Enantioselective total synthesis of batzelladine F: structural revision and stereochemical definition.

In 1997, Patil and co-workers reported the isolation of batzelladines F-I from a red Jamaican sponge incorrectly identified at the time as Batzella sp.1,2 These alkaloids each contain two tricyclic guanidines and were found to induce dissociation of protein tyrosine kinase p56lck from CD4. It was postulated that disruption of this interaction could be used to treat autoimmune disorders. Our interest in batzelladine F (1) was 2-fold. First, we were interested in preparing compounds that inhibit specific protein-protein interactions, and second, we sought to define totally the stereochemistry of batzelladine F, much of which was unclear at the outset of this work. The relative configuration of the right-hand tricyclic portion of batzelladine F (C20 through C29) was assigned1 by comparison of its 13C NMR spectrum to that of batzelladine D,3 the configuration of which had been established by synthesis.4 The lefthand tricyclic moiety was originally proposed to have an anti relationship between the angular hydrogens at C4 and C7. This relative configuration was subsequently revised to syn based on model studies by Snider and Murphy.5 There was no information that related the relative configurations of the two tricyclic guanidines nor specified the configuration at C18. Thus, there were eight compounds (four pairs of enantiomers) that fit the available data for the revised structure of batzelladine F. It did not become clear until we had synthesized one enantiomer of each structure that the proposed connectivity of batzelladine F was also incorrect.6 Herein, we report our enantioselective total synthesis of the correct structure 1 of batzelladine F. Our synthesis strategy is outlined in Scheme 1.7 We envisaged the right-hand tricyclic guanidine as evolving from pentacyclic bisguanidine 2. This intermediate would be the product of a highly convergent tethered Biginelli condensation8 between â-keto ester 3 and guanidine hemi-aminal 4; a synthesis of an analogue of 4 bearing a nonyl side chain had been described by us earlier.4b Triazaacenaphthalene 3 was seen as arising from a convergent,