Compounds, compositions and methods for synthesis
Inventors
Butler, David Charles Donnell • Hencken, Christopher P. • Iwamoto, Naoki • Kandasamy, Pachamuthu • Lanao, Alvaro Andres • Lu, Genliang • Shimizu, Mamoru • Divakaramenon, Sethumadhavan • Vargeese, Chandra • Bommineni, Gopal Reddy • Marappan, Subramanian
Assignees
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Publication Number
US-11718638-B2
Publication Date
2023-08-08
Expiration Date
Abstract
The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.
Core Innovation
The invention relates to a compound having the structure of formula V-b, or a salt thereof, wherein the compound is of such a structure that it is a compound of formula I-e, or a salt thereof. The structure includes a phosphorus-containing scaffold, Ring A as an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms, and substituent positions defined by R1 through R6. The definition further specifies L8-H corresponding to the OH shown in formula I-e and t being 1.
Each of R1, R2, R3, R4, and R5 is independently selected from H, Ls-R, halogen, CN, NO2, Ls-Si(R)3, OR, SR, or N(R)2, while R6 is H and NHR5 is NR5R6 shown in formula I-e. Each Ls is independently a covalent bond or a bivalent, optionally substituted linear or branched group selected from C1-30 aliphatic and C1-30 heteroaliphatic groups having 1-10 heteroatoms, with one or more methylene units optionally replaced by additional groups and optional CyL or CyL groups. BA is an optionally substituted group selected from a natural nucleobase moiety and a modified nucleobase moiety.
The disclosure also specifies Rs and Ring As substitution and ring-forming relationships, including two or more R groups taken together with their atom(s) and intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms. The provided examples and variants include stereochemically defined compounds, salts, phosphoramidite or phosphoramidate derivatives, nucleoside-derived BA-containing compounds, and internucleotidic linkage structures, while maintaining the formula V-b to formula I-e correspondence.
Claims Coverage
One independent claim is explicitly identifiable across the input items. The consolidated claim coverage centers on a compound of formula V-b, or a salt thereof, constrained to correspond to formula I-e, or a salt thereof, with one core inventive scaffold and defined Ring A, substituent, linker, and BA limitations.
Formula V-b compound corresponding to formula I-e
A compound having the structure of formula V-b, or a salt thereof, wherein the structure is such that it is a compound of formula I-e, or a salt thereof, with L8-H corresponding to the OH shown in formula I-e and t being 1.
Optionally substituted Ring A with constrained heteroatom count
Ring A is an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms.
Defined substituent set for R1-R5 and fixed R6 relationship
Each of R1, R2, R3, R4, and R5 is independently H, Ls-R, halogen, CN, NO2, Ls-Si(R)3, OR, SR, or N(R)2; R6 is H; and NHR5 is NR5R6 shown in formula I-e.
Defined linker Ls with optional cyclic replacements
Each Ls is independently a covalent bond or a bivalent, optionally substituted linear or branched group selected from C1-30 aliphatic and C1-30 heteroaliphatic groups having 1-10 heteroatoms, with one or more methylene units optionally replaced by additional groups and optional CyL or CyL groups.
Nucleobase moiety BA
BA is an optionally substituted group selected from a natural nucleobase moiety and a modified nucleobase moiety.
Rs and ring-forming substituent options
Each Rs is independently H, halogen, CN, N3, NO, NO2, Ls-R', Ls-Si(R)3, Ls-OR', Ls-SR', or Ls-N(R')2, including O-Ls-linked variants; two or more R groups may be taken together to form an optionally substituted ring.
The claim coverage is directed to a structurally defined formula V-b scaffold that corresponds to formula I-e, with constraints on Ring A, linker groups, substituent sets, ring-forming options, and BA selection.
Stated Advantages
Unexpectedly high stereoselectivity in chirally controlled oligonucleotide preparation for compounds where the N-substituent attachment is not within a ring.
Unexpectedly high yield in chirally controlled oligonucleotide preparation for compounds where the N-substituent attachment is not within a ring.
Higher yields.
High stereoselectivity (reported as about 99:1).
Improved product purity.
Compatibility with varied chemical conditions for oligonucleotide synthesis.
Improved yields.
Improved stability.
Improved diastereoselectivity.
Documented Applications
Chirally controlled preparation of an oligonucleotide using stereochemical variants of the disclosed compounds, with effects on stereoselectivity and/or yield.
Stereoselective or chirally controlled synthesis of chiral internucleotidic linkages in nucleic acids during oligonucleotide synthesis, including phosphorothioate linkages.
Chirally controlled oligonucleotide synthesis using stereoselective behavior of enantiomeric and diastereomeric compound variants.
Use in challenging automated oligonucleotide synthesis, including dCdC dimers and SOSICS/DPSE cycle comparisons.
Comparative evaluation of dimer formation yields and HPLC-based purity metrics across specific monomers/activators and SOSICS/DPSE cycles.
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