Mark C. Noe

Highly enantioselective synthesis of cyclic and functionalized α-amino acids by means of a chiral phase transfer catalyst

The chiral quaternary ammonium salt 1 serves as phase transfer catalyst for the enantioselective conversion of the glycine derivative 2 to a variety of cyclic and acyclic chiral α-amino acids with enantioselectivities as high as 200:1 in alkylation and Michael addition reactions.

The first enantioselective synthesis of the chemotactic factor sirenin by an intramolecular [2 + 1] cyclization using a new chiral catalyst

Summary A simple, highly enantioselective synthesis of sirenin ( 1 ) (bioactive form) has been developed which depends on the intramolecular [2 +1] cycloaddition reaction of diazo ester 5 to form bicyclic ester 6 (95 : 5 enantioselectivity) using a new and remarkably stable monomeric chiral Cu(I) complex ( 2 ) whose structure was proven by X-ray diffraction analysis.

Linezolid, the first oxazolidinone antibacterial agent.

Linezolid (Zyvox™) is the first member of an entirely new class of antibiotics to reach the market in over 35 years; it was approved for use in 2000. A member of the oxazolidinone class of antibiotics, linezolid is highly effective for the treatment of serious Gram‐positive infections and has activity that compares favorably with vancomycin for most clinically relevant pathogens. Zyvox is approved for use against serious Gram‐positive infections, including those caused by Streptococcus pneumoniae, and the very challenging methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus faecium organisms. Zyvox inhibits bacterial protein synthesis by binding to 23S rRNA in the catalytic site of the 50S ribosome. It can be administered both orally and intravenously and has good tissue distribution. Recent results have demonstrated that oxazolidinone analogs related to linezolid are effective in treating pulmonary tuberculosis caused by resistant Mycobacterium tuberculosis in animal infection models and suggest additional new therapeutic applications for these antibiotics.

Pyridone Methylsulfone Hydroxamate LpxC Inhibitors for the Treatment of Serious Gram-Negative Infections

The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.

A short and convergent enantioselective synthesis of (3S)-2,3-oxidosqualene

Abstract A very useful synthesis of (3S)-2,3-oxidosqualene from geraniol, farnesol and E-1-bromo-4-chloro-3-methyl-2-butene is described which makes use of enantioselective and catalytic dihydroxylation of geranyl acetate and two E-stereospecific allylic coupling reactions mediated by E-prenylbarium reagents.

A mechanistically designed bis-cinchona alkaloid ligand allows position- and enantioselective dihydroxylation of farnesol and other oligoprenyl derivatives at the terminal isopropylidene unit

Summary The mechanistically designed bis-cinchona alkaloid derivative 3 serves as an excellent catalytic ligand in the OsO4-promoted catalytic enantioselective dihydroxylation of the terminal isopropylidene group infamesyl, geranylgeranyl, and solanesyl esters and also squalene, with selectivity as high as 120: 1 with E,E-farnesyl acetate. 1H NMR and X-ray studies support the conformation described by 3 in which the V-shaped catalytic binding pocket is composed of the two 6-(4-heptyloxy)-quinoline units (sides and rear) and the naphthopyridazine linker (bottom).

X-ray crystallographic studies provide additional evidence that an enzyme-like binding pocket is crucial to the enantioselective dihydroxylation of olefins by OsO4-bis-cinchona alkaloid complexes

X-Ray crystallographic analysis on single crystals and 1H NMR studies in solution of various bis-cinchona alkaloid derivatives reveal a general preference for a conformation which possesses a U-shaped binding pocket with favorable dimensions for the inclusion of olefinic substrates and the acceleration of face selective dihydroxylation by a proximate pentacoordinate OsO4.

Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

Synthesis and X-ray structure of a novel chiral trinuclear titanium-tetraol complex

This paper describes the synthesis of the chiral tetraol 1, and its conversion with Ti(IV) 1,1,1,3,3,3-hexafluoroisopropoxide to the novel linear trinuclear titanium complex 8 whose structure has been determined by spectroscopic and X-ray crystallographic analysis.

A mechanistically designed mono-cinchona alkaloid is an excellent catalyst for the enantioselective dihydroxylation of olefins

On the basis of ideas recently advanced regarding the origin of enantioselectivity in the OsO 4 -promoted dihydroxylation of olefins catalyzed by bis-cinchona alkaloid derivatives such as 1 , specifically strong evidence for reaction via transition state assembly 2 , the mono-quinidine derivative 3 was selected as a promising catalytic ligand. The experimental observation of high enantioselectivity promoted by 3 provides additional evidence in favor of transition-state 2 .