Palladium-Catalyzed Enantiospecific Three-Component Reaction for the Synthesis of 1,2,4-Trisubstituted Homoallylic Alcohols

Abstract

1,2,4-Trisubstituted chiral homoallylic alcohols are valuable intermediates in natural product synthesis and complex molecular architectures; however, their catalytic asymmetric synthesis remains challenging due to the need for precise control of regioselectivity, diastereoselectivity, E/Z geometry, and enantioselectivity. Herein, we report a palladium-catalyzed enantiospecific three-component reaction of aldehydes, borylated allyl acetates, and dimethylzinc for the efficient synthesis of 1,2,4-trisubstituted anti-(Z)-homoallylic alcohols. The present method employs readily accessible chiral borylated allyl acetates and proceeds with high levels of stereochemical control, providing a practical approach to structurally complex homoallylic alcohols.

1. Introduction

Chiral homoallylic alcohols constitute an important class of compounds that serve as key intermediates in the synthesis of a wide range of natural products and biologically active molecules owing to their versatile reactivity and well-defined stereochemical features [1,2,3]. As such, considerable efforts have been devoted to the development of efficient and stereoselective methods for their preparation. To date, a variety of catalytic asymmetric approaches have been reported using chiral Lewis acid or chiral Lewis base catalysts [4,5,6]. In addition, palladium [7], iridium [7], ruthenium [8], or copper [9] catalytic systems have enabled the construction of substituted chiral homoallylic alcohols with high levels of regio-, diastereo-, and enantioselectivity. Furthermore, notable recent examples include chromium-catalyzed asymmetric allylation of aldehydes with alkenes via allylic C(sp³)–H functionalization under photoredox conditions [10] and organophotoredox/nickel-cocatalyzed allylation of allenes [11], which enable access to chiral homoallylic alcohols with high diastereo- and enantioselectivity. While these catalytic methods have significantly expanded the synthetic toolbox for the stereoselective construction of substituted chiral homoallylic alcohols, the synthesis of 1,2,4-trisubstituted chiral homoallylic alcohols remains a formidable challenge due to the need for precise control of regio-, diastereo-, E/Z-, and enantioselectivity. Consequently, examples of such transformations remain limited [12,13,14]. In many cases, high enantioselectivity can be achieved through extensive ligand design and exhaustive screening of chiral ligands. As an alternative to catalytic asymmetric approaches, Aggarwal and co-workers developed an efficient method for accessing highly reactive chiral α-substituted allyl boranes via the reaction of vinyl boranes (9-BBN derivatives) with chiral sulfonium ylides, which undergo aldehyde allylation with excellent stereoselectivity [15]. While this method enables highly stereospecific carbonyl allylation and allows recovery of the chiral sulfide, its reliance on cryogenic conditions (e.g., −100 °C), precise temperature control, and careful stepwise manipulation limits its practical applicability.

We previously reported a palladium-catalyzed three-component reaction for the synthesis of 1,2,4-trisubstituted homoallylic alcohols that proceeds with excellent regio- and diastereoselectivity (Scheme 1) [16]. In this system, a carbonyl allylation reaction is initially performed using a borylated allyl acetate, thereby inherently minimizing regioselectivity issues, followed by sequential coupling with triethylborane. This method effectively circumvents the regioselectivity limitations commonly encountered in conventional allylation reactions. Encouraged by this study, we examined the possibility of extending this transformation to an enantiospecific process via chiral transfer. However, extension to an enantiospecific variant proved challenging as a significant loss of enantiospecificity was observed. This outcome is likely attributable to the slow transmetalation of π-allylpalladium intermediate A with Et₃B, which allows racemization to proceed through a redox pathway, leading to the formation of ent-A. We hypothesized that replacing Et₃B with an organozinc reagent would accelerate the transmetalation step and suppress racemization, inspired by the well-established efficiency of organozinc reagents in palladium-catalyzed umpolung allylation of aldehydes [17].

We herein report a palladium-catalyzed enantiospecific three-component reaction that enables the efficient and highly stereocontrolled synthesis of 1,2,4-trisubstituted anti-(Z)-homoallylic alcohols (Scheme 2). Chiral transfer reactions represent an attractive approach to asymmetric synthesis [18,19]. When optically active starting materials are readily accessible, stereochemical information can be transferred with high fidelity, and the desired products are difficult to obtain by alternative asymmetric methods. In this context, the readily accessible borylated chiral allyl acetates employed herein can be efficiently prepared, for example, via Sharpless–Katsuki asymmetric epoxidation [20].

2. Materials and Methods

Unless otherwise noted, all reactions were carried out in flame-dried glassware under an argon atmosphere. NMR spectra were recorded on Bruker AVANCE NEO 400 spectrometer (Bruker, Yokohama, Japan). Chemical shifts (δ) are reported in ppm from the solvent resonance or tetramethylsilane (TMS) as the internal standard (CDCl₃: 7.26 ppm, TMS: 0.00 ppm). Peak multiplicities are designated by the following abbreviations: s = singlet, d = doublet, q = quartet, m = multiplet, dm = double multiplet, dd = double doublet, dt = double triplet, ddd = double double doublet, ddq = double double quartet, brs = broad singlet, and coupling constants (J) are provided in Hz. ¹³C NMR spectra were recorded on Bruker AVANCE NEO 400 (100 MHz) spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from the solvent resonance as the internal standard (CDCl₃: 77.16 ppm). Some reported spectra in CDCl₃ include minor solvent impurities of water (¹H NMR δ 1.56 ppm) and/or silicone grease (¹H NMR δ 0.07 ppm, ¹³C NMR δ 1.19 ppm), which do not affect product assignments. Flash chromatography was performed with Fuji Silysia PSQ100B (100 μm) (Fuji Silysia, Aichi, Japan). Analytical thin-layer chromatography (TLC) was performed on Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm) (Merk, Darmstadt, Germany). High-resolution mass spectrometry (HRMS) spectral data were obtained on an Agilent 6546 LC/Q-TOF mass spectrometer (Agilent, Tokyo, Japan).

2.1. General Method for Arylation Process

A 20 mL two-necked round-bottom flask was charged with Pd(OAc)₂ (3.37 mg, 0.015 mmol), P(4-CF₃C₆H₄)₃ (14.0 mg, 0.03 mmol), and toluene (0.6 mL). The mixture was stirred at room temperature for 0.5 h, after which a solution of 2 (0.30 mmol) and aldehyde 1 (0.72 mmol) in toluene (0.6 mL) was added via cannula. After addition of dimethylzinc 3 (1 M in DME/Et₂O = 1.8:1, 0.72 mmol), the reaction mixture was stirred at 60 °C for 4 h. After completion, the reaction was diluted with EtOAc (10 mL) and washed successively with saturated aqueous NH₄Cl (2 × 20 mL), saturated aqueous NaHCO₃ (2 × 20 mL), and brine (2 × 20 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 4.

2.2. Characterization Data

anti-(Z)-1,2-Diphenylpent-3-en-1-ol (4a) was obtained as a yellow oil (99% ee of 2a was used. 42.9 mg, 60%, 93% ee, 93% es). ¹H NMR (CDCl₃, 400 MHz) δ 7.25–7.15 (m, 8H), 7.10–7.06 (m, 2H), 5.85 (m, 1H), 5.66 (ddq, J = 1.2, 11.2, 6.8 Hz, 1H), 4.82 (d, J = 7.6 Hz, 1H), 3.90 (dd, J = 7.6, 9.6 Hz, 1H), 2.27 (d, J = 2.4 Hz, 1H), 1.61 (dd, J = 1.6, 6.8 Hz, 3H). Spectroscopic data was consistent with the values reported in the literature [9].

anti-(Z)-1-(4-Trifluoromethylphenyl)-2-phenylpent-3-en-1-ol (4b) was obtained as a yellow oil (99% ee of 2a was used. 56.0 mg, 61% yield, 96% ee, 96% es, R_f = 0.53, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.46 (d, J = 8.0 Hz, 2H), 7.28–7.15 (m, 5H), 7.10–7.06 (m, 2H), 5.92–5.85 (m, 1H), 5.84–5.75 (m, 1H), 4.88 (dd, J = 2.0, 7.2 Hz, 1H), 3.86 (dd, J = 7.6, 9.6 Hz, 1H), 2.34 (d, J = 2.4 Hz, 1H), 1.60 (dd, J = 1.6, 6.8 Hz, 3H). Spectroscopic data was consistent with the values reported in the literature [21].

anti-(Z)-1-(4-Bromophenyl)-2-phenylpent-3-en-1-ol (4c) was obtained as a yellow oil (96.6% ee of 2a was used. 52.3 mg, 55% yield, 89% ee, 92% es, R_f = 0.48, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.35–7.30 (dm, J = 9.2 Hz, 2H), 7.25–7.10 (m, 3H), 7.08–7.00 (m, 4H), 5.87 (ddq, J = 10.8, 9.2, 1.6 Hz, 1H), 5.83–5.74 (m, 1H), 4.78 (dd, J = 2.0, 7.2 Hz, 1H), 3,83 (dd, J = 7.6, 9.6 Hz, 1H), 2.29 (d, J = 2.4 Hz, 1H), 1.62 (dd, J = 1.6, 6.8 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 141.1, 141.0, 131.1, 129.1, 128.72, 128.65, 128.5, 128.4, 126.8, 121.3, 77.6, 52.3, 13.4; HRMS-EI: [M-OH]⁺ calcd for C₁₇H₁₆Br: 299.0430, found: 299.0400.

anti-(Z)-1-(2-Bromophenyl)-2-phenylpent-3-en-1-ol (4d) was obtained as a yellow oil (96.6% ee of 2a was used. 54.1 mg, 57% yield, 93% ee, 96% es, R_f = 0.60, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.54 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 (dd, J = 7.6, 1.6 Hz, 1H), 7.42–7.40 (m, 2H), 7.34–7.29 (m, 3H), 7.23 (tt, J = 7.6, 1.6 Hz, 1H), 7.11 (dt, J = 7.6, 2.0 Hz, 1H), 5.98–5.92 (m, 1H), 5.64 (ddq, J = 11.2, 6.8, 1.2 Hz, 1H), 5.32 (t, J = 3.6 Hz, 1H), 4.20 (dd, J = 10.0, 4.0 Hz, 1H), 2.03 (d, J = 3.2 Hz, 1H), 1.27 (dd, J = 6.8, 1.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 142.14, 141.26, 132.5, 128.94, 128.85, 128.7, 128.3, 128.2, 127.3, 126.82, 126.78, 122.3, 76.7, 47.8, 13.0; HRMS-EI: [M-OH]⁺ calcd for C₁₇H₁₆Br: 299.0430, found: 299.0430.

anti-(Z)-1-(4-Methoxycarbonylphenyl)-2-phenylpent-3-en-1-ol (4e) was obtained as a yellow oil (96.6% ee of 2a was used. 50,6 mg, 57% yield, 89% ee, 92% es, R_f = 0.38, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (dm, J = 8.4 Hz, 2H), 7.22 (tm, J = 8.0 Hz, 4H), 7.17 (dm, J = 7.2 Hz, 1H), 7.06 (dm, J = 7.2 Hz, 2H), 5.89 (tq, J = 10.8, 1.6 Hz, 1H), 5.78 (ddq, J = 10.8, 6.8, 0.8 Hz, 1H), 4.87 (dd, J = 7.2, 2.0 Hz, 1H), 3.88 (s, 3H), 3.87 (dd, J = 9.2, 7.2 Hz, 1H), 2.35 (brs, 1H), 1.60 (dd, J = 7.8, 1.6 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ 167.2, 147.3, 140.9, 129.3, 129.2, 128.9, 128.8, 128.7, 128.4, 126.9, 126.7, 77.9, 52.3, 52.2, 13.4; HRMS (ESI-TOF) [M-OH]⁺ calcd for C₁₉H₁₉O₂: 279.1380, found: 279.1378.

anti-(Z)-1-(4-Methoxyphenyl)-2-phenylpent-3-en-1-ol (4f) was obtained as a yellow oil (99% ee of 2a was used. 34.6 mg, 43% yield, 61% ee, 61% es, R_f = 0.53, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.23–7.17 (m, 2H), 7.16–7.11 (m, 1H), 7.10–7.05 (m, 4H), 6.77–6.72 (m, 2H), 5.93–5.85 (m, 1H), 5.82–5.72 (m, 1H), 4.78 (dd, J = 2.0, 7.6 Hz, 1H), 3,87 (dd, J = 7.6, 10.0 Hz, 1H), 3.76 (s, 3H), 2.21 (d, J = 2.4 Hz, 1H), 1.62 (dd, J = 1.6, 6.8 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 158.9, 141.6, 134.3, 129.9, 128.5, 128.1, 127.9, 126.5, 113.4, 77.8, 55.3, 52.3, 13.4; HRMS (ESI-TOF) [M-OH]⁺ calcd for C₁₈H₂₀O₂: 251.1430, found: 251.1428.

anti-(Z)-2-Phenyl-1-(thiophen-2-yl)pent-3-en-1-ol (4g) was obtained as a yellow oil (96.6% ee of 2a was used. 47.6 mg, 65% yield, 90% ee, 94% es, R_f = 0.51, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.27–7.21 (m, 2H), 7.20–7.12 (m, 4H), 6.82 (dd, J = 3.2, 4.8 Hz, 1H), 6.65 (ddd, J = 0.8, 1.2, 3.2 Hz, 1H), 5.90 (ddq, J = 1.6, 9.2, 11.2 Hz, 1H), 5.80 (m, 1H), 5.11 (dd, J = 2.4, 7.6 Hz, 1H), 3.95 (dd, J = 7.6, 9.6 Hz, 1H), 2.41 (d, J = 2.4 Hz, 1H), 1.68 (dd, J = 1.6, 6.4 Hz, 3H). Spectroscopic data was consistent with the values reported in the literature [9].

anti-(Z)-1-(Furan-2-yl)-2-phenylhex-3-en-1-ol (4h) was obtained as a yellow oil (96.6% ee of 2a was used. 41.1 mg, 60% yield, 87% ee, 91% es, R_f = 0.40, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.33 (dd, J = 0.8, 1.6 Hz, 1H), 7.27–7.20 (m, 2H), 7.20–7.14 (m, 3H), 6.22 (dd, J = 1.6, 3.2 Hz, 1H), 6.06 (d, J = 3.2 Hz, 1H), 5.86 (ddq, J = 1.6, 9.2, 11.2 Hz, 1H), 5.77 (m, 1H), 4.86 (d, J = 7.6 Hz, 1H), 4.17 (dd, J = 7.6, 9.6 Hz, 1H), 2.24 (br s, 1H), 1.68 (dd, J = 1.6, 6.8 Hz, 3H). Spectroscopic data was consistent with the values reported in the literature [9].

anti-(Z)-1-Phenyl-2-(4-fluorophenyl)pent-3-en-1-ol (4k) was obtained as a light yellow oil (91.5% ee of 2b was used. 40.0 mg, 52% yield, 91% ee, 99% es, R_f = 0.60, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.25–7.18 (m, 3H), 7.16–7.12 (m, 2H), 7.05–6.98 (m, 2H), 6.92–6.86 (m, 2H), 5.87 (m, 1H), 5.77 (m, 1H), 4.77 (dd, J = 2.0, 7.6 Hz, 1H), 3.88 (dd, J = 7.6, 9.6 Hz, 1H), 2.24 (d, J = 2.0 Hz, 1H), 1.61 (dd, J = 1.6, 6.8 Hz, 3H). Spectroscopic data was consistent with the values reported in the literature [9].

anti-(Z)-1-Phenyl-2-(4-chlorophenyl)pent-3-en-1-ol (4l) was obtained as a brown oil (93% ee of 2c was used. 49.0 mg, 60% yield, 88% ee, 95% es, R_f = 0.55, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.25–7.19 (m, 3H), 7.18–7.13 (m, 4H), 7.02–6.98 (m, 2H), 5.86 (m, 1H), 5.77 (m, 1H), 4.78 (dd, J = 2.0, 7.6 Hz, 1H), 3.87 (dd, J = 7.6, 9.6 Hz, 1H), 2.27 (d, J = 2.4 Hz, 1H), 1.60 (dd, J = 1.6, 6.4 Hz, 3H). Spectroscopic data was consistent with the values reported in the literature [9].

anti-(Z)-1-Phenyl-2-[4-(trifluoromethyl)phenyl]pent-3-en-1-ol (4m) was obtained as a brown oil (94% ee of 2d was used. 44.1 mg, 48% yield, 93% ee, 99% es, R_f = 0.50, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.46 (d, J = 8.0 Hz, 2H),7.23-7.14 (m, 7H), 5.90 (m, 1H), 5.79 (m, 1H), 4.84 (dd, J = 2.0, 7.2 Hz, 1H), 3.96 (dd, J = 7.6, 9.6 Hz, 1H), 2.23 (d, J = 2.4 Hz, 1H), 1.59 (dd, J = 1.6, 6.8 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 145.7, 141.7, 128.9, 128.8 (q, J_C-F = 31.2 Hz), 128.8, 128.7, 128.2, 127.8, 126.7, 125.3 (q, J_C-F = 3.7 Hz), 124.3 (q, J_C-F = 270.2 Hz), 78.1, 52.0, 13.4; HRMS (ESI-TOF) m/z: [M-OH]⁺ Calcd for C₁₈H₁₆F₃O⁺: 311.1341, found: 311.1432.

anti-(Z)-2-(4-Methylphenyl)-1-phenylpent-3-en-1-ol (4n) was obtained as a yellow oil (75.7% ee of 2e was used. 37.9 mg, 50% yield, 65% ee, 86% es, R_f = 0.57, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.25–7.16 (m, 5H), 7.05–6.96 (m, 4H), 5.91–5.84 (m, 1H), 5.78–5.71 (m, 1H), 4.82 (dd, J = 2.0, 7.2 Hz, 1H), 3.88 (dd, J = 7.2, 10.0 Hz, 1H), 2.28 (s, 3H), 2.23 (d, J = 2.4 Hz, 1H), 1.60 (dd, J = 2.0, 6.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 142.2, 138.4, 136.1, 129.6, 129.2, 128.2, 127.99, 127.96, 127.4, 126.8, 78.2, 51.7, 21.1, 13.3; HRMS-EI: [M-OH]⁺ calcd for C₁₈H₂₀O: 235.1481, found: 235.1487.

anti-(Z)-2-(4-Methoxyphenyl)-1-phenylpent-3-en-1-ol (4o) was obtained as a yellow solid (97% ee of 2f was used. 38.6 mg, 48% yield, 54% ee, 56% es, R_f = 0.49, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.7.25–7.14 (m, 5H), 6.99 (md, J = 8.8 Hz, 2H), 6.75 (md, J = 8.8 Hz, 2H), 5.91–5.83 (m, 1H), 5.80–5.67 (m, 1H), 4.78 (dd, J = 5.2, 2.0 Hz, 1H), 3.85 (dd, J = 4.4, 2.8 Hz, 1H), 3.75 (s, 3H), 2.24 (d, J = 2.4 Hz, 1H), 1.60 (dd, J = 4.8, 2.0 Hz, 3H). Spectroscopic data was consistent with the values reported in the literature [9].

anti-(Z)-2-(4-Methoxyphenyl)-1-phenylpent-3-en-1-ol (4p) was obtained as a yellow solid (96.6% ee of 2a was used. 45.4 mg, 60% yield, 90.5% ee, 94% es, R_f = 0.50, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ 7.24–7.12 (m, 8H), 7.03 (dm, J = 6.8 Hz, 2H), 5.85 (m, 1H), 5.56–5.53 (m, 1), 4.70 (d, J = 7.2 Hz, 1H), 3.77 (dd, J = 7.2, 93.6 Hz, 1H9, 2.24 (s, 1H), 1.98–1.90 (m, 2H), 0.77 (t, J = 7.6 Hz, 3H). Spectroscopic data was consistent with the values reported in the literature [16].

3. Results and Discussion

At the beginning of the optimization studies, we systematically evaluated the effects of ligand, reaction time, and temperature on reaction efficiency and chirality transfer. The results are summarized in

Table 1. Reaction optimization ¹.

Entry	Ligand	Time (h)	4a (%)	ee (%) 2	es (%) 3
1 4	PPh3	4	44	88	88
24	P(4-MeOC6H4)3	6	43	84	84
3 4	P(4-CF3C6H4)3	overnight	44	88	88
4 5	PPh3	4	56	93	93
5 5	P(4-MeOC6H4)3	4	57	93	93
6 5	P(4-CF3C6H4)3	overnight	60	93	93
7 5,6	PPh3	48	26	–	–
8 5	PCyPh2	4	49	92	92

¹ Conditions: 1a (0.72 mmol), 2a (0.3 mmol), 3a (1 M in DME/Et₂O, 0.72 mmol), Pd(OAc)₂ (0.015 mmol), and ligand (0.03 mmol). ² Enantiomeric excess (ee) was determined by HPLC. ³ es (enantiospecificity) = (ee% of product)/(ee% of starting material). ⁴ Non-distilled Me₂Zn (containing LiCl) was used. ⁵ Distilled Me₂Zn (LiCl-free) was used. ⁶ Reaction was performed at 25 °C.

. As a model system, the palladium-catalyzed reaction of 1a with benzaldehyde (2a) and dimethylzinc (3a) was selected for optimization (see Supplementary Materials). Compound 3a was prepared from commercially available MeLi (1 M in DME solution) and ZnCl₂ and used after removal of insoluble LiCl by filtration. An initial examination using PPh₃ afforded 4a in 44% yield with high diastereoselectivity and 88% es (entry 1). When the reaction was conducted using an electron-deficient phosphine ligand, P(4-CF₃C₆H₄)₃, or an electron-donating phosphine ligand, P(4-MeOC₆H₄)₃, the desired product was obtained with comparable levels of chirality transfer (88% es and 84% es, respectively), indicating that the electronic properties of the ligands have only a minor influence on the reaction outcome. Notably, irrespective of the phosphine ligand employed, both the yield and enantiospecificity were improved when distilled 3a was used (entries 4–6). We next investigated the reaction under reduced temperature conditions (25 °C) with prolonged reaction times. However, even after 48 h, the desired product was obtained in only 26% yield, indicating a significant decrease in reaction efficiency at lower temperatures (entry 7). In addition, the reaction mixture became rather complex under these conditions. Furthermore, the use of PCyPh₂, which was employed in our previous study [16], resulted in decreased yield and enantiospecificity (entry 8). It is worth noting that no direct methylation of 1a by 3a was observed under the present catalytic conditions.

Under the optimized conditions, we next explored the applicability to the three-component reaction of 2a and 3a with a range of aldehydes (Scheme 3). The reaction was found to be sensitive to the electronic properties of substituents on benzaldehyde derivatives. For example, 4-(trifluoromethyl)benzaldehyde (1b) furnished the desired product 4b in 61% yield with 96% es, while 4- and 2-bromobenzaldehydes (1c and 1d) afforded the corresponding products 4c and 4d in 55% and 57% yields with 92% and 96% es, respectively, while leaving the bromo substituents intact. In addition, methyl 4-formylbenzoate (1e) furnished the corresponding product 4e with good enantiospecificity. In contrast, a marked decrease in enantiospecificity was observed for electron-rich 4-methoxybenzaldehyde (1f), providing 4f in 43% yield with 61% es. Heteroaryl aldehydes exhibited reactivity comparable to that of aromatic aldehydes. For example, the reaction of 2-thiophenecarboxaldehyde (1g) delivered 4g in 65% yield with 94% es. Similarly, 2-furaldehyde (1h) afforded 4h in 60% yield, albeit with slightly diminished enantiospecificity. Although aromatic aldehydes were generally compatible with the reaction conditions, aliphatic aldehydes failed to afford the corresponding products 4i and 4j.

Next, we examined the scope of borylated allyl acetates to evaluate the influence of the electronic properties of the aryl groups at the allylic position. Substrates 2b–d bearing electron-withdrawing substituents, such as fluoro, chloro, and trifluoromethyl substituents, were well suited to the present transformation, affording the corresponding products 4k–m with high enantiospecificity. In contrast, substrates bearing p-tolyl and p-methoxyphneyl groups afforded the desired products 4n and 4o with moderate to low enantiospecificity (86% es and 56% es, respectively). Overall, electron-withdrawing substituents on the aryl group at the allylic position promote efficient chirality transfer, whereas electron-donating substituents lead to diminished stereochemical control.

Organozinc reagents were subsequently examined (Scheme 4). When diethylzinc (3b) was used instead of dimethylzinc, the desired product 4p was obtained in 60% isolated yield with 94% es. In contrast, when diphenylzinc (3c), which is more nucleophilic than dimethylzinc, was employed [22], the three-component reaction did not proceed. Instead, phenylation of the benzaldehyde preferentially occurred.

Considering the results of our previous study [16,23], we propose a tentative reaction mechanism, as depicted in Scheme 5. π-allylpalladium intermediate A is generated via oxidative addition of the borylated allyl acetate 2 to a Pd⁰ species. Subsequent transmetalation of A with 3 affords the π-allylpalladium intermediate B, in which the palladium atom coordinates to the aldehyde 1 to form a six-membered cyclic transition state C. Steric repulsion between the B(pin) substituent and PdMeL_n enforces the B(pin) group into a pseudoaxial position. Subsequent umpolung allylpalladation of 1 generates the cis-vinylboronate intermediate D. The alkoxopalladium and cis-vinylboronate moieties in D can undergo intramolecular transmetalation to afford cis-vinylpalladium intermediate F via E. Reductive elimination of Pd species from F furnishes G. Meanwhile, anti-addition of another Pd⁰ species to A generates ent-A, and an equilibrium between A and ent-A forms accounts for the partial erosion of chirality transfer [24]. The decrease in enantiospecificity observed in the presence of lithium chloride (Table 1, entries 1–3) is likely attributable to the formation of an ate complex between lithium chloride and 3. This interaction inhibits coordination of 3 to the acetoxy oxygen atom of A, thereby retarding the transmetalation step and reducing the efficiency of chiral transfer.

4. Conclusions

We have developed a palladium-catalyzed enantiospecific three-component reaction for the synthesis of 1,2,4-trisubstituted chiral anti-(Z)-homoallylic alcohols. By employing readily accessible chiral borylated allyl acetates as starting materials, this strategy provides access to structurally complex homoallylic alcohols with good levels of stereochemical control and offers a useful platform for addressing the challenges associated with regio-, diastereo-, E/Z-, and enantioselective control in allylation reactions of unsymmetrical allylic substrates.