Succinyl anhydride, synthesis

Peptide coupling reagent bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrOP) was used in synthesis of 10-membered succinyl bis(amide) 27 in 57% yield (Equation 3) <2002TL2593>. Similarly, 1,6-diazacyclo-decane substituted on only one nitrogen atom was prepared by reaction of A -trityl-protected linear triamine with succinyl anhydride. The amides were further reduced to amines using LAH <2002TL2593>. 

PyBrOP-mediated cyclization of N -trity 1-protected linear triamine with succinyl anhydride was used to form the 14-membered triaza ring 40 in 56% yield (Equation 5) <2002TL2593>, which was further reduced to amine using LAH. Similar methodology was applied in synthesis of a 15-membered ring. 

Succinylated derivatives of nucleic acids may be prepared by reaction of the anhydride with available —OH groups. The reaction forms relatively stable ester derivatives that create car-boxylates on the nucleotide for further conjugation or modification (Figure 1.83). This method has been used in nucleic acid synthesis (Matteucci and Caruthers, 1980) and to derivatize nucleotide analogs such as AZT (Tadayoni et al., 1993). 

In both cases, the mixed anhydride is used to synthesize ATP from ADP. Hydrolysis of the anhydride liberates more energy than the hydrolysis of ATP to ADP and, therefore, can be linked to the enzymic synthesis of ATP from ADP. This may be shown mechanistically as a hydroxyl group on ADP acting as nucleophile towards the mixed anhydride, and in each case a new phosphoric anhydride is formed. In the case of succinyl phosphate, it turns out that GDP rather than ADP attacks the acyl phosphate, and ATP production is a later step (see Section 15.3). These are enzymic reactions therefore, the reaction and the nature of the product are closely controlled. We need not concern ourselves why attack should be on the P=0 rather than on the C=0. 

Many successful matrix metalloprotease inhibitors include various succinyl moieties attached to the hydroxamic acid function. During the synthesis, a number of intermediates were prepared and are shown in Schemes 4-8. The synthesis of actinonin 6 begins by reaction of pentylmaleic anhydride with O- benzylhydroxylamine (Scheme 4). The product... 

Procedure A (Figs. 2 and 3) This method, which uses succinic anhydride first to succinylate the LC A A-CPG, is the easiest route to derivatized CPG supports because it eliminates the synthesis of nucleoside-3 -succi-nate derivatives. 

Fig. 2. The synthesis and derivatization of succinylated LCAA-CPG (31). This method (procedure A), which uses succinic anhydride to succinylate the LCAA-CPG is the easiest method to prepare derivatized supports, because succinylated nucleosides are not required.

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