Batrachotoxinins syntheses

Kerb, U., H.-D. Berndt, U. Eder, R. Wiechert, P. Buchschacher, A. Furlenmeier, A. Furst, and M. Muller Zur Synthese des Batrachotoxinins Synthese von 3p-Acetoxy-16p,20p-dihydroxy-4 -methyl-18-nor-5p,14p-pregnano-[13,14-f]-hexahydro-r,4 -oxazepin-3 -on-(20a). Experientia 15, 759—761 (1971). 

The formation of dioxolane derivatives from a, p-unsaturated carbonyls is often accompanied by migration of the double bond and the extent of migration depends on the strength of the acid catalyst and the reaction conditions As can be seen from Scheme 2.32, weaker adds (pKa > 3) leave the double bond intact whereas stronger acids cause partial or complete isomerisation,70 The isomerisation of the double bond is not necessarily a disaster indeed, in some cases it can be a useful synthetic tool. For example. Kishi exploited the isomerisation in a concise synthesis of Batrachotoxinin A,71 the initial steps of which are shown in Scheme 2.33. and there are many other examples of a similar nature.72-76... 

A different approach (Scheme 39) to the synthesis of the 14,18-oxyethano-iV-methylimino-bridge of batrachotoxinin used the epoxy-pregnane (473) as starting material. This was converted by conventional techniques into the keto-lactone (474). Bromination and dehydrobromination of (474) gave the A -16-ketone, which was reduced to the allylic alcohol and epoxidized to (475). Hydride... 

The deoxygenation of the C6 position of an advanced intermediate was accomplished in a two-step procedure by Y. Kishi et al. in their synthesis of (+)-batrachotoxinin A. " The Luche reduction was followed by the formation of the C6 pyridylthioether, which was desulfurized using Raney nickel. 

A unique class of steroidal alkaloids, the batrachotoxinins, is isolated in small quantities from the skins of poison arrow frogs and also from the feather of a New Guinea bird. One of the key steps during the total synthesis of (+)-batrachotoxinin A by Y. Kishi et al. was a Michael addition to form a seven-membered oxazapane ring. The removal of the primary TBS protecting group was achieved by treatment with TASF and the resulting alkoxide attacked the enone at the 3-position to afford an enolate as the Michael adduct. The enolate was trapped with phenyl triflimide as the end triflate. 

The structure of batrachotoxin was confirmed by a partial synthesis from batrachotoxinin A. This proved feasible using a mixed anhydride prepared from 2,4-dimethylpyrrole-3-carboxylic acid and ethyl chlorofor-mate (Scheme I). A variety of analogs of batrachotoxin were prepared in a similar manner. These compounds are documented in Table 4. A dihydro-batrachotoxin was prepared by sodium borohydride reduction (Scheme II) and apparently is subject to allylic rearrangement to other dihydroproducts 251). 

Scheme I. Partial synthesis of batrachotoxin from batrachotoxinin A (257). A i) NaOH,...

Synthesis of batrachotoxinin A could now be realized based on the developed routes in thirty-six steps beginning with the readily available (20R)-3-P-acetoxy-20-hydroxy-5-a-pregnane (Scheme X) 144, 145). The overall yield for this impressive synthesis was 0.12%. 

Imhof, R., E. Gossinger, W. Graf, H. Berner, L. Berner-Fenz, and H. Wehrli Partial synthesis of batrachotoxinin A. Helv. Chim. Acta 55, 1151—1153 (1972). 

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