Distal two-bond versus three-bond electronegative oxo-substituent effect controls the kinetics and thermodynamics of the conversion of a C-nitroso function to the corresponding oxime in the conformationally locked pentofuranose (bicyclo[2.2.1]heptane) system.

We report the high-yielding and scalable diastereospecific synthesis of isomeric bicyclo[2.2.1]heptane-7- and -8-oximes and their corresponding C-nitroso derivatives, which are the key intermediates for the synthesis of carbanucleosides. Neither the (C7-R)-nitroso- nor (C8-S)-nitrosobicycloheptane system requires any external base in DMSO-d6 to afford the corresponding oxime, and no reverse isomerization from the oxime to the C-nitroso compound was observed. The conversion of the (C8-S)-nitroso compound to the E/Z-oximes was ∼8 times faster (at 40 °C) than that of the (C7-R)-nitroso derivative. The mechanism involves first-order reaction kinetics for the conversion of either the (C7-R)- or (C8-S)-nitroso derivative to the corresponding E/Z-oximes. The lower rate of conversion of the (C7-R)-nitroso compound to the corresponding oximes compared with that of the (C8-S)-nitroso derivative is attributed to the fact that the acidic H8 ionizing center is two bonds away from the OPMB group on C1 in the latter whereas H7 is three bonds away from the C1 OMe group in the former, making the effect of the electron-withdrawing group on C1 stronger in the latter.

Steric effects in the tuning of the diastereoselectivity of the intramolecular free-radical cyclization to an olefin as exemplified through the synthesis of a carba-pentofuranose scaffold.

Two free-radical cyclization reactions with the radical at the chiral C4 of the pentose sugar and the intramolecularly C1-tethered olefin (on radical precursors 8 and 17) gave a new diastereospecific C4-C8 bond in dimethylbicyclo[2.2.1]heptane 9, whereas the new C4-C7 bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave trans and cis diastereomers, in which the chirality of the C4 center is fully retained as that of the starting material. It has been shown how the chemical nature of the fused carba-pentofuranose scaffolds, dimethylbicyclo[2.2.1]heptane 9 vis-a-vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in the former versus 2-O- in the latter), dictates the stereochemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure 1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the α-face) with that of the 8(R)-CH(2)(•) radical in the ß-face. The conversion of 17 → 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the boat-like transition states is likely.

Studies on the synthesis of valienamine and 1-epi-valienamine starting from D-glucose or L-sorbose.

Two synthetic routes to a carbocyclic precursor to valienamine are reported, starting from either D-glucose or L-sorbose and using ring-closing metathesis as a key step. A low-yielding synthesis of 1-epi-valienamine is reported. Results from an abortive third possible route to valienamine based on an early introduction of nitrogen are discussed.

SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease.

We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.

Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease.

Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.