Lipid Metabolic Events Underlying the Formation of the Corneocyte Lipid Envelope

Cornified cells of the stratum corneum have a monolayer of an unusual lipid covalently attached to the outer surface. This is referred to as the corneocyte lipid envelope (CLE). It consists of a monolayer of ω-hydroxyceramides covalently attached to the outer surface of the cornified envelope. The CLE is essential for proper barrier function of the skin and is derived from linoleate-rich acylglucosylceramides synthesized in the viable epidermis. Biosynthesis of acylglucosylceramide and its conversion to the cornified envelope is complex. Acylglucosylceramide in the bounding membrane of the lamellar granule is the precursor of the CLE. The acylglucosylceramide in the limiting membrane of the lamellar granule may be oriented with the glucosyl moiety on the inside. Conversion of the acylglucosylceramide to the CLE requires removal of the glucose by action of a glucocerebrosidase. The ester-linked fatty acid may be removed by an as yet unidentified esterase, and the resulting ω-hydroxyceramide may become ester linked to the outer surface of the cornified envelope through action of transglutaminase 1. Prior to removal of ester-linked fatty acids, linoleate is oxidized to an epoxy alcohol through action of 2 lipoxygenases. This can be further oxidized to an epoxy-enone, which can spontaneously attach to the cornified envelope through Schiff’s base formation. Mutations of genes coding for enzymes involved in biosynthesis of the CLE result in ichthyosis, often accompanied by neurologic dysfunction. The CLE is recognized as essential for barrier function of skin, but many questions about details of this essentiality remain. What are the relative roles of the 2 mechanisms of lipid attachment? What is the orientation of acylglucosylceramide in the bounding membrane of lamellar granules? Some evidence supports a role for CLE as a scaffold upon which intercellular lamellae unfold, but other evidence does not support this role. There is also controversial evidence for a role in stratum corneum cohesion. Evidence is presented to suggest that covalently bound ω-hydroxyceramides serve as a reservoir for free sphingosine that can serve in communicating with the viable epidermis and act as a potent broad-acting antimicrobial at the skin surface. Many questions remain.

Oxygenated Theonellastrols: Interpretation of Unusual Chemical Behaviors Using Quantum Mechanical Calculations and Stereochemical Reassignment of 7α-Hydroxytheonellasterol

A total of eight new oxygenated 4-exo-methylene sterols, 1–8, together with one artifact 9 and six known sterols 11–16, were isolated from the marine sponge Theonella swinhoei collected from the Bohol province in Philippines. Structures of sterols 1–8 were determined from 1D and 2D NMR data. Among the sterols, 8α-hydroxytheonellasterol (4) spontaneously underwent an allylic 1,3-hydroxyl shift to produce 15α-hydroxytheonellasterol (9) as an artifact; this was rationalized by quantum mechanical calculations of the transition state. In addition, the 1,2-epoxy alcohol subunit of 8α-hydroxy-14,15-β-epoxytheonellasterol (5) was assigned using the Gauge-Independent Atomic Orbital (GIAO) NMR chemical shift calculations and subsequent DP4+ analysis. Finally, comparison of the 13C chemical shifts of isolated 7α-hydroxytheonellasterol (6) with the reported values revealed significant discrepancies at C-6, C-7, C-8, and C-14, leading to reassignment of the C-7 stereochemistry in the known structure.

A Synthetic Approach Toward a Brominated Oxocane Labdane Diterpenoid Isolated From Laurencia obtusa

The synthesis of a labdane oxocane epoxy-alcohol is described starting from the Wieland–Miescher ketone derivative via ring closing olefin metathesis of a diene derivative, targeting the total synthesis of a brominated oxocane labdane diterpenoid isolated from Laurencia obtusa.

Effect of an Al(III) Complex on the Regio- and Stereoisomeric Formation of Bicyclic Organic Carbonates

Valorization of carbon dioxide into organic molecules using catalytic approaches has witnessed an upsurge in recent years. Here, the influence of an Al(III) aminotriphenolate complex on the regio- and stereo-chemical features of the coupling between carbon dioxide and a cyclic epoxy alcohol has been studied. Three distinct bicyclic carbonate products were produced from a single starting material depending on the catalytic conditions. The proposed carbonate configurations were examined by solution and solid phase techniques including NMR spectroscopic and X-ray crystallographic analyses. Control experiments combined with DFT calculations provide a rationale for the distinct catalytic manifolds observed in the presence and absence of the Al(III) complex.

Effect of an Al(III) Complex on the Regio- and Stereoisomeric Formation of Bicyclic Organic Carbonates

Valorization of carbon dioxide into organic molecules using catalytic approaches has witnessed an upsurge in recent years. Here, the influence of an Al(III) aminotriphenolate complex on the regio- and stereo-chemical features of the coupling between carbon dioxide and a cyclic epoxy alcohol has been studied. Three distinct bicyclic carbonate products were produced from a single starting material depending on the catalytic conditions. The proposed carbonate configurations were examined by solution and solid phase techniques including NMR spectroscopic and X-ray crystallographic analyses. Control experiments combined with DFT calculations provide a rationale for the distinct catalytic manifolds observed in the presence and absence of the Al(III) complex.

Stereoselective Synthesis of Maresin-Like Lipid Mediators

14S,22-Dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (maresin-L1) and 14R,22-dihydroxy-docosa-4Z,7Z,10Z, 12E,16Z,19Z-hexaenoic acid (maresin-L2) were chemically synthesized. They were identical to activated macrophage-produced counterparts and their total synthesis was highly stereoselective, as revealed by chiral LC-UV-MS/MS analysis. The synthesis involved the following steps: (1) kinetic resolution of a racemic allylic alcohol by the asymmetric epoxidation; (2) transformation of the epoxy alcohol to γ-hydroxyenal derivative; and (3) the Wittig reaction to furnish the Z-olefin.

The Johnson Synthesis of Paspaline

Paspaline 3, isolated from the ergot fungus Claviceps paspali, is a Maxi-K channel antagonist, and so a potential lead for the treatment of Alzheimer’s disease. The selec­tive C–H functionalization that converted 1 to 2 was a key step in the synthesis of 3 reported (J. Am. Chem. Soc. 2015, 137, 4968; J. Org. Chem. 2015, 80, 9740) by Jeffrey S. Johnson of the University of North Carolina. The prochiral diketone 4 was the starting point for the assembly of 1. Selective reduction with a commercial strain of yeast set both the relative and the absolute con­figuration of 5. The ketone interfered with the subsequent acid-catalyzed cyclization of the epoxy alcohol, so it was protected as the tosylhydrazone 6. This set the stage for the direct Bamford– Stevens conversion to the fully-substituted alkene 7. Ireland–Claisen rearrangement of the isobutyrate derived from 7 proceeded with substantial preference for the equatorial diastereomer 8. This was carried on to the methyl ketone 9. Hydroboration of 9 showed substantial axial preference, to deliver, after oxidation, the equatorial aldehyde 10. Intramolecular aldol condensation to 11 followed by hydrogenation and benzyl oxime formation then completed the preparation of 1. Intramolecular Pd-catalyzed acetoxylation has been extensively studied by Sanford (Org. Lett. 2010, 12, 532). The Sanford conditions, carried out on a gram scale, conver­ted 1 into the equatorial diastereomer 2 with remarkable diastereoselectivity. The final carbocyclic ring was then added by vinyl Grignard addition to the derived keto alde­hyde 12. Grubbs cyclization gave 13, that on exposure to acid rearranged to the enone 14. Reduction of the ketone occurred from the open face to give an alcohol that then directed hydrogenation from the opposite face, leading to the desired trans-fused ketone. Sulfenylation then completed the synthesis of the ketone 15. At this point, the authors followed Smith (J. Am. Chem. Soc. 1985, 107, 1769) in using the Gassman protocol (J. Am. Chem. Soc. 1974, 96, 5495) to construct the indole. Amination of the sulfur of 15 with N-chloroaniline gave the sulfonium salt, that on exposure to Et3N rearranged to 16. Reductive desulfurization followed by cyclization completed the synthesis of paspaline 3.