Synthesis of -anatoxin

Total synthesis of anatoxin-a was achieved by Martin and Mori through the same strategy (Scheme 38). 

The key step is the construction of a bicyclo[4.2.1] system. To this end, pyrrolidine derivative 95 having fif-substituents is synthesized from (+)-pyroglutamic acid and subjected to enyne metathesis using Ig to result in formation of 96 in 84% yield. From 96, synthesis of (+)-anatoxin-a is straightforward and successfully achieved. 

The Pd-catalyzed intramolecular aminocarbonyiation has also been applied to the formal total synthesis of Anatoxin-A 219, an acetylcholine mimic (Equation (16)). Thus, the reaction of 5-(methoxycarbonylamino)-cyclooctene 216a in the presence of a catalytic amount of PdCl2 and cupric chloride (CUCI2) (3 equiv.) in methanol under ambient pressure of CO gave the desired azabicyclo[4.2.1]nonane 217 as the predominant product. The regioselectivity of this reaction is highly dependent on the nature of the A -substituent. Thus, the... 

Reproduced from Oh, C.-Y. Kim, K.-S. Ham, W.-H. A fonnal total synthesis of (+)-anatoxin-A by an intramolecular Pd-catalyzed aminocarbonylation reaction. Tetrahedron Lett. 1998, 39, 2133-2136, with pennission from Elsevier. 

Scheme 39 Synthesis of anatoxin-a precursor 118 via MeLi mediated [3-lactam ring opening...

Intramolecular aminocarboi lation (Chiou et al. 2005) was used in the synthesis of anatoxin-a by the Ham group. The key step involved an intramolecular palladium catalyzed aminocarboi lation reaction to reach the bicyclic ring skeleton characteristic of anatoxin-a (Oh et al. 1998) (Scheme 7.6). 

Continuing with palladium chemistiy, Trost proposed a new asymmetric synthesis of anatoxin-a (Trost and Oslob, 1999) and the crucial step was the introduction of chirality by a catalytic process involving an intramolecular asymmetric allylic alkylation (Trost 2004) of the intermediate ( )-29 affording (+)-31 (Scheme 7.7). This step was catalyzed by palladium in presence of a chiral phosphine ligand. 

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). 

Synthesis of Anatoxin-a via Intramolecular Cyclization of Iminium Ions... 

The most recent formal asymmetric synthesis of (+)-anatoxin-a was achieved through a highly diastereoselective [2+2] cycloaddition of dichloroketene with a chiral enol ether(63 Scheme 7.15) in order to reach the general stracture of 2,5-disubstituted pyrrolidine (66) for generating the acyliminum ion and getting the required bicycle skeleton (67) (Muniz et al. 2005). 

Aggarwal, VK., Humphries, P.S., and Fenwick, A. 1999. A formal asymmetric synthesis of (+ )-anatoxin-a using an enantios-elective deprotonation strategy on an eight-membered ring., 4ngew ChemintEd 3S, 1985-1986. 

Bates, H.A., and Rapoport, H. 1979. Synthesis of anatoxin-a via intramolecular cyclization of iminum salts. JAm Chem Soc 101, 1259-1265. 

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

Lindgren, B., Stjernolf, R, and Trogen, L. 1987. Synthesis of anatoxin-a. a constituent of blue-green freshwater algae. Acta Chem Scand B41, 180-183. 

Mori, M., Tomita, T, Kita, Y, and Kitamura, T. 2004. Synthesis of (+)-anatoxin-a using enyne metathesis. Tetrahedron Lett 45, 4397- 399. 

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. 

ShonOjT, Matsumura, Y., Uchida, K., andXagami, K. 1987. Anew method offormationof9-azabicyclo-[4.2.1]nonane skeleton and its application to synthesis of( )-anatoxin-a. Chem Lett 919-922. 

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

Trost, B.M., and Oslob, J.D. 1999. Asymmetric Synthesis of (—)-Anatoxin-a via an asymmetric cyclization using a new ligand for Pd-catalyzed alkylations. JAm Chem Soc 121, 3057-3064. 

The use of nitrones in the synthesis of anatoxin-a, very fast death factor. Tetrahedron 41, 3447-3453, and references therein about the regioselectivity of nitrone cyclization. 

Vernon, P, and Gallagher, T. 1987. Neurotoxic Alkaloids Synthesis of ( )-anatoxin-a. J Chem Soc Chem Commun 245-246. 

This type of allylic alkylation has been applied in the asymmetric total synthesis of (—)-anatoxin-a (7) using a N-nucleophile and Pd-based bpchH2 complexes in an intramolecular reaction to form the 9-azabicyclo[4.2.1]non-2-ene system (eq 3). ... 

Interestingly, the balance can be tipped toward formation of the seven-membered ring by simply placing an electron-withdrawing group on the terminal carbon of the dipolarophile (Scheme IS). Tliis leads to polarization of the alkene and to an FMO-controlled process. Incidentally, the reaction shown proved critical in a total synthesis of anatoxin a, the so-called very fast death factor . ... 

---