David Askin

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.

A highly catalytic robust palladium catalyzed cyanation of aryl bromides

Abstract A dependable high yielding palladium catalyzed aryl bromide cyanation procedure has been developed. The optimized cyanation features extremely low levels of palladium and DPPF ligand.

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.

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.

Synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677

Abstract The preparation of the Merck Growth Hormone Secretagogue; MK-677 is described. A Fischer indole/reduction based strategy provides the novel spiroindoline nucleus of this potent compound. This optimized sequence necessitates the isolation of only one intermediate 10 and provides MK-677 in 48% overall yield from isonipecotic acid 3.

An efficient asymmetric synthesis of (R)-3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one

Abstract Two approaches for the asymmetric preparation of (−)- or (+)- α-aminobenzlactam 1 are described. One route is based on the asymmetric hydrogenation of enamide 5 and the other on the racemization/resolution of (±)- 1 .

Thiol addition to aryl propargyl alcohols under mild conditions: an accelerating neighboring group effect

Abstract Aryl alkynols provide a convenient entry into α-hydroxyketones via thiol addition followed by hydrolysis. Thiols have been added to several non-activated alkynes under mild, basic conditions. A coordinating functional group in close proximity to the triple bond facilitates this reaction.

A diastereospecific, non-racemic synthesis of the C.10–C.18 segment of FK-506

Abstract An efficient stereocontrolled route to construct the C.10–C.18 moiety of FK-506 is reported.

Asymmetric synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine via ring expansion

Abstract A catalytic highly enantioselective (99% ee) preparation of N - tert -butyloxycarbonyl-(2 S ,3 S )-3-hydroxy-2-phenyl-piperidine and N - tert -butyloxycarbonyl-(2 S )-2-phenyl-piperidin-3-one was developed using an intramolecular epoxide opening followed by ring expansion. The cis -epoxide starting material was available in high ee via Jacobsen epoxidation.