Organic Process Research & Development 2008, 12, 399–410
UnyLinker: An Efficient and Scaleable Synthesis of Oligonucleotides Utilizing a Universal Linker Molecule: A Novel Approach To Enhance the Purity of Drugs Vasulinga T. Ravikumar,*,† R. Krishna Kumar,† Phil Olsen,† Max N. Moore,† Recaldo L. Carty,† Mark Andrade,† Dennis Gorman,† Xuefeng Zhu,† Isaiah Cedillo,† Zhiwei Wang,† Lucio Mendez,† Anthony N. Scozzari,† Gerardo Aguirre,‡ Ratnasamy Somanathan,*,‡ and Sylvain Bernee`s§ Isis Pharmaceuticals, Inc. 2282 Faraday AVenue, Carlsbad, California 92008 U.S.A., Centro de Graduados e InVestigacio´n del Instituto Tecnolo´gico de Tijuana, Apdo. Postal 1166, Tijuana, B.C., Me´xico, and DEP, Facultad de Ciencias Quı´micas, UANL, Guerrero y Progreso S/N, Col. TreVin˜o, 64570, Monterrey, N.L., Me´xico
Abstract: A novel universal linker (UnyLinker) molecule which has a conformationally rigid and chemically stable bridge head ring oxygen atom carrying a conventional 4,4′-dimethoxytrityl (DMT) and succinyl groups locked in a syn orientation has been developed to carry out oligonucleotide synthesis efficiently and smoothly. The geometry of the vicinal syn oxygen functionalized group allows fast and clean cleavage under standard aqueous ammonia deprotection conditions to afford high-quality oligonucleotides. No base modification is observed, based on the ion-pair HPLC-UV-MS (IP-HPLC-UV-MS) method with detection limit of
