Enantioselective Synthesis of 7(S)-Hydroxydocosahexaenoic Acid, a Possible Endogenous Ligand for PPARα.

We report the first total synthesis of the polyunsaturated fatty acid 7-hydroxydocosahexaenoic acid (7-HDHA) in racemic form and the enantioselective synthesis of 7-(S)-HDHA. Both syntheses follow a convergent approach that unites the C1-C9 and C10-C22 fragments using Sonogashira coupling and Boland reduction as key steps. These syntheses enabled the unambiguous characterization of this natural product for the first time and helped establish 7(S)-HDHA as a possible endogenous ligand for peroxisome proliferator-activated receptor alpha.

Synthetic studies on palmerolide C: synthesis of an advanced intermediate towards the revised structure of palmerolide C.

A stereoselective synthesis of the highly advanced intermediates towards the revised structure of palmerolide C and 10-epi-palmerolide C is described in this paper. The required key fragments C1-C6, C7-C14 and C15-C23 have been successfully assembled in a convergent manner to access the C1-C23 framework bearing all the five stereocenters present in the natural product. The synthesis involves the Julia-Kocienski reaction, Yamaguchi esterification, Takai olefination and regioselective epoxide opening as key steps. The proposed route is flexible and could also be applied to the synthesis of structurally related palmerolides.

Alkylidene Dihydropyridines Are Surrogates for Pyridylic Anions in the Conjugate Addition to α,ß-Unsaturated Ketones.

We show that alkylidene dihydropyridines, readily prepared from 4-alkylpyridines, behave as soft nucleophiles toward a range of α,ß-unsaturated ketones under the influence of silyl Lewis acids to give the products of conjugate addition. In contrast to existing methods, which use strongly basic pyridylic anions, this reaction tolerates a wide array of functional groups, providing access to useful heterocyclic scaffolds.

Synthesis of Nitrone-derived Pyrrolidine Scaffolds and Their Combinatorial Libraries to Develop Selective α-l-Rhamnosidase Inhibitors.

A general and flexible approach toward the development of α-l-rhamnosidase (α-l-Rha-ase) inhibitors is described. Five enantiopure poly-substituted pyrrolidine-based scaffolds bearing the C1-aminomethyl moiety were designed and synthesized from five-membered cyclic nitrones. Each structurally diversified amide library of these scaffolds was rapidly generated via combinatorial parallel synthesis and applied for in-situ inhibition study against α-l-Rha-ase, allowing us to efficiently identify new inhibition hits. Surprisingly, all promising inhibitors are derived from the same scaffold 3. Among them, the most potent and selective inhibitor is pyrrolidine 19 with Ki =0.24 µM, approximately 24-fold more potent than the reference compound DAA (Ki =5.7 µM). It is the first study to comprehensively prepare pyrrolidine-based scaffolds and libraries for inhibition study against α-l-Rha-ase.

Further Insights on Structural Modifications of Muramyl Dipeptides to Study the Human NOD2 Stimulating Activity.

A series of muramyl dipeptide (MDP) analogues with structural modifications at the C4 position of MurNAc and on the d-iso-glutamine (isoGln) residue of the peptide part were synthesized. The C4-diversification of MurNAc was conveniently achieved by using CuAAC click strategy to conjugate an azido muramyl dipeptide precursor with structurally diverse alkynes. d-Glutamic acid (Glu), replaced with isoGln, was applied for the structural diversity through esterification or amidation of the carboxylic acid. In total, 26 MDP analogues were synthesized and bio-evaluated for the study of human NOD2 stimulation activity in the innate immune response. Interestingly, MDP derivatives with an ester moiety are found to be more potent than reference compound MDP itself or MDP analogues containing an amide moiety. Among the varied lengths of the alkyl chain in ester derivatives, the MDP analogue bearing the d-glutamate dodecyl (C12) ester moiety showed the best NOD2 stimulation potency.

A domino enyne/IMDA approach to the core structure of (-) vinigrol.

We report here an enantioselective formal synthesis of vinigrol involving a 1-2-3 strategy: one pot and two reactions with the formation of three rings leading to the core structure of vinigrol from its stereochemically well-defined acyclic precursor.