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A convenient method for the synthesis of gamma-spirolactams in only three steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of chloroacetonitrile affords nitriles in moderate to good yields. Suitable precursors are methyl-substituted benzoic acids, naphthoic, and anthroic acid. Subsequent catalytic hydrogenation proceeds smoothly with PtO2 or Raney Ni as catalysts and lactams are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation at different pressures, affording products with 0, 1, or 2 double bonds. Overall, more than 15 new gamma-spirolactams have been synthesized in analytically pure form.
A convenient synthesis of gamma-spirolactams in only two steps was developed. Birch reduction of benzoic acids and immediate alkylation with chloroacetonitrile afforded cyclohexadienes in high yields. The products could be isolated by crystallization on a large scale in analytically pure form. Subsequent hydrogenation with platinum(IV) oxide as the catalyst reduced the nitrile functionality and the double bonds in the same step with excellent stereoselectivity. The relative configurations were determined unequivocally by X-ray analyses. Direct cyclization of the intermediary formed amino acids afforded the desired gamma-spirolactams in excellent overall yields. The procedure is characterized by few steps, cheap reagents, and can be performed on a large scale, interesting for industrial processes.