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Publication Number
US-11136346-B2
Publication Date
2021-10-05
Expiration Date
Abstract
To provide a chiral reagent or a salt thereof.The chiral reagent has following chemical formula (I). In the formula (I), G1 and G2 are independently a hydrogen atom, a nitro group (—NO2), a halogen atom, a cyano group (—CN), a group of formula (II) or (III), or both G1 and G2 taken together to form a group of formula (IV).
Core Innovation
The invention relates to stereocontrolled phosphorus-atom-modified oligonucleotide derivatives and chiral nucleoside 3′-phosphoramidite monomers. The described compounds are represented by formula (Va), (Vb), (Va′), or (Vb′), with defined substituents, nucleobases, and protecting groups, and include chiral oxazaphospholidine/DMT-protected nucleoside oxazaphospholidine monomers and their stereochemical variants.
The monomers and intermediates are defined by substituent variables including G1, G2, G3, G4, G5, R2, R3, Y1, and Bs, with allowed options set by formulas (II), (III), (IV), (V), and Bs selected from formula (VI) to (XI) or derivatives thereof. The disclosure includes examples with DMTr, TOM, OTOM, and 5′-O-(DMTr)-2′-O-TOM protecting group patterns, as well as uridine, cytidine, guanosine, and adenosine derivatives.
The material further describes a stereospecific synthesis framework for producing chiral X-phosphonate oligonucleotides and stereocontrolled phosphorus-atom-modified oligonucleotide derivatives, using condensation of an achiral H-phosphonate with activating reagents and the chiral reagent to form a monomer or condensed intermediate, followed by conversion to a nucleic acid with a chiral X-phosphonate moiety. Stable, commercially available starting materials, reduced degradation during deprotection, and isolation of targeted chiral oligonucleotide derivatives are stated.
Claims Coverage
The independent claims cover compound structures and selected labeled compounds. Across the claims, the inventive features center on compounds represented by formula (Va) or (Vb) with defined substituent-variable constraints, a heteroatom-containing ring formed by G3 and G4, Bs selected from formula (VI) to (XI), and selected labeled compounds with defined meanings for DMTr and TOM.
Substituted nucleoside phosphoramidite compounds of formula (Va) or (Vb)
A compound represented by formula (Va) or (Vb), with G1 and G2 chosen from hydrogen, nitro, halogen, cyano, or groups of formula (II), (III), or (V), or with G1 and G2 taken together forming formula (IV). The claim set also defines G3, G4, G5, R2, R3, Y1, and Bs with specified allowed options.
Heteroatom-containing ring constraint formed by G3 and G4
G3 and G4 are independently hydrogen, C1-3 alkyl, or C6-14 aryl, or G3 and G4 are taken together to form a heteroatom-containing ring having 3 to 16 carbon atoms.
Protecting group and substituent parameterization for phosphoramidite monomer
G5 is a protective group of a hydroxyl group, R2 is hydrogen, halogen, or alkyl-Y1, alkenyl-Y1, alkynyl-Y1, aryl-Y1, or heteroaryl-Y1 with Y1 being O, and R3 is —CH2—, —(CH2)2—, —CH2NH—, or —CH2N(CH3)—.
Nucleobase substituent selection for Bs from formula (VI) to (XI)
Bs is selected from groups represented by formula (VI) to (XI) or derivatives thereof.
Selected labeled compound with defined DMTr and TOM
A compound selected from the specified labeled set, wherein DMTr represents a 4,4′-dimethoxytrityl group and TOM represents a triisopropylsiloxymethyl group.
The claims collectively define stereocontrolled phosphorus-atom-modified oligonucleotide precursor compounds through detailed substituent-variable formulas, a heteroatom-containing ring constraint, and selected labeled compounds with defined DMTr and TOM meanings.
Stated Advantages
Reduced degradation during deprotection.
Improved monomer isolate yields greater than 80%.
Reduced incomplete deprotection products and reduced side products.
Facilitated isolation of targeted chiral oligonucleotide derivatives.
Use of stable, commercially available starting materials and avoidance of special capping agents.
Documented Applications
Synthesis of stereocontrolled phosphorus-atom-modified oligonucleotide derivatives using asymmetric induction with chiral reagent and corresponding chiral nucleoside 3′-phosphoramidite monomers.
Production of targeted chiral oligonucleotide derivatives.
Product distribution and failure sequences referenced by FIG. 2.
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