J. Edward Semple

Concise total synthesis of the prolyl endopeptidase inhibitor eurystatin A via a novel Passerini reaction-deprotection-acyl migration strategy †

Abstract The Passerini reaction between suitably protected alaninal, leucine isonitrile, and ornithine components delivered adducts 10a , b in high yield. Orthogonal N -deprotection of 10a led, via a smooth O - to N -acyl migration, to 11 , which constitutes the entire skeleton of the eurystatins. Subsequent deprotection, macrocyclization, elaboration, and final oxidation steps efficiently afforded eurystatin A 1a in high overall yield.

Synthesis of functionalized tetrahydrofurans

Abstract A novel cyclization reaction is described which affords readily manipulable 3(2H)-dihydrofuranone ethylene ketals, useful in the total synthesis of an ascofuranone model, bullatenone, and muscarine analogs.

Design and synthesis of a novel class of thrombin inhibitors incorporating heterocyclic dipeptide surrogates

Abstract Several potent and selective inhibitors of thrombin incorporating novel heterocyclic peptide surrogates in the P3-P2 position of peptidyl argininals have been discovered. Illustrated in this article are three classes of heterocycles: pyridones, uracils, and pyrimidinones. The synthesis and biological activities of these unique aromatic heterocyclic derivatives are reported herein.

Rational design, synthesis, and serine protease inhibitory activity of a novel P1-argininal derivative featuring a conformationally constrained P2–P3 bicyclic lactam moiety

Abstract Based on molecular modeling and judicious combination of the salient topographic features of the recently discovered P3-lactam derivative 1 with the P2-prolyl derivatives 2a, b, the novel thrombin inhibitor 3a was designed. Inhibitor 3a incorporates a fused bicyclic lactam as a novel type of P2–P3 dipeptide surrogate. The synthesis and biological activity of this potent serine protease inhibitor is presented.

Synthesis and biological activity of P2–P4 azapeptidomimetic P1-argininal and P1-ketoargininamide derivatives: a novel class of serine protease inhibitors

Abstract Molecular modeling and topographic considerations of the thrombin-specific sequences Boc-Asp-Pro-Arg-TS or Ac-d-Phe-Pro-Arg-TS (TS = transition state analog electrophilic center) and related scaffolds led to the design of novel P 2 –P 4 -azapeptidomimetic P 1 -argininal and P 1 -ketoargininamide derivatives ( 3a-j ). The synthesis and biological activity of these potential serine protease inhibitors are presented.

Novel benzo-fused lactam scaffolds as factor Xa inhibitors

Rigid benzolactam P3-P2 dipeptide mimics were designed and prepared as potential inhibitors of blood coagulation factor Xa. Methoxy substitution of the tetrahydrobenzazepinone scaffold led to potent and selective inhibitors. The synthesis and biological activities of these derivatives are reported herein.

Novel and general method for the preparation of peptidyl argininals

Abstract A general method for the synthesis of peptidyl argininals was developed which utilizes the novel building block N g -nitro-L-argininal ethyl aminal·HCl. The final aldehyde structure is generated by hydrolysis of the peptidic aminal moiety and can be applied to highly functionalized peptidic structures. The method is amenable to the preparation of large quantities of enantiomerically pure peptidyl argininals and was applied to the synthesis of two potent thrombin inhibitors.

Novel, Potent Non-Covalent Thrombin Inhibitors Incorporating P3-Lactam Scaffolds

Evolution of P(1)-argininal inhibitor prototypes led to a series of non-covalent P(3)-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S(1), S(2), and S(3) specificity pockets of thrombin. Rigid P(1)-arginine surrogates possessing a wide range of basicity (calcd pK(a)s approximately neutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented.

Asymmetric synthesis of novel quaternary α-hydroxy-δ-lactam dipeptide surrogates

Application of the Sharpless AD protocol to a series of α-(E)-benzylidene-δ-lactam precursors followed by selective deoxygenation provided efficient synthetic routes to the chiral quaternary α-hydroxy-γ-lactam derivatives 4 and 5. These functionalized intermediates and the diol precursors 3 are regarded as novel types of D-Phe-Pro dipeptide surrogates that are useful as enzyme active site probes.

Potent and selective thrombin inhibitors featuring hydrophobic, basic P3P4-aminoalkyllactam moieties

Abstract Crystal structure and evolving SAR considerations of potent, selective benzylsulfonamide lactam thrombin inhibitors and related serine protease inhibitors have led to the design of novel thrombin inhibitors 1a-g , featuring hydrophobic, basic, P 4 -alkylaminolactam scaffolds that serve as novel types of P 3 P 4 dipeptide mimics. The design, synthesis, and biological activity of these targets is presented.