Abstract

Convergent synthesis of cyclic branched tetraribonucleotide 9, modelling the lariat of pre-mRNA processing reaction (Splicing), is reported. The first key step in the present strategy involves the condensation of the appropriately protected 5'-O-levulinyl-G3'p5'U3' phosphodiester block 4 with the 3'5'-dihydroxy-6-N-benzoyl-2'-O-pixy(9-phenylxanthen-9-yl)adenosine 5, in presence of an activating agent, to give 6a (53%). Chemospecific phosphorylxation of 3'-OH of 6a afforded the intermediate 6b (88%) which was treated with mild acid to achieve a regiospecific removal of the 2'-O-pixyl group to give compound 6c (99%). The second key step involved the introduction of biscyanoethylphosphotriester moiety to the 2'-OH of the branch-point adenosine in 6c, in one single step using (biscyanoethoxy)-(diisopropylamino)phosphine to give the crucial branch-point building block 6d (68%), with two dissimilar vicinal phosphates at 2'- and 3'- of the branch-point. 6d was then condensed with N-4-benzoyl-2',3'-di-O-acetylcytidine to afford the fully protected intermediate 7a (75%). The 5'-O-levulinyl protecting group was then specifically removed from 7a by hydrazine hydrate to give the intermediate 7b (83%) which was subsequently treated with a bulky tertiary amine to give the branch-point-2'-cyanoethylphosphodiester block 7c (74%). A unique intramolecular 5' --> 2' cyclization was then brought about in 7c by treatment with an activating agent under a high dilution condition to afford the fully protected cyclic branched tetramer 8 (61%). This oligomer was then deprotected in the usual manner and purified to give the cyclic branched tetramer 9 in 30% isolated yield, the first synthetic lariat known to date. Detailed 500 MHz H-1-NMR and 202.4 MHz P-31-NMR studies on 9 have unequivocally established its purity. Detailed spectroscopic studies such as COSY, HOHAHA, ROESY & P-31-H-1-NMR shift correlation spectroscopy have clearly established the structural integrity of the tetrameric lariat RNA.

Published in

Tetrahedron
1991, Volume: 47, number: 46, pages: 96749659
Publisher: PERGAMON-ELSEVIER SCIENCE LTD

UKÄ Subject classification

Organic Chemistry


Publication identifier

DOI: https://doi.org/10.1016/S0040-4020(01)91031-2

Permanent link to this page (URI)

https://res.slu.se/id/publ/83898