Karl B. Lindsay

Synthesis of (+)-(1R,2S,9S,9aR)-octahydro-1H-pyrrolo[1,2-a]azepine-1,2,9-triol: a potential glycosidase inhibitor

The title compound was prepared as a potential glycosidase inhibitor. Key steps in the synthesis are vinyl epoxide aminolysis, ring-closing metathesis, cis-dihydroxylation and then ring closure.

Further Studies toward the Stereocontrolled Synthesis of Silicon-Containing Peptide Mimics

Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant silanediol dipeptide mimics are also described. This includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide.

Importance of C-N bond rotation in N-acyl oxazolidinones in their SmI2-promoted coupling to acrylamides.

A detailed mechanistic investigation was undertaken to determine the dominating factors of the postelectron transfer steps in the SmI(2)-promoted carbon-carbon bond forming reaction between N-acyl oxazolidinones and acrylamides. Competition experiments were performed by reacting two N-acyl oxazolidinones with a limiting amount of N-t-butyl acrylamide, and from the product distribution, the relative reactivity values (RV) for a series of N-acyl oxazolidinones were then calculated against N-pivaloyl oxazolidinone as the reference. An almost linear correlation was obtained for the simple alkyl N-acyl oxazolidinones when ln RV was plotted against the activation barriers for C-N bond rotation (s-trans to s-cis) obtained by DFT calculations, implying that C-N bond rotation from the s-trans to s-cis conformation is one of the essential parameters controlling the reactivity. These results were substantiated by other competition experiments carried out for the corresponding imide derivatives, where rotation is not necessary for obtaining bidentate coordination and where no such correlation as described above was observable. The finding that the reactivity of the simple N-acyl oxazolidinones for these SmI(2)-mediated transformations correlates with the activation barriers for C-N bond rotation may have implications for other useful synthetic organic reactions involving similar substrates. Finally, these studies were extrapolated to understanding the poor reactivity of N-acyl oxazolidinones, as those derived from Evans chiral auxiliaries, with N-tert-butyl acrylamide. These couplings appear to be dominated by the activation energy for addition because of arising syn-pentane interactions in the transition-state for C-C bond formation. We demonstrate that the addition of Lewis acids can have a beneficial effect on the coupling yields.

Asymmetric Synthesis of (–)-Swainsonine

This paper describes a new synthesis of (–)-swainsonine via the ring-closing metathesis reaction of a substituted 3-allyl-4-vinyloxazolindin-2-one and subsequent diastereoselective syn-dihydroxylation of the resulting pyrrolo- [1,2-c]oxazol-3-one.

Stereocontrolled Synthesis of 2-Substituted-1,3-Azasilaheterocycles

Chiral alpha-silylsulfinamides, prepared by the treatment of an alkyldiphenylsilane with lithium followed by its addition to a sulfinimine, can be applied to the synthesis of 1,3-azasilaheterocycles as derivatives of cyclic alkaloids. This synthetic route, which involves intramolecular substitution of an amino alcohol or cyclization of an amino acid promoted by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), represents a convenient means for accessing these silicon-containing heterocycles.

Direct entry to peptidyl ketones via SmI2-mediated C-C bond formation with readily accessible N-peptidyl oxazolidinones.

In this work, a new method for the preparation of peptidyl ketones is presented employing a SmI(2)/H(2)O-mediated coupling of N-peptidyl oxazolidinones with electron-deficient alkenes. The requisite peptide imides were easily prepared by solution-phase peptide synthesis starting from an N-acyl oxazolidinone derivative of an amino acid. Importantly, they could be used directly in the C-C bond-forming step without the need for further functionalization. Coupling of these peptide derivatives with a second peptide possessing an N-terminal acryloyl group leads to ketomethylene isosteres of glycine-containing peptides. This method represents an alternative means for ligating two small peptides through a C-C bond-forming step.