James M. McNamara

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 .

Stereospecific synthesis of chiral tertiary alkyl-aryl ethers via Mitsunobu reaction with complete inversion of configuration

Mitsunobu reaction of chiral tertiary alcohol (S)-2 with phenol 3 provides the desired ether (R)-1 in moderate yields at elevated temperatures (80–100°C). The SN2 displacement pathway is evident by complete inversion of the (S)-alcohol to (R)-ether.

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.

Practical routes to the triarylsulfonyl chloride intermediate of a β3 adrenergic receptor agonist

Abstract A β3 adrenergic receptor agonist was prepared on a multi-kilogram scale in high yield and purity via a convergent synthesis. A key intermediate in this synthesis was an arylthiazolylbenzenesulfonyl chloride. The triaryl segment of this sulfonyl chloride was assembled at the thiazole ring via coupling of α-haloketone and thiobenzamide precursors (Hantzsch synthesis). Three strategies for introducing the para-sulfonyl chloride moiety were developed and evaluated. The sulfonation/chlorination and diazotization/chlorosulfonylation routes were found the most efficient.

Asymmetric hydrogenation of 3-alkylidene-2-piperidones using Noyori's catalyst. Effect of N-substituents on the enantioselectivity

Abstract The enantioselectivity in the asymmetric hydrogenation of 3-alkylidene-2-piperidones catalyzed by BINAP-Ru(II) complex was found to be significantly effected by the internal substituents on the lactam nitrogen, affording the corresponding 3-alkyl-2-piperidones in 52–92% ee.

Reductive decyanation of pyrazinecarbonitriles

Pyrazinecarbonitriles can be decyanated by hydrogenation with platinum on carbon in the presence of activated carbon under acidic conditions. Pyrazine carbonitrile-N-oxides undergo a stepwise reduction to the deoxy-pyrazinecarbonitriles followed by decyanation to give pyrazines in good yields.

Asymmetric bioreduction of benzyl acetoacetate to its corresponding alcohol, benzyl (S)-(+)-3-hydroxybutyrate by the yeast Candida schatavii MY 1831

The screening of 35 microbial strains yielded 13 of them as suitable biocatalysts for the asymmetric bioreduction of benzyl acetoacetate to its corresponding alcohol benzyl (S)-(+)-3-hydroxybutyrate. The production of benzyl (S)-(+)-3-hydroxybutyrate with an elevated optical purity of 93% was achieved when employing the yeast Candida schatavii strain MY 1831.

A convenient synthesis of 3-aryl-δ-lactones

Abstract Various (±)-3-aryl-δ-lactones have been prepared from the corresponding arylacetic acids. The lithium dianion of the acid is alkylated with 1-bromo-3-chloropropane and the unpurified product is cyclized with DBU in typically ca. 80% yield over both steps. We have shown that lactones of this type can be converted to their corresponding 5,6-dihydropyan-2-ones and pyran-2-ones, which potentially provide useful sites for further functionalization of the lactone ring.

A convergent synthesis of a novel non-peptidyl growth hormone secretagogue, L-692,429

Abstract A practical, convergent synthesis of L-692,429 (1) from three key intermediates - the 3- aminobenzlactam 2, the β-lactam 3 and the biphenyltetrazole 4 is described. The mechanism of the coupling reaction in which 3 is used as a β-aminoacid equivalent is also presented.

Enzymes and practical asymmetric synthesis

A practical, chemoenzymatic, four-step synthesis of the LTD4 antagonist MK-0679 is described. The key steps are enzymatic hydrolysis of the prochiral diester to the ester-acid in 99% enantiomeric excess followed by aluminum mediated amidation of the methyl ester to afford MK-0679 in high overall yield. This synthesis is superior to the synthesis of the racemate MK-0571.