Synthesis and oligomerization of y,4-Diamino-2-oxo-1(2H)-pyrimidinepentanoic acid Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/6d570025c

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  • Described herein is the synthesis of an uncharged stereoregular oligonucleotide analog consisting of cytosine bases linked at specific intervals to a polyamide backbone derived from (L)-glutamic acid. Preparation of this analog entailed borane reduction of (L)- pyroglutamic acid to give optically pure lactam alcohol 9. Tosylation and alkylation with cytosine provided alkylated lactam 10. The use of amidine -type protecting groups on the amino group of 10 was necessary to allow selective t-butoxycarbonylation of the lactam, which serves to activate the lactam toward ring-opening. The amidine was selectively cleaved with hydrazine derivatives, the cytosine amine group acylated and the lactam ring opened with hydroxide to provide the key subunit 31. For the block synthesis of oligomers, two separate series of compounds were developed. In the oligornerization sequence, each series of compounds relied on the activation of monomeric free acid 31 by conversion to the p-nitrophenyl ester, 32. The activated ester was reacted with 2-(methylamino)ethanol to provide 34, containing a blocked acid terminus. This end-capping sequence, which provided one of the two series of compounds in the block synthetic pathway, served to prohibit a charged carboxyl terminus on the completed polymer during biophysical binding studies. The free alcohol was further protected as the t-butylbenzoyl ester 35 which allowed easy chromatographic purification of coupling products. Reaction of 40, formed by trifluoroacetic acid deprotection of 35, with active ester 32, gave the cap-protected dimer 41 in good yield. The same sequence of reactions was followed to provide the desired cap-protected trimer 43. Reaction of p-nitrophenyl ester 32 with 1-amino-piperidine led to C-terminal hydrazide monomer 33, which served as a temporarily masked acid terminus, and which could also be easily purified by flash chromatography. This series was oligomerized in a fashion similar to the former series by reaction of 36 formed by trifluoroacetic acid deprotection of 33, with active ester 32 to provide the hydrazide masked dimer 37. This was elaborated to the trimer 39 in the same manner. The carboxyl group was unmasked with aqueous N-bromosuccinimide, converted to the pnitrophenyl ester, and coupled with the cap-protected trimer free amine 44 to give fully protected hexamer 45.
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