Synlett 2014; 25(20): 2947-2952
DOI: 10.1055/s-0034-1378901
letter
© Georg Thieme Verlag Stuttgart · New York

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

Alice Lefranc
a  Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland   Fax: +41(22)3793215   Email: alexandre.alexakis@unige.ch
,
Laure Guénée
b  Laboratory of Crystallography, University of Geneva, Quai Ernest Ansermet 24, 1211 Geneva 4, Switzerland
,
Sylvie Goncalves-Contal
a  Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland   Fax: +41(22)3793215   Email: alexandre.alexakis@unige.ch
,
Alexandre Alexakis*
a  Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland   Fax: +41(22)3793215   Email: alexandre.alexakis@unige.ch
› Author Affiliations
Further Information

Publication History

Received: 30 July 2014

Accepted after revision: 29 September 2014

Publication Date:
06 November 2014 (online)


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.

Supporting Information

 
  • 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; Rf 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, CAr–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 Cq), 172.2 (amide Cq), 168.8 (ester Cq), 139.0 (Cq), 137.9 (Cq), 128.9 (CAr–H), 128.7 (CAr–H), 128.6 (CAr–H), 127.8 (2 × CAr–H), 127.7 (CAr–H), 80.3 (Cq COHCONHBn), 62.9 (Cq 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); Rf 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, CAr–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 Cq), 196.7 (ketone Cq), 170.6 (amide Cq), 159.9 (ester Cq), 138.5 (Cq), 136.9 (Cq), 129.8 (CAr–H), 128.9 (CAr–H), 128.5 (CAr–H), 128.0 (CAr–H), 127.9 (CAr–H), 127.5 (CAr–H), 64.55 (Cq), 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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