Chiral phosphoramidite auxiliaries and methods of their use
AssigneeSirius Therapeutics, Inc.
InventorsSukumar Sakamuri, Curt W. Bradshaw, Dingguo Liu, Laxman Eltepu
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Abstract
Disclosed are chiral phosphoramidite auxiliary compositions for diastereoselective synthesis of stereochemically enriched oligonucleotides, and nucleoside phosphoramidite compounds comprising the same. Exemplary structures of the chiral phosphoramidite auxiliary compositions include Formulas (IA) and (IB).
Claims20
A compound of formula (IIIA) or (IIIB):
- wherein
- is a single carbon-carbon bond or a double carbon-carbon bond;
- A is an optionally substituted C1-12 alkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkyl-C1-6-alkyl, optionally substituted C1-9 heterocyclyl, optionally substituted C1-9 heterocyclyl-C1-6-alkyl, sugar analogue, nucleoside, nucleotide, or oligonucleotide;
- each of R1 and R2 is independently an optionally substituted C1-6 alkyl or optionally substituted C6-10 aryl, or R1 and R2, together with the atoms to which each is attached, combine to form an optionally substituted 5- to 8-membered ring;
- and
- each of R3 and R4 is independently H, optionally substituted C1-6 alkyl, or optionally substituted C6-10 aryl.
A nucleoside phosphoramidite comprising a sugar bonded to a nucleobase and to a phosphoramidite of the following structure:
- wherein
- is a single carbon-carbon bond or a double carbon-carbon bond;
- each of R1 and R2 is independently an optionally substituted C1-6 alkyl or optionally substituted C6-10 aryl, or R1 and R2, together with the atoms to which each is attached, combine to form an optionally substituted 5- to 8-membered ring;
- and
- each of R3 and R4 is independently H, optionally substituted C1-6 alkyl, or optionally substituted C6-10 aryl.
A method of preparing the nucleoside phosphoramidite comprising a sugar bonded to a nucleobase and phosphoramidite of the following structure:
- wherein
- is a single carbon-carbon bond or a double carbon-carbon bond;
- each of R1 and R2 is independently an optionally substituted C1-6 alkyl or optionally substituted C6-10 aryl, or R1 and R2, together with the atoms to which each is attached, combine to form an optionally substituted 5- to 8-membered ring;
- and
- each of R3 and R4 is independently H, optionally substituted C1-6 alkyl, or optionally substituted C6-10 aryl;
- the method comprising reacting a sugar bonded to a nucleobase with a compound of formula (VIIIA) or (VIIIB):
- wherein
- X is a halogen or pseudohalogen.
An oligonucleotide comprising one or more internucleoside groups independently selected from the group consisting of linkers of formulas (XIA), (XIB), (XIIA) and (XIIB):
- where
- is a single carbon-carbon bond or a double carbon-carbon bond;
- each of R1 and R2 is independently an optionally substituted C1-6 alkyl or optionally substituted C6-10 aryl, or R1 and R2, together with the atoms to which each is attached, combine to form an optionally substituted 5- to 8-membered ring;
- each of R3 and R4 is independently H, optionally substituted C1-6 alkyl, or optionally substituted C6-10 aryl;
- and
- R7 is acyl.
Dependencies are inferred from the claim text.