Generation of metal carbenoids and the total synthesis and structural revision of pipercyclobutanamide A and piperchabamide G

Metal carbenoids are versatile intermediates in organic synthesis and they are involved in numerous reactions such as cyclopropanation, C-H insertion and metathesis reactions. We have developed a general strategy for the diastereo- and enantioselective introduction of four different substituents to a cyclobutane ring: the three substituents on the cyclopropane ring could be transferred regioselectively and stereospecifically to the cyclobutenoate product via a cyclopropyl metal carbenoid intermediate. A RhI-catalyzed conjugate addition of aryl boronic acid to this cyclobutenoate afforded the fourth substituent diastereoselectively. Proposed structures for pipercyclobutanamide A and piperchabamide G were completed and they were revised to their six-membered ring isomers chabamide and nigramide F, respectively. The structures of natural products pipercyclobutanamide B and piperchabamide H were also revised to their six-membered ring isomers.;Decomposition of diazo compounds or related derivatives is still one of the most frequently used and efficient methods to generate metal carbenoids. However, considering the hazardous and potential explosive nature of diazo compounds, other alternative carbene precursors are highly desirable. We developed two efficient methods to generate &agr;-imino and oxo metal carbenoids respectively. 1. N-sulfonyl-1,2,3-triazoles can act as the carbene precursor. We developed an efficient method for the preparation of highly substituted cyclobutenes from alkynyl cyclopropanes which involved &agr;-imino metal carbenoid as the key intermediate. The tandem process was facilitated by a dual catalyst system (CuTc and AgOTf). Various cyclobutenes with aldehyde or sulfonamide functionality could be prepared. 2. Metal complex [Rh(CO) 2Cl]2/P[OCH(CF3)2]3 is acidic enough to active ynamide for the addition of pyridine followed by the cleavage of N-O bond to generate &agr;-oxo Rh(I) carbenoid intermediates. The &agr;-oxo Rh(I) carbenoids could undergo ring expansion with adjacent cyclopropanes to afford cyclobutenes, or metathesis with a tethered alkyne to form 2-oxo-pyrrolidines, and cyclopropanation with a tethered alkene to afford 3-azabicyclo[3.1.0]hexanes.