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Synthetic Studies on (−)-Lemonomycin: An Efficient Asymmetric Synthesis of Lemonomycinone Amide

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journal contribution
posted on 06.03.2009, 00:00 by Yan-Chao Wu, Guillaume Bernadat, Géraldine Masson, Cédric Couturier, Thierry Schlama, Jieping Zhu
Asymmetric synthesis of lemonomycinone amide (2) was accomplished from readily accessible starting materials. Enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester (11) by 5-tert-butyldimethylsilyloxy-2,4-dimethoxy-3-methylbenzyl bromide (10) in the presence of Corey-Lygo’s phase transfer catalyst [O-(9)-ally-N-(9′-anthracenylmethyl) cinchonidium bromide, 0.1 equiv] afforded, after chemoselective hydrolysis of the imine function (THF/H2O/AcOH), the substituted l-tert-butyl phenylalanate 13 in 85% yield. A Pictet−Spengler reaction of 14 with benzyloxyacetaldehyde (15) provided the 1,3-cis-disubstituted tetrahydroisoquinoline 16 in 85% yield as a single diastereomer. Coupling of hindered secondary amine 16 with amino acid 9 was accomplished under carefully controlled conditions to furnish the amide 22, which was in turn converted to hemiaminal 24. A hafnium triflate catalyzed conversion of hemiaminal to α-amino thioether followed by a silver tetrafluoroborate promoted intramolecular Mannich reaction of 26 afforded the tetracycle 27 in excellent overall yields. Debenzylation of 27 [Pd(OH)2, H2, MeOH, 0 °C], removal of N-Boc function (aqueous 3 N HCl, MeOH/H2O), and oxidation of hydroquinone to quinone [(NH4)2Ce(NO3)6, H2O, rt] afforded the lemonomycinone amide 2 in 76% yield over three steps.