Debenzylation trifluoroacetic acid

Primary benzenesufonamides have been notoriously difficult to protect. Theodore S. Widlanski of Indiana University has now found (Tetrahedron Lett. 2004,45, 8483) that while N-benzyl sulfonamides such as 1 are resistant to hydrogenolytic debenzylation, the easily-prepared Boc derivative 2 is smoothly debenzylated. Brief exposure of 3 to trifluoroacetic acid then gives the primary sulfonamide 4. 

In order to introduce the carboxylic function, azide 30 was regioselectively debenzylated at the primary hydroxyl group by controlled treatment with acetic anhydride and trifluoroacetic acid, (14) followed by saponification of the acetate at C-5. The product 31 was finally converted into the carboxylic acid 32 by Jones oxidation. 

This intermediate was alkylated with tert. -butyI-cj-iodohexanoate to the ester 30. Conversion to the acid 31 was achieved by cleavage of the fed.-butylester with trifluoroacetic acid at low temperature. The triple bond was reduced to a trans-double bond and simultanously the benzylether groups had been removed with lithium in ethylamine, under formation of the desired 15-deoxy-7-oxaprostaglandin Fla 32 in crystalline form. The ds-isomer was prepared by first reducing the triple bond of compound 30 with palladium on barium sulfate to 33, removal of the ted. -butylgroup with formic acid to 34 and debenzylation of the acid with lithium in ethylamine to 35. 

The corresponding acid 64 was prepared with anhydrous trifluoroacetic acid. This same acid was also obtained by selective debenzylation of the above mentioned dibenzylether 30, which links this synthesis with that of 7-oxa-PGFla. The keto acid 65 was prepared with Jones reagent and the ketogroup then protected as the ethylene ketal by converting the acid simultanously to the ester 66. 

Alkaline hydrolysis led to the acid 67 which was debenzylated and reduced with lithium in methylamine to the olefinic acid 68. Introduction of the 15-hydroxy group 69 into the 7-oxaprostanoid was possible as in the PGF, series with Se02. ( )-7-oxa-PGEj 70 and its 15-epimer were then obtained by removal of the ketal group with trifluoroacetic acid and chromatography on silica gel columns. 

Nonphenolic isoquinolines 99a,b were subjected to oxidation with TTFA (54) and with RUTFA (55) to give the homoaporphines 100a,b. Moreover, oxidation of 99c with TTFA in trifluoroacetic acid gave 100c, while 99d provided 101 under the same conditions. Treatment of 101 with sulfuric acid resulted in smooth dienone-phenol rearrangement with concomitant debenzylation to give an 81% yield of ( )-multifloramine (83e) (56). 

The FDP-aldolase catalyzed DHAP-addition to glyoxylic acid, examined in detail by Wandrey and Bossow-Berke under continuous flow reaction conditions [18], required the determination of the relative and absolute configuration. Employing the SAMP-/RAMP-hydrazone method, the aldol reaction of 1 with benzyl glyoxylate afforded a doubly protected adduct, which was deprotected with trifluoroacetic acid anhydride (TFAA) and subsequent debenzylation with H2/ Pd-C to give the final product, identical with the enzyme product. The independent chemical synthesis and the enzymatic route are compared in scheme 4. It... 

During a synthesis of the protein kinase C inhibitor Balanol. Lampe and co-workers77 found that deprotection of the tert-butyl ester 30.1 [Scheme 6.30] with trifluoroacetic or formic acid was accompanied by substantial quantities of a debenzylated by-product. The same side reaction accompanied thermolytic cleavage of the terf butyl ester in neutral solvents presumably due to add catalysis by the carboxylic acid product 30.2. Thermolysis in quinoline at 205 °C led cleanly to the desired benzophenone carboxylic acid 30.2 in 68% yield. 

---