Biginelli Reaction tethered

Overman has extended his tethered Biginelli reaction to include alkenes and dienes instead of p-keto esters to deliver 51 diastereoselectively over 52 in the presence of Cu(OT02. 

A double tethered Biginelli reaction was carried out on the simple five-membered urea aldehyde 305 that reacted with the aliphatic and aromatic bis-ketoesters 306 and 307 giving compounds 308 and 309, respectively, in good yield, albeit with a diasteromeric ratio of 1 3. A series of different polycyclic bis-guanidines resembling betzelladine alkaloids were prepared <2003OL4485>. 

The only way to realize an enantioselective Biginelli reaction is to conduct it intramolecularly where the enantiopure urea and aldehyde portions are tethered. This reaction was the key step in L.E. Overman s total synthesis of guanidine alkaloid 13,14,15-lsocrambescidin 800. An optically active guanidine aminal was reacted with an enantiopure (3-keto ester in trifluoroethanol to afford 1-iminohexahydropyrrolo[1,2-c]pyrimidine carboxylic ester with a 7 1 trans selectivity between CIO and Cl3 positions. 

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. 

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