Enantioselective Synthesis of Spiro‐oxiranes: An Asymmetric Addition/Aldol/Spirocyclization Domino Cascade

Abstract

Enantioenriched spiro‐oxiranes bearing three contiguous stereocenters were synthesized using a rhodium‐catalyzed asymmetric addition/aldol/spirocyclization sequence. Starting from a linear substrate, the cascade enabled the formation of a spirocyclic framework in a single step. sp2‐ and sp‐hybridized carbon nucleophiles were found to be competent initiators for this cascade, giving arylated or alkynylated products, respectively. Derivatization studies demonstrated the synthetic versatility of both the epoxide and the alkyne moieties of the products. DFT calculations were used to reconcile spectroscopic discrepancies observed between the solution‐ and solid‐state structures of the products.

Recent Developments in Enantioselective Domino Reactions. Part A: Noble Metal Catalysts

“…In the same year, Lautens et al disclosed enantioselective rhodium-catalyzed domino Michael/aldol/spirocyclization reactions of α-bromoketoenones 291 with nucleophiles such as aryl boronic acids 20. [86] A preformed rhodium catalyst derived from chiral diene ligand 292 was employed at 2.5 mol% of catalyst loading in DCE as solvent, allowing by heating at 85 °C the formation of chiral densely functionalized spiro-oxiranes 293 exhibiting three stereocenters to be achieved in moderate to good yields (40-85%) and good to excellent enantioselectivities (70-> 99% ee), as presented in Scheme 76. The domino reaction evolved through successive Michael addition, aldol condensation and spirocyclization.…”

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

“…Finally, the alkynylation of the enone is followed by the cyclization step which yields the α-propargyl-β-hydroxyketones 201 in good yields and excellent diastereo- and enantiopurities. Soon after, the Lautens group has further extended their methodology to the synthesis of spirooxirane derivatives 203 by implementing a spiro-cyclization step following the aldol reaction ( Scheme 51B ) [ 94 ]. Giving only a single diastereomer with good enantioselectivity using a Rh/bicyclo[2.2.2]octane-2,5-diene (bod) complex, a broad variety of spiro compounds were isolated in good to excellent yields.…”

New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling

“…The proposed route allows not only the introduction of various functional groups at the C-3 position with high stereoselectivity but also the preservation of the hydroxyl group at the C-3 position. A similar strategy is widely represented in the chemistry of natural compounds [24][25][26][27][28]. As for the carboxyl group in the side chain, we decided not to modify it since the presence in the design molecules of three polar groups (two hydroxyl and carboxyl) will allow us to reduce excessive lipophilicity of the obtained inhibitors based on DCA.…”