Asymmetric Synthesis of Secondary Alcohols and 1,2-Disubstituted Epoxides via Organocatalytic Sulfenylation

Dedicated to Professor Steven V. Ley CBE FRS; Happy 70^th B’DA-y Steve!

Abstract

Enantioenriched secondary alcohols can be prepared via a short reaction sequence involving asymmetric organocatalytic sulfenylation of an aldehyde, organometallic addition, and desulfurization. This process provides access to enantioenriched alcohols with sterically similar groups attached to the alcohol carbon atom. The intermediate β-hydroxysulfides can also serve as precursors to enantioenriched 1,2-disubstituted epoxides via alkylation of the sulfur and subsequent base-mediated ring closure.

Key words

asymmetric synthesis - organocatalysis - alcohols - sulfur - epoxides

• References and Notes

• 1 Current address: Dr. Filippo Rota, Principal Scientist, Abcam, Unit 3, Avon Riverside Estate, Victoria Rd, Bristol BS11 9DB, UK.
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• 12 General Procedure for the Preparation of β-Hydroxysulfides 5 A solution of aldehyde (1 equiv) and catalyst 2 (0.1 equiv) was stirred in toluene (1.3 M) for 15 min. A solution of sulfenyltriazole 3 (1.3 equiv) in toluene (1.6 M) was added dropwise, and the resulting mixture was stirred under argon at r.t. for 24 h. The reaction mixture was then quickly sucked under vacuum through a pre-wet (toluene) pad of silica (ca. 1.5 g per 100 mg of aldehyde) and washed with toluene (10 mL per 100 mg of aldehyde). The filtrate was added dropwise to a solution of the organometallic reagent (3–4 equiv) cooled to –78 °C (for Li reagents) or –10 °C (for Grignard reagents). The reaction was monitored by TLC and stirred until all the intermediate α-sulfenyl­aldehyde was consumed. The reaction was then quenched with sat. NH₄Cl and partitioned between H₂O and Et₂O. The aqueous layer was extracted with Et₂O, and the combined organic layers were washed with brine, dried over MgSO₄, filtered, and evaporated to dryness. The crude β-hydroxysulfide was purified by column chromatography (PE–Et₂O). (2R,3S)-3-(Phenylthio)octan-2-ol (5a) [α]_D ²⁵ –4.2 (c 1.0, CHCl₃). IR (film): ν_max = 3414, 3060, 2959, 2929, 2858, 1584, 1466, 1439, 1279, 1139 cm^–1. Isolated as a 91:9 mixture of diastereoisomers. ¹H NMR (600 MHz, CDCl₃): δ (major isomer): 0.88 (3 H, t, J = 6.8 Hz, CH₂CH ₃), 1.19 (3 H, d, J = 6.4 Hz, CHCH ₃), 1.27–1.71 (8 H, m, 4 × CH₂), 2.33 (1 H, br s, OH), 3.16 (1 H, ddd, J = 9.4, 5.8, 3.2 Hz, SCH), 3.89 (1 H, qd, J = 6.4, 3.2 Hz, CHOH), 7.22–7.30 (3 H, m, 3 × ArH), 7.44 (2 H, d, J = 7.7 Hz, 2 × ArH). ¹³C NMR (150 MHz, CDCl₃): δ = 14.2, 19.1, 22.6, 27.5, 30.1, 31.8, 58.7, 68.3, 127.1, 129.2, 132.0, 135.5. ¹H NMR (600 MHz, CDCl₃): δ (minor isomer): 0.88 (3 H, t, J = 6.8 Hz, CH₂CH ₃), 1.25 (3 H, d, J = 6.1 Hz, CHCH ₃), 1.27–1.71 (8 H, m, 4 × CH₂), 2.91 (1 H, ddd, J = 9.6, 6.5, 3.2 Hz, SCH), 3.72 (1 H, dq, J = 6.5, 6.1 Hz, CHOH), 7.22–7.30 (3 H, m, 3 × ArH), 7.44 (2 H, d, J = 7.7 Hz, 2 × ArH). ¹³C NMR (150 MHz, CDCl₃): δ = 14.2, 20.2, 22.7, 27.0, 30.1, 31.1, 59.3, 68.3, 127.3, 129.1, 132.5, 135.5. HRMS (EI): m/z calcd for C₁₄H₂₂OS: 238.13859; found: 238.13884 [M]⁺.
• 13 The absolute stereochemistry of the alcohol 5l was determined by NMR analysis of the Mosher’s ester derivatives (see ref. 11). Full experimental details are provided in the Supporting Information.
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• 15 General Procedure for the Preparation of Alcohols 6 A solution of β-hydroxysulfide (1 mmol) and Raney Ni (2 g) in EtOH (0.05 M) was stirred at reflux for 2–4 h. The mixture was cooled to r.t. and filtered through a pad of Celite. The filtrate was evaporated to dryness to afford the alcohol. (R)-Octan-2-ol (6a) [α]_D ²⁵ –5.4 (c 1.0, CHCl₃). IR (film): ν_max = 3339, 2960, 2927, 2857, 1462, 1373, 1279, 1177, 1141, 1115 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.91 (3 H, t, J = 6.9 Hz, CH₂CH ₃), 1.21 (3 H, d, J = 6.1 Hz, CHCH ₃), 1.27–1.51 (10 H, m, 5 × CH₂), 3.81 (1 H, m, CHOH). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 22.6, 23.5, 25.7, 29.3, 31.8, 39.4, 68.2. These spectroscopic data are in agreement with those reported previously: Maywald M, Pfaltz A. Synthesis 2009; 3654
• 16 The diastereomeric β-hydroxysulfides were not readily separable. Thus, the er of the alcohol 6 was calculated from the enantiopurity of the intermediate α-sulfidoaldehyde (determined by reducing a sample to the primary alcohol 4) and the dr of the purified β-hydroxysulfide 5 used in the desulfurization reaction. Please see Supporting Information for further details.
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