Several natural products contain cyclobutane rings thought to be biosynthesized via the [2+2] cycloaddition of alkenes. This reaction has been co-opted for the chemical synthesis of several cyclobutanes but is not suitable for the preparation of unsymmetrical compounds. Two reports now describe alternate routes to the proposed structure of the unsymmetrical pipercyclobutanamide A (shown), a P450 inhibitor isolated from the flowering vines Piper nigrum and Piper chaba. In particular, Gutekunst et al. use a desymmetrized cyclobutane derivative as a precursor for arylation and a rare olefination of an unactivated sp3 carbon. In contrast, Liu et al. use their recent methodology to expand a cyclopropane to a cyclobutenoate poised for conjugate addition of the final aryl substituent. Inclusion of an alkene reduction step allowed these authors to make the proposed structure for the related piperchabamide G as well. Surprisingly, both papers noted that the chemical characterization of the newly synthesized molecules did not match that of the natural product. On the basis of NMR analysis and the potential for a [4+2] cycloaddition to form a cyclohexene scaffold from the same precursors, Liu et al. examined all six-membered ring products from P. nigrum and P. chaba. This analysis revealed pipercyclobutanamide A and piperchabamide G to be identical to chabamide (also shown) and nigramide F, respectively, correcting the record for further biological application of these molecule.
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Goodman, C. Cyclobutanes prove charlatans. Nat Chem Biol 8, 678 (2012). https://doi.org/10.1038/nchembio.1032