Denice M. Spero

Regiospecific control of Rh(II) carbenoids in the C-H insertion reaction

Abstract Electronic and conformational effects of Rh(II) catalyzed intramolecular C-H insertions of 2-diazoketo tetrahydropyrans 5a-3 were studied. The C-6H/C-4H insertion ratio was modulated by the electron withdrawing or donating capacity of the substituted oxygen at C-4.

Synthesis of protected, chiral α,α-disubstituted α-amino acids via a Beckmann rearrangement

Abstract The synthesis of chiral, nonracemic, fully protected α,α-disubstituted α-amino acids via the Beckmann rearrangement of tosylated oximes 1 is described. The desired amino acids were obtained in good yields with excellent enantioselectivities in relatively few steps.

The design of potent hydrazones and disulfides as cathepsin S inhibitors.

The design and synthesis of dipeptidyl disulfides and dipeptidyl benzoylhydrazones as selective inhibitors of the cysteine protease Cathepsin S are described. These inhibitors were expected to form a slowly reversible covalent adduct of the active site cysteine of Cathepsin S. Formation of the initial adduct was confirmed by mass spectral analysis. The nature and mechanism of these adducts was explored. Kinetic analysis of the benzoyl hydrazones indicate that these inhibitors are acting as irreversible inhibitors of Cathepsin S. Additionally, the benzoylhydrazones were shown to be potent inhibitors of Cathepsin S processing of Class II associated invariant peptide both in vitro and in vivo.

Enantioselective synthesis of the (syn,anti)-1-amino-2,3-diol subunit of renin inhibitors by reaction of β-Lactams with a Grignard reagent

A new approach to the BOC-protected amino diol 1a via the opening of 3,4-cis-disubstituted β-lactam 3 with isobutylmagnesium chloride is described. Nonracemic β-lactam 3 could be obtained by enzymatic resolution of the 3-acetoxy-β-lactam 4 or from a chiral precursor, methyl (R)-(−)-mandelate.

Automatable Formats of Higher Throughput ADMET Profiling for Drug Discovery Support

An evolving union of high throughput screening (HTS) and absorption, distribution, metabolism, excretion, and toxicology (ADMET) technologies have transformed drug discovery. Human tissue-based, in vitro ADMET assays can efficiently generate reliable profiles for structure-activity or structure-property relationships of compounds from screening “hit sets” or libraries. The process of identifying discovery compounds with desirable “druglike” properties has consequently become increasingly data-driven. Chemists and biologists initiate the process by submitting requests to our laboratory through an intranet database. A Caco-2 cell model, automated on a Tecan Genesis workstation, evaluates the intestinal absorption of drug candidates. Distribution properties are determined with a high-throughput equilibrium dialysis technique for measuring plasma protein binding. Drug metabolism can be evaluated on a Genesis workstation via measurements of metabolic stability in liver microsomes. Drug-drug interactions can be predicted with HTS techniques using human recombinant hepatic CYP450 isoforms. A Genesis workstation, integrated with a fluorescence plate reader, executes CYP450 inhibition assays. Cell toxicity assays using human hepatocytes can serve as early, high-throughput indicators of potential systemic drug toxicity. The early availability of ADMET profiling data can now enable discovery scientists to quickly evaluate the factors that influence the pharmacodynamic and pharmacokinetic properties of compounds in lead optimization.

AMINES via NUCLEOPHJLIC 1,2-ADDITION TO KETIMINES. CONSTRUCTION OF NITROGEN-SUBSTITUTED QUATERNARY CARBON ATOMS. A REVIEW

INTRODUCTION .............................................................................................................................. 207 .................................................................................................. I . ADDITION TO KETIMINES 208 1 . General ................................................................................................................................. 208 2 . Addition to Open-chain Ketimines ....................................................................................... 209 a) With N-Alkyl or N-Aryl Substituents .............................................................................. 2~ b) With Electron-withdrawing Substituent on Imino Nitrogen .......................................... 213 c) With N-Metal Substituent ................................................................................................ 217 3 . Addition to Cyclic Ketiinines ................................................................................................ 218 I1 . ADDITION TO KETOXIME ETHERS ................................................................................. 224 1 . General ................................................................................................................................. 224 2 . Addition to Open-chin Oxime Ethers ................................................................................. 225 3 . Addition to Cyclic Oxime Ethers .......................................................................................... 226 111 . ADDITION TO KETOHYDRAZONES ................................................................................. 226 1 . General ................................................................................................................................. 226 2 . Addition to Open-chain Hydra:ones .................................................................................... 226 a) With N-Alkyl or N-Aryl Substituents .............................................................................. 226 b) With Electron-withdrawing Substituent on Imino Nitrogen .......................................... 227 Addition to Cyclic Hvdrcizones ............................................................................................. 227 1V . ADDITlON TO KETONITRONES ........................................... ....... 227 1 . General ................................................................................................................................. 227 2 . Addition to Open-chain Ketunitrones .................................................................................. 228 3 . Addition to Cvclic Ketonitrones ........................................................................................... 228 V . CONCLUSION ........................................................................................................................... 229 REFERENCES .................................................................................................................................... 229 3 .

N-Acetylcysteine methyl ester : an efficient sulfur transfer agent

Abstract The sulfur transfer capability of N-acetylcysteine methyl ester is illustrated by its addition to a 2-fluorophenylcarbodiimide followed by β-elimination and cyclization in a novel route to aminobenzothiazoles.