Synthesis of -batzelladine

There is a primary alcohol-to-aldehyde step in the synthesis of (+)-batzelladine A, and it was suggested that the oxidation of the primary alcohol (1) with TRAP/ NMO/PMS/CH Cl proceeds through an iminium-Ru alkoxide complex (2), rearranging as in (3)-(4) to give the aldehyde (5) (Fig. 1.13) [101] (a similar mechanism was proposed for the Ru-catalysed oxidative cyanation of tertiary amines [403] cf. 5.1.3.4, Fig. 5.3). 

Scheme 10. Partial synthesis of batzelladine B and improved Biginelli condensation.

The [2+4] diastereoselective annulation of vinyl carbodiimides 48 to cyclic N-alkylimines 49 affords the S,S-diastereomer of the bicyclic dihydropyrimidine 50. This reaction is used in the synthesis of batzelladin alkaloids. 

Cohen, F., Overman, L. E. Enantioselective total synthesis of batzelladine F structural revision and stereochemical definition. J. Am. Chem. Soc. 2001, 123, 10782-10783. 

Butynoate was reacted with TMGA (28) to give p-azido acrylate as a mixture of geometric isomers. The 1,4-conjugate addition product served as the diene component in the [4 + 2] annulation reaction after conversion to vinyl carbodirmides by Staudinger-aza-Wittig condensation with benzylisocyanate [110], These reactions are key steps in the total synthesis of batzelladine alkaloids (Scheme 4.44). 

Cohen, R and Overman, L.E. (2006) Enantioselective total synthesis of batzelladine F and definition of its structure. Journal of the American Chemical Society, 128, 2604—2608. 

Shimokawa, J., Ishiwata, T., Shirai, K. et al. (2005) Total synthesis of (+)-batzelladine A and (—)-batzelladine D, and identification of their target protein. Chemistry -A European Journal, 11, 6878-6888. 

Frairklin, A.S., Ly, S.K., Mackin, G.H., Overman, L.E., and Shaka, A.J. (1999) Application of the tethered Biginelli reaction for enantioselective synthesis of batzelladine alkaloids. Absolute coirfigmation of the tricyclic guanidine portion of batzelladine B. J. Org. Chem., 64,1512-1519. 

Elliott, M.C. and Loirg, M.S. (2004) Studies toward the total synthesis of batzelladine A Org. Biomol. Chem., 2, 2003-2011. 

Other procedures using TPAP/NMO/PMS/CH Cl include steps in the synthesis of (+)-altholactone (lactol to lactone) [78] antheliolide A [168] the AChE inhibitor (+)-arisugacin A and B (primary alcohol to aldehyde step also) [83] the marine macrolide amphidinolide T1 [169] the alkaloid (+)-batzelladine D cf. mech. 

The isolation of the batzelladines attracted the attention of several groups, and some work has appeared in recent years concerned with partial syntheses, mainly in the racemic series 17, 18, 19]. The efforts of Snider culminated in a nine-step synthesis of racemic batzelladine E, following the biomimetic strategy [ 18bj. The only enan-tioselective synthesis reported to date established the absolute. stereochemistry of batzelladine B (Scheme 10) [20a], Diol 39 (obtained by /(-keto ester chemistry) was transformed into guanidine 41 via the diazide. An improved Biginelli type condensation with methyl acetoacetate in tri-... 

The structural disclosure of ptilomycalin A in 1989 ushered in a new era of aza-annulation strategies to synthesize the core 2,2a,3,4,5,7,8, 8a-octahydro-lH-2a, 5,6-triazaacenaphthylene structure. The subsequent disclosure of batzelladines and crambescidins beckoned research groups to develop new methods for their synthesis. Early work by Snider utilized a biomimetic double Michael addition for the ptilomycalin A core that set the precedent for all subsequent strategies (94JA549). 

Rao, A.V.R., Gurjar, M.K., and Vasudevan, J. (1995) An enantiospecific synthesis of the tricychc guanidine segment of the anti-HIV marine alkaloid batzelladine A. J. Chem. Soc. Chem. Common., 1369-1370. 

Evans, PA., Qin, (., Robinson, J.E., and Bazin, B. (2007) Enatioselective total synthesis of the polycyclic guanidine-containing marine alkaloid (—)-batzelladine D. Angew. Chem. Int. Ed., 46, 7417-7419. 

Yu, M., Podiapsky, S.S., and Snidei B.B. (2008) Synthesis of 7-epiptilocaulin, mirabilin B, and isoptilocaulin. A unified biosynthetic proposal Ibr the ptilocaulm and batzelladine alkaloids. Synthesis and structure revision of netamines E and G. J. Org. Chem., 73,9065-9074. 

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