Highly Catalytic Enantioselective Reformatsky Reaction with Aldehydes and Ketones Using an Available Prolinol Ligand

Abstract

A highly Me₂Zn-mediated catalytic enantioselective Reformatsky reaction of aldehydes and ketones with ethyl iodoacetate using a readily available prolinol ligand is reported. This reaction provides an efficient method for the construction of β-hydroxy esters in up to 98% yield and 95% enantiomeric excess (ee) value. A wide range of functional groups are tolerated and the practicality of this protocol is demonstrated by performing the reaction on a gram scale.

Introduction

The Reformatsky reaction was first discovered in 1887; it involved the zinc-induced synthesis of β-hydroxy esters through the addition of zinc enolate to aldehydes or ketones.¹ Since its introduction, the Reformatsky reaction has emerged as one of the most widespread strategies for the formation of new carbon–carbon bonds.² To date, various methods based on metal-mediated Reformatsky reactions of α-halo carbonyl compounds with aldehydes or ketones have been widely developed.³⁻¹² Among the reported methods, homogeneous enantioselective Reformatsky-type reactions based on the use of Me₂Zn have been successfully employed to generate chiral β-hydroxy esters.⁴ A breakthrough in the development of Me₂Zn-mediated catalytic enantioselective Reformatsky reactions with aldehydes or ketones as electrophiles has been made by Cozzi and coauthors. Medium yields and high enantioselectivities have been obtained by the use of a chiral amino alcohol ligand for the reaction of aldehydes and chiral [MnCl(salen)] ligands for the reaction of ketones (Scheme 1a).¹³ Feringa and co-workers also have described an efficient catalytic enantioselective Reformatsky reaction with aldehydes and ketones using Binol derivatives as the chiral ligands (Scheme 1b).¹⁴ In 2008, a Me₂Zn-mediated reaction with a Schiff base ligand for an asymmetric Reformatsky reaction of aldehydes was achieved (Scheme 1c).¹⁵ Afterward, ethyl-3-hydroxy-3-phenylpropanoates with up to 80% enantiomeric excess (ee) were produced using a chiral bisoxazolidine ligand (Scheme 1d).¹⁶

Scheme 1. Methods for Catalytic Enantioselective Reformatsky Reactions.

Although breakthrough processes on enantioselective Reformatsky reaction have been made,¹³⁻¹⁶ high yields and excellent enantioselectivity are still an imposing challenge for chemists. Our group has previously developed an efficient asymmetric Michael reaction of aldehydes to nitroalkenes by the use of chiral diphenylperhydroindolinol silyl ethers as catalysts.¹⁷ Hydroindolinol derivatives were found to facilitate the Michael reactions efficiently, providing the corresponding products in good yields and high diasteroselectivities. In addition, a catalytic highly enantioselective aza-Reformatsky reaction with cyclic imines using a chiral diary prolinol ligand was reported.¹⁸ Hence, it is highly desirable to explore a practical protocol for the Reformatsky reaction with both aldehydes and ketones in high yields and excellent enantioselectivities.

Inspired by the reported advances and based on our previous work,¹³⁻¹⁸ we envisioned that since a catalytic enantioselective aza-Reformatsky reaction with imines is feasible, highly enantioselective Reformatsky reactions with aldehydes and ketones using hydroindolinols might represent a possible alternative strategy to realize the construction of β-hydro esters. Fortunately, a highly Me₂Zn-mediated enantioselective Reformatsky reaction with aldehydes and ketones that affords a variety of β-hydro ester derivatives has been developed (Scheme 1e).

Results and Discussion

We began our investigation with the reaction of low-activity 2,3,6-trimethylbenzaldehyde (1a), previously reported in the asymmetric catalytic Reformatsky reaction,^4a,13a with ethyl iodoacetate (2a) in the presence of chiral indolinols, Ph₃P=O (20 mol %), and mediated by Me₂Zn (Scheme 2). Fortunately, our attempts with the use of perhydroindolinols (L1, L2) and indolinols (L3, L4) led to excellent yields and medium to good enantioselectivities. Based on the above-mentioned features reported for the catalytic enantioselective aza-Reformatsky reaction with imines,¹⁸ we then chose a series of chiral prolinols as ligands to study the Reformatsky reaction with aldehydes (L5–L8). To our delight, the reactions using prolinols L1 and L2 gave the products 3a in excellent yields and enantioselectivities.

Scheme 2. Ligand Screening^,,

The reaction was performed using 1a (0.5 mmol), 2 (1.0 mmol), ligand (20 mol %), Me₂Zn (4.0 mol), Ph₃P=O (20 mol %), and Et₂O (5 mL) under air, and stirred at 0 °C for 12 h.

Isolated yields.

ee values were determined by high-performance liquid chromatography (HPLC) with an OD-H column.

Further solvent screening showed that all of the solvents performed the reaction with excellent yields (Table 1, entries 1–10). Among the solvents screened, Et₂O gave rise to the best enantioselectivity (93% ee) (Table 1, entry 10). Further investigation revealed that 40 mol % amount of prolinol (L5) and 8.0 equiv amount of Me₂Zn exhibited the best reaction efficiency and enantioselectivity in up to 95% yield and 96% ee at 0 °C for 12 h (Table 1, entries 11–13).

Table 1. Optimization of Reaction Conditions^a.

entry	solvent	yield / %b	ee / %c
1	THF	90	77
2	Toluene	93	75
3	Hexane	91	63
4	DCM	92	81
5	CH3CN	93	78
6	DCE	92	80
7	MTBE	91	71
8	Xylene	92	75
9	1,2-dichlorobenzene	93	73
10	Et2O	94	93
11	Et2O	94d	93
12	Et2O	95e	96
13	Et2O	93f	90

^aA mixture of 1a (0.5 mmol, 1 equiv), 2 (1.0 mmol, 2 equiv), Me₂Zn (2.0 mmol, 4 equiv), L5 (20 mol %), Ph₃P=O (20 mol %), and solvent (5 mL) was sealed in a 25 mL Schlenk tube at 0 °C for 12 h under air.

^bYields of the isolated product.

^cDetermined by an OD-H column.

^d60 mol % L5 was used.

^e40 mol % L5 and 8.0 equiv Me₂Zn were used.

^fPerformed at −10 °C.

With the optimized conditions established, we next explored the reactivity of different aldehydes (Scheme 3). A series of multisubstituted aryl aldehydes with electron-donating substituents were all well tolerated, giving the obtained products 3a–3e in 88–95% yields with 93–96% ee. Additionally, a variety of dimethyl-substituted aryl aldehydes in the para-, meta-, or ortho-position of the benzene ring were also converted to the corresponding β-hydro esters 3d–3g with high yields (92–95%) and good enantioselectivities (77–91% ee). Moreover, substituents with difluoro-functional groups at the para- or meta-position of the arene proceeded smoothly to afford the Reformatsky reaction products (3h, 3i). Furthermore, substrates with electron-neutral (-H), electron-donating (−Me, CH₃O−), and electron-withdrawing (−F, −Cl, −Br) functional groups at the para- or ortho-position of the phenyl ring were found to be suitable substrates, and the corresponding products were formed in 88–98% yields with 70–84% ee (3j–3q). Of particular note is that substrates with electron-rich groups at 2,6-positions of the arene contributed to the efficiency of high enantioselectivities (3a–3d). Importantly, the heteroaryl substrates were also compatible with this transformation (3r, 3s). Delightfully, the polyarene naphthalene ring substrates could react efficiently, which gave 3t and 3u in 77 and 91% ee, respectively. Notably, an alkenyl-substituted aldehyde could also be employed in this transformation to generate 3v in 91% yield with moderate enantioselectivity, which is currently underway in our laboratory.

Scheme 3. Substrate Scope of Aldehydes^,,

The reaction was performed using 1 (0.5 mmol, 1 equiv), 2 (1.0 mmol, 2 equiv), ligand (40 mol %), Me₂Zn (4.0 mol, 4 equiv), Ph₃P=O (20 mol %), and Et₂O (5 mL) under air, and was stirred at 0 °C for 12 h.

Isolated yields.

ee values were determined by HPLC with an OD-H column.

To further explore the scope of the electrophile substrate, a variety of ketones were examined (Scheme 4). To our delight, excellent yields and good enantioselectivities were obtained with a range of substituents in the para- and ortho-position of the aryl ketones (5a–5e). The introduction of electron-donating (CH₃O−) or electron-withdrawing (−CF₃) as well as halo-functional groups (−F, −Br) does not compromise the efficiency of the Reformatsky reaction (5b–5g). Heterocyclic ketones were also suitable for this transformation (5h, 5i). Note that the naphthalene substituent was tolerated with 93% yield and 81% ee (5j). Importantly, the cyclic aromatic ketones afforded the products 5k and 5l in 93% yield with 82% ee and 90% yield with 92% ee, respectively.

Scheme 4. Substrate Scope of Ketones^,,

The reaction was performed using 4 (0.5 mmol, 1 equiv), 2 (1.0 mmol, 2 equiv), ligand (40 mol %), Me₂Zn (4.0 mol, 8 equiv), Ph₃P=O (20 mol %), and Et₂O (5 mL) under air, and stirred at 0 °C for 12 h.

Isolated yields.

ee values were determined by HPLC with an OD-H column.

To evaluate the potential synthetic utility of this Reformatsky reaction, gram-scale reactions of 1j and 1s were carried out under the standard conditions (Scheme 5). The corresponding desired products 3j and 3s, which are important in synthesis because they serve as useful precursors to (R)-tomoxetine and (R)-duloxetine,¹⁹ were finally isolated in good to excellent yields and enantioselectivities.

Scheme 5. Gram-Scale Reaction Synthesis.

Based on our previous works¹⁷ and the reported literature by Cozzi¹³ and the Feringa group,¹⁴ a similar mechanism for our catalytic cycle was proposed in Scheme 6. Me radicals were first generated from Me₂Zn in the presence of air, and the zinc species played a key role in the high enantioselectivities for the Reformatsky reactions.

Scheme 6. Proposed Reaction Mechanism.

Conclusions

We have presented a practical highly Me₂Zn-mediated catalytic enantioselective Reformatsky reaction of aldehydes and ketones with ethyl iodoacetate using an available chiral prolinol ligand. This procedure provided an efficient method for the construction of β-hydroxy esters in good to excellent yields and enantioselectivities. The synthetic utility of this transformation was demonstrated by performing the reaction on a gram scale, which would extend the potential application of β-hydroxy esters in pharmaceutical and synthetic chemistry.

Experimental Section

General Information

Commercially available reagents were purchased and used without further purification. The starting materials of ethyl iodoacetate, aldehydes, ketones, and prolinols (L5–L8) were commercially available. Indolin ligands (L1–L4) were synthesized as previously reported.¹⁷ Thin-layer chromatography was performed on regular 250 μm silica gel plates using ultraviolet light as a visualizing agent. NMR spectra were recorded using a 400 MHz NMR spectrometer. Chemical shifts were referenced to residual CDCl₃ solvent signals, which referenced at δ_H 7.26 ppm and δ_C 77.16 ppm. Gas chromatography–mass spectrometry (GC–MS) was performed using electron ionization. HPLC analyses were performed using a Chiralcel OD-H, Chiralpak AD-H, or AS-H column (0.46 cm diameter × 25 cm length). Optical rotations were recorded on a PerkinElmer polarimetry.

General Procedures for the Synthesis of Indolin Ligands (L3 and L4)

RMgBr (40 mL; 40 mmol, 4 equiv, 1 M in Et₂O) was added dropwise to a solution of 1-(tert-butyl) 2-methyl (S)-indoline-1,2-dicarboxylate²⁰ (2.77 g, 10 mmol, 1 equiv) in 20 mL of Et₂O at 0 °C and the resulting mixture was stirred at 0 °C for 4 h. Then, the reaction was quenched with a saturated aqueous solution of NH₄Cl and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO₄, and concentrated under vacuum. The residue was used in the next procedure without purification. CF₃COOH (5 mL) was added to the above residue in 20 mL of dichloromethane (DCM) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 12 h. The solvent was then evaporated under vacuum after completion. A saturated aqueous Na₂CO₃ solution was added to neutralize the solution. The aqueous phase was extracted with CH₂Cl₂, washed with brine, dried over MgSO₄, and concentrated under vacuum. The residue was purified on a column chromatograph to afford a pure product.

General Procedure for the Synthesis of β-Hydroxy Esters

In a 25 mL dried single-neck round-bottom flask equipped with a CaCl₂ tube, 50.6 mg of L5 (0.2 mmol, 40 mol%) was added at room temperature. The flask was transferred to 0 °C and 5 mL of Et₂O was added, stirring for 15 min, after which 60 μL of ethyl iodoacetate (0.5 mmol, 1.0 equiv) and 1.7 mL of Me₂Zn (2.0 mmol, 4 equiv, 1.2 M solution in toluene) were added. Subsequently, benzaldehydes or ketones (0.5 mmol, 1.0 equiv) and 27.8 mg of Ph₃PO (0.1 mmol, 20 mol%) were added immediately. After another 15 min, 1.7 mL of Me₂Zn (2.0 mmol, 4 equiv, 1.2 M solution in toluene) and 60 μL of ethyl iodoacetate (0.5 mmol, 1.0 equiv) were added again. The outlet of the other end of the CaCl₂ tube directly contacts the atmosphere so that air could enter into the reaction flask. The resulting solution was stirred for 12 h and quenched by 1 M HCl aqueous after completion and then extracted with Et₂O (5 mL × 2). The combined organic phase was then dried over anhydrous MgSO₄ and concentrated in vacuum. The residue was purified by silica gel flash column chromatography eluting with the mixture of ethyl acetate/petroleum ether (1/10 v/v), which eventually afforded the pure product. The enantioselectivities of the products are determined by a Chiralcel OD-H column.

Procedure for Gram-Scale Synthesis of β-Hydroxy Esters

In a 250 mL dried single-neck round-bottom flask equipped with a CaCl₂ tube, 1.012 g of L5 (4.0 mmol, 40 mol %) was added at room temperature. The flask was transferred to 0 °C, and 100 mL of Et₂O was added. The mixture was stirred for 15 min, after which 1.2 mL of ethyl iodoacetate(10.0 mmol, 1.0 equiv) and 34 mL of Me₂Zn (40.0 mmol, 4 equiv, 1.2 M solution in toluene) were added. Subsequently, benzaldehydes (10 mmol, 1.0 equiv) and 556 mg of Ph₃PO (2.0 mmol, 20 mol %) were added immediately. After another 15 min, 34 mL of Me₂Zn (40.0 mmol, 4 equiv, 1.2 M solution in toluene) and 1.2 mL of ethyl iodoacetate (10.0 mmol, 1.0 equiv) were added again. The outlet of the other end of the CaCl₂ tube directly contacts the atmosphere so that air could enter into the reaction flask. The resulting solution was stirred for 18 h and quenched by 1 M HCl aqueous after completion and then extracted with Et₂O (100 mL × 2). The combined organic phase was then dried over anhydrous MgSO₄ and concentrated in vacuum. The residue was purified by silica gel flash column chromatography eluting with the mixture of ethyl acetate/petroleum ether (1/10 v/v), which eventually afforded the pure product. The enantioselectivities of the products are determined by a Chiralcel OD-H column.

Ethyl-3-hydroxy-3-mesitylpropanoate (3a)

[α]_D²⁰ = −21.8 (c 0.15, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 6.83 (s, 2H), 5.61 (dd, J = 10.6, 2.1 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.05 (dd, J = 16.5, 10.7 Hz, 1H), 2.64 (s, 1H), 2.54 (dd, J = 16.6, 2.3 Hz, 1H), 2.43 (s, 6H), 2.25 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 136.9, 136.1, 134.5, 130.1, 67.5, 60.8, 40.0, 20.7, 20.6, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 208 nm, t_major = 7.819 min, t_minor = 10.562 min, 96% ee.

Ethyl-3-hydroxy-3-(4-methoxy-2,3,6-trimethylphenyl)propanoate (3b)

[α]_D²⁰ = −22.5 (c 0.28, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 6.53 (s, 1H), 5.64 (d, J = 10.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.09 (dd, J = 16.6, 10.6 Hz, 1H), 2.84 (s, 1H), 2.56 (dd, J = 16.6, 3.3 Hz, 1H), 2.41 (d, J = 13.6 Hz, 6H), 2.13 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 156.3, 136.6, 133.9, 129.9, 123.9, 110.8, 67.5, 60.7, 55.4, 40.5, 21.2, 16.7, 14.1, 11.6. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 8.735 min, t_minor = 12.383 min, 94% ee; HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₅H₂₂O₄Na, 289.1410; found, 289.1382.

Ethyl-3-hydroxy-3-(2,3,4,5,6-pentamethylphenyl)propanoate (3c)

[α]_D²⁰ = −11.8 (c 0.44, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 5.82 (dt, J = 10.7, 3.1 Hz, 1H), 4.25 (qd, J = 7.1, 0.8 Hz, 2H), 3.17 (dd, J = 16.6, 10.7 Hz, 1H), 2.91 (d, J = 3.1 Hz, 1H), 2.63 (dd, J = 16.6, 3.2 Hz, 1H), 2.43 (s, 6H), 2.27 (d, J = 9.9 Hz, 9H), 1.34 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 135.1, 134.4, 133.3, 131.8, 68.0, 60.7, 40.5, 17.0, 17.0, 16.6, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 6.894 min, t_minor = 9.474 min, 95% ee. HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₆H₂₄O₃Na, 287.1618; found, 287.1593.

Ethyl-3-(2,6-dimethylphenyl)-3-hydroxypropanoate (3d)

[α]_D²⁰ = −13.5 (c 0.28, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.12–7.06 (m, 1H), 7.02 (d, J = 7.3 Hz, 2H), 5.66 (d, J = 10.6 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.08 (dd, J = 16.5, 10.7 Hz, 1H), 2.99 (s, 1H), 2.58 (dd, J = 16.8, 2.5 Hz, 1H), 2.48 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 137.4, 136.1, 129.4, 127.4, 67.6, 60.8, 39.8, 20.7, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 8.463 min, t_major = 9.276 min, 91% ee.

Ethyl-3-(2,4-dimethylphenyl)-3-hydroxypropanoate (3e)

[α]_D²⁰ = −20.1 (c 0.53, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.99 (s, 1H), 5.38–5.30 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.30 (s, 1H), 2.76–2.62 (m, 2H), 2.34 (d, J = 4.5 Hz, 6H), 1.31 (t, J = 7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 137.5, 137.0, 134.1, 131.1, 126.9, 125.1, 66.7, 60.7, 42.1, 20.9, 18.8, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 10.159 min, t_major = 10.758 min, 87% ee. HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₃H₁₈O₃Na, 245.1148; found, 245.1133.

Ethyl-3-(2,3-dimethylphenyl)-3-hydroxypropanoate (3f)

[α]_D²⁰ = −33.5 (c 0.16, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J = 7.5 Hz, 1H), 7.19–7.10 (m, 2H), 5.44 (dd, J = 8.2, 4.5 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.29 (s, 1H), 2.75–2.65 (m, 2H), 2.32 (s, 3H), 2.26 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 140.4, 136.8, 132.8, 129.1, 125.7, 122.9, 67.2, 60.8, 42.2, 20.5, 14.5, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 9.766 min, t_major = 12.00 min, 82% ee. HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₃H₁₈O₃Na, 245.1148; found, 245.1133.

Ethyl-3-(2,5-dimethylphenyl)-3-hydroxypropanoate (3g)

[α]_D²⁰ = −27.5 (c 0.21, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 6.97 (q, J = 7.7 Hz, 2H), 5.28 (d, J = 9.1 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.40 (s, 1H), 2.68–2.56 (m, 2H), 2.28 (d, J = 11.4 Hz, 6H), 1.24 (td, J = 7.1, 1.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.4, 140.2, 135.5, 130.8, 130.1, 128.0, 125.7, 66.7, 60.6, 42.1, 20.8, 18.3, 13.9. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 9.976 min, t_major = 10.272 min, 77% ee. HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₃H₁₈O₃Na, 245.1148; found, 245.1133.

Ethyl-3-(2,6-difluorophenyl)-3-hydroxypropanoate (3h)

[α]_D²⁰ = −6.4 (c 0.17, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.26 (td, J = 8.2, 4.3 Hz, 1H), 6.95–6.83 (m, 2H), 5.55 (dt, J = 9.4, 4.9 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.26 (d, J = 6.1 Hz, 1H), 3.15 (dd, J = 16.3, 9.5 Hz, 1H), 2.75 (dd, J = 16.4, 4.2 Hz, 1H), 1.26 (td, J = 7.2, 1.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.6, 162.2 (d, J = 8.0 Hz), 159.8 (d, J = 9.0 Hz), 129.7, 117.5, 111.86, 111.8, 111.7, 62.2, 60.9, 40.8, 40.8, 40.8, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 98:2, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 38.572min, t_minor = 41.707 min, 81% ee. HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₁H₁₂F₂O₃Na, 253.0647; found, 253.0633.

Ethyl-3-(2,3-difluorophenyl)-3-hydroxypropanoate (3i)

[α]_D²⁰ = −26.3 (c 0.29, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.32–7.27 (m, 1H), 7.12–7.05 (m, 2H), 5.42 (dd, J = 8.9, 3.4 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.74 (s, 1H), 2.75 (qd, J = 16.5, 6.3 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.1, 150.2 (dd, J = 13.0 Hz, J = 247.0 Hz), 147.3 (dd, J = 13.0 Hz, J = 246.0 Hz), 131.9 (d, J = 10.0 Hz), 124.2 (q, J = 5.0 Hz, J = 7.0 Hz), 121.8 (t, J = 3.0 Hz), 116.2 (d, J = 17.0 Hz), 64.2, 61.0, 41.7, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel AS-H column, hexane/i-PrOH 98:2, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 17.499 min, t_minor = 20.280 min, 66% ee. HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₁H₁₂F₂O₃Na, 253.0647; found, 253.0633.

(S)-Ethyl-3-hydroxy-3-phenylpropanoate (3j)^14a

[α]_D²⁰ = −25.5 (c 0.22, CH₂Cl₂). ¹H NMR (400 MHz,) δ 7.38–7.32 (m), 7.30–7.25 (m), 5.16–5.08 (m), 4.17 (q, J = 7.1 Hz), 3.36 (d, J = 3.4 Hz), 2.78–2.66 (m), 1.25 (t, J = 7.1 Hz).¹³C NMR (100 MHz, CDCl₃) δ 172.3, 142.5, 128.5, 127.7, 125.6, 70.3, 60.8, 43.3, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 11.207 min, t_minor = 12.868 min, 81% ee.

Ethyl-3-hydroxy-3-(p-tolyl)propanoate (3k)

[α]_D²⁰ = −30.1 (c 0.16, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 5.08 (dd, J = 9.0, 3.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.30 (s, 1H), 2.70 (qd, J = 16.3, 6.5 Hz, 2H), 2.33 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.4, 139.6, 137.4, 129.1, 125.6, 70.1, 60.8, 43.3, 21.0, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel AS-H column, hexane/i-PrOH 98:2, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 25.515 min, t_major = 27.005 min, 83% ee.

Ethyl-3-(4-fluorophenyl)-3-hydroxypropanoate (3l)

[α]_D²⁰ = −21.5 (c 0.14, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.31 (m, 2H), 7.07–6.99 (m, 2H), 5.14–5.06 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.39 (d, J = 2.6 Hz, 1H), 2.76–2.64 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.3, 162.3 (d, J = 244 Hz), 138.3, 127.4, 115.3, 69.7, 60.9, 43.3, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 57.433 min, t_major = 59.097 min, 82% ee.

(S)-Ethyl-3-(4-chlorophenyl)-3-hydroxypropanoate (3m).^14a

[α]_D²⁰ = −37.9 (c 0.11, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.33–7.27 (m, 4H), 5.08 (dd, J = 8.2, 4.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.57 (s, 1H), 2.73–2.62 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.1, 141.0, 133.3, 128.6, 127.0, 69.5, 60.9, 43.2, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel AD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 16.849 min, t_minor = 18.165 min, 84% ee.

Ethyl-3-hydroxy-3-(o-tolyl)propanoate (3n)

[α]_D²⁰ = −44.6 (c 0.52, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 7.6 Hz, 1H), 7.19 (ddd, J = 30.6, 15.8, 7.7 Hz, 3H), 5.35 (dt, J = 6.4, 2.9 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.23 (d, J = 2.8 Hz, 1H), 2.73–2.62 (m, 2H), 2.35 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 140.4, 134.2, 130.4, 127.5, 126.4, 125.2, 66.9, 60.9, 42.1, 19.0, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 16.773 min, t_major = 21.200 min, 82% ee.

Ethyl-3-hydroxy-3-(2-methoxyphenyl)propanoate (3o)

[α]_D²⁰ = −42.7 (c 0.46, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.43 (dd, J = 7.5, 1.1 Hz, 1H), 7.28–7.24 (m, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.36 (dd, J = 9.2, 3.6 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.82 (dd, J = 16.1, 3.6 Hz, 1H), 2.70 (dd, J = 16.1, 9.2 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 156.0, 130.5, 128.6, 126.6, 120.8, 110.3, 66.6, 60.7, 55.3, 41.7, 14.2. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel AS-H column, hexane/i-PrOH 98:2, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 23.861 min, t_minor = 27.973 min, 78% ee.

Ethyl-3-(2-fluorophenyl)-3-hydroxypropanoate (3p)

[α]_D²⁰ = −22.7 (c 0.42, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (t, J = 7.5 Hz, 1H), 7.30–7.22 (m, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.06–6.97 (m, 1H), 5.45–5.36 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.64 (d, J = 4.0 Hz, 1H), 2.82–2.67 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.31, 159.3 (d, J = 245 Hz), 129.4, 129.0, 127.1, 124.3, 115.1, 64.5, 60.8, 41.8, 41.8, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 15.333 min, t_major = 18.309 min, 70% ee.

Ethyl-3-(2-bromophenyl)-3-hydroxypropanoate (3q)

[α]_D²⁰ = −45.9 (c 0.33, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.51 (dd, J = 7.9, 1.1 Hz, 1H), 7.37–7.31 (m, 1H), 7.14 (td, J = 7.7, 1.7 Hz, 1H), 5.43 (dt, J = 9.6, 2.5 Hz, 1H), 4.23–4.17 (m, 2H), 3.66 (d, J = 3.4 Hz, 1H), 2.85 (dd, J = 8.4, 2.7 Hz, 1H), 2.55 (dd, J = 16.6, 9.8 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.4, 141.4, 132.6, 129.0, 127.8, 127.3, 121.3, 69.2, 61.0, 41.4, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OJ-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 12.830 min, t_minor = 16.016 min, 83% ee.

(S)-Ethyl-3-(furan-2-yl)-3-hydroxypropanoate (3r)^14a

[α]_D²⁰ = −14.0 (c 0.14, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.38 (dd, J = 1.8, 0.8 Hz, 1H), 6.34 (dd, J = 3.2, 1.8 Hz, 1H), 6.28 (d, J = 3.3 Hz, 1H), 5.14 (dt, J = 8.6, 4.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.23 (d, J = 5.0 Hz, 1H), 2.94–2.81 (m, 2H), 1.28 (d, J = 3.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.9, 154.7, 142.2, 110.2, 106.3, 64.2, 61.0, 39.7, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 8.648 min, t_minor = 25.430 min, 54% ee.

Ethyl-3-hydroxy-3-(thiophen-2-yl)propanoate (3s)

[α]_D²⁰ = −9.7 (c 0.15, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.24 (dd, J = 4.7, 1.6 Hz, 1H), 6.96 (dd, J = 3.9, 2.7 Hz, 2H), 5.35 (d, J = 5.2 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.64 (s, 1H), 2.83 (dd, J = 14.1, 9.9 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 146.3, 126.6, 124.7, 123.5, 66.4, 60.9, 43.1, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 8.363 min, t_minor = 17.743 min, 81% ee.

Ethyl-3-hydroxy-3-(naphthalen-2-yl)propanoate (3t)

[α]_D²⁰ = −35.1 (c 0.13, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.85 (dd, J = 5.2, 2.8 Hz, 4H), 7.54–7.46 (m, 3H), 5.32 (dd, J = 8.6, 3.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.67 (s, 1H), 2.84 (qd, J = 16.2, 6.5 Hz, 2H), 1.30–1.25 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.3, 139.9, 133.1, 132.9, 128.2, 127.9, 127.6, 126.1, 125.8, 124.4, 123.7, 70.3, 60.8, 43.3, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel AS-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 16.891 min, t_major = 19.909 min, 77% ee.

Ethyl-3-hydroxy-3-(naphthalen-1-yl)propanoate (3u)

[α]_D²⁰ = −114.2 (c 0.09, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 8.10–8.06 (m, 1H), 7.89 (dd, J = 7.4, 2.1 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.57–7.47 (m, 3H), 5.94 (dt, J = 9.1, 2.9 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.67 (d, J = 3.4 Hz, 1H), 2.95–2.82 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 138.0, 133.6, 129.8, 128.8, 128.1, 126.1, 125.5, 125.4, 122.8, 122.7, 67.2, 60.8, 42.7, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 23.334 min, t_minor = 29.751 min, 91% ee.

(S)-Ethyl-(E)-3-hydroxy-5-phenylpent-4-enoate (3v)^14a

[α]_D²⁰ = −2.6 (c 0.38, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.34 (m, 2H), 7.33–7.28 (m, 2H), 7.26–7.21 (m, 1H), 6.65 (dd, J = 15.9, 0.9 Hz, 1H), 6.22 (dd, J = 15.9, 6.1 Hz, 1H), 4.72 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.24 (d, J = 3.8 Hz, 1H), 2.69–2.57 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.2, 136.3, 130.6, 129.9, 128.5, 127.7, 126.5, 68.8, 60.8, 41.5, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 22.528 min, t_major = 34.451 min, 46% ee.

(R)-Ethyl-3-hydroxy-3-phenylbutanoate (5a)^13b

[α]_D²⁰ = +12.0 (c 0.03, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.43 (m, 2H), 7.36–7.31 (m, 2H), 7.26–7.21 (m, 1H), 4.41 (s, 1H), 4.05 (q, J = 7.1 Hz, 2H), 2.98 (d, J = 15.9 Hz, 1H), 2.79 (d, J = 15.9 Hz, 1H), 1.54 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 146.8, 128.2, 126.8, 124.4, 77.3, 60.7, 46.4, 30.6, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 6.465 min, t_major = 7.081 min, 87% ee.

(S)-Ethyl-3-(4-bromophenyl)-3-hydroxybutanoate (5b)^13b

[α]_D²⁰ = +19.3 (c 0.16, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 4.44 (s, 1H), 4.06 (tt, J = 7.2, 3.7 Hz, 2H), 2.92 (d, J = 16.0 Hz, 1H), 2.76 (d, J = 16.0 Hz, 1H), 1.50 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 146.0, 131.2, 126.4, 120.8, 72.5, 60.8, 46.1, 30.5, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 6.430 min, t_major = 7.317 min, 83% ee.

Ethyl-3-hydroxy-3-(4-(trifluoromethyl)phenyl)butanoate (5c)

[α]_D²⁰ = +16.9 (c 0.21, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.63–7.56 (m, 4H), 4.54 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 2.98 (d, J = 16.1 Hz, 1H), 2.82 (d, J = 16.1 Hz, 1H), 1.54 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 150.9, 129.1 (q, J = 32.0 Hz, J = 64.0 Hz), 124.1, 125.2 (q, J = 4.0 Hz, J = 7.0 Hz), 125.0, 72.6, 60.9, 46.0, 30.5, 13.8. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 5.450 min, t_major = 6.362 min, 73% ee.

Ethyl-3-(2-bromophenyl)-3-hydroxybutanoate (5d)

[α]_D²⁰ = +45.9 (c 0.33, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.99 (s, 1H), 5.34 (dt, J = 9.2, 3.0 Hz, 1H), 4.25–4.19 (m, 2H), 3.21 (d, J = 3.1 Hz, 1H), 2.75–2.65 (m, 2H), 2.33 (d, J = 5.9 Hz, 6H), 1.29 (d, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 137.5, 137.1, 134.2, 131.2, 127.0, 125.2, 66.8, 60.8, 42.1, 20.9, 18.9, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel AS-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 9.957 min, t_major = 10.649 min, 85% ee.

Ethyl-3-hydroxy-3-(2-methoxyphenyl)butanoate (5e)

[α]_D²⁰ = +7.3 (c 0.30, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J = 7.7, 1.7 Hz, 1H), 7.23 (ddd, J = 8.1, 7.5, 1.7 Hz, 1H), 6.96 (td, J = 7.6, 1.1 Hz, 1H), 6.88 (dd, J = 8.2, 0.9 Hz, 1H), 4.58 (s, 1H), 3.98 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.28 (d, J = 15.0 Hz, 1H), 2.85 (d, J = 15.0 Hz, 1H), 1.63 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 155.8, 133.7, 128.4, 126.7, 120.7, 111.0, 72.5, 60.3, 55.2, 45.0, 27.4, 13.9. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel AS-H column, hexane/i-PrOH 98:2, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 22.861 min, t_minor = 27.973 min, 80% ee.

Ethyl-3-(3-bromo-4-fluorophenyl)-3-hydroxybutanoate (5f)

[α]_D²⁰ = +18.2 (c 0.07, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.66 (dd, J = 6.6, 2.3 Hz, 1H), 7.33 (ddd, J = 8.6, 4.5, 2.3 Hz, 1H), 7.05 (t, J = 8.5 Hz, 1H), 4.49 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 2.90 (d, J = 16.0 Hz, 1H), 2.75 (d, J = 16.0 Hz, 1H), 1.50 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.39, 157.9 (d, J = 245), 144.4, 130.0, 125.2, 116.0, 108.8, 72.1, 60.9, 46.1, 30.6, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel AS-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 9.386 min, t_major = 10.395 min, 83% ee. HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₂H₁₄BrFO₃Na, 327.0003; found, 327.0067.

Ethyl-3-(3,4-difluorophenyl)-3-hydroxybutanoate (5g)

[α]_D²⁰ = +19.6 (c 0.21, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.28 (m, 1H), 7.17–7.06 (m, 2H), 4.52 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.92 (d, J = 16.0 Hz, 1H), 2.78 (d, J = 16.0 Hz, 1H), 1.51 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.40, 150.8 (dd, J = 12.0 Hz, J = 88.0 Hz), 148.3 (dd, J = 13.0 Hz, J = 90.0 Hz), 144.2, 120.4 (q, J = 4.0 Hz, J = 6.0 Hz), 116.8 (d, J = 17.0 Hz), 114.1(d, J = 19.0 Hz), 72.1, 60.9, 46.0, 30.5, 13.9. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 7.700 min, t_major = 8.981 min, 78% ee. HRMS (ESI, m/z): [M + H]⁺ Calcd for C₁₂H₁₅F₂O₃, 245.0984; found, 245.1351.

Ethyl-3-hydroxy-3-(thiophen-2-yl)butanoate (5h)

[α]_D²⁰ = +15.5 (c 0.26, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J = 5.0 Hz, 1H), 6.94–6.91 (m, 1H), 6.89 (d, J = 3.4 Hz, 1H), 4.76 (s, 1H), 4.12 (d, J = 7.1 Hz, 2H), 2.98 (d, J = 16.0 Hz, 1H), 2.81 (d, J = 16.0 Hz, 1H), 1.63 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, Acetone) δ 172.3, 152.2, 126.6, 123.9, 121.9, 71.8, 60.9, 46.8, 31.3, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 11.162 min, t_minor = 12.474 min, 85% ee.

Ethyl-2-(4-hydroxychroman-4-yl)acetate (5i)

[α]_D²⁰ = +36.3 (c 0.16, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.44 (dd, J = 7.8, 1.6 Hz, 1H), 7.18 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 6.93 (td, J = 7.9, 1.2 Hz, 1H), 6.83 (dd, J = 8.2, 1.1 Hz, 1H), 4.28 (ddd, J = 11.8, 7.3, 4.6 Hz, 1H), 4.21 (ddd, J = 14.2, 5.9, 2.4 Hz, 3H), 4.12 (s, 1H), 3.06 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.7 Hz, 1H), 2.23–2.16 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.1, 154.0, 129.2, 126.6, 126.0, 120.6, 117.0, 66.7, 62.8, 60.9, 45.0, 35.3, 14.0. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 12.703 min, t_major = 13.893 min, 92% ee.

Ethyl-3-hydroxy-3-(naphthalen-2-yl)butanoate (5j)

[α]_D²⁰ = +16.9 (c 0.21, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.89–7.83 (m, 3H), 7.59 (dd, J = 8.6, 1.8 Hz, 1H), 7.53–7.46 (m, 2H), 4.65 (s, 1H), 4.07 (qd, J = 7.1, 3.6 Hz, 2H), 3.13 (d, J = 15.9 Hz, 1H), 2.92 (d, J = 15.9 Hz, 1H), 1.66 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 144.1, 133.1, 132.3, 128.1, 127.9, 127.4, 126.0, 125.7, 123.1, 123.0, 72.9, 60.7, 46.2, 30.6, 13.9. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_major = 11.128 min, t_minor = 12.328 min, 81% ee.

Ethyl-2-(5-fluoro-1-hydroxy-2,3-dihydro-1H-inden-1-yl)acetate (5k)

[α]_D²⁰ = −4.9 (c 0.53, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.27 (dd, J = 9.1, 5.2 Hz, 1H), 6.94–6.85 (m, 2H), 4.24–4.15 (m, 3H), 3.06–2.96 (m, 1H), 2.88–2.76 (m, 2H), 2.68 (d, J = 15.9 Hz, 1H), 2.29 (t, J = 7.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 163.2 (d, J = 243 Hz), 145.1, 141.6, 124.1, 113.8, 111.7, 80.3, 60.9, 43.9, 40.5, 29.2, 29.2, 14.1. The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 8.334 min, t_major = 15.408 min, 82% ee.

Ethyl-2-(1-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (5l)

[α]_D²⁰ = −7.2 (c 0.24, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.64 (dd, J = 7.7, 1.4 Hz, 1H), 7.25–7.17 (m, 2H), 7.10–7.06 (m, 1H), 4.20–4.14 (m, 2H), 3.94 (s, 1H), 2.97–2.88 (m, 2H), 2.80–2.72 (m, 2H), 2.31–2.22 (m, 1H), 2.07–1.98 (m, 1H), 1.81–1.74 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H). The enantiomeric excess was determined by HPLC using the Daicel Chiralcel OD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 220 nm, t_minor = 5.590 min, t_major = 7.735 min, 92% ee. HRMS (ESI, m/z): [M + Na]⁺ Calcd for C₁₅H₂₀NaO₃Na, 271.1305; found, 271.1287.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c02400.

• Schematic diagram for the synthesis of ligands (L1–L4); HPLC spectra; ¹H and ¹³C NMR spectra of all compounds prepared (PDF)

The authors declare no competing financial interest.