Enantioselective Organocatalyzed Desymmetrization of 3-Substituted Cyclobutanones through Michael Addition to Nitroalkenes

Francesca Capitta; Angelo Frongia; Jean Ollivier; David J. Aitken; Francesco Secci; Pier Paolo Piras; Régis Guillot

doi:10.1055/s-0034-1379489

Synlett, Table of Contents

Synlett 2015; 26(01): 123-126
DOI: 10.1055/s-0034-1379489

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Enantioselective Organocatalyzed Desymmetrization of 3-Substituted Cyclobutanones through Michael Addition to Nitroalkenes

Francesca Capitta

^a Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, 09042 Monserrato (Cagliari), Italy Email: fsecci@unica.it

^b CP3A Organic Synthesis Group, Institut de Chimie Moléculaire et des Matériaux d’Orsay – ICMMO (CNRS UMR 8182), Université Paris-Sud, 15 rue Georges Clémenceau, 91405 Orsay cedex, France Fax: +39(70)6754388

,

Angelo Frongia

^a Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, 09042 Monserrato (Cagliari), Italy Email: fsecci@unica.it

,

Jean Ollivier*

^b CP3A Organic Synthesis Group, Institut de Chimie Moléculaire et des Matériaux d’Orsay – ICMMO (CNRS UMR 8182), Université Paris-Sud, 15 rue Georges Clémenceau, 91405 Orsay cedex, France Fax: +39(70)6754388

,

David J. Aitken

^b CP3A Organic Synthesis Group, Institut de Chimie Moléculaire et des Matériaux d’Orsay – ICMMO (CNRS UMR 8182), Université Paris-Sud, 15 rue Georges Clémenceau, 91405 Orsay cedex, France Fax: +39(70)6754388

,

Francesco Secci*

^a Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, 09042 Monserrato (Cagliari), Italy Email: fsecci@unica.it

,

Pier Paolo Piras

^a Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, 09042 Monserrato (Cagliari), Italy Email: fsecci@unica.it

,

Régis Guillot

^b CP3A Organic Synthesis Group, Institut de Chimie Moléculaire et des Matériaux d’Orsay – ICMMO (CNRS UMR 8182), Université Paris-Sud, 15 rue Georges Clémenceau, 91405 Orsay cedex, France Fax: +39(70)6754388

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Abstract

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Abstract

A new procedure for the desymmetrization of prochiral 3-substituted cyclobutanones has been established through organocatalyzed Michael addition to nitroalkenes. The approach provides enantiomerically enriched 2-alkyl-3-aryl(alkyl) cyclobutanones with three contiguous stereogenic centers. The optimum conditions were determined by screening of catalyst and reaction conditions and a transition-state model is proposed to account for the observed diastereomeric and enantiomeric selectivities.

Keywords

cyclobutanones - Michael addition - nitroalkenes - organocatalysis - stereoselectivity

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References

References and Notes

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10 Desymmetrization of 3-Substituted Cyclobutanones through Michael Addition to Nitroalkenes; Typical Procedure for 2-(2-Nitro-1-phenylethyl)-3-(4-tolyl)cyclobutanone (3a): A solution of cyclobutanone 1a (216 mg, 1.3 mmol), β-nitrostyrene 2a (0.387 mg, 2.6 mmol) and catalyst IV (10 mol%, 17.7 mg, 0.13 mmol) in anhydrous toluene (0.8 mL) was stirred at room temperature for 96 h. The reaction mixture was loaded directly onto a silica flash chromatography column and eluted with hexane–Et₂O (90:10 to 1:1) to afford the corresponding pure nitroalkyl cyclobutanone 3a as a 80:20 diastereoisomeric mixture (ee major 74%). Yield: 76%; yellow oil; [α]_D ²⁹ –24.1 (c 0.1, CHCl₃). IR (film): 3030, 1777 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.26 (s, 3 H), 3.19–3.37 (m, 3 H), 3.53–3.57 (m, 1 H), 3.82–3.87 (m, 1 H), 4.62–4.67 (m, 1 H), 5.05 (dd, J = 13.0, 5.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 2 H), 6.97 (d, J = 8.0 Hz, 2 H), 7.09–7.11 (m, 2 H), 7.22–7.24 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 20.9, 34.7, 44.6, 51.5, 68.9, 77.7, 110.0, 110.3, 126.1, 127.9, 128.1, 128.9, 129.1, 129.6, 136.2, 136.4, 138.5, 206.7. MS (ESI): m/z [M + Na] calcd. for C₁₉H₁₉NO₃Na: 332.1263; found: 332.1264. Chiral-phase HPLC [Daicel Chiralcel AD-H column; hexane–i-PrOH (95:5); flow rate = 1.0 mL/min; λ = 254 nm]: ee = 74%; t_R = 13.9 (major), 16.7 (minor) min.

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