Copper(I)-catalyzed enantioselective hydroboration of cyclopropenes: facile synthesis of optically active cyclopropylboronates

Abstract

Copper(I)-catalyzed enantioselective hydroboration of 3-aryl substituted cyclopropene-3-carboxylate is described, providing chiral cyclopropylboronates with excellent enantioselectivities (89–95% ee) in moderate to high yields (55–86%). The non-directing effect of the ester group was observed, and the reaction proceeded with solely trans-selectivity. The chiral boronates could be conveniently converted into chiral 1,2-diaryl substituted cyclopropane derivatives.

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Introduction

The chiral cyclopropane framework represents the smallest carbocycles existing in a wide range of naturally-occurring compounds,¹ chiral drugs, and insecticides, for instance, (+)-Coronatine,² Saxagliptin (Onglyza®),³ EBC-219,⁴ Milnacipran,⁵ Deltamethrin,⁶ and (+)-Tranylcypromine⁷ (Fig. 1). These three-membered carbocycles, due to their unique structural and electronic properties, serve as extremely significant versatile building blocks in organic synthesis.⁸ Thus, a few interesting and characteristic transformations have continually emerged.⁹ Owing to their important biological activities and wide applications in organic chemistry, much attention has been paid to their efficient enantioselective syntheses.

Fig. 1 Cyclopropane-containing natural products, chiral drugs and insecticides.

Through Suzuki–Miyaura coupling, C–N coupling, Tamao oxidation reaction, etc., cyclopropylboronates could be readily converted into structurally and functionally diverse cyclopropanes.¹⁰ Thus, efficient enantioselective synthesis of optically active cyclopropylboronates has gradually become a spotlight. Recently, Ito and co-workers successfully established copper(I)-catalyzed asymmetric cyclopropanation reactions of allylic phosphates and carbonates with bis(pinacolato)diboron (B₂pin₂), affording optically active trans-silyl- and trans-aryl-substituted cyclopropylboronates (Scheme 1a).^11,12 Gevorgyan and co-workers described rhodium-catalyzed asymmetric hydroboration of 3,3-disubstituted cyclopropenes, directly constructing enantiopure 2,2-disubstituted cyclopropylboronates. The directing effect of the ester group was found to be necessary for achieving cis-selectivity and high enantioselectivity (Scheme 1b).^13,14 Herein, we present our findings in copper(I)-catalyzed asymmetric hydroboration of 3,3-disubstituted cyclopropenes.¹⁵ Interestingly, the non-directing effect of the ester group was observed in this case, and the reaction proceeded with solely trans-selectivity (Scheme 1c).

Scheme 1 Enantioselective synthesis of optically active cyclopropylboronates.

Results and discussion

At the outset, a set of representative chiral phosphorus ligands were investigated for the Cu-catalyzed asymmetric hydroboration of the cyclopropene substrate 1f, and the screening results are summarized in Table 1. The chiral bisphosphine ligand, (R,S_p)-Josiphos (L1), has been successfully employed in the Cu-catalyzed asymmetric conjugate hydroboration reaction of α,β-unsaturated compounds.¹⁶ However, only 62% yield and 40% ee were observed in our hydroboration (Table 1, entry 1). Phosphoramidite ((R)-MonoPhos, L2)¹⁷ and (R)-MOP (L3) ligands were subsequently subjected to this reaction, but no promising outcomes were obtained (Table 1, entries 2 and 3). To our delight, the ligand (R)-BINAP (L4) could dramatically improve the yield and ee of hydroboration product 3f to 75% and 94%, respectively (Table 1, entry 4). Several electronically different bisphosphine ligands (L5–L8) were applied in this reaction, but no better results were achieved (Table 1, entries 5–8).

Table 1 Initial evaluation of various ligands and solvents^a

Entry	L*	Solvent	Time (h)	Yield^b (%)	ee^c (%)
a The reaction was carried out with 1f (0.15 mmol), B2Pin2 (2, 0.3 mmol), CuCl (10 mol%), chiral ligand (L*, 12 mol%) and NaOtBu (11 mol%) in anhydrous toluene (1.0 mL) at room temperature under a N2 atmosphere, unless otherwise noted. b Yield of the isolated product. c Determined by HPLC analysis using a chiral stationary phase. d At 0 °C. e L4 (15 mol%) was used. f L4 (20 mol %) was used. B2Pin2 = bis(pinacolato)diboron.
1	L1	Toluene	6	62	40
2	L2	Toluene	8	16	22
3	L3	Toluene	8	30	51
4	L4	Toluene	6	75	94
5	L5	Toluene	8	58	93
6	L6	Toluene	10	85	−89
7	L7	Toluene	12	60	93
8	L8	Toluene	16	40	79
9^d	L4	Toluene	24	46	90
10	L4	THF	6	44	84
11	L4	DCM	6	32	94
12^e	L4	Toluene	6	80	95
13^f	L4	Toluene	6	78	94

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Next, the reaction temperature and the solvent were investigated to further improve the enantioselectivity. Unfortunately, they led to different levels of erosion in yields and ee values (Table 1, entries 9–11). Increasing the ligand loading to 15 mol% resulted in a slight improvement of both yield and ee values (Table 1, entry 12). However, further increasing the ligand loading failed to give better results (Table 1, entry 13).

With the optimal reaction conditions identified, various aryl-substituted cyclopropenes were investigated, and the results are summarized in Table 2. All 4-substituted phenyl substrates, regardless of the electron-donating or electron-withdrawing properties of the substituent at the phenyl ring, afforded the hydroboration products in moderate to high yields (55–86%) and with high to excellent enantioselectivities (89–95% ee, Table 2, entries 1–7). Interestingly, p-, m-, and o-bromophenyl substituted cyclopropene substrates (1g, 1h, and 1i) gave almost the same yields with high to excellent levels of enantioselectivities (Table 2, entries 7–9). As for 2-naphthyl and disubstituted phenyl substrates, the hydroboration reaction also proceeded smoothly with high yields and excellent enantioselectivities (Table 2, entries 10–12). In general, cyclopropene substrates bearing electron-withdrawing phenyl substituents provided better yields (Table 2, entries 1–3 vs. 4–6, 12).

Table 2 Substrate scope of various aryl-substituted cyclopropenes^a

a The reaction was carried out with 1 (0.15 mmol), B₂Pin₂ (2, 0.3 mmol), CuCl (10 mol%), (R)-BINAP (L4, 15 mol%) and NaOtBu (11 mol%) in anhydrous toluene (1.0 mL) at room temperature under a N₂ atmosphere. b Reaction time. c Yield of the isolated product. d Determined by HPLC analysis using a chiral stationary phase.

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Given the highly enantioselective nature of this hydroboration reaction, the methyl substituted substrates 1n and 1o were tested under the standard conditions. Unfortunately, no desired products were observed, indicating that the α-substituent played an important role in the cyclopropene reactivity (Scheme 2, eqn (1) and (2)). As for the diester substrate 1p, the hydroboration reaction readily occurred with excellent enantioselectivity, albeit in a lower yield. This was partially attributed to the decomposition of the starting material (Scheme 2, eqn (3)).

Scheme 2 Cu-catalyzed asymmetric hydroboration of cyclopropenes 1n, 1o and 1p.

The relative configuration of hydroboration products 3 was determined using NOE interactions; for example, the NOE interactions between the aryl group and the boronate group in 3g and 3j clearly revealed that both of them were on the same side of the cyclopropane plane (Fig. 2). Thus trans-cyclopropylboronates were achieved in this Cu(I)-catalyzed asymmetric hydroboration of cyclopropenes.

Fig. 2 The NOE interactions between the aryl group and the boronate group in 3g and 3j.

To determine the absolute configurations of the hydroboration product 3a in Table 2,¹⁸ we converted cyclopropylboronate 3a, through Suzuki–Miyaura coupling with iodobenzene (4), into a known compound (1R,2S)-5 in almost quantitative yield with no loss of the enantiomeric excess.¹⁹ Thus, the absolute configuration of cyclopropylboronate 3a was unambiguously assigned as 1R,2R. The absolute configurations of other hydroboration products in Table 2 were assigned on the basis of their chemical correlation with (1R,2R)-3a (Scheme 3).

Scheme 3 Determining the absolute configuration of cyclopropylboronate 3a.

To probe the ‘hydrogen’ source of this hydroboration reaction, [D4]-methanol experiment was investigated. cis-Deuterated product 3a (50%) was observed, suggesting that the proton partially came from methanol and this hydroboration reaction was a syn-addition process (Scheme 4).

Scheme 4 [D4]-Methanol experiment.

Piecing together the above details and preceding results,²⁰ a plausible reaction mechanism is proposed in Fig. 3. Initiation of the reaction through the transmetallation of a (pinacolato)boron group (BPin) from boron to copper species A generated the borylated copper B, which subsequently underwent syn-addition from the aryl group side²¹ to the double bond of the cyclopropene substrate 1 to afford the borylated cyclopropyl-copper intermediate D. The intermediate D was readily protonated by trace water or methanol to regenerate A and liberate the trans-product 3. Due to the bigger steric hindrance of the methyl ester group (Cvs.E), the weak coordination between copper and carboxyl groups could not overcome this energy barrier. Therefore, the cis-product was not observed.

Fig. 3 Proposed mechanism.

Conclusions

In summary, copper-catalyzed asymmetric hydroboration reaction of 3-aryl, 3-methylester substituted cyclopropenes has been successfully established. This reaction proceeded smoothly at room temperature, affording optically active trans-cyclopropylboronates with excellent enantioselectivities (89–95% ee) in moderate to high yields (55–86%). The non-directing effect of the methylester group was observed and this method was actually complimentary to the earlier reported cis-borylated cyclopropane products through rhodium catalysis. The chiral boronates could be readily transformed to chiral 1,2-diaryl substituted cyclopropanes through Suzuki–Miyaura coupling reaction. Further studies on the applications of cyclopropylboronates are in progress in our laboratories.

Experimental section

General information

All solvents were dried before use by following the standard procedures. Unless otherwise indicated, all starting materials purchased from commercial suppliers were used without further purification. The ¹H and ¹³C NMR spectra were recorded on a Bruker AV 400 MHz in the indicated solvents. Chemical shifts are reported in δ (ppm) referenced to the internal standard TMS for ¹H NMR and to CDCl₃ (δ = 77.10 ppm) for ¹³C NMR. Coupling constants (J) are quoted in Hz. Optical rotations were measured on a JASCO P-1030 polarimeter. IR spectra were recorded on a Nicolet iN 10 MX. ESI mass spectra were recorded on an Agilent 1200/G6100A. HRMS of boron-containing compounds is based on ¹⁰B. For the preparation of substrates 4a, see the ESI.†

General procedure for Cu-catalyzed hydroboration of 3,3-disubstituted cyclopropenes

A dried Schlenk flask was charged with CuCl (1.5 mg, 0.015 mmol, 10 mol%), (R)-(+)-BINAP (14 mg, 0.0225 mmol, 15 mol%), B₂pin₂ (2, 76.2 mg, 0.3 mmol, 2.0 equiv.), NaOtBu (1.6 mg, 0.0165 mmol, 11 mol%) and anhydrous toluene (1.0 mL) under a nitrogen atmosphere. After the mixture was stirred at room temperature for 40 min, a solution of cyclopropene 1 (0.15 mmol) in anhydrous toluene (0.5 mL) was added, followed by anhydrous MeOH (12.2 μL, 0.30 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for the time indicated in Table 2, then filtered through Celite®, and concentrated in vacuo. The residue was purified by silica gel (300–400 mesh) column chromatography using hexane–ethyl acetate (15 : 1) as an eluent to afford the desired product 3.

(1R,2R)-Methyl 1-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3a). Colorless oil. 29.9 mg, 66% yield. [α]²⁸_D −206.8 (c 1.0, CHCl₃) for 94% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.35–7.21 (m, 5H), 3.60 (s, 3H), 1.70 (dd, J = 10.4 Hz, 3.2 Hz, 1H), 1.62 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 1.28 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 1.05 (s, 6H), 0.82 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 174.96, 137.76, 131.17 (2C), 127.87 (2C), 127.15, 83.37 (2C), 52.56, 33.83, 24.89 (2C), 24.44 (2C), 18.78. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 325.1; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₂₃¹⁰BO₄Na^⊕ 324.1618, found 324.1614; IR (KBr) ν (cm⁻¹) 3451, 3086, 3047, 3027, 2979, 2954, 1961, 1726, 1602, 1429, 1372, 1264, 1166, 1142, 1062, 971, 858, 733, 698, 637, 503; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 6.4 min (R,R-isomer), 8.2 min (S,S-isomer).

(1R,2R)-Methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-p-tolylcyclopropanecarboxylate (3b). Colorless oil. 26.1 mg, 55% yield. [α]²⁶_D −158.5 (c 1.0, CHCl₃) for 94% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.30–7.21 (m, 2H), 7.07 (d, J = 7.6 Hz, 2H), 3.60 (s, 3H), 2.31 (s, 3H), 1.68 (dd, J = 10.0 Hz, 3.2 Hz, 1H), 1.58 (dd, J = 8.4 Hz, 3.2 Hz, 1H), 1.32–1.20 (m, 1H), 1.06 (s, 6H), 0.84 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 175.16, 136.74, 134.74, 131.01 (2C), 128.56 (2C), 83.37 (2C), 52.58, 33.43, 24.89 (2C), 24.45 (2C), 21.21, 18.86. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 339.2; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₈H₂₅¹⁰BO₄Na^⊕ 338.1774, found 338.1758; IR (KBr) ν (cm⁻¹) 2978, 2951, 2924, 1723, 1515, 1436, 1410, 1371, 1329, 1285, 1263, 1215, 1165, 1142, 963, 858, 821, 751, 583, 504; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 6.7 min (R,R-isomer), 7.8 min (S,S-isomer).

(1R,2R)-Methyl 1-(4-methoxyphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3c). Colorless oil. 28.9 mg, 58% yield. [α]²⁶_D −190.1 (c 1.0, CHCl₃) for 93% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.25 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.78 (s, 3H), 3.60 (s, 3H), 1.69 (dd, J = 10.0 Hz, 3.2 Hz, 1H), 1.57 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 1.24 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 1.07 (s, 6H), 0.86 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 175.08, 158.65, 132.08 (2C), 129.95, 113.20 (2C), 83.26 (2C), 55.26, 52.42, 32.93, 24.87 (2C), 24.36 (2C), 18.62. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + H]^⊕ 333.3; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₈H₂₅¹⁰BO₅Na^⊕ 354.1724, found 354.1729; IR (KBr) ν (cm⁻¹) 3542, 2979, 2952, 2837, 1723, 1614, 1582, 1517, 1440, 1409, 1331, 1264, 1247, 1165, 1143, 1034, 858, 834, 689, 548; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 9.6 min (R,R-isomer), 12.4 min (S,S-isomer).

(1R,2R)-Methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4-(trifluoromethyl)phenyl)cyclopropanecarboxylate (3d). White semisolid. 47.7 mg, 86% yield. [α]²⁵_D −128.2 (c 1.0, CHCl₃) for 92% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.54 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 3.62 (s, 3H), 1.76 (dd, J = 10.0 Hz, 3.2 Hz, 1H), 1.64 (dd, J = 8.4 Hz, 3.2 Hz, 1H), 1.31 (dd, J = 10.0 Hz, 8.4 Hz, 1H), 1.04 (s, 6H), 0.81 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 174.13, 142.00, 131.58 (2C), 129.45, 124.79 (q, J_CF = 3.5 Hz, 2C), 83.54 (2C), 52.68, 33.69, 24.77 (2C), 24.38 (2C), 18.82. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) EI-MS, 370 (M.^⊕), 355 (M^⊕ − CH₃), 312 (M^⊕ − CO₂CH₃). HRMS (FTMS-EI) calcd for C₁₈H₂₂¹⁰BF₃O₄ (M.^⊕) 369.1600, found 369.1597; IR (KBr) ν (cm⁻¹) 3430, 2980, 1726, 1607, 1514, 1437, 1372, 1332, 1287, 1263, 1223, 1165, 1143, 1102, 971, 858, 837, 689, 579, 543; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 99/1; flow rate = 1.0 mL min⁻¹; retention time: 5.4 min (R,R-isomer), 7.4 min (S,S-isomer).

(1R,2R)-Methyl 1-(4-fluorophenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3e). White semisolid. 39.8 mg, 83% yield. [α]²⁶_D −163.0 (c 1.0, CHCl₃) for 95% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.32–7.28 (m, 2H), 7.00–6.92 (m, 2H), 3.60 (s, 3H), 1.72 (dd, J = 10.0 Hz, 3.2 Hz, 1H), 1.58 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 1.26 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 1.07 (s, 6H), 0.86 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 174.61, 161.92 (d, J_CF = 244.4 Hz), 160.70, 133.61 (d, J_CF = 3.0 Hz), 132.66 (d, J_CF = 8.4 Hz, 2C), 114.56 (d, J_CF = 21.3 Hz, 2C), 83.36 (2C), 52.46, 33.01, 24.81 (2C), 24.34 (2C), 18.86. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + H]^⊕ 321.0; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₂₂¹⁰BFO₄Na^⊕ 342.1524, found 342.1519; IR (KBr) ν (cm⁻¹) 2983, 1960, 1720, 1618, 1430, 1392, 1382, 1327, 1296, 1268, 1165, 1141, 1115, 1064, 1018, 877, 837, 765, 608; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 4.5 min (R,R-isomer), 5.9 min (S,S-isomer).

(1R,2R)-Methyl 1-(4-chlorophenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3f). White semisolid. 40.3 mg, 80% yield. [α]²⁶_D −175.7 (c 1.0, CHCl₃) for 95% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.29–7.23 (m, 4H), 3.60 (s, 3H), 1.72 (dd, J = 10.0 Hz, 3.2 Hz, 1H), 1.57 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 1.27 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 1.07 (s, 6H), 0.86 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 174.36, 136.35, 132.86, 132.47 (2C), 127.88 (2C), 83.42 (2C), 52.50, 33.16, 24.79 (2C), 24.34 (2C), 18.78. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 359.0; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₂₂¹⁰B³⁵ClO₄Na^⊕ 358.1228, found 358.1241; IR (KBr) ν (cm⁻¹) 2978, 2955, 1918, 1723, 1490, 1446, 1372, 1337, 1279, 1259, 1192, 1146, 1098, 1067, 1010, 967, 864, 752, 664, 542; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 5.2 min (R,R-isomer), 6.5 min (S,S-isomer).

(1R,2R)-Methyl 1-(4-bromophenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3g). White semisolid. 42.9 mg, 75% yield. [α]²⁶_D −79.8 (c 1.0, CHCl₃) for 89% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.40 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 3.60 (s, 3H), 1.71 (dd, J = 10.0 Hz, 3.2 Hz, 1H), 1.57 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 1.27 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 1.07 (s, 6H), 0.86 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 174.27, 136.87, 132.84 (2C), 130.84 (2C), 120.98, 83.42 (2C), 52.51, 33.25, 24.79 (2C), 24.34 (2C), 18.74. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 403.1; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₂₂¹⁰B⁷⁹BrO₄Na^⊕ 402.0723, found 402.0719; IR (KBr) ν (cm⁻¹) 3062, 3045, 2987, 2945, 2848, 1724, 1486, 1424, 1325, 1265, 1193,1141, 1012, 856, 826, 768, 757, 539, 510; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 7.3 min (R,R-isomer), 9.6 min (S,S-isomer).

(1R,2R)-Methyl 1-(3-bromophenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3h). White semisolid. 43.9 mg, 77% yield. [α]²⁶_D −152.5 (c 1.0, CHCl₃) for 93% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.48 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.28–7.25 (m, 1H), 7.14 (t, J = 7.6 Hz, 1H), 3.61 (s, 3H), 1.72 (dd, J = 10.0 Hz, 3.6 Hz, 1H), 1.56 (dd, J = 8.0 Hz, 3.6 Hz, 1H), 1.26 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 1.09 (s, 6H), 0.88 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 174.20, 140.19, 134.34, 130.17, 129.70, 129.33, 121.71, 83.46 (2C), 52.56, 33.48, 24.87 (2C), 24.42 (2C), 18.85. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 403.1; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₂₂¹⁰B⁷⁹BrO₄Na^⊕ 402.0733, found 402.0723; IR (KBr) ν (cm⁻¹) 3419, 3048, 2983, 2951, 1723, 1597, 1566, 1479, 1404, 1260, 1281, 1260, 1166, 1138, 998, 977, 854, 716, 695, 686, 574, 564; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 5.4 min (R,R-isomer), 6.9 min (S,S-isomer).

(1R,2R)-Methyl 1-(2-bromophenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3i). White semisolid. 42.2 mg, 74% yield. [α]²⁶_D −219.3 (c 1.0, CHCl₃) for 94% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.51 (d, J = 8.0 Hz, 1H), 7.31–7.24 (m, 2H), 7.13–7.11 (m, 1H), 3.62 (s, 3H), 1.79–1.44 (m, 2H), 1.31–1.26 (m, 1H), 1.07 (s, 6H), 0.88 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 173.78, 132.28, 128.42, 126.81, 83.18 (2C), 52.59, 35.46, 24.76 (2C), 24.25 (2C), 21.37. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 403.0; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₂₂¹⁰B⁷⁹BrO₄Na^⊕ 402.0723, found 402.0719; IR (KBr) ν (cm⁻¹) 3061, 3018, 2978, 2954, 2931, 1721, 1592, 1567, 1431, 1411, 1332, 1285, 1169, 1143, 993, 860, 759, 666, 561; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 7.9 min (R,R-isomer), 10.9 min (S,S-isomer).

(1R,2R)-Methyl 1-(naphthalen-2-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3j). Colorless oil. 31.2 mg, 59% yield. [α]²⁶_D −194.7 (c 1.0, CHCl₃) for 92% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.80–7.73 (m, 4H), 7.50–7.42 (m, 3H), 3.60 (s, 3H), 1.79 (dd, J = 10.0 Hz, 3.2 Hz, 1H), 1.74 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 1.35 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 1.00 (s, 6H), 0.67 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 174.86, 135.28, 133.05, 132.61, 129.58, 129.43, 127.76, 127.50, 127.25, 125.80, 125.65, 83.28 (2C), 52.47, 33.92, 24.73 (2C), 24.27 (2C), 18.94. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 375.0; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₂₁H₂₅¹⁰BO₄Na^⊕ 374.1774, found 374.1771; IR (KBr) ν (cm⁻¹) 2999, 2982, 1724, 1618, 1438, 1410, 1265, 1168, 1147, 1128, 1113, 1070, 1016, 974, 858, 759, 660, 608, 531; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 8.7 min (R,R-isomer), 12.3 min (S,S-isomer).

(1R,2R)-Methyl 1-(3,4-dichlorophenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3k). White semisolid. 43.3 mg, 78% yield. [α]²⁶_D −98.4 (c 1.0, CHCl₃) for 92% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.43 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 3.62 (s, 3H), 1.74 (dd, J = 10.0 Hz, 3.2 Hz, 1H), 1.54 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 1.30–1.24 (m, 1H), 1.09 (s, 6H), 0.90 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 173.95, 138.32, 133.38, 131.70, 131.19, 130.57, 129.77, 83.66 (2C), 52.71, 33.16, 24.93 (2C), 24.49 (2C), 19.08. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 393.0; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₂₁¹⁰B³⁵Cl₂O₄Na^⊕ 392.0838, found 392.0830; IR (KBr) ν (cm⁻¹) 2979, 2952, 1727, 1558, 1474, 1435, 1411, 1380, 1372, 1333, 1262, 1224, 1193, 1167, 1140, 1104, 1071, 1031, 971, 945, 857, 833, 758, 737, 666, 597; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 5.2 min (R,R-isomer), 6.5 min (S,S-isomer).

(1R,2R)-Methyl 1-(3,5-difluorophenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (3m). White semisolid. 42.1 mg, 83% yield. [α]²⁶_D −96.1 (c 1.0, CHCl₃) for 93% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 6.89–6.86 (m, 2H), 6.69 (t, J = 9.2 Hz, 1H), 3.62 (s, 3H), 1.73 (dd, J = 10.0 Hz, 3.6 Hz, 1H), 1.55 (dd, J = 8.4 Hz, 3.6 Hz, 1H), 1.27 (dd, J = 10.0 Hz, 8.4 Hz, 1H), 1.10 (s, 6H), 0.92 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 173.78, 162.46 (dd, J_CF = 246, 12.9 Hz, 2C), 141.81 (t, J_CF = 9.1 Hz), 114.30 (dd, J_CF = 18.2 Hz, 6.1 Hz, 2C), 102.68 (t, J_CF = 25.0 Hz), 83.62 (2C), 52.71, 33.69, 24.93 (2C), 24.46 (2C), 19.02. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + Na]^⊕ 361.3; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₂₁BF₂O₄Na^⊕ 360.1429, found 360.1434; IR (KBr) ν (cm⁻¹) 3438, 3085, 1981, 1728, 1624, 1599, 1435, 1409, 1372, 1334, 1269, 1216, 1142, 1100, 1077, 990, 966, 857, 759, 736, 685, 532, 511; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 4.4 min (R,R-isomer), 5.6 min (S,S-isomer).

(R)-Dimethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1,1-dicarboxylate (3p). Colorless oil. 16.6 mg, 39% yield. [α]_D²⁴ −59.8 (c 1.06, CHCl₃) for 95% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 3.73 (s, 3H), 3.71 (s, 3 H), 1.54–1.52 (m, 2H), 1.23 (s, 6H), 1.22 (s, 6H), 1.12–1.08 (m, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 170.88, 169.23, 83.93 (2C), 52.77, 52.54, 33.71, 24.84 (2C), 24.81 (2C), 18.98. (The carbon directly attached to the boron atom was not detected, likely due to quadrupole relaxation.) ESI-MS: [M + H]^⊕ 285.2; HRMS (FTMS-ESI): [M + H]^⊕ calcd for C₁₃H₂₂¹⁰BO₆^⊕ 285.1504, found 285.15; IR (KBr) ν (cm⁻¹) 2980, 2954, 1735, 1436, 1414, 1381, 1373, 1338, 1290, 1271, 1234, 1208, 1167, 1142, 1079, 971, 879, 858, 835, 772, 758, 669; HPLC: Phenomenex Lux 5u Cellulose-2 (PC-2) Column; detected at 220 nm; n-hexane–i-propanol = 98/2; flow rate = 1.0 mL min⁻¹; retention time: 11.8 min (S-isomer), 12.9 min (R-isomer).

(1R,2S)-Methyl 1,2-diphenylcyclopropanecarboxylate (5). A mixture of 3a (30.2 mg, 0.1 mmol), iodobenzene (4, 30.6 mg, 0.15 mmol), Pd(PPh₃)₄ (11.6 mg, 0.01 mmol), and Cs₂CO₃ (97.5 mg, 0.3 mmol) in toluene (1 mL) was stirred at 80 °C under a N₂ atmosphere overnight. After cooling to room temperature, the reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash column chromatography using hexane–ethyl acetate (8 : 1) as an eluent to afford the desired product 5 (25 mg, 99% yield). [α]²⁶_D −38.9 (c 1.0, CHCl₃) for 94% ee; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.05–6.94 (m, 8H), 6.70–6.68 (m, 2H), 3.58 (s, 3H), 3.06–3.01 (m, 1H), 2.06 (dd, J = 9.2 Hz, 4.8 Hz, 1H), 1.82–1.78 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 174.42, 136.42, 134.80, 131.99, 128.40, 128.10, 127.76, 127.09, 126.37, 52.68, 37.45, 33.19, 20.54; ESI-MS: [M + Na]^⊕ 275.1; HRMS (FTMS-ESI): [M + Na]^⊕ calcd for C₁₇H₁₆O₂Na^⊕ 275.1043, found 275.1037; IR (KBr) ν (cm⁻¹) 3648, 3412, 3061, 3086, 3029, 2953, 1966, 1897, 1720, 1602, 1496, 1456, 1447, 1428, 1376, 1342, 1255, 1205, 1189, 1104, 1050, 989, 865, 788, 760, 742, 702, 650, 545; HPLC: OJ-H Column; detected at 214 nm; n-hexane–i-propanol = 95/5; flow rate = 0.7 mL min⁻¹; retention time: 11.5 min (R,S-isomer), 16.3 min (S,R-isomer).

Acknowledgements

Financial support for this work was generously provided by the National Natural Science Foundation of China (NSFC 21372243, 21232009, 21102161), the Shanghai Municipal Committee of Science and Technology (13JC1406900), and the State Key Laboratory of Bioorganic and Natural Products Chemistry. We thank Dr Hanqing Dong (Arvinas Inc.) for his help in the preparation of this manuscript.

Notes and references

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21. In the cyclopropene substrate 1, the aryl group was almost vertical to the cyclopropene plane. As a result, the aryl group side was supposed to be less hindered than the methyl ester side.

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Footnotes

† Electronic supplementary information (ESI) available: Preparation of substrates, characterization data, ¹H, ¹³C NMR, MS and IR spectra. CCDC 1004894. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4qo00157e

‡ These authors contributed equally to this work.

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