Steroide und Sexualhormone. 246. Mitteilung [1]. Die Partialsynthese von Batrachotoxinin A

Abstract

Mitteilung [l]Szimmary : In addition to the preliminary communication Ll] a detailed description of the first partial synthcsis of steroidal alkaloid batrochotoxinin A (1) is presented. Zwischen 1963 und 1969 berichteten Witkop et al. uber die Isolierung der drei Steroidalkaloide Batrachotoxinin A (l), Batrachotoxin ( 2 ) und Homobatrachotoxin (3) aus der Haut des kolumbianischen Pfeilgiftfrosches Phyllobates aurotaeizia [2] [3] [4] [5] sowie iiber die rontgenographische Strukturaufklarung des Grundkorpers 1 [4] [6] und dessen Uberfuhrung in die Pyrrolester 2 und 3 151. Die ungewohnliche, ausserordentlich komplexe Struktur von Batrachotoxinin A (1) sowie die hohe Toxizitat l) bei gleichzeitig bemerkenswerten pharmakologisclien Eigenschaften z, veranlassten uns 1969 zur Aufnahme voii Studien zur partialsynthetischen Erschliessung des aus naturlichen Quellen nur sehr schwer zuganglichen Grundkorpers Batrachotoxinin A (1). In1 Rahmen dieses Arbeitsprogrammes berichteten wir seither uber die Darstellung der Modellverbindungen 10 [8] [9], 16 [lo], 26 1111, 35 [I21 [13] (141 und 46 [14],

Synthesis of propellane-containing natural products

“…It has been synthesized partially from steroid precursors by Wehrli and co-workers. 231,232 A total synthesis was published by the Kishi group in 1998 (Scheme 55). 233 The synthesis features an exo-selective intramolecular Diels-Alder reaction (step a) and an oxy-Michael addition (step d).…”

Total Synthesis of (−)-Batrachotoxinin A: A Local-Desymmetrization Approach

“…Isolated together with 1 , (−)-batracho­toxinin A ( 2 ) is significantly less potent, but it could be readily converted to 1 or other batracho­toxin analogs that serve different purposes for investigating Na V ’s. , The complex structure and the uniqueness of 1 as a Na V ’s agonist have made this family of natural products attractive synthetic targets for organic synthesis. As early as 1972, Imhof et al reported a semi-synthesis of 2 starting from 11α-acetoxy­progesterone . The first total synthesis of 2 was achieved by Kishi’s group in a racemic manner, whereas Du Bois and co-workers accomplished a 24-step synthesis of (−)-batracho­toxin ( 1 ) by employing an elegant radical cascade reaction .…”

“…We envisaged that the C20 hydroxyl group of 2 (batracho­toxin numbering, throughout) could be introduced using the singlet oxygen ene reaction of C17–C20 alkene in 3 . The seven-membered lactam ring would be traced back to aldehyde 4 by the well-established reductive amination/acylation/cyclization sequence, , while the C11 hydroxyl group might be constructed concomitantly during the reduction process. By connecting C18 and C21, we recognized a hidden symmetry of 4 that allowed us to propose a key synthetic intermediate, 5 (a shorter non-desymmetrization strategy was also attempted without success and is detailed in the Supporting Information (SI); see Scheme S1), which could be obtained from 6 by engaging the bromide to internally differentiate the two carbonyl groups (C14 and C18).…”

“… All of the analytic data for the synthesized sample of 2 were consistent with those reported in the literature (Table S3). , …”

Synthesis of the Tetracyclic Structure of Batrachotoxin Enabled by Bridgehead Radical Coupling and Pd/Ni-Promoted Ullmann Reaction

“…Batrachotoxin belongs to the class of steroids yet possesses unique structural features such as C7- and C16-double bonds, a C9α-oxygen atom that forms the six-membered C3-hemiacetal across the AB-ring, and a C18-nitrogen atom that forms the seven-membered oxazepane ring on the CD-ring. Various creative routes to this complex architecture have been pursued, culminating in the successful total syntheses of batrachotoxinin A, a C20-OH analogue, by the groups of Wehrli and Kishi . Most recently, the Du Bois group disclosed an efficient assembly of both enantiomers of batrachotoxin and demonstrated their agonistic activities against the channels …”