Реакция #1340596

Уравнение реакции

vinylsulfone

( 16 )

(S)-tert-butyl 4-(3-(methoxy(methyl)amino)-3-oxo-2-(tritylamino)propyl)benzylcarbamate

compound 15

tert-Butyl 4-((S)-2-amino-3-((R)-2-methyloxiran-2-yl)-3-oxopropyl)benzylcarbamate TFA salt

→

compound 18

(S,E)-tert-butyl 4-(4-(methylsulfonyl)-2-aminobut-3-en-1-yl)benzylcarbamate

Условия реакции

Методика

Retro-synthetically, the modified oligopeptides can be prepared from tripeptide hydrazide N3Phe-Leu-Leu-NHNH2 and the properly protected warhead amines in an (epimerization free) azide coupling. The synthesis of P1-benzyl amine containing vinyl sulfone and epoxyketone warheads leading to inhibitors 4a and 4b is shown in Scheme 3. The synthetic scheme commenced with the introduction of the aminomethylene substituent on L-phenylalanine 8, by performing an electrophilic aromatic substitution with N-(hydroxymethyl) trichloroacetamide under acidic conditions. In this reaction both the ortho and the para substituted isomers were formed, which could be separated by column chromatography. The desired para substituted isomer was obtained in 35% yield. After Cbz-protection of the α-amine, compound 9 was obtained. Basic removal of the trichloroacetamide group followed by Boc protection of the formed amine gave 10, which was coupled to N,O-dimethylhydroxylamine to give Weinreb-amide 11. Upon a reaction with 2-lithiumpropene the α′,β′-unsaturated ketone 12 was obtained. Stereoselective reduction to the allylic alcohol 13 and subsequent asymmetric epoxidation and Dess-Martin oxidation resulted in epoxyketone 14. This compound was α-amine deprotected by hydrogenation, which finalized the synthesis of compound 15. The vinylsulfone analogue was created by α-amine deprotection of compound II, followed by tritylation (16). Reduction of the Weinreb-amide, followed by a Horner-Wadworth-Emmons reaction and de-tritylation finally resulted in compound 18.

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