A general strategy was developed for the diastereo-and enantioselective synthesis of cyclobutanes with four different substituents. It consists of three transition metal-catalyzed reactions -a Rh IIcatalyzed cyclopropanation, a Ag I -catalyzed regioselective and stereospecific ring expansion, and a Rh I -catalyzed addition reaction. Structures of pipercyclobutanamide A and piperchabamide G were synthesized and revised. Keywords cyclobutane; pipercyclobutanamide; piperchabamide; chabamide; nigramide Four-membered rings are important structural motifs frequently present in bioactive natural products and pharmaceutical agents. [1] Pipercyclobutanamides, piperchabamides, nigramides, and dipiperamides ( Figure 1) are tetrasubstituted cyclobutanes isolated from Piper nigrum and Piper chaba, the source of white and black pepper and component of traditional medicine. [2][3][4][5][6][7] Isolation of various polyene precursors and stereoisomeric cyclobutanes from these Pipers suggested that the four-membered rings might be derived from non-selective photolytic [2+2] cycloaddition of alkenes. Cyclobutanes isolated from Piper nigrum and Piper chaba have broad pharmacological activities. [5][6][7] For example, pipercyclobutanamide A (1) and dipiperamide E (6) are selective inhibitors for CYP2D6 and CYP3A4 respectively, two main P450s responsible for drug metabolism. [4, 7] Piperchabamide G, isolated in 2009, inhibits D-GalN/tumor necrosis factor-α-induced death of hepatocytes and has hepatoprotective effect. [6] Among dozens of pipercyclobutanamides, piperchabamides, nigramides, and dipiperamides, only the symmetric achiral dipiperamide A (5) has been synthesized. [8,9] The originally proposed structure 4 for dipiperamide A [3] was revised to 5 after Kibayashi's synthesis. [9] A solid state [2+2] photolytic homodimerization was employed by Kibayashi to construct the four-membered ring with center-symmetry. Extensive optimization was conducted for the crystallization of ferulic acid derivatives to obtain the α-form crystal, [8] which was required for the regio-and diastereoselective photolytic homodimerization. Research groups of Bergman, Ellman, and Jia used the same protocol to prepare the symmetric cyclobutane core of incarvillateine. [10] The [2+2] cycloaddition has been the main strategy for the synthesis of four-membered ring natural products [11] with a few exceptions. [12] However, it remains a demanding synthetic challenge to prepare unsymmetrical cyclobutanes from heterodimerization of two olefins with high chemo-, regio-, diastereo-, and enantioselectivity. [13] Recently, an elegant sequential cyclobutane C-H arylation strategy was developed by Baran's group for the diastereoselective synthesis of pseudosymmetric cyclobutanes such as piperarborenine B (7) and the proposed structure of piperarborenine D (8). [14] The originally proposed structure 8 [3] for piperarborenine D was revised to structure 9 after Baran's synthesis. We herein report our strategy for diastereo-and enantioselective introduction of ...
