Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts

Abstract

Chiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy-Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multipoint recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2-position, which are prevalent in insect pheromones. Optically active (2S,5S)-chalcogran, a pheromone of the six-spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product.

Dynamic Kinetic Spiroketalization/Oxa‐Michael Addition Cascade of Alkoxyboronates and Peroxyacetals: Enantio‐ and Diastereoselective Synthesis of Benzannulated Spiroketals

“…Inspired by the recent success of enantioselective oxa‐Michael addition using bifunctional organocatalysts, we envisioned the generation of spiroketals, which is outlined in Scheme , using two alternating paths. Firstly, the alkoxyboronate spiro‐ketatalization/dynamic kinetic oxa‐Michael addition cascade pathway (path a); secondly, a dynamic kinetic peroxy hemiacetalization/dynamic kinetic spiroketalization/oxa‐Michael addition cascade pathway (path b) …”

Designed Spiroketal Protein Modulation

“…Spiroketals are archetypal spirocyclic compounds, found abundantly in the CAS registry (Supporting Information), of which many are bioactive natural products . Besides being attractive targets for total synthesis, spiroketal‐derived natural products have contributed to a renaissance of thinking towards intelligent library design, grounded in principles of diversity‐oriented synthesis (DOS) and biology‐oriented synthesis (BIOS) . Spiroketals are arguably well‐adapted to both philosophical approaches in being biologically relevant while fulfilling the three criteria for molecular diversity set out by Schreiber and co‐workers—appendage, stereochemistry, skeletal diversity—owing in particular to the conformational and configurational flexibility of these scaffold structures.…”

Designed Spiroketal Protein Modulation

“…Spiroketals are archetypal spirocyclic compounds, found abundantly in the CAS registry (Supporting Information), of which many are bioactive natural products . Besides being attractive targets for total synthesis, spiroketal‐derived natural products have contributed to a renaissance of thinking towards intelligent library design, grounded in principles of diversity‐oriented synthesis (DOS) and biology‐oriented synthesis (BIOS) . Spiroketals are arguably well‐adapted to both philosophical approaches in being biologically relevant while fulfilling the three criteria for molecular diversity set out by Schreiber and co‐workers—appendage, stereochemistry, skeletal diversity—owing in particular to the conformational and configurational flexibility of these scaffold structures.…”