N-Hydroxyphthalimide esters

Carbobenzoxy-L-phenylalanine N-hydroxyphthalimide ester and ethyl glycinate hydrochloride dissolved in a small amount of dimethylformamide, cooled to ca. —10°, 2 moles of triethylamine added with stirring, and the product isolated after 1 min. ethyl carbobenzoxy-L-phenylalanylglycinate. Y 96%.—N-Hy-droxyphthalimide liberated during the reaction can be easily removed. F. e. s. G. H. L. Nefkens, G. I. Tesser, and R. J. F. Nivard, R. 81, 683 (1962) with N-hydroxysuccinimide esters cf. G. W. Anderson, J. E. Zimmerman, and F. M. Callahan, Am. Soc. 85, 3039 (1963). 

DCC can be used to prepare 5-alkyl and 5-aryl thiocarboxylates (1) from carboxylic acids and thiols according to equation (5). This method has been successfully applied to the synAesis of thiol esters with sensitive substituents, e.g. 5-methyl thioacrylate, a natural product. In particular, N-protected amino acid and peptide 5-phenyl esters, which are useful building blocks in peptide synthesis, are obtained in excellent yields without racemization. N-Hydroxyphthalimide and DMAP have been used as cocatalysts to facilitate the reaction. The preparation of the Wittig reagent (5) by this route is shown in equation (6). 

Two different N-protected hydroxylamines have been used to accomplish the synthesis of these novel hydroxylamine-functionalized resins. fV-Hydroxy-phthalimide has been employed in two ways first, as a nucleophile to splace either a resin-bound chloride ion (30) or a resin-bound mesylate ion (31) Figure 8a) and second, to generate the active phosphonium species required to perform a Mitsunobu reaction on a hydroxyl-functionalized resin (32) (Figure 8b). In both cases, the resin-bound iV-hydroxyphthalimide ester that is generated is subsequently treated with hydrazine to afford resin-bound hydroxylamine. 

Peptide Bond Formation. The most important use of N-hydroxysuccinimide is in the formation of (isolable) activated derivatives of -protected a-amino acids, which subsequently undergo generally smooth coupling reactions with amino esters. Typically, 1,3-Dicyclohexylcarbodiimide (DCC) is used as the initial coupling agent (the HOSu-DCC method) (eq 1). N-Hydroxyphthalimide can be employed in much the same way, but a distinct advantage in the case of HOSu is its high water solubility, which facilitates product purification. 

In order to preserve optimal stability in the hybridization of RNA by sugar-modified oligonucleotides, nucleosides substituted at the 2 -position must retain a C3 -endo puckered conformation. To this end, the 2 -0- 2-[iV,N-(dimethylamino)oxy]ethyl and the 2 -0- 2-[Ar,lV-(diethylamino)oxy]-ethyl 3 -phosphoramidite derivatives of thymidine (38a, 38b) have been synthesised. The nucleoside precursors were prepared from a phthalimido-derivative obtained from 2,2 -anhydro-5-methyluridine which had been treated, after appropriate protection, with a borate ester generated in situ and then reacted with PPha, DEAD and AT-hydroxyphthalimide. The incorporation of (38a) and (38b) in oligonucleotides and oligodeoxynucleotides resulted in high binding affinity for... 

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