Modular synthesis of the pentacyclic core of batrachotoxin and select batrachotoxin analogue designs

Abstract

Pentacyclic analogues of the potent voltage-gated sodium ion channel agonist batrachotoxin can be accessed through an intermediate furan by exploiting Diels-Alder cycloaddition reactions with ring-strained dienophiles. The use of 3-bromofuran as a 1,2-dianion equivalent, the application of carbamate reductive N-alkylation for homomorpholine ring assembly, and the demonstration of CsF as an effective reagent for generating benzyne, cyclohexyne, and related dienophiles underscore this work.

Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against Na V

“…Completion of the carbon skeleton of (-)-BTX was accomplished through a palladium-catalyzed cross-coupling of tributyl(1-ethoxyvinyl)tin to vinyl triflate 15 (Fig. 3A) (38). In situ hydrolysis of the incipient enol ether with 1 M oxalic acid supplied enone 16 (77%).…”

“…We hypothesize that the Lewis-basic lactam (or a reduced form) acts as a pivotal stereocontrolling element, as treatment of enone 15 with alternative hydride reducing agents [e.g., AlH 3 •NMe 2 Et, NaBH 4 , NH 3 •BH 3 , (S)-Me-CBSoxazaborolidine/BH 3 , or L-selectride] delivered the undesired C-11b alcohol exclusively. The use of AlH 3 also favored generation of the correct C-20 allylic alcohol epimer, a sterochemical outcome that can be rationalized through a model invoking chelation control (38). Deprotection of the product from AlH 3 reduction under acidic conditions afforded (-)-BTX-A in 83% yield (17).…”

Inhibition of Sodium Ion Channel Function with Truncated Forms of Batrachotoxin

“…As part of this program, we have prepared simplified BTX-like structures 1 (Figure 1). [11] Electrophysiology recordings with wild-type and mutant Na V isoforms demonstrate that BTX analogues comprising the C, D, and E rings of the natural product block Na V current – a stark contrast to the behavior of BTX itself. Protein mutagenesis data suggest that BTX analogues lodge in the inner pore lining of the channel, thus sharing a common receptor site with the parent compound.…”

Synthesis of a 3-Amino-2,3-dihydropyrid-4-one and Related Heterocyclic Analogues as Mechanism-Based Inhibitors of BioA, a Pyridoxal Phosphate-Dependent Enzyme

“…Phthalimide deprotection requires relatively harsh conditions that would be incompatible with the remaining heterocycle, while the bis-Boc derivative is extremely bulky and would be highly susceptible to intramolecular cyclization with the β-alkoxy generated from alkynyllithium addition to form a stable oxazolidinone. Instead, we decided to adopt the approach reported by Devlin & Du Bois 46 which utilized dual Boc and MOM protecting groups to protect an amine. This appeared ideal for our system, as MOM and Boc share similar stability profiles as well as deprotection conditions, and a MOM group is both less electron withdrawing and smaller than a Boc group, making intramolecular cyclization to form an oxazolidinone much slower.…”