Alkaloids 7-deoxypancratistatin

A 6-exo-trig cyclization of a pyran derived radical onto an oxime has been employed as the key step in the synthesis of Amaryllidace alkaloid (+)-7-deoxypancratistatin [95JA7289], Treatment of 202 under reductive cyclization conditions gave 203 as a single stereoisomer in good yield. The compatibility of the radical reaction conditions with the dense functionality present in 202 is noteworthy. 

The Amaryllidaceae alkaloid 7-deoxypancratistatin 21 has potent antiviral activity. A challenge in the assembly of 21 is that the ring fusion is trans, less stable than the corresponding cis diastereomer. The s mthesis of 21 J. Org. Chem. 2007, 72, 2570) by Albert Padwa of Emory University started with 17, the preparation of which by the combination 15 and 16 he had previously reported in the course of his s mthesis of lycoricidine OHL December 11, 2006). Ester 17 had the desired trans ring fusion, but with an angular ester substituent that had to be removed. 

Conversion of 77 into the O-benzylhydroxamicacid derivative 78 followed by O-desilylation and oxidation of the resulting lactol furnished the lactone 79. The trifluoroacetamide 80 obtained by successive treatment of 79 with samarium (II) iodide and acidic Dowex resin, on exposure to methanolic potassium carbonate generated, (+)-7-deoxypancratistatin (67). The overall yield of the alkaloid starting from D-gulonolactone was 7%. 

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. 

Several members of the Amaryllidaceae family of alkaloids display pronounced biological activities, and some Amaryllidaceae plants have played an important role in traditional herbal medicine for the treatment of various ailments. The most prominent examples of Amaryllidaceae alkaloids of biological relevance are narciclasine (55) and its congeners (pancratistatin and 7-deoxypancratistatin) and galantamine (62) (also commonly spelled galanthamine). These natural products also find application in modem medicine, and in this respect, pancratistatin is used in clinical... 

Deoxypancratistatin Keck, 1998 In 1995, Keck reported his first synthesis of 7-deoxypancratistatin (298) with a radical cyclization as key step [178]. A few years later, a second-generation synthesis of this important Amaryllidaceae constituent was reported [173]. The route, outlined in Schemes 12.50 and 12.51, started from inexpensive and commercially available L-gulonolactone (289) and featured a highly efficient radical cyclization cascade, which established two ring systems of the natural product. This radical cyclization protocol is quite unique in the preparation of Amaryllidaceae alkaloids and constitutes an interesting alternative to commonly employed coupling protocols. 

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. 

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