Direct Organocatalytic Construction of Bicyclo[3.2.1]octanes by Domino Michael/Aldol Reaction with β,γ-Unsaturated 1,2-Keto Amides

Abstract

A direct construction of bicyclo[3.2.1]octanes by an organocatalytic domino Michael/Aldol reaction of cyclic 1,3-keto esters with β,γ-unsaturated 1,2-keto amides is reported. Formation of a precipitate corresponding to the racemic co-crystals of the bicyclic compound was observed in toluene, whereas a homogeneous solution was obtained in dichloromethane. Preliminary mechanistic investigations on the reversibility of the system allowed enhancing the selectivity (>20:1 dr, 73% ee). Relative configuration of the bicyclic compound was determined by X-ray crystal structure analyses.

Key words

domino - organocatalysis - bicyclo[3.2.1]octane - β,γ-unsaturated 1,2-keto amide

• References and Notes

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• 15 Domino Michael/Aldol Reaction; General Procedure: To a solution of β,γ-unsaturated 1,2-keto amide 1a (26.6 mg, 0.1 mmol, 1 equiv) in the appropriate solvent (0.5 mL) were added successively the catalyst III (11.9 mg, 0.02 mmol, 20 mol%) and 1,3-keto ester 2a (31.2 mg, 0.2 mmol, 2 equiv). The mixture was stirred at the corresponding temperature for the time listed in the Tables. Then the reactive mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (c-hexane–EtOAc, 7:3), affording bicyclo[3.2.1]octanone 3a.
• 16 Bicyclo[3.2.1]octane 3a: Compound 3a was prepared according to the general procedure previously described. At r.t. after 60 h, 3a was obtained as a white solid. Yield: 75% (30.6 mg, 0.075 mmol); dr >20:1 (determined by ¹H NMR of the crude reactive mixture); mp 120–122 °C; R_f 0.3 (silica gel, c-hexane–EtOAc, 7:3). The enantiomeric excess was determined by chiral SFC Chiralpak OD-3 [20% MeOH to 25% MeOH in CO₂ (1%/min gradient), 30 °C]: t ₁= 11. 3 min, t ₂ = 8.8 min; [α]_D ²² 25.14 (c = 1.0 in CHCl₃, 54% ee). ¹H NMR (400 MHz, CDCl₃): δ = 7.22–7.34 (m, 10 H, C_Ar–H), 4.41 (m, 2 H, PhCH ₂NHCO), 3.94 (dd, J = 13.6, 4.8 Hz, 1 H, CHPhCH₂), 3.57 (s, 3 H, Me), 3.00 (t, J = 14.8 Hz, 1 H, CHPhCH ₂), 2.84 (1 H, OH), 2.65–2.75 (m, 1 H, CHCH ₂CH₂), 2.43–2.54 (m, 3 H, CHCH₂CH₂, CHCH₂CH ₂), 1.94–2.04 (m, 1 H, CHCH ₂CH₂), 1.87 (dd, J = 15.1, 4.9 Hz, 1 H, CHPhCH ₂). ¹³C NMR (100 MHz, CDCl₃): δ = 209.2 (ketone C_q), 172.2 (amide C_q), 168.8 (ester C_q), 139.0 (C_q), 137.9 (C_q), 128.9 (C_Ar–H), 128.7 (C_Ar–H), 128.6 (C_Ar–H), 127.8 (2 × C_Ar–H), 127.7 (C_Ar–H), 80.3 (C_q COHCONHBn), 62.9 (C_q CCO₂Me), 54.2 (CHCH₂CH₂), 52.3 (Me), 47.6 (CHPhCH₂), 43.5 (PhCH₂NHCO), 34.6 (CHPhCH₂), 20.6 (CHCH₂ CH₂), 18.7 (CHCH₂CH₂). IR (thin film): 3356, 1755, 1723, 1641, 1451, 1275, 1114, 1026, 908, 695 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₆NO₅: 408.1806; found: 408.1815.
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• 18 Substrates with a tert-butyl group or tertiary amide showed no reactivity.
• 19 Intermediate 4a of the Domino Michael/Aldol Reaction: To a solution of β,γ-unsaturated 1,2-keto amide 1a (26.6 mg, 0.1 mmol, 1 equiv) in CH₂Cl₂ (0.5 mL) were added successively the catalyst III (11.9 mg, 0.02 mmol, 20 mol%) and 1,3-keto ester 2a (31.2 mg, 0.2 mmol, 2 equiv). The mixture was stirred at r.t. for 1.3 h. Then the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (c-hexane–EtOAc 8:2), affording the 1,2-keto amide intermediate 4a as a colorless oil. Yield: 74% (30 mg, 0.074 mmol); dr >20:1 (determined by ¹H NMR of the crude reaction mixture); R_f 0.2 (silica gel, c-hexane–EtOAc, 7:3). The enantiomeric excess was determined by chiral SFC Chiralpak OJ-3 [10% MeOH to 25% MeOH in CO₂ (1%/min gradient), 30 °C]: t ₁= 10.1 min, t ₂ = 9.5 min; [α]_D ²² 0.17 (c = 1.0 in CHCl₃, 4% ee). ¹H NMR (400 MHz, CDCl₃): δ = 7.16–7.33 (m, 10 H, C_Ar–H), 4.35–4.40 (m, 2 H, PhCH ₂NHCO), 4.19 (d, J = 10.4, 4.0 Hz, 1 H, CHCH₂COCONHBn), 3.78 (dd, J = 18.4, 10.5 Hz, 1 H, CHCH ₂COCONHBn), 3.72 (s, 3 H, Me), 3.26 (dd, J = 18.4, 4.0 Hz, 1 H, CHCH ₂COCONHBn), 2.57 (m, 1 H, CH₂), 2.19–2.26 (m, 1 H, CH₂), 2.08–2.15 (m, 1 H, CH₂), 1.75–1.87 (m, 1 H, CH₂), 1.61–1.69 (m, 1 H, CH₂), 1.50–1.60 (m, 1 H, CH₂). ¹³C NMR (100 MHz, CDCl₃): δ = 213.5 (ketone C_q), 196.7 (ketone C_q), 170.6 (amide C_q), 159.9 (ester C_q), 138.5 (Cq), 136.9 (C_q), 129.8 (C_Ar–H), 128.9 (C_Ar–H), 128.5 (C_Ar–H), 128.0 (C_Ar–H), 127.9 (C_Ar–H), 127.5 (C_Ar–H), 64.55 (C_q), 53.0 (Me), 43.5 (PhCH₂NHCO), 43.2 (CH), 38.8 (CH₂), 38.2 (CHCH₂COCONHBn), 29.34 (CH₂), 19.7 (CH₂). IR (thin film): 3322, 2960, 1744, 1676, 1453, 1231, 1149, 702 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₆NO₅: 408.1806; found: 408.1806.
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