Sunday, August 25, 2013
Recent Synthetic Studies Targeting the Steroidal Alkaloid Batrachotoxin
The steroidal alkaloid batrachotoxin (BTX, 1) functions as a selective agonist of voltage-gated sodium channels and is one of the most potent non-peptidic toxins known. BTX-induced lethality results from a permanent blockade of nerve signal transmission to muscles. The LD50 of 1 (0.1 micrograms per mouse or 2 micrograms kg-1) is approximately tenfold more potent than that of tetrodotoxin and attests to the severe toxicity associated with the pharmacological properties of this small family of steroidal alkaloids. Batrachotoxins have proven historically valuable as neurochemical agents for the study of voltage-dependent sodium-ion transport in nerve and muscle. Batrachotoxins share certain structural motifs with subcategories of cardiotonic steroid glycosides known as cardenolides and bufadienolides. These architectural commonalities include a steroidal core skeleton with A/B and C/D cis-ring junctions and oxygenated functionality at C3 and C14 in a b orientation. However, certain structural features of the batrachotoxins are unique as compared with other naturally occurring pregnanes, such as the intramolecular C3-hemiketal (BTX’s unique 3b-hydroxy-3a,9a-oxido arrangement is the first reported occurrence in Nature), the seven-membered 14b,18b-heterocyclic oxazapane ring spanning the C/D-ring junction, the 9a-hydroxyl, the D16,17 unsaturation and the substituted pyrrole ester linked to the C20a-hydroxyl. BTX has received limited attention from the synthetic community (previous efforts reviewed here) and a practical and modular synthetic approach to analogues of 1 is not currently available. Du Bois and co-workers have recently disclosed a novel strategy to access BTX congeners bearing a fully elaborated eastern C/D/E substructural framework.
Du Bois’ approach, reminiscent of Kishi’s previous total synthesis of BTX, relies on a key furan (as diene) Diels–Alder cycloaddition reaction to fashion a segment of the steroidal architecture. Whereas Kishi’s late-stage intramolecular cycloaddition forged the eastern C/D ring system, Du Bois’ related intermolecular [4+2] reaction, conducted on furanyl intermediates bearing an intact C/D/E substructure, introduces the western A-ring moiety. The furan, in the latter case, serves as the B-ring surrogate and offers flexibility to facilitate A-ring analogue production. Du Bois’ forward synthesis begins with nucleophilic addition of 2-lithio-3-bromofuran, a vicinal dianion equivalent, to the diketo-aldehyde 2 to provide a diastereomeric mixture of hemiacetals. Subsequent exposure of this product distribution to MOM-chloride under basic conditions then affords the cis-fused bicyclic tetrahydrofuranyl-cyclopentanones 3 in a 2:1 diastereomeric ratio favoring the endo isomer (depicted above). The major diastereomer (endo-3) is now nicely predisposed for formation of the C/D ring system of BTX with control of the relative stereochemistry between positions C11 and C14. In the event, intramolecular anion addition to the C14 carbonyl of 3 furnishes 4 in a highly stereocontrolled fashion. Intermediate 4 is then easily elaborated to 5, the substrate for a critical reduction of the C20 enone. Diastereoselective reduction of 5 with DIBAL-H generates a product of 1,2-reduction (6) that is consistent with a chelate addition model. The advanced intermediate 6 is then elaborated to the fully functionalized C/D/E core structure 7 in a straightforward fashion.
Diels-Alder reactions between the advanced tetracyclic furan derivative 7 and ring-strained dienophiles including a cyclohexyne (derived from 8) and a cyclopropene (derived from 10) produce highly complex A-ring-containing cycloadducts (9 and 11), albeit with a modest degree of selectivity for approach of the dienophile from the desired b-face of the furan. A logical synthetic pathway leading to 1 from the advanced intermediates 9 or 11 is not readily apparent. The authors note that the evaluation of these BTX derivatives as modulators of voltage-gated sodium channels is currently underway. The unassuming architectural complexities embedded within the polycyclic steroidal framework of BTX (1) become more readily apparent when one considers that Du Bois and co-workers have previously synthesized daunting targets including zaragozic acid, saxitoxin and tetrodotoxin, with relative ease. However, as of 2013, a modular and scalable synthesis of 1 still eludes the modern synthetic chemist.