Edward J. J. Grabowski

A new general method for preparation of N-methoxy-N-methylamides. Application in direct conversion of an ester to a ketone

Abstract The reaction of an ester with N , O -dimethylhydroxylamine and a suitable organomagnesium reagent or lithium amide base provides a general method for the preparation of N -methoxy- N -methylamides. Application in the direct conversion of a highly hindered ester to a ketone, the azasteroid 5α-reductase inhibitor MK-0434, is described.

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%.

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.

Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: asymmetric synthesis of the reverse transcriptase inhibitor L-743,726

Abstract The asymmetric synthesis of L-743,726 was achieved in six steps with an overall yield of 31%. The asymmetry was introduced using a lithiated ephedrine to mediate acetylide addition to a trifluoromethyl ketone with an enantiomeric excess of 96–98%.

Selective monolithiation of 2,5-dibromopyridine with butyllithium

Abstract Selective monolithiation of 2,5-dibromopyridine at either the 2-position or the 5-position is reported. Solvent and concentration strongly influence the selectivity. Coordinating solvents and higher concentration favor the 5-position while non-coordinating solvents and lower concentration favor the 2-position.

Eine neue, hochenantioselektive Alkinylierung von Ketonen, die durch chirale Zinkaminoalkoxide gesteuert wird

Im Kilogramm-Masstab gelang die Synthese von Efavirenz, einem zugelassenen Hemmstoff der Reversen Transkriptase des HI-Virus. Dabei wurde die hochenantioselektive Alkinylierung der prochiralen Ketone 1 mit Alkinyllithium- oder Alkinylmagnesiumreagentien durch chirale Zinkaminoalkoxide unterstutzt. Mit 2,2,2-Trifluorethanol als achiralem Hilfsstoff (R3 = CF3CH2) wurde die Efavirenz-Vorstufe 2 (R1 = H, R2 = Cyclopropyl) in 99.2 % ee erhalten.

Enantioselective 1,4-addition of aryllithium reagents to α,β-unsaturated tert-butyl esters in the presence of chiral additives

Abstract Reaction of t-BuLi with a mixture of aryl bromide and chiral diamine, amino ether or diether, in toluene at −78°C provided chiral aryllithium complexes efficiently. Reaction of these aryllithium complexes with α,β-unsaturated tert-butyl esters afforded the 1,4-addition products in up to 88% ee.

Synthetic approaches to thienamycin: Carbon-carbon bond formation at C-4 of azetidin-2-ones

Abstract A mild and efficient method of β-lactam alkylation has been achieved using 4-acetoxy-2-azetidinone and a variety of silyl enol ethers.

Practical chemoenzymatic synthesis of a 3-pyridylethanolamino β3 adrenergic receptor agonist

Abstract A chemoenzymatic synthesis of β 3 agonist 1 suitable for large scale preparation is described. The key chiral 3-pyridylethanolamine intermediate ( R )- 7 was prepared via an improved Neber rearrangement and a yeast-mediated asymmetric reduction. The tetrazolone fragment of the molecule was constructed via a dipolar cycloaddition between 1-(cyclopentyl)-3-propylazide and p -chlorosulfonyl phenylisocyanate. Sulfonamide coupling of these two intermediates under Shotten-Baumann conditions, followed by a borane reduction of the amide afforded 1 in 20–32% overall yield from 3-acetylpyridine.