Construction of the Tricyclo[5.3.1.0^1,5]undecane System by a Novel Tandem Pinacol Rearrangement-Ene Strategy:  A Formal Total Synthesis of (±)-Perhydrohistrionicotoxin

Abstract

Histrionicotoxin derivatives have long been attractive targets for synthetic chemists as a result of their useful neurophysical properties, low natural abundance, and the unique structural features of the azaspiro[5.5]undecane ring system. Utilizing our tandem pinacol rearrangement-ene strategy and regiospecific Baeyer-Villiger oxidation as key steps, we have successfully synthesized an advanced synthetic intermediate, spiro[5.4]decane 4, which has previously been converted to (+/-)-perhydrohistrionicotoxin (5b). Pinacol rearrangement of simple Diels-Alder derived bicyclo[2.2.2]octene system 2a, followed by an ene reaction, led to the efficient formation of the highly fuctionalized tricyclo[5.3.1.0(1,5)]undecane system 1a. This tricyclic system 1a was selectively transformed into spiro[5. 4]decane system 4 via a regiospecific Baeyer-Villiger oxidation reaction. We also report the results of systematic studies of Baeyer-Villiger oxidation reactions of tricyclo[5.3.1.0(1, 5)]undecanone systems to elucidate the origin of the regioselectivity of this process.

Semipinacol Rearrangement in Natural Product Synthesis

“…In the formal synthesis of (±)-perhydrohistrionicotoxin (Scheme ), Kim et al used a tandem pinacol rearrangement/ene reaction to transform a bicyclo-[2.2.2]-octene to a tricycle-[5.3.1.01,5]-undecane system . When alcohol 416 , derived from a Diels–Alder adduct, was treated with p -TsOH, a stereospecific 1,2-shift of the bridged C–C bond occurred readily to give the bicycle-[3.2.1]-octane 418 .…”

The Baeyer−Villiger Reaction: New Developments toward Greener Procedures

“…In this case, the electron-poor CHF group can achieve the required alignment more easily and is “forced” to migrate. Thus, at least in these cases, the primary stereoelectronic effect is more important than the migratory aptitude …”

Design and Synthesis of Natural Product Inspired Libraries Based on the Three-Dimensional (3D) Cedrane Scaffold: Toward the Exploration of 3D Biological Space

“…To generate one- and multidimensional libraries containing a cedrane core, a scaffold with three orthogonally reactive chemical handles was synthesized on a 5 g scale (Scheme ). − Briefly, the methylation of 7 with iodomethane was promoted by potassium carbonate in refluxing acetone to give 8 in 85% yield . Then, Birch reduction of 8 yielded 9 (70%).…”

“…Ketone 12 was then treated with 2-(2-bromoethyl)-1,3-dioxane and magnesium turnings in THF to obtain a readily separable mixture of endo (13a) and exo alcohols (13b) in 62:38 ratio in good yield (75%). In the final step, the mixture of alcohols 13 underwent pinacol rearrangement to yield ketone 14, upon treatment with p-TsOH (1.3 equiv) in refluxing acetone for 16 h. 40 This strategy provided 5 g of scaffold with three orthogonally reactive chemical handles allowing decoration at positions 3, 5, and 9 to generate 1D, 2D, and 3D libraries that sample the diversity of the natural products. The overall approach for library generation is outlined in Scheme 2.…”