Sulfonylated tyrosine

This methodology has been applied to the multistep synthesis of a sulfonylated tyrosine derivative, a highly potent analog of the antithrombic drug tirofiban according to Scheme 5.5-30. The target compound was obtained in 11% yield over 5 steps after purification by preparative HPLC (Scheme 5.5-35). 

A sulfonyl chloride group rapidly reacts with amines in the pH range of 9-10 to form stable sulfonamide bonds. Under these conditions, it also may react with tyrosine —OH groups, aliphatic alcohols, thiols, and histidine side chains. Conjugates of sulfonyl chlorides with sulf-hydryls and imidazole rings are unstable, while esters formed with alcohols are subject to nucleophilic displacement (Nillson and Mosbach, 1984 Scouten and Van der Tweel, 1984). The only stable derivative with proteins therefore is the sulfonamide, formed by reaction with e-lysine... 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

Miller and Stanley (209) after benzene sulfonylation of tobacco mosaic virus for various periods of time, foimd that the activity went down slowly but at two different rates, depending upon which of two hosts was employed for testing the derivatives. They also observed a 70% drop in the amino nitrogen and a 28% decrease in the tyrosine color value which did not return on treatment with dilute alkali. 

The appropriate aromatic or heteroaromatic substrate 515 was reacted with excess chlorosulfonic acid to yield the sulfonyl chloride 516, which was condensed with an amino acid in aqueous THF-triethylamine to give the sulfonylamino acid 517. THF was discovered to be the optimum solvent for the reaction. The amino acids employed included glycine, L-alanine, DL-valine, l-leucine, L-phenylalanine, L-tyrosine and L-proline. 

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