Paul J. Reider

A NOVEL CHROMIUM TRIOXIDE CATALYZED OXIDATION OF PRIMARY ALCOHOLS TO THE CARBOXYLIC ACIDS

Abstract A novel CrO 3 catalyzed oxidation of primary alcohols to the carboxylic acids is reported. The oxidation proceeds smoothly with only 1–2 mol % of CrO 3 and 2.5 equivalents of H 5 IO 6 in wet MeCN to give the carboxylic acids in excellent yield. No significant racemization is observed for alcohols with adjacent chiral centers. Secondary alcohols are cleanly oxidized to ketones.

A Novel, Highly Enantioselective Ketone Alkynylation Reaction Mediated by Chiral Zinc Aminoalkoxides

Kilogram-scale synthesis of the HIV reverse transcriptase inhibitor efavirenz was achieved by means of a highly enantioselective alkynylation of prochiral ketones 1 with alkynyllithium or alkynylmagnesium reagents in the presence of chiral zinc aminoalkoxides as mediators. With the achiral auxiliary 2,2,2-trifluoroethanol (R3 =CF3 CH2 ), the efavirenz precursor 2 (R1 =H, R2 =cyclopropyl) was obtained with an ee of 99.2%.

Simple and efficient resolution of l,1′-bi-2-naphthol

Abstract Acetonitrile is a crucial solvent for a simple and efficient resolution of l,l′-bi-2-naphthol using N -benzylcincbonidium chloride. Both enantiomers can be easily obtained with ≥95% yield and ≥99% ee.

Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524

Abstract Reaction of chiral amide enolate Li-1 with (S)-glycidyl tosylate 11 affords the epoxide 3 in 72% yield with high diastereoselectivity. Epoxide 3 is converted to the orally-active HIV-1 protease inhibitor L-735,524 in 71% isolated yield.

Total synthesis of thienamycin: a new approach from aspartic acid

Abstract A practical stereospecific synthesis of thienamycin 1 has been achieved. Key steps include a lead tetracetate oxidative decarboxylation and subsequent insertion of a four carbon diazo containing unit into a 3-acetoxy-2-azetidinene.

The behavior of indene oxide in the ritter reaction: A simple route to cis-aminoindanol

Abstract A regio- and stereoselective synthesis of cis-1-aminoindan-2-ol via a Ritter reaction is described.

Asymmetric hydrogenation of tetrahydropyrazines: Synthesis of (S)-piperazine-2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor indinavir

Abstract Hydrogenation of tetrahydropyrazine 4g with [(R)-BINAP(COD)Rh]TfO gave piperazine 6g in 96% yield and 99% ee. Simple hydrogenolytic deprotection and crystallization afforded the key chiral (S)-N-Boc-piperazine MK-639 intermediate 1 in high yield and enantiomeric purity.

Nosylaziridines: Activated aziridine electrophiles

Abstract Nosylaziridines are highly reactive electrophiles towards a variety of nucleophiles yielding the corresponding S n 2 adducts without competing attack on the nosyl functionality (S n Ar). The resulting primary nosylamide adducts can be readily cleaved under mild conditions to provide the primary amines.

[2.2]PHANEPHOS-Ruthenium(II) complexes: Highly active asymmetric catalysts for the hydrogenation of β-ketoesters

Abstract The application of the planar chiral [2.2]PHANEPHOS ligand in the Ru(II)-catalyzed asymmetric hydrogenation of β-ketoesters gave up to 96% ee involving a practical and reproducible procedure using the defined and readily prepared [2.2]PHANEPHOS-Ru(II)bis(trifluoroacetate) salt in the presence of a halide source.

Design, synthesis, and biological evaluation of potent c-Met inhibitors.

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.