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Linear Synthesis of Chiral cyclo Sal‐Pronucleotides
Author(s) -
Morales Edwuin Hander Rios,
Román Cristina Arbelo,
Thomann Jens Oliver,
Meier Chris
Publication year - 2011
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201100334
Subject(s) - chemistry , moiety , stereochemistry , stereospecificity , prodrug , stereoselectivity , chiral auxiliary , chirality (physics) , convergent synthesis , enantiopure drug , pyrrolidine , diastereomer , diol , nucleoside , chemical synthesis , combinatorial chemistry , enantioselective synthesis , organic chemistry , catalysis , chiral symmetry , biochemistry , nambu–jona lasinio model , physics , quantum mechanics , quark , in vitro
Cyclo Sal‐nucleosyl‐phosphate triesters are a known class of highly effective nucleotide prodrugs (pronucleotides) of antivirally active nucleoside analogues. Until recently, the synthesis of these compounds always gave diastereoisomeric mixtures. Then, a convergent route for the stereospecific synthesis of cyclo Sal‐triesters was described to give isomerically pure cyclo Sal‐prodrugs for the treatment of viral diseases. Here, the development of a stereoselective synthesis of these pronucleotides using various chiral auxiliaries is described. In contrast to pyrrolidine‐ or pyrrolidinone derivatives it was found that a thiazolidine derived from valinol fulfilled all three requirements to act as a suitable chiral moiety, allowing: (i) strong chirality transfer, (ii) the formation of separable diastereoisomeric intermediates, and (iii) a suitable leaving group that allows the introduction of the nucleoside analogue (e.g., d4T) in the final step under mild reaction conditions. The title compounds were obtained with very high diastereoisomeric excesses of more than 95 %.