Asymmetric synthesis of β-substituted Baylis–Hillman products via lithium amide conjugate addition

• Published in: Tetrahedron Vol. 63; no. 30; pp. 7036 - 7046
• Main Authors: Chernega, Alexander, Davies, Stephen G., Elend, Dirk. L., Smethurst, Christian A.P., Roberts, Paul M., Smith, Andrew D., Smyth, G. Darren
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 23.07.2007; Elsevier
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; PRESSURE; COPE ELIMINATION; 4-OXOAZETIDINE-2-CARBALDEHYDES; ALDOL REACTION; ESTERS; CARBON BOND-FORMATION; AMINO ALDEHYDES; ADDUCTS; EQUIVALENTS; CYCLIZATION
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2007.05.015

A three-step protocol for the asymmetric synthesis of a range of β-substituted Baylis–Hillman products has been developed. This procedure involves the diastereoselective conjugate addition of lithium ( R)- N-methyl- N-(α-methylbenzyl)amide to an α,β-unsaturated ester to generate an N-protected β-amino ester in high de. Subsequent asymmetric aldol reaction via deprotonation with LDA, transmetallation with B(OMe) 3 and addition of an aldehyde gives a range of syn-aldol products in moderate to high de. Purification of the syn-aldol products to homogeneity followed by tandem N-oxidation and Cope elimination gives the desired β-substituted Baylis–Hillman products in good yield and high de and ee. [Display omitted] The conjugate addition of lithium ( R)- N-methyl- N-(α-methylbenzyl)amide, followed by an asymmetric aldol reaction and subsequent tandem N-oxidation and Cope elimination affords homochiral β-substituted Baylis–Hillman products in good yield.