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/H(2)O/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 alpha-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), H(2), MeOH, 0 degrees C], removal of N-Boc function (aqueous 3 N HCl, MeOH/H(2)O), and oxidation of hydroquinone to quinone [(NH(4))(2)Ce(NO(3))(6), H(2)O, rt] afforded the lemonomycinone amide 2 in 76% yield over three steps.

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The dimeric cyclization reaction offers great potential to rapidly form highly substituted complex cyclic molecules from a simple starting material. However, such appealing process is often hampered by the lack...