Stereo‐ and Regioselective Synthesis of Tricyclic Spirolactones by Diastereoisomeric Differentiation of a Collective Key Precursor

Abstract

A general, parallel, and collective synthesis of 5/5/5- and 5/5/6-ring fusion topologies of tricyclic spiranoid lactones through the controlled cyclizations of easily accessible, common key precursors is described. The rapid composition of key cycloalkyl methylene precursors yielded an assembly of bicyclic diastereoisomeric iodolactones, which were individually converted into a wide range of tricyclic, angularly fused spiranoid lactones in a regioselective and stereodirected fashion through the diastereoisomeric differentiation of a collective key precursor. The critical stereochemical assignment of the bicyclic starting materials, as well as the tricyclic targets, was confirmed by X-ray crystal structure determination.

Tricyclic Spirolactones as Modular TRPV1 Synthetic Agonists

“…23−26 Recently, we reported general and collective syntheses of phylogenetically different tricyclic, angularly fused spirolactones via controlled cyclizations of easily accessible common cycloalkylmethylene key precursors (Figure 2E). 21,22 We operated under the assumption that novel synthetic scaffolds, which are small, rigid, and highly reminiscent of natural scaffolds, could serve as operational ligands for TRPV1. Many spiranoid lactones have been firmly established to demonstrate pharmacological activity.…”

“…Although our compounds are less hydrophobic than other VBS-binding molecules (e.g., capsaicin), most synthesized compounds could not be prepared in physiological salt solutions (i.e., Ringer) at concentrations greater than 1 mM without adding cytotoxic levels of DMSO. To avoid any nonspecific cellular activation, we did not exceed were designed according to the reported methodology (E) 21,22 and were grouped according to the scaffold topology. 0.1% of DMSO in the final solutions.…”

“…The OH-bearing compounds 21 and 22 (Figure 4) were modified by the installation of aromatic groups at different sites (compounds 27−29 were designed according to reported methodology). 22 In a similar fashion, compounds 13, 15, and 17 (Figure 2) were anchored with benzyl and vanilloid groups to generate architectures 30−33.…”

Radical‐Mediated Non‐Dearomative Strategies in Construction of Spiro Compounds

“…In this way, Tsvelikhovsky group realized synthesis of tricyclic spirolactones 10 from easily accessible iodo derivatives 9 (Scheme 1). [11] Under reflux conditions and in the presence of Bu 3 SnH and AIBN, spiranoid lactone 10 was accessed in a regioselective and stereoselective fashion with moderate yields.…”

A Neural Network Model Informs Total Synthesis of Clovane Sesquiterpenoids

“…The synthetically useful yield predicted for compound 7 is expected as such a disconnection with a polarized alkene is the conventional strategy for eliciting the 6-endo mode of cyclization. Although conventional logic would have discouraged the selection of 8 and 9 due to limited available precedent for cyclizations of this type (25), the model's encouraging predictions for 8 and 9 mitigated that concern and neutralized any perceived benefit to the lower risk strategy via 7. Finally, compound 8 was selected, as 8 has a comparable predicted yield and represents a more innovative disconnection (9) that leads to greater synthetic accessibility (26).…”