Bufadienolide synthesis

Brizzi, R., Delfino, G. and Pellegrini, R. (2002) Specialized mucous glands and their possible adaptive role in the males of some species of Rana (Amphibia, Anura). J. Morph. 254, 328-341. Chen, C. and Osuch, M. V. (1969) Biosynthesis of bufadienolides - 3Bhydroxycholonates as precursors in Bufo marinus bufadienolides synthesis. Biochem. Pharmacol. 18, 1797-1802. Chivers, D. P. and Smith, R. J. F. (1998) Chemical alarm signalling in aquatic predator-prey systems a review and prospectus. Ecosci. 5, 338-352. 

A neat way of preparing96 the system (215) (useful in bufadienolide synthesis) from (214) is illustrated for compound (216). Bromination to (217) followed by dehydrobromination with lithium bromide in DMF gave the dienone (218), which on triethylsilane reduction produced (219) and thence, by condensation with diethyl oxalate, (220). Methylthiotoluene-p-sulphonate in ethanol-potassium acetate now produced (221) whose oxidation with N-chlorosuccinimide in 2% methanolic sulphuric acid gave (223). A previous route to such compounds was by way of the a-acetoxy-ketones (219) but suffers from a low yield at the acetoxylation step, (219) —> (222). 

This direct synthesis of steroidal pyrones should make a variety of structures related to the lucibufagins (as well as to the toad-derived bufadienolides) readily available for biological investigation for the first time. How the insects themselves manage to obtain their defensive pregnanes and steroidal pyrones remains a mystery, since insects are generally considered to lack the enzymatic machinery essential for steroid biosynthesis (19). In fact, we do not yet know whether these insect defensive steroids are produced de novo or whether they are derived... 

A simple two-step synthesis of the a-pyrone ring system209 has been applied to the synthesis of bufadienolides.210 Reaction of the known a/3-unsaturated aldehyde (416) with the dimethyl acetal of chloroketen [ClCH=C(OMe)2] gave a 57% yield of the intermediate 2,2-dimethoxy-3 -chloro-3,4-dihydropyran (417) which on reaction with sodium methoxide in DMSO afforded the a-pyrone (418) directly in 64% yield. 

Total synthesis in the bufadienolide field is of recent date and only during the last year have detailed papers appeared that elaborated on previous communications. 

In an interesting new synthesis of a bufadienolide from cholanic acid (pregnane derivatives have been used previously), Sarel et al.1 obtained as the penultimate product a /3,-y-unsaturated 8-lactone (1), which required dehydrogenation to the desired a-pyrane (2). The lactone (1) was found to be relatively inert to DDQ in... 

A similar rearrangement of the 20,21-epoxide (613) with boron trifluoride to give the aldehyde (614) is a key step in a synthesis of the bufadienolide system. ... 

Bufadienolides.— The difficulties associated with the construction of a 14 -hydroxy-17/8-a-pyrone system have been successfully overcome at last in the first reported synthesis " of a naturally occurring bufadienolide (Scheme 1). 

Isomeric cardenolldes (27), prepared by synthesis, have been described in the patent literature. Two accounts on hellebrigenin (a bufadienolide) with cytotoxic and potent Na-K ATFase inhibition activity have appeared5 >55... 

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