The preparation of simplified scyphostatin analogues using a tethered aminohydroxylation (TA) strategy

The first tethered aminohydroxylation reaction employing a tertiary alcohol is reported as part of a route to prepare analogues of the naturally occurring sphingomyelinase inhibitor, scyphostatin. The tethered aminohydroxylation of 1-allylcyclohexanol produces the β-amino alcohol product, in protected form, with the required regiochemistry. Two approaches to the installation of the lipophilic side chain are described and the successful route used to prepare five novel scyphostatin analogues, one containing the natural lower side chain.     

Synthesis of sphingomyelin difluoromethylene analogue

As a new sphingomyelinase inhibitor, a novel sphingomyelin CF₂ analogue was designed and synthesized. One key step of this synthesis is the very mild hydrolysis of the oxazolidinone ring, a suitable intermediate for the introduction of a diethyl difluoromethylphosphonate group, by utilizing the characteristic electron withdrawing nature of the nosyl group at the oxazolidinone ring in an alcoholic solvent to produce the corresponding carbonate attaching at the secondary hydroxy group. The synthesized CF₂ analogue inactivated toward B. cereus sphingomyelinase with nearly the same attitude as the nitrogen analogue that we previously reported.     

Enantiocontrolled synthesis of the epoxycyclohexenone moieties of scyphostatin, a potent and specific inhibitor of neutral sphingomyelinase

The epoxycyclohexenone moieties 2 and 3b of scyphostatin (1), a potent and specific inhibitor of neutral sphingomyelinase, were synthesized in enantiomerically pure forms starting from (−)-quinic acid (11). The synthetic method features (i) the preparation of the olefin masked enones 25 and 29, the precursors for the key aldol-type coupling reaction, (ii) the efficient and stereocontrolled aldol-type coupling reactions between 25 (or 29) and benzaldehyde (8) and Garner's aldehyde analogue 9 to deliver alcohols 23 and 24, respectively, both of which possess the requisite asymmetric quaternary carbon center at the C6 position, and (iii) the stereospecific S_N2-type epoxide ring formation of the mesylates 35 and 47 under mild basic conditions to produce the targeted compounds 2 and 3b, respectively.     

Ceramide-enriched microdomains in planar membranes

Ceramide has a large effect on the properties of biological membranes, increasing lipid order and promoting lateral phase separation, and plays an important role in cell signaling. This review provides an overview of recent studies of the effects of direct ceramide incorporation and enzymatic ceramide generation on planar supported membranes, including lipid monolayers and supported lipid bilayers. Recent studies have focused on understanding the nucleation, growth and morphology of ceramide gel domains, characterizing the properties of ceramide-rich membrane phases and investigating the effects of ceramide on phase-separated membranes with co-existing liquid-ordered and fluid phases, as models for cellular membranes.