Palladium-Catalyzed Chiral Transfer Three-Component Reaction for the Synthesis of 1,2,4-Trisubstituted 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.[4,5,6,7] In addition, palladium[8], ruthenium[9], iridium[8], or copper catalytic systems[10] have enabled the construction of substituted chiral homoallylic alcohols, allowing precise control over 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[11], as well as organophotoredox/nickel-cocatalyzed allylation of allenes, which enables diastereo- and enantioselective access to chiral homoallylic alcohols.[12] These catalytic methods significantly expand the synthetic toolbox for the stereoselective construction of substituted chiral homoallylic alcohols, although the development of more general, practical, and modular methods with broad substrate scope remains an important challenge. Despite these significant advances, the synthesis of 1,2,4-trisubstituted chiral homoallylic alcohols remains a formidable challenge, as it requires the simultaneous and precise control of regioselectivity, diastereoselectivity, E/Z geometry, and enantioselectivity; consequently, such examples remain limited.[13,14,15,16] In many cases, high enantioselectivity can be achieved through extensive ligand design and exhaustive screening of chiral ligands.

We have previously reported a three-component reaction for the synthesis of homoallylic alcohols that exhibits excellent regio- and diastereoselectivity (eqn 1)[17]. In this approach, carbonyl allylation reaction is initially performed using a borylated allyl acetate, for which regioselectivity concerns are inherently minimized, followed by a sequential coupling reaction with organoboranes. This sequence effectively circumvents the regioselectivity limitations commonly encountered in conventional allylation reactions.

We herein report the extension of this three-component reaction to a chiral transfer reaction for the synthesis of 1,2,4-trisubstituted anti-(Z)-chiral homoallylic alcohol derivatives (eqn 2). Chiral transfer reactions represent an attractive approach to asymmetric synthesis[18] when optically active starting materials are readily accessible, stereochemical information is transferred with high fidelity, and the desired products are difficult to obtain by alternative asymmetric methods. The borylated chiral allyl acetates employed herein can be prepared efficiently, for example, via Sharpless-Katsuki asymmetric epoxidation[19]. Accordingly, their application as starting materials in chiral transfer reactions enables an efficient and highly stereocontrolled synthesis of 1,2,4-trisubstituted anti-(Z)-chiral homoallylic alcohols.

2. Results and Discussion

Initially, we selected the palladium-catalyzed reaction of 1a with benzaldehyde (2a) and dimethylzinc (3) as a model system and commenced optimization of the reaction conditions for the chiral transfer reaction (Table 1). 3 was prepared from commercially available MeLi (1 M in DME sol.) and ZnCl₂ and used after filtration of the insoluble LiCl. The first examine using PPh₃ gave 4aa in 44% yield with high diastereoselectivity and 88% es (entry 1). When the chiral transfer reaction was conducted using an electron-withdrawing ligand, P(4-CF₃C₆H₄)₃, or an electron-donating ligand, P(4-MeOC₆H₄)₃, the desired product was obtained with good chirality transfer of 88% es and 84% es, respectively, indicating that the electronic properties of the ligands had only a minor influence on the reaction outcome. Interestingly, regardless of the phosphine ligand employed, both the product yield and enantiospecificity were improved when the distilled 3 was used (entries 4–6).

Under the optimized conditions, we next explored the applicability of the optimized conditions in the three-component reaction of 2a and 3 with a range of aldehyde electrophiles (Scheme 1). The reaction proved to be sensitive to the electronic nature of substituents on benzaldehyde derivatives. For example, 4-(trifluoromethyl)benzaldehyde (1b) furnished the desired product 4ba in 61% yield with 96% es, while 4-bromobenzaldehyde (1c) afforded 4ca in 55% yield with 92% es. In contrast, a marked decrease in enantiospecificity was observed for electron rich 4-methoxybenzaldehyde (1d), providing the (Z)-enynyl homoallylic alcohol 4da in 43% yield with 61% es. Heteroaryl aldehydes exhibited reactivity comparable to that of aromatic aldehydes. For example, the reaction of 2-thiophenecarboxaldehyde (1e) delivered 4ea in 69% yield with 94% es. Similarly, 2-furaldehyde (1f) afforded 4fa in 69% yield, albeit with slightly diminished enantiospecificity relative to 4ea. Although aromatic aldehydes were generally compatible with the reaction conditions, aliphatic aldehydes failed to afford the corresponding products 4ga and 4ha.

Next, we examined the scope of borylated allyl acetates to evaluate the influence of the electronic nature of the aryl groups at the allylic position. When substrate 2b bearing a p-tolyl group was employed, the desired product 4ba was obtained with moderate chirality transfer (87% es). In contrast, substrates 2c–e bearing electron-withdrawing substituents, such as fluoro, chloro, and trifluoromethyl groups, were well suited to the present transformation, affording the corresponding products 4ac–ae with high levels of chirality transfer. Overall, electron-withdrawing substituents on the aryl group at the allylic position favored efficient chirality transfer, whereas an electron-donating substituent led to diminished stereochemical control

Considering the results of our previous study[19], we propose a tentative reaction mechanism as depicted in Scheme 2. 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 in B coordinates to aldehyde to form a six-membered cyclic transition state C. Steric repulsion between B(pin) substituent and PdMeLn enforces the B(pin) group into a pseudoaxial position. Subsequent umpolung allylpalladation of the aldehyde 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.[21] The decrease in enantiospecificity observed in the presence of lithium chloride (Table 1, entries 1–3) is likely attributable to the formation of a complex between lithium chloride and 3, which inhibits coordination to the acetoxy oxygen atom of A, thereby retarding the transmetalation step and reducing the efficiency of chiral transfer.

3. Materials and Methods

Unless otherwise noted, the reactions were carried out in flame-dried glassware under argon atmosphere. NMR spectra were recorded on Bruker AVANCE NEO 400 spectrometer. 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, t = triplet, q = quartet, m = multiplet, br = broad 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 impact product assignments. Flash chromatography was performed with Fuji Silysia PSQ100B (100 μm). Analytical thin layer chromatography (TLC) was performed on Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm). High-resolution mass (HRMS) spectral data were obtained on an Agilent 6546 LC/Q-TOF mass spectrometer.

3.1. 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 (20 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.

Characterization Data

anti-(Z)-1,2-Diphenylpent-3-en-1-ol (4aa) 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 (dqd, J = 1.2, 6.8, 11.2 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.[10]

anti-(Z)-1-(4-Trifluoromethylphenyl)-2-phenylpent-3-en-1-ol (4ba) 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.[22]

anti-(Z)-1-(4-Bromophenyl)-2-phenylpent-3-en-1-ol (4ca) 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 = 1.6, 9.2, 10.8 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 141.0, 140.8, 131.0, 129.0, 128.5, 128.3, 128.34, 128.28, 126.7, 121.1, 77.5, 52.2, 13.3; HRMS-EI: [M-OH]⁺ calcd for C₁₇H₁₇BrO: 299.0430, found: 299.0400.

anti-(Z)-1-(4-Methoxyphenyl)-2-phenylpent-3-en-1-ol (4da) 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 158.8, 141.4, 134.2, 129.7, 128.3, 128.0, 127.8, 126.4, 113.3, 77.7, 55.2, 52.2, 13.3; 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 (4ea) was obtained as a yellow oil (96.6% ee of 2a was used. 47.6 mg, 65% yield, 90.3% 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.[10]

anti-(Z)-1-(Furan-2-yl)-2-phenylhex-3-en-1-ol (4fa) was obtained as a yellow oil (96.6% ee of 2a was used. 41.1 mg, 60% yield, 87.3% 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.[10]

anti-(Z)-2-(4-Methylphenyl)-1-phenylpent-3-en-1-ol (4ab) was obtained as a yellow oil (75% ee of 2b was used. 37.9 mg, 50% yield, 65.3% ee, 87% es, R_f = 0.57, AcOEt/Hex = 3/7). ¹H NMR (CDCl₃, 400 MHz) δ7.25-7.16 (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)-1-Phenyl-2-[4-(fluoromethyl)phenyl]pent-3-en-1-ol (4ac) was obtained as a light yellow oil (91% ee of 2c was used. 40.0 mg, 52% yield, 91% ee, 96% 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. [10]

anti-(Z)-1-Phenyl-2-[4-(chloromethyl)phenyl]pent-3-en-1-ol (4ad) was obtained as a brown oil (93% ee of 2d 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. [10]

anti-(Z)-1-Phenyl-2-[4-(trifluoromethyl)phenyl]pent-3-en-1-ol (4ae) was obtained as a brown oil (94% ee of 2e was used. 44.1 mg, 48% yield, 92.7% 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.

4. Conclusions

We have developed a palladium-catalyzed chiral transfer three-component reaction that enables the efficient and highly stereocontrolled synthesis of 1,2,4-trisubstituted chiral anti-(Z)-homoallylic alcohols. By employing readily accessible chiral homoallylic alcohol derivatives as starting materials, this strategy circumvents the challenges associated with regioselectivity, diastereoselectivity, E/Z geometry, and enantioselectivity that are inherent to conventional allylation reactions of unsymmetrical allyl alcohol derivatives.