Total Synthesis of -7-Deoxypancratistatin

Abstracted with permission from J. Am. Chem. Soc., 1995,7/7, 7289 1995 American Chemical Society 

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Synthesis of (+)-7-Deoxypancratistatin. Different approaches to the total synthesis of (+)-7-deoxypancratistatin have been reported recently because of the promising biological properties shown by this alkaloid. An elegant synthesis of (+)-7-deoxypancratistatin has been achieved from furan and t runs-1,2-bis(phenylsulfonyl)ethylene (Eq. 155).265 This synthesis clearly illustrates the utility of alkenyl sulfones as Michael acceptors and dienophiles for cycloaddition reactions. 

The Lewis acid-catalyzed aza-Payne rearrangement was utilized in the total synthesis of ep/-7-deoxypancratistatin by T. Hudlicky and co-workers. The 2,3-aziridino alcohol was treated with f-BuLi, to generate the epoxy amide that was trapped with piperonyl bromide. 

Rinner, U., Siengalewicz, P., Hudlicky, T. Total synthesis of epi-7-deoxypancratistatin via aza-Payne rearrangement and intramolecular... 

Since the isolation and discovery of the significant biological activity of 7-deoxypancratistatin (210) and pancratistatin (211), which have more oxygenated functional substituents than lycoricidine (204), synthetic studies have been performed extensively. The total synthesis of optically active (-1-)-7-deoxypancratistatin (210) and (+)-pancratistatin (211) has been reported independently by four research groups. 

This consecutive carbon-carbon bond formation approach was further applied for the synthesis of DL-modhephene [32], DL-cedrene [33], and DL-pentalelene [34]. Recently Keck successfully completed the total synthesis of (-f)-7-deoxypancratistatin using a radical cyclization of A-aziridinylimine as a key step [35]. The formation of two carbon-carbon bonds in a consecutive manner through radical cyclization of A-aziridinylimine is indicated by solid lines as shown in Scheme 12. 

The completion of the synthesis required oxidation of the benzylic position and subsequent lactone-lactam rearrangement. This strategy has been commonly employed in the synthesis of AmaryUidaceae alkaloids and has been developed by Danishefsky in the first total synthesis of pancra-tistatin [180]. Reductive cleavage of the N—O bond in 296 with Sml and installation of the trifluoroacetamide in a one-pot procedure were foUowed by PCC oxidation of the benzylic ether to afford lactone 297. The acetonide moiety and the silyl ether were removed with BF EtjO and the resulting tiiol was treated with K COj in methanol, resulting in the aforementioned rearrangement of the lactone to the more stable lactam. 7-Deoxypancratistatin (298) was isolated in exceUent overaU yield and only 13 linear steps from iodopiperonol. 

Hudlicky, T., Tian, X., Konigsberger, K., Mauiya, R., Rouden, J. and Fan, B. (1996c) Toluene-dioxygenase-mediated as-dihydroxylation of aromatics in enantioselective synthesis. Asymmetric total syntheses of pancratistatin and 7-deoxypancratistatin, promising antitumor agents. J. Am. Chem. Soc., 118, 10752-10765. 

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