10-step Synthesis of 20-nor-Salvinorin A by Dynamic Strategic Bond Analysis

Abstract

Salvinorin A (SalA) is a plant metabolite that agonizes the human <i>kappa</i>-opioid receptor (κ-OR) with high affinity and high selectivity over <i>mu- </i>and <i>delta-</i>opioid receptors. Its therapeutic potential has stimulated extensive semi-synthetic studies and total synthesis campaigns. However, structural modification of SalA has been complicated by its instability, and efficient total synthesis has been frustrated by its dense, complex architecture. Treatment of strategic bonds in SalA as dynamic and dependent on structural perturbation enabled the identification of an efficient retrosynthetic pathway. Here we show that deletion of C20 simultaneously stabilizes the SalA skeleton, simplifies its synthesis and retains its high affinity and selectivity for the κ-OR. The resulting 10-step synthesis now opens the SalA scaffold to deep-seated property modification.

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

“…In previous publications a variety of different binding modes SalA (and close derivatives) bound to the KOR were postulated but with conflicting orientations [20,22,25,[49][50][51][52][53][54][55][56] causing confusion within the community. The binding poses were guided by mutational data available for SalA at the KOR rather than SAR data.…”

“…The binding poses were guided by mutational data available for SalA at the KOR rather than SAR data. Most studies [22,25,[49][50][51][52]54] predicted a vertically orientation of SalA within the KOR binding pocket to account for the far distance between the residues highlighted as important for SalA's affinity and potency at KOR in mutagenesis studies (from Y320 7.43 at the mid of TM7 to residues belonging to ECL2). However, horizontal binding modes were proposed as well [53,55].…”

“…The majority of studies evaluating SalA's binding mode were conducted before the publication of the active-state KOR structure (PDB-ID: 6B73 [22]) in 2018. Homology models based on other active-state GPCR structures (like rhodopsin [52] or MOR [50,54]) or active-like KOR models [20,49,51] based on the inactive-state KOR crystal structure (PDB-ID: 4DJH [20]) were used instead. Those KOR models differ in overall receptor architecture as well as side chain orientations from the experimentally solved active state Xray KOR crystal structure used by Che and coworkers [22] and within this study.…”

“…The rational design of new analogs to explore the chemical space around SalA is hampered by the still unknown binding mode of SalA at the KOR. Several different and conflicting binding modes for SalA at the KOR were proposed [22,25,[49][50][51][52][53][54][55][56]. For example, Vardy an coworkers [49] as well as Roach and coworkers [50] postulated binding modes in which the furan moiety of SalA points upwards towards the extracellular portion of the KOR while Che and coworkers [22] and Kane and coworkers [25] postulated the opposed orientation.…”

Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

“…To stabilize the core and attenuate epimerization, our group deleted the C20 methyl from the target (Figure 15a, 38). 101 This new structure not only probed our strain driven epimerization hypothesis but also changed the available retrosynthetic disconnections. Deletion of the C20 methyl stabilized decalone intermediates and significantly enhanced access to simple starting materials, resulting in a 10-step synthesis, which compares favorably to the 20-29-step syntheses of SalA itself.…”