determined via ¹H NMR analysis of the reaction mixtures. All yields were isolated yields. All ee of major product were determined via HPLC analysis on a chiral stationary phase; ^b: 1a and CeCl₃ were stirred for 5 min; ^c: 1a and CeCl₃ were stirred for 30 min; THF: tetrahydrofuran; MTBE: methyl tert-butyl ether; DEMS: diethoxymethylsilane; NMR: nuclear magnetic resonance; HPLC: high-performance liquid chromatography.

With the optimal conditions in hand, we commenced studying the generality and limitations of the method. As displayed in Scheme 2, the R¹ moiety can be both electron-rich and electron-deficient aryl groups, delivering 2b and 2c efficiently with a high level of enantioselectivity (Scheme 2, 2b and 2c). In addition, when R¹ is 2-naphthyl, thienyl, or 3-Me-4-FC₆H₃, the corresponding products were obtained in high yields with 90-96% ee (Scheme 2, 2d-2f). Subsequently, we surveyed the scope of the R² moiety. The use of 2-MeC₆H₄, 4-FC₆H₄, or furyl groups proved compatible with the reaction, generating 2g-2i smoothly (Scheme 2, 2g-2i). Pleasingly, we found that when an alkyl type R² unit was introduced, the reactions proceeded well to produce the related products with high to excellent ee (Scheme 2, 2j-2l). Moreover, the simultaneous variation of both R¹ and R² was also successful. For example, 2m, bearing an aryl and an alkyl substituent, was obtained in 70% yield with a good level of dr and ee (Scheme 2, 2m); diaryl products bearing diverse phenyl substituents such as 2n and 2o were also formed with good results (Scheme 2, 2n and 2o), and the substrate having a terminal alkene unit was able to give 2p in 72% yield with 86% ee (Scheme 2, 2p). In addition, the substrates having trisubstituted alkene moieties were also suitable for the reaction, releasing 2q and 2r with excellent 97% and 99% ee, respectively (Scheme 2, 2q and 2r). We also checked alkyl type R¹ substituents and found that this class of substrates was tolerated under the optimal conditions, delivering 2s and 2t with high to excellent ee values (Scheme 2, 2s and 2t). Additionally, when both R¹ and R² were alkyl groups, the corresponding products were produced with excellent 91-95% ee values (Scheme 2, 2u-2w). Moreover, we tested the substrate containing a NO₂ substituent, a highly electron-withdrawing group, and found that the corresponding product 2x was formed in moderate yield with high dr and ee (Scheme 2, 2x). Finally, we also evaluated the diketone without a vinyl moiety such as 1y, and we were delighted to find that syn-diol 2y was produced in good yield with excellent dr and high ee (Scheme 2, 2y).

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Scheme 2. Substrate scope. ^a: 1 (0.1 mmol), Cu(OAc)₂•H₂O (10 mol%), L4 (11 mol%), CeCl₃ (0.5 equiv), DEMS (2.75 equiv), Et₂O (0.4 mL), MTBE (0.1 mL), 0 °C, 8 h, argon. All yields were of isolated products based on 1; dr values were determined via ¹H NMR analysis of the reaction mixtures; ee values were tested by HPLC; ^b: The reaction was allowed to proceed for 2 h; ^c: The reaction was allowed to proceed for 14 h; ^d: Copper bis(2-ethylhexanoate) (10 mol%), L4 (11 mol%), CeCl₃ (1.2 equiv), DEMS (2.75 equiv), Et₂O (0.4 mL), MTBE (0.1 mL), 0 °C, 8 h, argon. ^eCu(OAc)₂•H₂O (20 mol%), L4 (22 mol%), CeCl₃ (0.5 equiv), DEMS (2.75 equiv), Et₂O (2 mL), MTBE (0.5 mL), CH₂Cl₂ (0.5 mL), 0 °C, 20 h, argon; MTBE: methyl tert-butyl ether; DEMS: diethoxymethylsilane; NMR: nuclear magnetic resonance.

The reaction of 2a with 4-chlorobenzoyl chloride afforded ester 3a, which was determined via single-crystal X-ray diffraction (SCXRD) analysis (Scheme 3a). Furthermore, NIS-mediated annulation of 2b led to the formation of tetrasubstituted tetrahydrofuran 3b and 3b’ with excellent ee values, and their structures were also determined via the SCXRD method (Scheme 3b). The alkene unit within the product could also undergo CuH-catalyzed stereoselective hydroamination to provide amino alcohol 4b (Scheme 3c).

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Scheme 3. Synthetic applications. NIS: N-iodosuccinimide; THF: tetrahydrofuran; CCDC: Cambridge Crystallographic Data Centre.

4. Mechanistic Studies

To gain more mechanistic insights into the reaction, we conducted ¹H NMR monitoring experiments to track the reaction process. As shown in Scheme 4a, the amounts of the mono-reduction products 3a and 4a increased rapidly at the beginning of the reaction but gradually diminished, while the amount of diol 2a kept increasing, indicating that the reaction proceeds through both 3a’ and 4a’ as transient intermediates. To verify this pathway, we subjected the racemic mixture of 3a’ and 4a’ to the standard conditions (Scheme 4b), which afforded 2a (29% yield, 3:1 dr, 81/1% ee) and 4a (41% yield, 97% ee). When the same mixture was treated at room temperature (Scheme 4c), 2a was obtained in 82% yield (3:1 dr, 79/53% ee) alongside 4a (7% yield, 80% ee). These results suggest that at 0 °C a kinetic resolution (KR) operates during the reduction of hydroxyketones 3a’ and 4a’ to diol 2a, but when the reaction is conducted at room temperature (25 °C), a dynamic kinetic resolution (DKR) process occurs.

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Scheme 4. Mechanistic studies. DEMS: diethoxymethylsilane; NMR: nuclear magnetic resonance.

A probable mechanism for the formation of diol 2a is depicted in Scheme 5a. The reaction proceeds via two distinct pathways simultaneously. In the presence of CeCl₃, the copper hydride active species L4-CuH reacts with the carbonyl group of the substrate that is closer to the phenyl ring to give int-I. Int-I then undergoes transmetallation with hydrosilane to give int-II, regenerating L4-CuH. Subsequently, int-II reacts with another equivalent of L4-CuH to give int-III, which undergoes transmetallation with hydrosilane to give the product precursor 2a’, again regenerating L4-CuH to continue the catalytic cycle. On the other hand, in the presence of CeCl₃, the copper hydride species L4-CuH reacts with the carbonyl group proximal to the alkenyl group of the substrate, affording int-IV. Int-IV then undergoes transmetallation with hydrosilane to generate int-V and regenerate L4-CuH. Subsequently, int-V reacts with L4-CuH to form int-VI, which, upon transmetallation with hydrosilane, gives the product precursor 2a’ and regenerates L4-CuH. Finally, 2a’ is quenched with NH₄F to deliver the desired product 2a.

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Scheme 5. Proposed mechanism.

The proposed transition states that rationalize the enantioselectivity are depicted in Scheme 5b. Among them, TS-I, TS-III, TS-V, and TS-VII are sterically accessible and lead preferentially to (S)-3a’, (S)-4a’, and (S,S)-2a’. In contrast, the formation of the (R)-counterparts is disfavored due to unfavorable steric repulsion between the phenyl group of the substrate and the phenyl moieties of the chiral ligand.

5. Conclusion

In summary, the CuH-catalyzed asymmetric reduction of vinyl-substituted 1,2-diketones has been achieved, which allows access to a range of vinyl 1,2-diols with high to excellent enantioselectivities. The method shows good tolerance for both aryl and alkyl groups, although in certain cases the alkyl-substituted substrates afforded only moderate yields. The protocol addresses the challenges encountered in conventional reports. The work also indicates the potential of 1,2-diketones in organic synthesis and will inspire further novel applications of 1,2-diketones.

Supplementary materials

The supplementary material for this article is available at: Supplementary materials.

Authors contribution

Xu C, Shi S, Cui Q: Resources.

Liu J: Validation.

Yang S: Validation, writing-review & editing.

Fang X: Supervision, writing-original draft.

Jiang C, Lan S: Conceptualization, data curation, methodology.

Conflicts of interest

The authors declare no conflicts of interest.

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Not applicable.

Availability of data and materials

The data reported in this paper are available in the main text or supplementary information, including methods, NMR data, HRMS data, HPLC spectra Crystal data and NMR spectra. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2542001 (3a), 2542002 (3b), and 2542003 (3b’).

Funding

This project was supported by the National Natural Science Foundation of China (Nos. 22571300 and 22071242), the Self-deployment Project Research Program of Haixi Institutes, Chinese Academy of Sciences (No. CXZX-2022-GH03), and the supporting program of State Key Laboratory of Structural Chemistry (E555YA4001).

Copyright

© The Author(s) 2026.