Ralph P. Volante

A new, highly efficient method for the conversion of alcohols to thiolesters and thiols

Abstract Various alcohols were converted to their corresponding thiolacetates by treatment with triphenylphosphine and diisopropyl azodicarboxylate in the presence of thiolacetic acid. The overall conversion was both highly efficient (89–99% yields) and stereoselective (99.5% inversion).

Amination of aryl halides using copper catalysis

Bromopyridine 4 was converted into aminopyridine 5 under Cu2O catalysis with an ethylene glycol solution of ammonia in excellent yield (90%). The amination reaction features low (0.5 mol%) catalyst loading, mild reaction temperature (80°C) and low reaction pressure (50 psi). This protocol is further studied in the amination of a variety of aryl halides.

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.

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.

[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.

Synthesis of an HMG-COA reductase inhibitor; A diastereoselective aldol approach

Abstract The synthesis of the β-hydroxy-δ-lactone moiety of an HMG-CoA reductase inhibitor in its correct absolute configuration (94% ee) has been accomplished via a diastereoselective aldol reaction between aldehyde 4 and the magnesium enolate of S(+)1,2,2-triphenylethylacetate, Claisen condensation, and hydroxyl directed reduction of the resulting δ-hydroxy-β-keto ester.

AN EFFICIENT ASYMMETRIC HYDROGENATION APPROACH TO THE SYNTHESIS OF THE CRIXIVAN PIPERAZINE INTERMEDIATE

Abstract The Crixivan ® HIV protease inhibitor piperazine intermediate 2 was prepared by a four step sequence using a chiral hydrogenation of the tetrahydropyrazine 9 to establish the absolute stereochemistry.

Stereocontrolled addition of propionate homoenolate equivalents to chiral α-amino aldehydes

Abstract A highly efficient route is presented for preparation of the medicinally important hydroxyester and lactone intermediates 1 and 2 from chiral α-amino aldehydes via homoenolate methodology. Several reaction variables were found to influence the ratio of chelation controlled versus Felkin-Ahn products.

Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate

Abstract Reaction of 2-alkyl-4-enamides 2, 9–15 with NIS and aqueous sodium bicarbonate results in the diastereoselective formation of the corresponding iodohydrins 3, 16–22 with essentially no iodolactone by-product. This methodology has been successfully employed for the synthesis of the epoxide intermediate 4 of the orally active Merck HIV-1 protease inhibitor L-735,524.

A diastereospecific, non-racemic synthesis of a novel β-hydroxy-δ-lactone HMG-CoA reductase inhibitor

Abstract The coupling of acyl anion equivalent 12b with chiral synthon 14 , derived from isoascorbic acid, and a highly stereospecific reduction of the resulting β-hydroxy ketone 3 highlight an efficient synthesis of β-hydroxy-δ-lactone 2 .