A simple synthetic method for chiral 1,2-epoxides and the total synthesis of a chiral pheromone epoxide

Abstract

Chiral 1,2-epoxyalkan-3-ol tosyl esters 4a–h were successfully synthesized from alkynols or allyl chlorides in three steps using Sharpless AD reaction as a key step in good yields. The chiral insect pheromone epoxide (6Z,9S,10R)-9,10-epoxyhenicos-6-ene 9 was thus smoothly synthesized from the corresponding key intermediate 4g.

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Introduction

Synthetic chemists always face a major challenge in the preparation of chiral compounds with high optical purity. The need for pure enantiomers is particularly apparent in the field of insect pheromone chemistry, since insect chemoreception can be highly stereoselective.^1–3 Optically active epoxides are an important class of natural products encountered as sex attractants of Lepidopteran pests, ⁴ and self-defensive substances against rice blast disease.⁵ The optically active 1,2-epoxyalkan-3-ols are key intermediates in the synthesis of those insect pheromones because they can be easily converted to the corresponding optically active 2,3-epoxyalkan-1-ols through the Payne rearrangement ⁶ or to optically active internal epoxides via an alkylative rearrangement of the corresponding toluene-p-sulfonate (tosyl) esters.⁷ In order to obtain the chiral epoxides in those synthetic approaches, until now the mostly used key reaction has been the Sharpless AE reaction on the Z-allylic alcohols.^7–9 Herein we report two further synthetic methods for the chiral 1,2-epoxyalkan-3-ol tosyl esters 4a–h using Sharpless AD ¹⁰ as the key reaction, and the total synthesis of the insect sex pheromone (6Z,9S,10R)-9,10-epoxyhenicos-6-ene 9 with full experimental details.¹¹

Results and discussion

Sharpless AD reaction on the starting materials 2 possessing different, long alkyl chains, prepared by reduction of the corresponding alkynols 1 ¹² using LiAlH₄ in THF, installed the two stereogenic centers, with 95–97% enantiomeric excess (ee).¹³ The resulting triols 3 were subsequently treated with NaH and Tos-Im ¹⁴ in THF to produce the key intermediates 4 in good yield (Scheme 1). To the best of our knowledge, this new synthetic approach is the shortest and the most efficient among those reported in previous literature.^7–9 Thus 1,2-epoxy-3-tosyl esters (4a–h) with different alkyl chains were obtained as colorless solids or oils. Only one diastereoisomer was detected during this reaction. Their total yields in three steps, specific optical rotations and mps are summarized in Table 1. The chemical yields of 4a–h slightly increased with an increase in the alkyl chain length. The specific optical rotation of the key intermediate 4g was very close to that reported in the literature {lit.,⁸ [α]²⁰_D +8.3 (c 1, CHCl₃)}.

Table 1 Yields and physical properties of the obtained 1,2-epoxy-3-tosyl esters 4a–h

Compound	R	Mp (T/°C)	[α]^20D (c 1, CHCl3)	Yield (%) ^a
a Total yields in three steps.
4a	C5H11	oil	+8.5	42
4b	C6H13	oil	+8.2	45
4c	C7H15	54–55	+8.5	47
4d	C8H17	57–58	+8.0	48
4e	C9H19	59–60	+8.7	48
4f	C10H21	72–74	+8.3	50
4g	C11H23	71–72	+8.6	54
4h	C12H25	85–86	+8.0	57

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Scheme 1 Reagents, conditions and yields: (a) LiAlH₄, THF, reflux; 83–94%; (b) K₃Fe(CN)₆, K₂CO₃, NaHCO₃, MeSO₂NH₂, (DHQ)₂PHAL, K₂OsO₂(OH)₄, ^tBuOH–H₂O (1∶1), 0 °C; 68–89%; (c) NaH, Tos-Im, THF; 53–66%.

In the meantime, another alternative synthetic procedure, which is very similar to that mentioned above, also can be utilized to the preparation of 4a–h using the corresponding allyl chlorides 5 as starting materials (Scheme 2). The chemical yields and reaction conditions are shown in Scheme 2 and the obtained chiral diols 6a–h with 94–97% ee ¹³ were directly transferred to the next reaction without purification to give epoxy tosyl esters 4 (step b, c) which have similar specific optical rotations and the same spectral data as those obtained in Scheme 1. The two synthetic routes are very convenient and useful for the synthesis of 4, and this clearly suggests that Sharpless AD is a very powerful and useful synthetic method for the construction ion of the chiral center on many substrates. Indeed, the chiral epoxides 4a–h can obviously be obtained by kinetic resolution using Sharpless AE reaction (Scheme 3). However, the direct asymmetric synthesis using Sharpless AD reaction is much more effective because all the starting materials could be transferred to the desired chiral compounds.

Scheme 2 Reagents, conditions and yields: (a) K₃Fe(CN)₆, K₂CO₃, NaHCO₃, MeSO₂NH₂, (DHQ)₂PHAL, K₂OsO₂(OH)₄, ^tBuOH–H₂O (1∶1), 0 °C; 84–88%; (b) K₂CO₃, MeOH, rt; (c) NaH, Tos-Im, THF; 50–56% (two steps).

Scheme 3

The synthesis of the sex pheromone of Phragmatobia fuliginosa is depicted in Scheme 4. The epoxide 4g was opened by 1-lithioheptyne in the presence of BF₃·Et₂O to afford compound 7. Treatment of 7 with K₂CO₃ in methanol gave another epoxide 8 in good yield. Catalytic hydrogenation of 8 over Lindlar catalyst easily gave the target compound (6Z,9S,10R)-9,10-epoxyhenicos-6-ene 9 in moderate yield. The specific optical rotation of our synthetic compound 9 is very close to those values reported in the literature {9: [α]²⁰_D +8.7 (c 0.97, CHCl₃); lit.,¹⁵ [α]²⁰_D +9.4 (c 0.55, CHCl₃)}. Its ¹H NMR spectral data are completely consistent with those reported in the literature.^15,16

Scheme 4 Reagents, conditions and yield: (a) Hept-1-yne, n-BuLi, BF₃·OEt₂, THF, −78 °C; 70%; (b) K₂CO₃, CH₃OH, rt, 60%; (c) Pd–CaCO₃, H₂; 80%.

In conclusion, we have developed two efficient and convenient procedures for the stereocontrolled synthesis of the chiral 1,2-epoxy-3-tosyl esters 4a–h from which the important chiral pheromone epoxide 9 has been successfully synthesized. This new synthetic approach using Sharpless AD reaction will certainly open a new and effective synthetic route to the preparation of those highly stereoselective chemoreception insect pheromones. In order to disclose the relationship between structure and biological activity, syntheses of their pheromone analogs are in progress.

Experimental

Mps were obtained with a Yanagimoto micro-melting-point apparatus and are uncorrected. Optical rotations were determined for solutions in CHCl₃ or MeOH at 20 °C by using a Perkin-Elmer-241 MC digital polarimeter; [α]_D-values are given in units of 10⁻¹ deg cm² g⁻¹. ¹H NMR spectra were determined for solutions in CDCl₃ with tetramethylsilane (TMS) as internal standard on a Bruker AMX-300 spectrometer; J-values are in Hz. IR spectra were determined by a Perkin-Elmer 983 spectrometer. Mass spectra were recorded with an HP-5989 instrument. High-resolution mass spectra were recorded on a Finnigan MA+ instrument. All solid compounds reported in this paper gave satisfactory CHN microanalyses with an Italian Carlo-Erba 1106 analyzer. Petroleum spirit refers to the fraction with distillation range 60–70 °C. Hydroquinine phthalazine-1,4-diyl diether (DHQ)₂PHAL was purchased from Aldrich.

Typical reaction procedure for the preparation of E-allylic alcohols

(E )-Tetradec-2-en-1-ol 2g.. To a stirred solution of tetradec-2-yn-1-ol 1g (7.56 g, 36 mmol) in dry THF (100 ml) was added LiAlH₄ (3.14 g, 82.6 mmol) slowly at 0 °C under nitrogen atmosphere. After stirring for 20 min, the mixture was heated under reflux for 6 h. The reaction was quenched by adding water at 0 °C. The mixture was filtered, and extracted with diethyl ether. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to afford 2g as a colorless liquid (7.47 g, 98%); bp 104 °C/1 mmHg; IR (neat) ν 3324, 2920, 1597, 1466 cm⁻¹; ¹H NMR (CDCl₃) δ 0.89 (3H, t, J 6.6, CH₃), 1.20–1.40 (18H, m, CH₂), 1.95–2.10 (2H, m, CH₂), 2.20–2.30 (1H, br s, OH), 4.1 (2H, d, J 5.0, CH₂), 5.46–5.70 (2H, m, CH[double bond, length half m-dash]CH); MS (EI) m/z 212 (M⁺) [Calc. for C₁₄H₂₈O (212.3715): C, 79.18; H, 13.29. Found: C, 79.12; H, 13.22%].

Compounds 2a–f and 2h were prepared in the same manner to that described above.

(E )-Oct-2-en-1-ol 2a.. A colorless liquid (3.83 g, 83%); bp 88 °C/1 mmHg; IR (neat) ν 3324, 2923, 1669, 1466 cm⁻¹; ¹H NMR (CDCl₃) δ 0.89 (3H, t, J 6.3, CH₃), 1.20–1.40 (6H, m, CH₂), 1.96–2.08 (2H, m, CH₂), 1.80–1.90 (1H, br s, OH), 4.0 (2H, d, J 4.9, CH₂), 5.43–5.60 (2H, m, CH[double bond, length half m-dash]CH); MS (EI) m/z 128 (M⁺) [Calc. for C₈H₁₆O (128.2120): C, 74.94; H, 12.58. Found: C, 74.86; H, 12.60%].

(E )-Non-2-en-1-ol 2b.. A colorless liquid (4.78, g 93%); bp 90 °C/1 mmHg; IR (neat) ν 3323, 2924, 1704, 1468 cm⁻¹; ¹H NMR (CDCl₃) δ 0.89 (3H, t, J 6.5, CH₃), 1.20–1.42 (8H, m, CH₂), 1.98–2.10 (2H, m, CH₂), 2.60–2.70 (1H, br s, OH), 4.08 (2H, d, J 4.9, CH₂), 5.40–5.60 (2H, m, CH[double bond, length half m-dash]CH); MS (EI) m/z 142 (M⁺) [Calc. for C₉H₁₈O (142.2386): C, 76.00; H, 12.76. Found: C, 75.87; H, 12.92%].

(E )-Dec-2-en-1-ol 2c.. A colorless liquid (5.28 g, 94%); bp 94 °C/1 mmHg; IR (neat) ν 3326, 2925, 1667, 1463 cm⁻¹; ¹H NMR (CDCl₃) δ 0.85 (3H, t, J 6.7, CH₃), 1.20–1.48 (10H, m, CH₂), 1.95–2.05 (2H, m, CH₂), 2.40–2.80 (1H, br s, OH), 4.05 (2H, d, J 4.1, CH₂), 5.45–5.70 (2H, m, CH[double bond, length half m-dash]CH); MS (EI) m/z 156 (M⁺) [Calc. for C₁₀H₂₀O (156.2652): C, 76.86; H, 12.90. Found: C, 76.90; H, 12.70%].

(E )-Undec-2-en-1-ol 2d.. A colorless liquid (5.93 g, 92%); bp 98 °C/1 mmHg; IR (neat) ν 3330, 2924, 2853, 1669, 1462 cm⁻¹; ¹H NMR (CDCl₃) δ 0.85 (3H, t, J 6.1, CH₃), 1.20–1.40 (12H, m, CH₂), 1.95–2.05 (2H, m, CH₂), 2.40–2.80 (1H, br s, OH), 4.0 (2H, d, J 4.8, CH₂), 5.45–5.70 (2H, m, CH[double bond, length half m-dash]CH); MS (EI) m/z 170 (M⁺) [Calc. for C₁₁H₂₂O (170.2918): C, 77.58; H, 13.02. Found: C, 77.54; H, 13.06%].

(E )-Dodec-2-en-1-ol 2e.. A colorless liquid (6.16 g, 93%); bp 100 °C/1 mmHg; IR (neat) ν 3326, 2922, 2852, 1597, 1466 cm⁻¹; ¹H NMR (CDCl₃) δ 0.85 (3H, t, J 6.7, CH₃), 1.20–1.48 (14H, m, CH₂), 1.60–1.80 (1H, br s, OH), 1.98–2.10 (2H, m, CH₂), 4.05 (2H, d, J 5.05, CH₂), 5.45–5.70 (2H, m, CH[double bond, length half m-dash]CH); MS (EI) m/z 184 (M⁺) [Calc. for C₁₂H₂₄O (184.3184): C, 78.20; H, 13.12. Found: C, 78.12; H, 13.17%].

(E )-Tridec-2-en-1-ol 2f.. A colorless liquid (6.42 g, 90%); bp 104 °C/1 mmHg; IR (neat) ν 3328, 2924, 2854, 1597, 1466 cm⁻¹; ¹H NMR (CDCl₃) δ 0.88 (3H, t, J 6.6, CH₃), 1.20–1.40 (16H, m, CH₂), 2.05–2.12 (2H, m, CH₂), 2.40–2.80 (1H, br s, OH), 4.10 (2H, d, J 5.0, CH₂), 5.45–5.70 (2H, m, CH[double bond, length half m-dash]CH); MS (EI) m/z 198 (M⁺) [Calc. for C₁₃H₂₆O (198.3449): C, 78.72; H, 13.21. Found: C, 78.54; H, 13.17%].

(E )-Pentadec-2-en-1-ol 2h.. A colorless liquid (7.32 g, 90%); bp 140 °C/1 mmHg; IR (neat) ν 3326, 2926, 2855, 1597, 1464 cm⁻¹; ¹H NMR (CDCl₃) δ 0.85 (3H, t, J 6.6, CH₃), 1.20–1.40 (20H, m, CH₂), 1.60–1.70 (1H, br s, OH), 2.05–2.12 (2H, m, CH₂), 4.10 (2H, d, J 5.0, CH₂), 5.45-5.70 (2H, m, CH[double bond, length half m-dash]CH); MS (EI) m/z 226 (M⁺) [Calc. for C₁₅H₃₀O (226.3981): C, 79.58; H, 13.36. Found: C, 79.50; H, 13.47%].

Typical reaction procedure for the preparation of triols 3

(2S,3S )-Tetradecane-1,2,3-triol 3g.. To a stirred mixture of K₂CO₃ (0.83 mg, 6 mmol), K₃Fe(CN)₆ (2 g, 6 mmol), NaHCO₃ (0.51 g, 6 mmol) and CH₃SO₂NH₂ (0.2 mg, 2 mmol) in a mixture of 10 ml water and 10 ml t-BuOH were added (DHQ)₂PHAL (16 mg, 0.02 mmol) and K₂OSO₂(OH)₂ (7.5 mg, 0.02 mmol) and the reaction mixture was cooled to 0 °C. Compound 2g (424 mg, 2 mmol) was added into the reaction mixture, which was stirred for 6 h at 0 °C. The reaction was quenched by adding 3 g of anhydrous Na₂SO₃ at room temperature and the mixture was stirred for 30 min. After filtration the mixture was extracted with EtOAc several times, the combined extracts were washed successively with 5% HCl and brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatograph (eluent: petroleum spirit–EtOAc 1∶10) to obtain 3g as a white solid (443 mg, 90%); mp 82–83 °C; [α]_D −6.8 (c 1.0, CH₃OH); IR (KBr) ν 3330, 2928, 1230, 563 cm⁻¹; ¹H NMR (CDCl₃) δ 0.9 (3H, t, J 7.0, CH₃), 1.15–1.40 (18H, m, CH₂), 1.50–1.60 (2H, m, CH₂), 2.12–2.30 (2H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.57 (1H, m), 3.60–3.90 (3H, m); MS (EI) m/z 247 (MH⁺), 229 (M − H₂O) [Calc. for C₁₄H₃₀O₃ (246.3862): C, 68.25; H, 12.27. Found: C, 68.20; H, 12.13%].

Compounds 3a–f and 3h were prepared in the same manner to that described above.

(2S,3S )-Octane-1,2,3-triol 3a.. A white solid (220 mg, 68%); mp 62–64 °C; [α]_D −5.8 (c 1.0, CH₃OH); IR (KBr) ν 3324, 2928, 1145, 546 cm⁻¹; ¹H NMR (CDCl₃) δ 0.9 (3H, t, J 7.0, CH₃),1.15–1.42 (6H, m, CH₂), 1.50–1.60 (2H, m, CH₂), 2.12–2.30 (2H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.60 (1H, m), 3.60–3.90 (3H, m); MS (EI) m/z 162 (M⁺), 144 (M − H₂O) [Calc. for C₈H₁₈O₃ (162.2267): C, 59.23; H, 11.18. Found: C, 59.12; H, 11.02%].

(2S,3S )-Nonane-1,2,3-triol 3b.. A white solid (264 mg, 75%); mp 73–75 °C; [α]_D −6.0 (c 1.0, CH₃OH); IR (KBr) ν 3335, 2928, 1230, 563 cm⁻¹; ¹H NMR (CDCl₃) δ 0.88 (3H, t, J 7.0, CH₃), 1.14–1.42 (8H, m, CH₂), 1.47–1.58 (2H, m, CH₂), 2.12–2.30 (2H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.45–3.58 (1H, m), 3.60–3.90 (3H, m); MS (EI) m/z 177 (MH⁺), 159 (MH − H₂O) [Calc. for C₉H₂₀O₃ (176.2533): C, 61.33; H, 11.44. Found: C, 61.52; H, 11.26%].

(2S,3S )-Decane-1,2,3-triol 3c.. A white solid (297 mg, 78%); mp 76–77 °C; [α]_D −6.2 (c 1.0, CH₃OH); IR (KBr) ν 3341, 2928, 1225, 569 cm⁻¹; ¹H NMR (CDCl₃) δ 0.88 (3H, t, J 7.0, CH₃), 1.14–1.42 (10H, m, CH₂), 1.47–1.60 (2H, m, CH₂), 2.12–2.30 (2H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.48–3.58 (1H, m), 3.60–3.90 (3H, m); MS (EI) m/z 191 (MH⁺), 173 (MH − H₂O) [Calc. for C₁₀H₂₂O₃ (190.2799): C, 63.12; H, 11.65. Found: C, 63.22; H, 11.67%].

(2S,3S )-Undecane-1,2,3-triol 3d.. A white solid (322 mg, 79%); mp 79–80 °C; [α]_D −6.8 (c 1.3, CH₃OH); IR (KBr) ν 3330, 2928, 1250, 543 cm⁻¹; ¹H NMR (CDCl₃) δ 0.90 (3H, t, J 7.0, CH₃), 1.14–1.40 (12H, m, CH₂), 1.50–1.56 (2H, m, CH₂), 2.12–2.30 (2H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.58 (1H, m), 3.60–3.92 (3H, m); MS (EI) m/z 205 (MH⁺), 187 (MH − H₂O) [Calc. for C₁₁H₂₄O₃ (204.3065): C, 64.67; H, 11.84. Found: C, 64.52; H, 11.87%].

(2S,3S )-Dodecane-1,2,3-triol 3e.. A white solid (349 mg, 84%); mp 79–80 °C; [α]_D −6.8 (c 1.0, CH₃OH); IR (KBr) ν 3328, 2928, 1267, 547 cm⁻¹; ¹H NMR (CDCl₃) δ 0.89 (3H, t, J 7.0, CH₃), 1.14–1.42 (14H, m, CH₂), 1.50–1.56 (2H, m, CH₂), 2.12–2.30 (2H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.58 (1H, m), 3.60–3.92 (3H, m); MS (EI) m/z 219 (MH⁺), 201 (MH − H₂O) [Calc. for C₁₂H₂₆O₃ (218.3330): C, 66.01; H, 12.00. Found: C, 66.22; H, 12.11%].

(2S,3S )-Tridecane-1,2,3-triol 3f.. A white solid (408 mg, 88%); mp 80–81 °C; [α]_D −7.0 (c 1.3, CH₃OH); IR (KBr) ν 3330, 2928, 1272, 551 cm⁻¹; ¹H NMR (CDCl₃) δ 0.88 (3H, t, J 7.0, CH₃), 1.14–1.40 (16H, m, CH₂), 1.50–1.58 (2H, m, CH₂), 2.12–2.30 (2H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.58 (1H, m), 3.62–3.90 (3H, m); MS (EI) m/z 233 (MH⁺), 215 (MH − H₂O) [Calc. for C₁₃H₂₈O₃ (232.3596): C, 67.20; H, 12.15. Found: C, 67.08; H, 12.27%].

(2S,3S )-Pentadecane-1,2,3-triol 3h.. A white solid (438 mg, 89%); mp 85–87 °C; [α]_D −7.0 (c 1.0, CH₃OH); IR (KBr) ν 3329, 2927, 1230, 562 cm⁻¹; ¹H NMR (CDCl₃) δ 0.92 (3H, t, J 7.0, CH₃), 1.14–1.40 (20H, m, CH₂), 1.52–1.62 (2H, m, CH₂), 2.12–2.30 (2H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.57 (1H, m), 3.60–3.90 (3H, m); MS (EI) m/z 247 (MH⁺), 229 (MH − H₂O) [Calc. for C₁₅H₃₂O₃ (260.4128): C, 69.18; H, 12.39. Found: C, 69.22; H, 12.37%].

Typical reaction procedure for the preparation of 1,2-chiral epoxides 4

(2S,3S )-1,2-Epoxy-3-(tosyloxy)tetradecane 4g.. To a solution of 3g (246 mg, 1 mmol) in dry THF was added 95% NaH (72 mg, 3 mmol) and the mixture was stirred for 30 min at room temperature. Then Tos-Im was added into the reaction solution, which was further stirred for 6 h before being poured into ice–water and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatograph (eluent: EtOAc–petroleum spirit 1∶6) to give compound 4g as a colorless solid (241 mg, 63%); mp 71–72 °C, [α]_D +8.6 (c 1, CHCl₃); IR (KBr) ν 3202, 1599, 1350 cm⁻¹; ¹H NMR (CDCl₃) δ 0.90 (3H, t, J 6.5, CH₃), 1.25–1.50 (18H, m, CH₂), 1.65–1.85 (2H, m, CH₂), 2.45 (3H, s, CH₃), 2.60 (1H, dd, J 5.0, 2.5), 2.78 (1H, t, J 5.0), 3.05–3.12 (1H, m), 4.35 (1H, q, J 6.0, CH), 7.35 (2H, d, J 7.5, ArH), 7.8 (2H, d, J 7.5, ArH); MS (EI) m/z 383 (MH⁺), 227 (M⁺ − C₁₁H₂₃) [Calc. for C₂₁H₃₄O₄S (382.5583): C, 65.93; H, 8.96. Found: C, 65.82; H, 8.97%].

Compounds 4a–f and 4h were prepared in the same manner to that described above.

(2S,3S )-1,2-Epoxy-3-(tosyloxy)octane 4a.. A colorless oil (158 mg, 53%); [α]_D +8.5 (c 1.0, CHCl₃); IR (KBr) ν 3200, 1597, 1350 cm⁻¹; ¹H NMR (CDCl₃) δ0.92 (3H, t, J 6.5, CH₃), 1.25–1.50 (6H, m, CH₂), 1.65–1.85 (2H, m, CH₂), 2.44 (3H, s, CH₃), 2.65 (1H, dd, J 4.6, 2.5, CH), 2.75 (1H, t, J 4.5, CH), 3.0–3.10 (1H, m, CH), 4.35 (1H, q, J 6.0), 7.35 (2H, d, J 7.5, ArH), 7.85 (2H, d, J 7.5, ArH); MS (EI) m/z 299 (MH⁺) [Calc. for C₁₅H₂₂O₄S (298.3988): C, 60.38; H, 7.43. Found: C, 60.52; H, 7.33%].

(2S,3S )-1,2-Epoxy-3-(tosyloxy)nonane 4b.. A colorless oil (172 mg, 55%); [α]_D +8.2 (c 1.0, CHCl₃); IR (KBr) ν 3200, 1597, 1350 cm⁻¹; ¹H NMR (CDCl₃) δ0.92 (3H, t, J 6.5, CH₃), 1.25–1.50 (8H, m, CH₂), 1.65–1.85 (2H, m, CH₂), 2.43 (3H, s, CH₃), 2.65 (1H, dd, J 4.6, 2.5, CH), 2.75 (1H, t, J 4.5, CH), 3.0–3.10 (1H, m, CH), 4.35 (1H, q, J 6.0, 15.0, CH), 7.35 (2H, d, J 7.6, ArH), 7.85 (2H, d, J 7.5, ArH); MS (EI) m/z 313 (MH⁺) [Calc. for C₁₆H₂₄O₄S (312.4254): C, 61.51; H, 7.74. Found: C, 61.46; H, 7.70%].

(2S,3S )-1,2-Epoxy-3-(tosyloxy)decane 4c.. A white solid (186 mg, 57%); mp 54–55 °C; [α]_D +8.5 (c 1.0, CHCl₃); IR (KBr) ν 3205, 1597, 1350 cm⁻¹; ¹H NMR (CDCl₃) δ 0.9 (3H, t, J 6.5, CH₃), 1.25–1.50 (10H, m, CH₂), 1.65–1.85 (2H, m, CH₂), 2.45 (3H, s, CH₃), 2.65 (1H, dd, J 4.6, 2.6, CH), 2.78 (1H, t, J 4.6, CH), 3.10 (1H, m, CH), 4.35 (1H, q, J 6.0, 15.0, CH), 7.35 (2H, d, J 7.5, ArH), 7.85 (2H, d, J 7.5, ArH); MS (EI) m/z 327 (MH⁺) [Calc. for C₁₇H₂₆O₄S (326.4519): C, 62.55; H, 8.03. Found: C, 62.52 ; H, 8.17%].

(2S,3S )-1,2-Epoxy-3-(tosyloxy)undecane 4d.. A white solid (204 mg, 60%); mp 57–58 °C; [α]_D +8.0 (c 1.0, CHCl₃); IR (KBr) ν 3205, 1597, 1350 cm⁻¹; ¹H NMR (CDCl₃) δ 0.9 (3H, t, J 6.5, CH₃), 1.25–1.50 (12H, m, CH₂), 1.65–1.85 (2H, m, CH₂), 2.45 (3H, s, CH₃), 2.65 (1H, dd, J 4.6, 2.6, CH), 2.78 (1H, t, J 4.6, CH), 3.0–3.10 (1H, m, CH), 4.35 (1H, q, J 6.0, CH), 7.35 (2H, d, J 7.5, ArH), 7.85 (2H, d, J 7.5, ArH); MS (EI) m/z 341 (MH⁺) [Calc. for C₁₈H₂₈O₄S (340.4785): C, 63.50; H, 8.29. Found: C, 63.72; H, 8.07%].

(2S,3S )-1,2-Epoxy-3-(tosyloxy)dodecane 4e.. A white solid (205 mg, 58%); mp 59–60 °C; [α]_D +8.7 (c 1.0, CHCl₃); IR (KBr) ν 3205, 1597, 1350 cm⁻¹; ¹H NMR (CDCl₃) δ0.9 (3H, t, J 6.5, CH₃), 1.25–1.50 (14H, m, CH₂), 1.70–1.90 (2H, m, CH₂), 2.45 (3H, s, CH₃), 2.65 (1H, dd, J 4.6, 2.5, CH), 2.75 (1H, t, J 4.5, CH), 3.0-3.10 (1H, m, CH), 4.35 (1H, q, J 6.0, CH), 7.35 (2H, d, J 7.5, ArH), 7.85 (2H, d, J 7.5, ArH); MS (EI) m/z 355 (MH⁺) [Calc. for C₁₉H₃₀O₄S (354.5051): C, 64.37; H, 8.53. Found: C, 64.33; H, 8.67%].

(2S,3S )–1,2-Epoxy-3-(tosyloxy)tridecane 4f.. A white solid (206 mg, 56%); mp 72–74 °C; [α]_D +8.3 (c 1.0, CHCl₃); IR (KBr) ν 3205, 1597, 1350 cm⁻¹; ¹H NMR (CDCl₃) δ 0.9 (3H, t, J 6.5, CH₃), 1.27–1.52 (16H, m, CH₂), 1.70–1.90 (2H, m, CH₂), 2.43 (3H, s, CH₃), 2.65 (1H, dd, J 4.6, 2.5, CH), 2.75 (1H, t, J 4.5, CH), 3.0–3.10 (1H, m, CH), 4.35 (1H, q, J 6.0, CH), 7.35 (2H, d, J 7.5, ArH), 7.85 (2H, d, J 7.5, ArH); MS (EI) m/z 369 (MH⁺) [Calc. for C₂₀H₃₂O₄S (368.5317): C, 65.18; H, 8.75. Found: C, 65.11; H, 8.91%].

(2S,3S )-1,2-Epoxy-3-(tosyloxy)pentadecane 4h.. A white solid (262 mg, 66%); mp 85–86 °C; [α]_D +8.0 (c 1.0, CHCl₃); IR (KBr) ν 3205, 1597, 1350 cm⁻¹; ¹H NMR (CDCl₃) δ0.9 (3H, t, J 6.5, CH₃), 1.25–1.50 (20H, m, CH₂), 1.65–1.85 (2H, m, CH₂), 2.43 (3H, s, CH₃), 2.60 (1H, dd, J 5.0, 2.5, CH), 2.78 (1H, t, J 4.5, CH), 3.0–3.10 (1H, m, CH), 4.35 (1H, q, J 5.0, CH), 7.35 (2H, d, J 7.5, ArH), 7.85 (2H, d, J 7.5, ArH); MS (EI) m/z 397 (MH⁺) [Calc. for C₂₂H₃₆O₄S (396.5848): C, 66.63; H, 9.15. Found: C, 66.78; H, 9.27%].

The preparation of diols 6

The reaction procedure is the same as that described in the preparation of diol 3, but starting from the E-allyl chlorides 5.

(2S,3S )-1-Chlorooctane-2,3-diol 6a.. A white solid (302 mg, 84%); mp 76–78 °C; [α]_D −9.5 (c 1.0, CH₃OH); IR (KBr) ν 3324, 2928, 1145, 546 cm⁻¹; ¹H NMR (CDCl₃) δ 0.9 (3H, t, J 7.0, CH₃), 1.15–1.42 (6H, m, CH₂), 1.50–1.60 (2H, m, CH₂), 2.12–2.30 (1H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.48–3.60 (2H, m), 3.60–3.96 (2H, m); MS (EI) m/z 178, 180 (M⁺), 162 (M − H₂O) [Calc. for C₈H₁₇ClO₂ (180.6721): C, 53.18; H, 9.48. Found: C, 53.02; H, 9.32%].

(2S,3S )-1-Chlorononane-2,3-diol 6b.. A white solid (330 mg, 85%); mp 82–84 °C; [α]_D −9.0 (c 1.0, CH₃OH); IR (KBr) ν 3335, 2928, 1230, 563 cm⁻¹; ¹H NMR (CDCl₃) δ 0.88 (3H, t, J 7.0, CH₃), 1.14–1.42 (8H, m, CH₂), 1.47–1.58 (2H, m, CH₂), 2.12–2.30 (1H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.45–3.60 (2H, m), 3.70–3.97 (2H, m); MS (EI) m/z 192, 194 (M⁺), 176 (M − H₂O) [Calc. for C₉H₁₉ClO₂ (194.6987): C, 55.52; H, 9.84. Found: C, 55.62; H, 9.98%].

(2S,3S )-1-Chlorodecane-2,3-diol 6c.. A white solid (363 mg, 88%); mp 86–87 °C; [α]_D −9.6 (c 1.0, CH₃OH); IR (KBr) ν 3341, 2928, 1225, 569 cm⁻¹; ¹H NMR (CDCl₃) δ 0.88 (3H, t, J 7.0, CH₃), 1.14–1.42 (10H, m, CH₂), 1.47–1.60 (2H, m, CH₂), 2.12–2.30 (1H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.48–3.58 (2H, m), 3.70–4.0 (2H, m); MS (EI) m/z 206, 208 (M⁺), 192 (M − H₂O) [Calc. for C₁₀H₂₁ClO₂ (208.7252): C, 57.54; H, 10.14. Found: C, 57.29; H, 10.27%].

(2S,3S )-1-Chloroundecane-2,3-diol 6d.. A white solid (382 mg, 86%); mp 87–89 °C; [α]_D −9.6 (c 1.3, CH₃OH); IR (KBr) ν 3330, 2928,1250, 543 cm⁻¹; ¹H NMR (CDCl₃) δ 0.90 (3H, t, J 7.0, CH₃), 1.14–1.40 (12H, m, CH₂), 1.50–1.56 (2H, m, CH₂), 2.12–2.30 (1H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.47–3.58 (2H, m), 3.70–3.97 (2H, m); MS (EI) m/z 220, 222 (M⁺), 204 (M − H₂O) [Calc. for C₁₁H₂₃ClO₂ (222.7518): C, 59.31; H, 10.41. Found: C, 59.42; H, 10.67%].

(2S,3S )-1-Chlorododecane-2,3-diol 6e.. A white solid (394 mg, 84%); mp 89–90 °C; [α]_D −9.8 (c 1.0, CH₃OH); IR (KBr) ν 3328, 2928, 1267, 547 cm⁻¹; ¹H NMR (CDCl₃) δ 0.89 (3H, t, J 7.0, CH₃), 1.14–1.42 (14H, m, CH₂), 1.50–1.56 (2H, m, CH₂), 2.12–2.30 (1H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.62 (2H, m), 3.70–3.98 (2H, m); MS (EI) m/z 234, 236 (M⁺), 218 (M − H₂O) [Calc. for C₁₂H₂₅ClO₂ (236.7784): C, 60.87; H, 10.64. Found: C, 60.72; H, 10.61%].

(2S,3S )-1-Chlorotridecane-2,3-diol 6f.. A white solid (440 mg, 88%); mp 90–91 °C; [α]_D −9.7 (c 1.3, CH₃OH); IR (KBr) ν 3330, 2928, 1272, 551 cm⁻¹; ¹H NMR (CDCl₃) δ 0.88 (3H, t, J 7.0, CH₃), 1.14–1.40 (16H, m, CH₂), 1.50–1.58 (2H, m, CH₂), 2.12–2.30 (1H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.60 (2H, m), 3.72–3.97 (2H, m); MS (EI) m/z 248, 250 (M⁺), 232 (M − H₂O) [Calc. for C₁₃H₂₇ClO₂ (250.8050): C, 62.26; H, 10.85. Found: C, 62.14; H, 10.67%].

(2S,3S )-1-Chlorotetradecane-2,3-diol 6g.. A white solid: yield 454 mg, 86%); mp 89–90 °C; [α]_D −6.8 (c 1.0, CH₃OH); IR (KBr) ν 3330, 2928, 1230, 563 cm⁻¹; ¹H NMR (CDCl₃) δ 0.9 (3H, t, J 7.0, CH₃), 1.15–1.40 (18H, m, CH₂), 1.50–1.60 (2H, m, CH₂), 2.12–2.30 (1H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.50–3.60 (2H, m), 3.60–3.98 (2H, m); MS (EI) m/z 262, 264 (M⁺), 246 (M − H₂O) [Calc. for C₁₄H₂₉ClO₂ (264.8316): C, 63.49; H, 11.04. Found: C, 63.31; H, 11.11%].

(2S,3S )-1-Chloropentadecane-2,3-diol 6h.. A white solid (478 mg, 86%); mp 92–93 °C; [α]_D −7.0 (c 1.0, CH₃OH); IR (KBr) ν 3329, 2927, 1230, 562 cm⁻¹; ¹H NMR (CDCl₃) δ 0.92 (3H, t, J 7.0, CH₃), 1.14–1.40 (20H, m, CH₂), 1.52–1.62 (2H, m, CH₂), 2.12–2.30 (1H, br s, OH), 2.60–2.70 (1H, br s, OH), 3.53–3.62 (2H, m), 3.64–4.0 (2H, m); MS (EI) m/z 276, 278 (M⁺), 260 (M − H₂O) [Calc. for C₁₅H₃₁ClO₂ (278.8581): C, 64.61; H, 11.21. Found: C, 64.46; H, 11.42%].

Compounds 6a–h can be easily transformed into the corresponding epoxy tosyl esters 4a–h upon treatment with K₂CO₃–MeOH and NaH–Tos-im. The typical procedure is as follows.

To a solution of 1.74 g of 6g (6.64 mmol) in methanol (10 ml) was added potassium carbonate (1.08 g, 7.82 mmol) and the reaction mixture was stirred at room temperature for 8 h. The reaction was quenched by addition of water (20 ml) and the mixture was extracted with ethyl acetate (10 ml × 3). The combined organic layer was dried over MgSO₄ and concentrated under reduced pressure. The residue was treated with NaH (60%) (266 mg, 6.64 mmol) in anhydrous THF (20 ml) at 0 °C and the mixture was stirred at room temperature for 15 min. Tos-Im (1.45 g, 6.64 mmol) was added and the mixture was stirred for 1.5 h. The mixture was poured into ice–water and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc–petroleum spirit 1∶6) to obtain compound 4g as a colorless solid (1.28 g, 50%); mp 53–56 °C; [α]_D +8.4 (c 1, CHCl₃).

The synthesis of insect pheromone (6Z,9S,10R)-9,10-epoxyhenicosadec-6-ene 9

(8S,9S )-9-Hydroxy-10-(tosyloxy)icos-6-yne 7.. To a solution of hept-1-yne (300 mg, 3.6 mmol) in 5 ml of anhydrous THF was added a solution of n-BuLi (2.0 M; 1.8 ml, 3.6 mmol) in hexane at −78 °C. The resulting dark yellow solution was stirred for 30 min and then treated with boron trifluoride–diethyl ether (0.45 ml, 511 mg, 3.6 mmol) with syringe. After stirring of the mixture for another 30 min, a solution of 4g (500 mg, 1.3 mmol) in anhydrous THF (5 ml) was added and the mixture was stirred for 2 h at −78 °C. The reaction mixture was quenched by adding water, washed with aq. NH₄Cl and extracted with diethyl ether. The organic layer was washed successively with water and brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 7 (425 mg, 70%) as a colorless liquid, [α]_D +6.4 (c 1, CHCl₃) IR(neat) ν 3400, 2210 cm⁻¹; ¹H NMR (CDCl₃): δ 0.89 (3H, t, J 6.0, CH₃), 0.91 (3H, t, J 6.0, CH₃), 1.10–1.70 (26H, m, CH₂), 2.10–2.25 (2H, m, CH₂), 2.27 (1H, br s, OH), 2.30–2.40 (2H, m, CH₂), 2.45 (3H, s, CH₃), 3.80 (1H, m, CH), 4.60–4.70 (1H, m, CH), 7.30 (2H, d, J 7.5, ArH), 7.80 (2H, d, J 7.5, ArH); MS (EI) m/z 479 (MH⁺) [Calc. for C₂₈H₄₆O₄S (478.7284): C, 70.25; H, 9.69. Found: C, 70.56; H, 9.77%].

(9S,10R)-9,10-Epoxyhenicosadec-6-yne 8.. To a solution of 7 (580 mg, 1 mmol) in anhydrous methanol (20 ml) was added, in small portions, anhydrous potassium carbonate (5 mol equiv.) at room temperature. After 30 min, the solvent was removed under reduced pressure and the mixture was directly purified by flash chromatography (eluent: ethyl acetate–petroleum spirit 10∶90) to give the pure compound 8 (180 mg, 60%), [α]_D +26.2 (c 1.2, CH₂Cl₂); IR (neat) 2940, 2210 cm⁻¹; ¹H NMR (CDCl₃) δ 0.89 (3H, t, J 6.5, CH₃), 0.91 (3H, t, J 6.5, CH₃), 1.10–1.40 (24H, m, CH₂), 1.42–1.60 (2H, m, CH₂), 2.17 (2H, tt, J 7.2, 2.1, CH₂), 2.22 (1H, ddt, J 16.5, 7.7, 2.4, CH), 2.56 (1H, ddt, J 16.5, 5.4, 2.1, CH), 2.95 (1H, dt, J 5.7, 2.4, oxirane CH), 3.08–3.17 (1H, m, oxirane CH); MS (EI) m/z 307 (MH⁺) [Calc. for C₂₁H₃₈O (306.5258): C, 82.28; H, 12.50. Found: C, 82.12; H, 12.76%].

(6Z,9S,10R)-9,10-Epoxyhenicosadec-6-ene 9.. To a solution of 8 (300 mg, 1 mmol) in methanol (20 ml) was added Lindlar catalyst (10 mg). The reaction mixture was stirred under a hydrogen atmosphere for 1 h. After filtration off of the catalyst and concentration under reduced pressure, the residue was purified by flash chromatography (eluent: ethyl acetate–hexane 10∶90) to give the pure insect pheromone 9 (241 mg, 80%), [α]_D +8.7 (c 0.97, CHCl₃); IR (neat) ν 2910, 1610 cm⁻¹; ¹H NMR (CDCl₃) δ 0.91 (6H, t, J 6.0, CH₃), 1.10–1.60 (26H, m, CH₂), 1.90–2.50 (4H, m, CH₂), 2.80–3.10 (2H, m), 5.40–5.70 (2H, m, HC[double bond, length half m-dash]CH); MS (EI) m/z 309 (MH⁺) [Calc. for C₂₁H₄₀O (308.5417): C, 81.75; H, 13.07. Found: C, 81.80; H, 13.12%].

Acknowledgements

We thank the National Natural Sciences Foundation of China for financial support.

References

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