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Organic Chemistry Highlights

Total Synthesis

Monday, October 5, 2020
Douglass F. Taber
University of Delaware

The Luo Synthesis of Batrachotoxinin A

Batrachotoxinin A (3) and its derivatives, although highly toxic, are useful tools for studying the function of voltage-gated sodium channels. Tuoping Luo of Peking University envisioned a succinct convergent approach to 3, a key step of which was the selective reductive cyclization of 1 to 2 (J. Am. Chem. Soc. 2020, 142, 3675. DOI: 10.1021/jacs.9b12882).

The bicyclic diketone 7 was assembled starting from cyclopentenone 4. Following the Kim protocol, coupling with ethyl acrylate 5 delivered the enone 6. Hydrogenation followed by cyclization then completed the preparation of 7.

Following Du Bois, the construction of 1 began with the commercial enantiomerically-pure Hajos-Parrish ketone 8. Ketalization and hydrogenation led to 9, that was ring expanded to the alkenyl bromide 10. Coupling with 11 led to 12, that was brominated to give 13. Coupling with 7 then completed the assembly of 1.

The cyclization of 1 to 2 proceeded with remarkable diastereocontrol. The product was isolated as the more stable enol ether 14.

With the two cyclopentanes differentiated, the completion of the synthesis proceeded via ring cleavage. Oxidation of 14 with stoichiometric Pd(OAc)2 gave the enone 15, that was reduced to the triol 16. This was processed to the acetonide 17, that was carried on to an intermediate aldehyde (not illustrated). Reductive amination of the aldehyde with methyl amine followed by acylation with chloroacetyl chloride gave an amide, that was cyclized to 18. Exposure to singlet oxygen led to an aldehyde, that on addition of methyl magnesium bromide, reduction and hydrolysis delivered batrachotoxinin A (3).

It is instructive to compare this synthesis to the recent Du Bois route to batrachotoxin, an ester of 3, that also proceeded via the enone 10 (The Du Bois Synthesis of Batrachotoxin 2017, June 5).

D. F. Taber, Org. Chem. Highlights 2020, October 5.