Anatoxin enantioselective synthesis

Simpkins and co-workers were the first to use an asymmetric catalytic process in (-)-anatoxin-a synthesis (Newcombe and Simpkins, 1995) instead of resorting to the chiral pool strategy. Their total synthesis of (-)-anatoxin-a relied on an enantioselective enolisation reaction of a readily available ( )-3-tropinone (33), by a chiral lithium amide base (34) (Bunn et al. 1993a, 1993b) and subsequent cyclopropanation/ring expansion reaction giving the ketone 37 (Scheme 7.8). 

Somfai et al. demonstrated that it is also possible to use A-sulphonyl groups (Somfai and Ahman 1992 Ahman and Somfai 1992 Weinreb 1997) using the same concept for the cyclization step developed by Speckamp with the allylsilanes (Esch et al. 1987). In this case, the starting product was the L-pyroglutamic acid, inside the succinimide (Esch et al. 1987), allowing the enantioselective synthesis of the (+)-anatoxin-a. The key step consisted of an intramolecular cyclization of an 7V-tosyl iminium ion, catalysed by a Lewis acid, TiCl, to set up the desired bicyclic ring system (Somfai and Ahman 1992). 

Brenneman, J.B., Machauer, R., and Martin, S.E 2004. Enantioselective synthesis of (+)-anatoxin-a via enyne metathesis. Tetrahedron 60, 7301-7314. 

Somfai, R, and Ahman, J. 1992. A short and enantioselective synthesis of (+)-anatoxin-a. Tetrahedron Lett 33, 3791-3794. 

Tomita T, Kita Y, Kitamura T, Sato Y, Mori M (2006) Further studies on enantioselective synthesis of (-l-)-anatoxin-a using en5oie metathesis unexpected inversion of chirality via a skeletal rearrangement of 9-azabicyclo[4.2.1]nonene derivative. Tetrahedron 62 10518-10527. doi 10.1016/j.tet.2006.05.088... 

Newcombe, N.J., and Simpkins, N.S. 1995. A concise asymmetric synthesis of (—)-anatoxin-a using an enantioselective enolisation strategy. J Chem Soc Chem Commun 831-832. 

Recently Ahman and Somfai [43] have used an AT-sulfonyl iminium ion-alkene cyclization as a key step in an enantioselective total synthesis of the alkaloid anatoxin A (Scheme 20). a-Hydroxy sulfonamide 55 was prepared from L-pyro-glutamic acid (cf Scheme 12) and was transformed in 6 steps into enone 112. Exposure of 112 to acid led to a mixture of bridged enone 114 and /3-chloro ketone 113. The latter compound could be converted into the desired enone with DBU. Detosylation of 114 provided the natural product (+)-anatoxin A. 

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