Electrophilic Epoxidation of α,β-Unsaturated Oximes with Dioxiranes and Ring Opening of the Epoxides

Abstract

α,β-Unsaturated oximes underwent electrophilic epoxidation with in-situ-generated dimethyldioxirane to give the corresponding epoxides in good yields. This reaction is an example of “carbonyl umpolung” by transformation of α,β-unsaturated ketones to their oximes. Nucleophilic ring-opening reactions of the epoxides afforded α-substituted products. Shi asymmetric epoxidation of the oximes proceeded with moderate enantioselectivity.

Introduction

α,β-Unsaturated carbonyl compounds undergo nucleophilic reaction at electron-deficient carbon–carbon double bonds, as well as cycloaddition with diene or a 1,3-dipole having a high highest occupied molecular orbital (HOMO) energy level. The character of the enones and enals can be transformed from electron-deficient to electron-rich by conversion to the corresponding hydrazones and oximes because of the electron-donating ability of an electron pair (umpolung)^1–5) (Fig. 1).

Fig. 1. Umpolung of α,β-Unsaturated Carbonyl Compounds

(Color figure can be accessed in the online version.)

With this idea in mind, we have recently reported inverse-electron-demand (IED) 1,3-dipolar cycloaddition of α,β-unsaturated oximes with nitrones,⁶⁾ IED Diels–Alder reaction of α,β-unsaturated hydrazones with α-pyrones,⁷⁾ and IED hetero-Diels–Alder reaction of α,β-unsaturated hydrazones with oxadienes⁸⁾ (Fig. 2). More recently, we have also reported C–H functionalization of β-position of α,β-unsaturated oximes by using cationic Pd(II) catalysts.^9,10)

Fig. 2. Reactive Electrophiles with α,β-Unsaturated Oximes or Hydrazones

(Color figure can be accessed in the online version.)

Here, we focused on epoxidation of α,β-unsaturated oximes.^11–19) We show herein that α,β-unsaturated O-alkyl or O-silyl oximes readily react with electrophilic dioxiranes^20–23) to give α,β-epoxy oximes in high yields. The results of ring opening of the epoxides with nucleophiles and an examination of Shi asymmetric epoxidation of the oximes are also reported (Eq. 1).

  

(1)

First, we synthesized the oximes. Thus, O-benzyl oximes 2a–d were prepared by treatment of carbonyl compounds 1a–d with O-benzylhydroxylamine hydrochloride and sodium acetate in methanol. Condensation of carbonyl compounds 1a and 1c with O-silyl hydroxylamine afforded O-silyl oximes 3a and 3c. O-Silyl oxime 3b was obtained from carbonyl compound 1b by treatment with hydroxylamine hydrochloride and sodium acetate in methanol followed by silylation under usual conditions (Chart 1).

Chart 1.

The epoxidation of α,β-unsaturated oximes was next examined and dimethyldioxolane (DMDO) was found to be a suitable reagent (Table 1). Thus, exposure of five-membered O-benzyloxime 2a to in-situ-generated DMDO at room temperature for 1 d afforded the corresponding epoxide 4a in 86% yield, whereas treatment with m-chloroperbenzoic acid (mCPBA) gave only 26% yield of 4a (entry 1 vs. footnote a). Six-membered 2b, seven-membered 2c and acyclic 2d also underwent epoxidation with DMDO to yield epoxides 4b–d in 94, 88, and 88% yields, respectively (entries 2–4). On the other hand, the reactivity of O-silyl oximes 3a–c was highly dependent on the ring size. Five-membered O-silyl oxime 3a reacted with DMDO to afford epoxide 5a in 88% yield, whereas six-membered and seven-membered oximes 3b and 3c furnished epoxides 5b and 5c in 58 and 34% yields, respectively (entries 5–7).

Table 1. Epoxidation of Oximes 2 and 3

^a) Use of mCPBA gave a only 26% yjeld of epoxjde 4a.

Since nucleophilic ring opening of epoxides is synthetically important, we next examined ring opening of epoxy oximes 4a–c. All epoxides reacted at the α-position of the oxime functionalities, although β-unsubstituted epoxy oximes have been reported to react at the β-position^17,18) (Table 2). Thus, mild heating of epoxide 4a with sodium azide in N,N-dimethylformamide (DMF) afforded β-hydroxy α-azide oxime 6a with trans-stereochemistry in 40% yield (entry 1). Oxime 4a also reacted with benzylamine in dimethyl sulfoxide (DMSO) at 110 °C to give 7a in 84% yield (entry 2). When oxime 4a was left with K₂CO₃ in MeOH at room temperature for 2 d, ring opening occurred cleanly to give 8a in 93% yield (entry 3). Oxime 4a, on treatment with 4-tert-butylbenzenethiol under basic conditions, underwent ring-opening reaction to afford 9a in quantitative yield (entry 4). These conditions using thiol were also applied to 4b and 4c, affording 9b and 9c in 99 and 95% yields, respectively (entries 5 and 6). The structure of 9b was ambiguously established by X-ray diffraction analysis²⁴⁾ (Fig. 3). The structures of other adducts 6a–8a and 9a, c were assigned the same regio and stereochemistry as 9b. The high regioselectivity of ring opening of epoxides appears to show the reactivity of α-position of oxime functionality for nucleophiles similar to that of allylic position.

Table 2. Ring Opening Reaction of Epoxy Oximes 4a–c

Fig. 3. ORTEP Drawing of Compound 9b

(Color figure can be accessed in the online version.)

It is reported that α,β-unsaturated oxime 2b undergoes radical addition at the β-position followed by oxidation at the α-position to afford 9b′, which has opposite regiochemistry to 9b²⁵⁾ (Chart 2). Thus, the two-step sequence of epoxidation of α,β-unsaturated oxime 2 followed by ring opening by thiol may be complementary to oxidative radical addition of thiol to 2 followed by oxidation, as depicted in Chart 2.

Chart 2.²⁵⁾

Several examples of carbon–carbon bond formation through ring opening of epoxy oximes are known,^11,12,19) so we examined the reaction of our epoxy oxime 4a with Grignard reagent and silyl enol ether in the presence of Lewis acid (Chart 3). However, only halogen adducts 10a and 12a were obtained instead of the expected products 11a and 13a. The structure of 10a was confirmed by X-ray diffraction analysis²⁴⁾ (Fig. 4).

Chart 3.

Fig. 4. ORTEP Drawing of Compound 10a

(Color figure can be accessed in the online version.)

The possibility of asymmetric epoxidation²⁶⁾ of α,β-unsaturated oximes 2 and 3 was next explored (Table 3). Oxime 2a was treated under chiral dioxirane-mediated Shi epoxidation conditions^27,28) in the presence of catalyst 14a²⁹⁾ to give (1S)-4a in 61% yield with 60% enantiomeric excess (ee). In contrast, the use of 14b³⁰⁾ gave only (1S)-4a in 14% yield with 9% ee (entry 1). Although the chemical and asymmetric yields (62%, 59% ee) of 4b were similar to those of 4a (entry 2), the seven-membered oxime 4c was obtained in a similar chemical yield (67%), but as a racemate (entry 3). In the case of O-silyl oximes 3a–c, both the chemical yields and asymmetric yields (ee) were highly dependent on the ring size. Epoxidation of five-membered oxime 3a proceeded in moderate chemical yield and ee (entry 4), whereas six-membered oxime 3b and seven-membered oxime 3c furnished very low chemical and asymmetric yields (entries 5 and 6).

Table 3. Asymmetric Epoxidation of Oximes 2 and 3

^a) Use of 14b in place of 14a resulted in a low yield (14%) with only 9%ee.

The stereochemistry of epoxide (1S)-4a was confirmed by chemical modification and the modified Mosher method³¹⁾ (Chart 4). Ring opening of epoxide (1S)-4a in MeOH with K₂CO₃ followed by acylation of the hydroxyl group of (2S)-8a with (R)-α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) and (S)-MTPA afforded 15a and 15b, respectively. The ¹H-NMR chemical shift differences (Δδ = (δS–δR), CDCl₃) of 15a and 15b are shown in Chart 4, confirming the stereochemistry.

Chart 4.

Conclusion

Electrophilic epoxidation of α,β-unsaturated oximes with dimethyldioxirane affords epoxides, which undergo nucleophilic ring-opening reaction at the α-position with trans-stereochemistry. Shi epoxidation was found to exhibit moderate asymmetric selectivity. Since various asymmetric epoxidation methods similar to Shi’s, using in-situ-generated chiral dioxiranes, are known, this approach may be a powerful method for obtaining enantio-enriched epoxides.

Experimental

General

IR spectra (IR) were recorded with a Shimadzu FTIR-3200 A. ¹H-NMR spectra were recorded on a JEOL JNM-AL300 (300 MHz), JEOL-ECZ400S (400 MHz), or a JEOL JNM-AL 600 (600 MHz) spectrometer. The chemical shifts are expressed in ppm downfield from tetramethylsilane (δ = 0) as an internal standard (CDCl₃ solution). ¹³C-NMR spectra were recorded on a JEOL JNM-AL300 (75 MHz), JEOL-ECZ400S (100 MHz), or a JEOL JNM-AL 600 (150 MHz) spectrometer. The chemical shifts are reported in ppm, relative to the central line of the triplet at 77.0 ppm for CDCl₃. Measurements of mass spectra (MS) and high-resolution MS (HRMS) were performed with a JEOL JMS-700 or a JMS-T100LP mass spectrometer. Column chromatography was carried out on silica gel (silica gel 40–50 mm neutral, Kanto Chemical Co., Inc., Tokyo, Japan). Merck precoated TLC plates (silica gel 60 F254, 0.25 µm, Art 5715) were used for TLC analysis. Compounds 2a,²⁵⁾2b,²⁵⁾2d,⁸⁾ and 3a⁶⁾ were prepared by reported methods.

(E)-Cyclohept-2-en-1-one O-Benzyloxime (2c)

To a mixture of O-benzylhydroxylamine hydrochloride (2.61 g, 16.3 mmol) and sodium acetate (1.34 g, 16.3 mmol) in MeOH (80 mL) was added cyclohept-2-en-1-one (0.900 g, 8.17 mmol) at room temperature. The mixture was stirred for 2 h, then concentrated under reduced pressure, and the residue was partitioned between CH₂Cl₂ and H₂O. The organic layer was washed with brine, dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane–AcOEt, 25/1) to give (E)-oxime 2c (0.834 g, 47%) as a pale yellow oil. IR (KBr) 2928, 1497 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.37–7.26 (5H, m), 6.07 (1H, dt, J = 12.3, 1.8 Hz), 5.94 (1H, dt, J = 12.3, 4.8 Hz), 5.12 (2H, s), 2.74–2.70 (2H, m), 2.33–2.28 (2H, m), 1.77–1.64 (4H, m); ¹³C-NMR (75 MHz, CDCl₃) δ: 160.7, 138.0, 136.0, 128.3, 127.9, 127.7, 126.3, 75.9, 30.7, 28.4, 26.8, 23.6; HRMS (FAB) m/z Calcd for C₁₄H₁₈NO [M + H]⁺ 216.2038, Found 216.1384.

(E)-Cyclohex-2-en-1-one O-(tert-Butyldiphenylsilyl)oxime (3b)

To a stirred solution of cyclohex-2-en-1-one oxime³²⁾ (1.25 g, 11.3 mmol) in CH₂Cl₂ (23 mL) was added tert-butylchlorodiphenylsilane (3.71 g, 13.5 mmol) and imidazole (1.53 g, 22.5 mmol) at 0 °C, and stirring was continued for 1 h. The mixture was partitioned between CH₂Cl₂ and H₂O, and the organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane–CH₂Cl₂, 2/1) to give 3b (1.37 g, 35%) as a colorless oil. IR (NaCl) 2934, 1427 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.75–7.65 (4H, m), 7.39–7.26 (6H, m), 6.16 (2H, s), 2.79 (2H, t, J = 6.8 Hz), 2.13 (2H, td, J = 6.8, 2.0 Hz), 1.75 (2H, quin, J = 6.8 Hz), 1.11 (9H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 160.5, 136.3, 135.4, 133.9, 129.5, 127.5, 124.8, 27.1, 25.2, 22.9, 20.9, 19.4; HRMS (electrospray ionization (ESI)) m/z Calcd for C₂₂H₂₈NOSi [M + H]⁺ 350.1940, Found 350.1925.

(E)-Cyclohept-2-en-1-one O-(tert-Butyldiphenylsilyl)oxime (3c)

To a stirred solution of O-(tert-butyldiphenylsilyl)hydroxylamine³³⁾ (0.804 g, 2.96 mmol) in CH₂Cl₂ (40 mL) was added dropwise cyclohept-2-en-1-one (0.330 mL, 2.96 mmol) at room temperature. The mixture was stirred at the same temperature for 24 h, then washed with H₂O, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane–CHCl₃, 2/1) to give 3c (0.237 g, 32%) as crystals. mp 50.5–51.5 °C; IR (NaCl) 2933, 1427 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.74–7.67 (4H, m), 7.39–7.26 (6H, m), 6.12 (1H, dt, J = 12.4, 2.0 Hz), 5.92 (1H, dt, J = 12.4, 4.8 Hz), 2.96–2.89 (2H, m), 2.35–2.27 (2H, m), 1.81–1.69 (4H, m), 1.10 (9H, s); ¹³C-NMR (100 MHz, CDCl3) δ: 165.2, 136.0, 135.4, 133.9, 129.5, 127.5, 126.8, 30.8, 28.3, 27.1, 26.9, 23.7, 19.5; HRMS (ESI) m/z Calcd for C₂₃H₃₀NOSi [M + H]⁺ 364.2097, Found 364.2082.

(E)-6-Oxabicyclo[3.1.0]hexan-2-one O-Benzyloxime (4a): Typical Procedure for Epoxidation

To solution of 2a (0.494 g, 2.64 mmol) in acetone–H₂O (3/1, 88 mL) were added successively NaHCO₃ (1.33 g, 15.8 mmol) and 2KHSO₅·KHSO₄·K₂SO₄ (2.68 g, 4.35 mmol) at room temperature, and the mixture was stirred at the same temperature for 24 h. After evaporation of the acetone, the residue was extracted with AcOEt. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane–AcOEt, 10/1) to give 4a (0.462 g, 86%) as an oil. IR (KBr) 2935, 1496 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.37–7.27 (5H, m), 5.15 (1H, d, J = 12.0 Hz), 5.10 (1H, d, J = 12.0 Hz), 3.80–3.76 (2H, m), 2.73 (1H, ddd, J = 17.4, 9.3, 0.9 Hz), 2.24–2.02 (2H, m), 1.96–1.83 (1H, m); ¹³C-NMR (75 MHz, CDCl₃) δ: 160.8, 137.7, 128.4, 128.0, 127.9, 76.1, 58.4, 56.1, 25.1, 21.8; HRMS (electron impact ionization (EI)) m/z Calcd for C₁₂H₁₃NO₂ [M]⁺ 203.0946, Found 203.0941.

(E)-7-Oxabicyclo[4.1.0]heptan-2-one O-Benzyloxime (4b)

According to the typical procedure, crude 4b was obtained from 2b (70.0 mg, 0.348 mmol), NaHCO₃ (0.175 g, 2.09 mmol), and 2KHSO₅·KHSO₄·K₂SO₄ (0.353 g, 0.574 mmol) in acetone–H₂O (3/1, 12 mL). Purification by column chromatography on silica gel (hexane–AcOEt, 10/1) gave 4b (0.071 g, 94%) as an oil. IR (KBr) 2943, 1497 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.38–7.27 (5H, m), 5.15 (2H, s), 3.50 (2H, dt, J = 6.6, 3.9 Hz), 2.71 (1H, dt, J = 18.9, 3.9 Hz), 2.18 (1H, ddd, J = 13.8, 6.6, 3.0 Hz), 2.06–1.94 (1H, m), 1.79–1.60 (2H, m), 1.53–1.41 (1H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 154.3, 137.7, 128.4, 128.0, 127.8, 76.1, 53.0, 52.1, 23.4, 22.4, 14.5; HRMS (EI) m/z Calcd for C₁₃H₁₅NO₂ [M]⁺ 217.1103, Found 217.1092.

(E)-8-Oxabicyclo[5.1.0]octan-2-one O-Benzyloxime (4c)

According to the typical procedure, crude 4c was obtained from 2c (70.0 mg, 0.325 mmol), NaHCO₃ (0.164 g, 1.95 mmol), and 2KHSO₅·KHSO₄·K₂SO₄ (0.329 g, 0.535 mmol) in acetone–H₂O (3/1, 11 mL). Purification by column chromatography on silica gel (hexane–AcOEt, 12/1) gave 4c (66.2 mg, 88%) as an oil. IR (KBr) 2932, 1497 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.38–7.27 (5H, m), 5.12 (2H, s), 3.57 (1H, dd, J = 4.5, 0.9 Hz), 3.29–3.21 (2H, m), 2.37–2.27 (1H, m), 1.82- 1.41 (5H, m), 1.01–0.87 (1H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 159.9, 137.9, 128.4, 128.0, 127.8, 75.9, 56.9, 55.9, 27.6, 25.0, 24.2, 23.6; HRMS (EI) m/z Calcd for C₁₄H₁₇NO₂ [M]⁺ 231.1259, Found 231.1261.

(E)-Oxiranecarboxaldehyde O-Benzyloxime (4d)

According to the typical procedure, crude 4d was obtained from 2d (70.0 mg, 0.434 mmol), NaHCO₃ (0.218 g, 2.60 mmol), and 2KHSO₅·KHSO₄·K₂SO₄ (0.440 g, 0.716 mmol) in acetone–H₂O (3/1, 15 mL). Purification by column chromatography on silica gel (hexane–AcOEt, 12/1) gave 4d (66.2 mg, 88%) as an oil. IR (KBr) 2959, 1589, 1487 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.40–7.26 (5H, m), 6.99 (1H, d, J = 8.1 Hz), 5.12 (2H, s), 3.52 (1H, ddd, J = 9.0, 6.0, 2.7 Hz), 3.02 (1H, dd, J = 6.0, 2.4 Hz), 2.78 (1H, dd, J = 6.0, 2.7 Hz); ¹³C-NMR (100 MHz, CDCl₃) δ: 148.7, 137.1, 128.5, 128.3, 128.1, 76.4, 48.7, 46.7; HRMS (ESI) m/z Calcd for C₁₀H₁₁NNaO₂ [M + Na]⁺ 200.0688, Found 200.0679.

(E)-6-Oxabicyclo[3.1.0]hexan-2-one O-(tert-Butyldiphenylsilyl)oxime (5a)

According to the typical procedure, crude 5a was obtained from 3a (70.0 mg, 0.209 mmol), NaHCO₃ (0.105 g, 1.25 mmol), and 2KHSO₅·KHSO₄·K₂SO₄ (0.212 g, 0.345 mmol) in acetone–H₂O (3/1, 7 mL). Purification by column chromatography on silica gel (hexane–CH₂Cl₂, 3/2) gave 5a (62.7 mg, 85%) as an oil. IR (KBr) 2959, 1589, 1487 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.75–7.70 (4H, m), 7.44–7.33 (6H, m), 3.80 (1H, d, J = 2.4 Hz), 3.78 (1H, d, J = 2.4 Hz), 3.04–2.90 (1H, m), 2.28–2.16 (2H, m), 2.03–1.83 (1H, m), 1.10 (9H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 166.0, 135.4, 133.4, 129.7, 127.6, 58.7, 55.9, 27.0, 24.9, 21.8, 19.4 (several signals overlapped); HRMS (ESI) m/z Calcd for C₂₁H₂₅NO₂SiNa [M + Na]⁺ 374.1552, Found 374.1568.

(E)-7-Oxabicyclo[4.1.0]heptan-2-one O-(tert-Butyldiphenylsilyl)oxime (5b)

According to the typical procedure, crude 5b was obtained from 3b (30.0 mg, 0.0858 mmol), NaHCO₃ (43.3 mg, 0.516 mmol), 2KHSO₅·KHSO₄·K₂SO₄ (87.2 mg, 0.142 mmol) in acetone–H₂O (3/1, 3 mL). Purification by column chromatography on silica gel (hexane–CH₂Cl₂, 3/2) gave 5b (18.7 mg, 58%) as an oil. IR (NaCl) 2932, 1429 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.72–7.67 (4H, m), 7.44- 7.33 (6H, m), 3.55 (1H, d, J = 4.0 Hz), 3.48 (1H, t, J = 2.6 Hz), 2.98–2.89 (1H, m), 2.25–2.12 (2H, m), 1.82–1.65 (2H, m), 1.57–1.48 (1H, m), 1.10 (9H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 159.3, 135.4, 133.6, 133.5, 129.7, 127.6, 53.1, 52.3, 27.1, 23.6, 22.4, 19.4, 14.6 (several signals overlapped); HRMS (ESI) m/z Calcd for C₂₂H₂₇NO₂SiNa [M + Na]⁺ 388.1709, Found 388.1713.

(E)-8-Oxabicyclo[5.1.0]octan-2-one O-(tert-Butyldiphenylsilyl)oxime (5c)

According to the typical procedure, crude 5c was obtained from 3c (60.0 mg, 0.165 mmol), NaHCO₃ (85.7 mg, 1.02 mmol), and 2KHSO₅·KHSO₄·K₂SO₄ (172.4 mg, 0.280 mmol) in acetone–H₂O (3/1, 6 mL). Purification by column chromatography on silica gel (hexane–AcOEt, 20/1) gave 5c (21.7 mg, 34%) as an oil. IR (NaCl) 2858, 1429 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.75–7.66 (4H, m), 7.46–7.33 (6H, m), 3.64–3.54 (2H, m), 3.28 (1H, t, J = 4.5 Hz), 2.24–2.28 (1H, m), 1.90–1.59 (5H, m), 1.10 (9H, s), 1.07–0.93 (1H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 164.5, 135.5, 133.7, 133.5, 129.6, 127.6, 127.5, 57.0, 55.9, 27.6, 27.1, 24.9, 23.8, 23.6, 19.4 (several signals overlapped); HRMS (ESI) m/z Calcd for C₂₃H₂₉NNaO₂Si [M + Na]⁺ 402.1865, Found 402.1855.

(2R*,3R*,E)-2-Azido-3-hydroxycyclopentan-1-one O-benzyl Oxime (6a)

To a solution of 4a (20.0 mg, 0.0984 mmol) in DMF (2.0 mL) was added NaN₃ (13.0 mg, 0.200 mmol) at room temperature. The mixture was stirred at 50 °C for 12 h, then diluted with H₂O, and extracted with hexane–Et₂O (1/1). The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane–Et₂O, 2/1) to give 6a (9.70 mg, 40%) as an oil. IR (NaCl) 3392, 2924, 2104, 1015 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.40–7.27 (5H, m), 5.15 (2H, s), 4.13 (1H, d, J = 5.2 Hz), 4.05 (1H, q, J = 5.2 Hz), 2.65 (1H, ddd, J = 19.2, 9.2, 6.4 Hz), 2.52 (1H, dddd, J = 19.2, 9.2, 6.4, 1.6 Hz), 2.15–2.04 (1H, m), 2.00 (1H, br), 1.82–1.70 (1H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 159.7, 137.4, 128.4, 128.2, 127.9, 76.6, 75.3, 67.4, 29.3, 24.0; HRMS (ESI) m/z Calcd for C₁₂H₁₄N₄O₂Na [M + Na]⁺ 269.1014, Found 269.1016.

(2R*,3R*,E)-2-(Benzylamino)-3-hydroxycyclopentan-1-one O-Benzyloxime (7a)

To a solution of 4a (50.0 mg, 0.246 mmol) in DMSO (2.5 mL) was added benzylamine (53.8 µL, 0.492 mmol) at room temperature. The mixture was stirred at 110 °C for 24 h, then concentrated under reduced pressure, and the residue was chromatographed on silica gel (CH₂Cl₂–MeOH, 20/1) to give 7a (64.4 mg, 84%) as an oil. IR (NaCl) 3310, 2925, 1454 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.42–7.27 (10H, m), 5.11 (2H, s), 4.02 (1H, d, J = 12.9 Hz), 3.95 (1H, q, J = 6.6 Hz), 3.86 (1H, d, J = 12.9 Hz), 3.38 (1H, dd, J = 6.6, 1.8 Hz), 2.61 (1H, ddd, J = 19.2, 9.0, 4.2 Hz), 2.44 (1H, dtd, J = 19.2, 9.0, 1.8 Hz), 2.21–1.88 (3H, m), 1.70–1.52 (1H, m); ¹³C-NMR (75 MHz, CDCl₃) δ: 162.8, 140.1, 138.1, 128.5, 128.31, 128.28, 128.1, 127.7, 127.1, 76.3, 76.0, 67.0, 51.8, 28.9, 23.9; HRMS (ESI) m/z Calcd for C₁₉H₂₂N₂O₂Na [M + Na]⁺ 333.1579, Found 333.1573.

(2R*,3R*,E)-3-Hydroxy-2-methoxycyclopentan-1-one O-Benzyloxime (8a)

To a stirred solution of 4a (20.0 mg, 0.0984 mmol) in MeOH (1.0 mL) was added K₂CO₃ (27.1 mg, 0.196 mmol) at 0 °C. The mixture was stirred at room temperature for 2 d, and then diluted with a saturated aqueous solution of NH₄Cl, and extracted with AcOEt. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane–AcOEt, 1/1) to give 8a (21.5 mg, 93%) as an oil. IR (NaCl) 3405, 2934, 1454, 1096 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.39–7.25 (5H, m), 5.15 (2H, s), 4.15 (1H, dd, J = 6.3, 2.5 Hz), 3.84 (1H, d, J = 2.5 Hz), 3.41 (3H, s), 2.63 (1H, dt, J = 14.4, 6.3 Hz), 2.49 (1H, dddd, J = 14.4, 7.2, 3.9, 0.9 Hz), 2.15–2.14 (1H, m), 1.99 (1H, s), 1.80–1.69 (1H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 161.9, 137.9, 128.3, 128.0, 127.7, 85.5, 76.0, 74.9, 57.1, 29.2, 23.6; HRMS (ESI) m/z Calcd for C₁₃H₁₇NO₃Na [M + Na]⁺ 258.1106, Found 258.1116.

(2R*,3R*,E)-2-((4-(tert-Butyl)phenyl)thio)-3-hydroxycyclopentan-1-one O-Benzyloxime (9a)

To a solution of 4-tert-butylbenzenethiol (0.820 mL, 4.88 mmol) in tetrahydrofuran (THF) (9.0 mL) was added dropwise a 1.6 M solution of n-butyllithium (0.490 mL, 0.784 mmol) in hexane at room temperature. The mixture was stirred at the same temperature for 30 min, then added dropwise to a solution of 4a (20.0 mg, 0.0984 mmol) in THF (1.0 mL) at 0 °C, and stirring was continued at the same temperature for 1.5 h. The mixture was diluted with a saturated aqueous solution of NH₄Cl (5 mL), and extracted with Et₂O. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane–AcOEt, 3/1) to give 9a (36.0 mg, 99%) as an oil. IR (NaCl) 3400, 2962, 1456 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.41–7.22 (9H, m), 5.09 (2H, s), 4.14 (1H, q, J = 3.6 Hz), 3.92–3.88 (1H, m), 2.67 (1H, dt, J = 19.0, 9.0 Hz), 2.52 (1H, dddd, J = 19.0, 9.0, 4.4, 1.2 Hz), 2.28–2.16 (1H, m), 2.04 (1H, br), 1.83–1.72 (1H, m), 1.29 (9H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 162.4, 151.1, 137.8, 132.9, 129.5, 128.3, 128.0, 127.7, 126.0, 76.0, 75.9, 56.2, 34.5, 31.2, 30.0, 24.6; HRMS (ESI) m/z Calcd for C₂₂H₂₇NO₂SNa [M + Na]⁺ 392.1660, Found 392.1644.

(2R*,3R*,E)-2-((4-(tert-Butyl)phenyl)thio)-3-hydroxycyclohexan-1-one O-Benzyloxime (9b)

Using a similar procedure to that described for 9a, crude 9b was obtained from 4-tert-butylbenzenethiol (0.820 mL, 4.88 mmol), 1.6 M n-butyllithium (0.490 mL, 0.784 mmol) in hexane, and 4b (21.3 mg, 0.0984 mmol). Purification by column chromatography on silica gel (hexane–AcOEt, 6/1) gave 9b (37.2 mg, 99%) as crystals. mp 123.0–123.5 °C; IR (KBr) 3331, 2953, 1026, 976 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.40–7.20 (9H, m), 5.05 (1H, d, J = 12.0 Hz), 4.98 (1H, d, J = 12.0 Hz), 4.17–4.07 (1H, m), 3.75 (1H, d, J = 4.0 Hz), 2.97 (1H, dt, J = 14.7, 4.0 Hz), 2.46–2.31 (1H, m), 2.22 (1H, brs), 2.14–1.99 (1H, m), 1.88–1.53 (3H, m), 1.28 (9H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 157.5, 150.6, 137.9, 132.1, 130.4, 128.3, 127.9, 127.6, 125.9, 75.5, 71.1, 55.4, 34.5, 31.2, 28.4, 22.0, 19.4; HRMS (ESI) m/z Calcd for C₂₃H₂₉NO₂SNa [M + Na]⁺ 406.1817, Found 406.1806. X-Ray diffraction analysis of 9b was conducted. The data have been deposited with the Cambridge Crystallographic Data Centre.²⁴⁾

(2R*,3R*,E)-2-((4-(tert-Butyl)phenyl)thio)-3-hydroxycycloheptan-1-one O-Benzyloxime (9c)

Using a similar procedure to that described for 9a, crude 9c was obtained from 4-tert-butylbenzenethiol (0.820 mL, 4.88 mmol), 1.6 M n-butyllithium (0.490 mL, 0.784 mmol) in hexane, and 4c (22.7 mg, 0.0984 mmol). Purification by column chromatography on silica gel (hexane–AcOEt, 6/1) gave 9c (36.9 mg, 95%) as an oil. IR (NaCl) 3420, 2936, 2961, 2866, 1015 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.37–7.17 (9H, m), 5.02 (1H, d, J = 12.4 Hz), 4.94 (1H, d, J = 12.4 Hz), 3.89 (1H, t, J = 7.6 Hz), 3.81 (1H, d, J = 7.6 Hz), 2.92 (1H, ddd, J = 14.4, 7.6, 3.0 Hz), 2.41 (1H, br s), 2.01 (1H, ddd, J = 14.4, 7.6, 3.0 Hz), 1.96–1.87 (1H, m), 1.87–1.77 (1H, m), 1.78–1.41 (4H, m), 1.28 (9H, s); ¹³C-NMR (100 MHz, CDCl₃) δ: 159.7, 150.7, 138.2, 132.3, 130.3, 128.3, 127.8, 127.6, 125.9, 75.5, 73.6, 60.5, 34.5, 34.3, 31.2, 26.1, 25.9, 25.6; HRMS (EI) m/z Calcd for C₂₄H₃₁NO₂S [M]⁺ 397.2075, Found 397.2076.

(2R*,3R*,E)-2-Bromo-3-hydroxycyclopentan-1-one O-Benzyloxime (10a)

To a solution of 4a (50.0 mg, 0.246 mmol) in THF (2 mL) was added dropwise a 1.0 M solution of EtMgBr (0.271 mL, 0.271 mmol) in THF at −78 °C. The mixture was stirred at −78 °C for 1 h, at 0 °C for 18 h, at room temperature for 3.5 h, and at 40 °C 5 h. It was then diluted with a saturated aqueous solution of NH₄Cl, and extracted with AcOEt. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane–AcOEt, 4/1) to give 10a (50.0 mg, 71%) as crystals. mp 59.5–60.0 °C; IR (KBr) 3287, 2960, 2886, 1371 cm⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ: 7.41–7.25 (5H, m), 5.17 (1H, d, J = 12.0 Hz), 5.12 (1H, d, J = 12.0 Hz), 4.49 (1H, d, J = 0.8 Hz), 4.33 (1H, s), 2.73–2.57 (2H, m), 2.42–2.29 (1H, m), 1.94–1.81 (1H, m) (OH signal was missing); ¹³C-NMR (100 MHz, CDCl₃) δ: 163.2, 137.3, 128.4, 127.92, 127.88, 77.3, 76.3, 51.2, 29.1, 23.6; HRMS (EI) m/z Calcd for C₁₂H₁₄BrNO₂ [M]⁺ 283.0208, Found 283.0208. X-Ray diffraction analysis of 10a was conducted. The data obtained have been deposited with the Cambridge Crystallographic Data Centre.²⁴⁾

(2R*,3R*,E)-2-Chloro-3-hydroxycyclopentan-1-one O-Benzyl Oxime (trans-12a) and Its (2R*,3S*,E)-Isomer (cis-12a)

To a stirred solution of 4a (80 mg, 0.394 mmol) in CH₂Cl₂ (1.8 mL) was added dropwise a 1 M solution of SnCl₄ in CH₂Cl₂ (1.18 mL, 1.18 mmol) at −78 °C. The solution was stirred at the same temperature for 10 min, and then a saturated aqueous solution of NaHCO₃ (8 mL) was added. The mixture was allowed to warm to room temperature, and extracted with CH₂Cl₂. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane–AcOEt, 3/1) to give a 1.5 : 1 mixture of trans-12a and cis-12a. Further chromatography on silica gel (hexane–AcOEt, 3/1) gave pure trans-12a and cis-12a. trans-12a (less polar): Rf 0.35 (hexane–AcOEt, 3/1); IR (KBr) 3430, 2924, 1454 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.38–7.27 (5H, m), 5.18 (1H, d, J = 12.0 Hz), 5.13 (1H, d, J = 12.0 Hz), 4.43–4.41 (1H, m), 4.43–4.27 (1H, br), 2.76–2.54 (2H, m), 2.30 (1H, m), 2.10 (1H, s), 1.90–1.81 (1H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 161.8, 137.4, 128.4, 128.1, 127.9, 77.5, 76.5, 61.6, 29.2, 23.7; HRMS (EI) m/z Calcd for C₁₂H₁₄ClNO₂ [M]⁺ 239.0713, Found 239.0707. cis-12a (more polar) Rf 0.25 (hexane–AcOEt, 3/1); IR (KBr) 3430, 2924, 1456 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 7.39–7.30 (5H, m), 5.17 (1H, d, J = 12.0 Hz), 5.12 (1H, d, J = 12.0 Hz), 4.72 (1H, d, J = 4.5 Hz), 4.29–4.19 (1H, m), 2.76–2.65 (1H, m), 2.43 (1H, dt, J = 19.5, 8.4 Hz), 2.24 (1H, d, J = 7.5 Hz), 2.09–1.91 (2H, m); ¹³C-NMR (100 MHz, CDCl₃) δ: 160.1, 137.3, 128.4, 128.1, 128.0, 76.5, 72.6, 63.4, 28.8, 23.8; HRMS (EI) m/z Calcd for C₁₂H₁₄ClNO₂ [M]⁺ 239.0713, Found 239.0708.

(1S,5R,E)-6-Oxabicyclo[3.1.0]hexan-2-one O-Benzyloxime [(1S)-4a]

To a solution of 2a (50.0 mg, 0.267 mmol) in CH₃CN (1.4 mL) was added an aqueous solution of Na₂(ethylenediaminetetraacetic acid (EDTA)) (1.0 × 10⁻⁴ M, 1.4 mL), n-Bu₄NHSO₄ (5.50 mg, 0.0162 mmol), and a mixture of NaHCO₃ (352 mg, 4.19 mmol) and 2KHSO₅·KHSO₄·K₂SO₄ (457 mg, 0.74 mmol) at 0 °C. A solution of 14a (21.8 mg, 0.0680 mmol) in CH₃CN (0.7 mL) was further added at the same temperature. The resulting mixture was stirred at room temperature for 17 h, diluted with H₂O, and extracted with AcOEt. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane–AcOEt, 10/1) to give (1S)-4a (33.7 mg, 61, 60% ee) as an oil. The enantiomeric excess was determined by chiral HPLC analysis (CHIRALPAK^® AD-3, solvent; hexane–ethanol, 94/6, flow rate; 1.0 mL/min, 25 °C, (1S)-4a: t₁ = 7.7 min; (1R)-4a: t₂ = 8.6 min). [α]_D²⁵ = –40.8 (c 0.316, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) δ: 7.39–7.27 (5H, m), 5.12 (2H, d, J = 2.1 Hz), 3.80–3.75 (2H, m), 2.73 (1H, ddd, J = 17.4, 9.3, 0.9 Hz), 2.23–2.01 (2H, m), 1.93–1.83 (1H, m). The spectrum is identical with that of 4a (racemate).

(1S,6R,E)-7-Oxabicyclo[4.1.0]heptan-2-one O-Benzyloxime [(1S)-4b]

Using a similar procedure to that described for (1S)-4a, crude (1S)-4b was obtained from 4b (30.0 mg, 0.149 mmol), an aqueous solution of Na₂(EDTA) (1.0 × 10⁻⁴ M, 0.8 mL), n-Bu₄NHSO₄ (3.40 mg, 0.01 mmol), NaHCO₃ (208.3 mg, 2.48 mmol), 2KHSO₅·KHSO₄·K₂SO₄ (270.5 mg, 0.439 mmol), and 14a (12.8 mg, 0.040 mmol). Purification by column chromatography on silica gel (hexane–AcOEt, 10/1) gave (1S)-4b (21.2 mg, 62, 59% ee) as an oil. The enantiomeric excess was determined by chiral HPLC analysis (CHIRALPAK^® AD-3, solvent; hexane–ethanol, 94/6, flow rate; 1.0 mL/min, 25 °C, (1S)-4b: t₁ = 5.6 min; (1R)-4b: t₂ = 6.1 min). [α]_D²⁵ = –13.8 (c 0.190, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) δ: 7.39–7.27 (5H, m), 5.15 (2H, s), 3.52 (1H, d, J = 4.4 Hz), 3.49 (1H, m), 2.75–2.67 (1H, m), 2.21–2.13 (1H, m), 2.05–1.94 (1H, m), 1.79–1.58 (2H, m), 1.50–1.41 (1H, m). The spectrum is identical with that of 4b (racemate).

(1R,2R,E)-3-((Benzyloxy)imino)-2-methoxycyclopentyl (R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate[(1R,2R,E)-15a] and Its (1S,2S,E)-Isomer[(1S,2S,E)-15a]

To a solution of (2R)-8a (5.00 mg, 21.3 µmol) obtained from (2S)-2a (60% ee) in CH₃CN (0.4 mL) was added (R)-(+)-MTPA (20.0 mg, 85.2 µmol), EDCI (16.3 mg, 85.2 µmol), and DMAP (a catalytic amount) at room temperature. The mixture was stirred the same temperature for 2 d, then diluted with H₂O, and extracted with CH₂Cl₂. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane–AcOEt, 10/1) to give an inseparable 81 : 19 mixture of (R)-MTPA esters, (1R,2R,E)-15a and (1S,2S,E)-15a (4.40 mg, 35%). IR (NaCl) 2918, 2806, 2361, 1754, 1171 cm⁻¹; ¹H-NMR (600 MHz, CDCl₃) δ: 7.51–7.7.27 (10H, m), 5.33–5.25 (1H, m), 5.20–5.06 (2H, m), 4.03 (1H × 8/10, s), 3.89 (1H × 2/10, s), 3.48 (3H × 2/10, s), 3.46 (3H × 8/10, s), 3.39 (3H × 8/10, s), 3.36 (3H × 2/10, s), 2.64–2.52 (1H, m), 2.52–2.42 (1H, m), 2.38–2.19 (1H, m), 1.92–1.80 (1H, m); ¹³C-NMR (150 MHz, CDCl₃, each signal of the minor isomer (1S,2S,E)-15a is marked with an asterisk) δ: 165.7, 160.3, 160.1*, 137.80, 137.75*, 131.9, 131.8*, 129.69*, 129.67, 128.4, 128.3, 127.86, 127.78, 127.3*, 127.2, 84.6, 84.4, 82.29*, 82.26, 78.84*, 78.75, 76.2, 56.91*, 56.89, 55.35, 55.28*, 27.2*, 27.1, 23.83*, 23.77 (all data are shown without distinction of the two isomers); HRMS (EI) m/z Calcd for C₂₃H₂₄F₃NO₅ [M]⁺ 451.1607, Found 451.1599.

(1R,2R,E)-3-((Benzyloxy)imino)-2-methoxycyclopentyl (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate[(1R,2R,E)-15b] and Its (1S,2S,E)-Isomer[(1S,2S,E)-15b]

Using the same procedure described for 15a, an inseparable 30 : 70 mixture of (S)-MTPA esters, (1R,2R,E)-15b and (1S,2S,E)-15b (5.80 mg, 46%), was obtained from (2R)-8a (5.00 mg, 21.3 µmol) derived from (2S)-2a (60% ee), (S)-MTPA (20.0 mg, 85.2 µmol), EDCI (16.3 mg, 85.2 µmol), and DMAP (a catalytic amount). IR (NaCl) 2915, 2849, 2360, 1751, 1171 cm⁻¹; ¹H-NMR (600 MHz, CDCl₃) δ: 7.53–7.27 (10H, m), 5.33–5.25 (1H, m), 5.20–5.06 (2H, m), 4.03 (1H × 3/10, s), 3.98 (1H × 7/10, s), 3.48 (3H × 7/10, s), 3.46 (3H × 3/10, s), 3.39 (3H × 7/10, s), 3.36 (3H × 7/10, s), 2.64–2.42 (2H, m), 2.38–2.19 (1H, m), 2.00–1.92 (1H, m); ¹³C-NMR (150 MHz, CDCl₃, each signal of the minor isomer ent-12a is marked with an asterisk) δ: 165.7, 160.3*, 160.1, 137.80*, 137.75, 131.9*, 131.8, 129.69, 129.67*, 128.5, 128.34*,128.33, 127.86, 127.78, 127.3, 127.2*, 84.66, 84.59*, 84.5, 84.4*, 82.29, 82.26*, 78.84, 78.75*, 76.23, 76.22*, 56.91, 56.89*, 55.35*, 55.28, 27.2, 27.1*, 23.83, 23.77* (all data are shown without distinction of the two isomers); HRMS (EI) m/z Calcd for C₂₃H₂₄F₃NO₅ [M]⁺ 451.1607, Found 451.1609.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

References and Notes

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