A domino Kornblum-DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines and application to the synthesis of the ceramide transport inhibitor (±)-HPA-12

Desymmetrization and Kinetic Resolution of Endoperoxides Using a Bifunctional Organocatalyst

“…The synthesis of 3,6-dihydro-1,2-dioxines was carried out using the dye-sensitized photooxidation of symmetrically substituted 1,3-butadienes . To prevent the KDM reaction products from rearranging to furan or diketones, the alkene in the endoperoxide was reacted with m -CPBA to provide the epoxide series 6a – o …”

“…The synthesis of 3,6-dihydro-1,2-dioxines was carried out using the dye-sensitized photooxidation of symmetrically substituted 1,3-butadienes. 25 To prevent the KDM reaction products from rearranging to furan or diketones, the alkene in the endoperoxide was reacted with m-CPBA to provide the epoxide series 6a−o. 9 The first attempts at ring opening diphenyl-substituted endoperoxide 6a using a catalytic amount of thiourea catalyst 8a at ambient temperature in CH 2 Cl 2 were met with success, and an 89:11 enantiomeric ratio (er) was obtained for 7a (Table 1).…”

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

“…However, a limited commercial availability and high cost of HPA-12 have hindered its application in basic researches involving CERT inhibition. For this, a number of groups have successfully accomplished the synthesis of HPA-12 [13–25]. The first synthesis of HPA-12 comprised [13] a three-component asymmetric Mannich reaction catalyzed by a chiral zirconium catalyst.…”

“…1) using a Zn-catalyzed asymmetric Mannich-type reaction in water, and unambiguously ascertained the revised configuration by X-ray crystallography [14]. The other syntheses of (1 R ,3 S )-HPA-12 ( 2 ) used the chiral pool approach [15–16], crystallization-induced asymmetric transformation [17], diastereoselective reduction of γ-aryl-γ-oxo-β-amino alcohol [18], cycloaddition of oxime with alkenes [19], enantioselective carbonyl reduction followed by an organocatalyzed α-amination reaction [20], tandem approach from ( S )-Wynberg lactone [21], chiral ruthenium-catalyzed N -demethylative rearrangement of 1,2-isoxazolidines [22], gold(I)-catalyzed cyclization of a propargylic N -hydroxylamine [23], from β-sulfinamido ketones derived from chiral sulfinimines [24], and a Kornblum–DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines followed by diastereoselective reduction [25]. Most of these methods employ starting materials or catalysts, which are not commercially available, and also require operationally demanding reaction conditions.…”