Compounds, compositions and methods for synthesis
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.
1. A compound having the structure of formula V-b:
or a salt thereof, wherein:
P L is P;
is of such a structure that
is a compound of formula I-e or a salt thereof:
wherein:
L 8 -H is the —OH shown in formula I-e;
t is 1;
Ring A is an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms;
each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently —H, -L s -R, halogen, —CN, —NO 2 ,
L s -Si(R) 3 , —OR, —SR, or —N(R) 2 ;
R 6 is —H;
—NHR 5 is —NR 5 R 6 shown in formula I-e;
each L s is independently a covalent bond, or a bivalent, optionally substituted, linear or branched group selected from a C 1-30 aliphatic group and a C 1-30 heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C 1-6 alkylene, C 1-6 alkenylene, —C≡C—, a bivalent C 1 -C 6 heteroaliphatic group having 1-5 heteroatoms, —C(R′) 2 —, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R′)—, —C(O)S—, —C(O)O—, —P(O)(OR′)—, —P(O)(SR′)—, —P(O)(R′)—, —P(O)(NR′)—, —P(S)(OR′)—, —P(S)(SR′)—, —P(S)(R′)—, —P(S)(NR′)—, —P(R′)—, —P(OR′)—, —P(SR′)—, —P(NR′)—, —P(OR′)[B(R′) 3 ]—, —OP(O)(OR′)O—, —OP(O)(SR′)O—, —OP(O)(R′)O—, —OP(O)(NR′)O—, —OP(OR′)O—, —OP(SR′)O—, —OP(NR′)O—, —OP(R′)O—, or —OP(OR′)[B(R′) 3 ]O—, and one or more carbon atoms are optionally and independently replaced with Cy L ;
each -Cy- is independently an optionally substituted bivalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms;
each Cy L is independently an optionally substituted tetravalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms;
each R′ is independently —R, —C(O)R, —C(O)OR, or —S(O) 2 R;
BA is an optionally substituted group selected from a natural nucleobase moiety and a modified nucleobase moiety;
each R s is independently —H, halogen, —CN, —N 3 , —NO, —NO 2 , -L s -R′, -L s -Si(R) 3 , -L s -OR′, -L s -SR′, -L s -N(R′) 2 , —O-L s -R′, —O-L s -Si(R) 3 , —O-L s -OR′, —O-L s -SR′, or —O-L s -N(R′) 2 ;
Ring A s is
wherein each of R 2s and R 4s is independently R s ;
R 5s is R s ;
each R is independently —H, or an optionally substituted group selected from C 1-30 aliphatic, C 1-30 heteroaliphatic having 1-10 heteroatoms, C 6-30 aryl, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1-10 heteroatoms, or
two R groups are optionally and independently taken together to form a covalent bond, or:
two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms; or
two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms.
2. The compound of claim 1 , wherein R 3 is —H.
3. The compound of claim 2 , wherein R 1 is optionally substituted C 1-6 aliphatic.
4. The compound of claim 3 , wherein R 1 is methyl.
5. The compound of claim 2 , wherein R 1 is optionally substituted phenyl.
6. The compound of claim 2 , wherein R 5 is optionally substituted C 1-6 aliphatic.
7. The compound of claim 3 , wherein R 5 is optionally substituted C 1-6 aliphatic.
8. The compound of claim 2 , wherein R 5 is optionally substituted C 1-6 aliphatic.
9. The compound of claim 6 , wherein R 5 is methyl.
10. The compound of claim 7 , wherein R 5 is methyl.
11. The compound of claim 8 , wherein R 5 is methyl.
12. The compound of claim 1 , wherein BA is an optionally substituted group which group is selected from
and tautomeric forms thereof.
13. The compound of claim 12 , wherein R 2s is —H.
14. The compound of claim 12 , wherein R 2s is —F.
15. The compound of claim 12 , wherein R 2s is —OR, wherein R is optionally substituted C 1-6 aliphatic.
16. The compound of claim 12 , wherein R 2s is —OMe.
17. The compound of claim 12 , wherein R 2s is -MOE.
18. The compound of claim 12 , wherein Ring A s is optionally substituted
19. A method for stereoselective synthesis of an oligonucleotide, comprising utilizing a compound of claim 1 for coupling.
20. A method for preparing an oligonucleotide, comprising steps of:
(1) coupling;
(2) optionally capping;
(3) optionally modifying;
(4) optionally deblocking; and
(5) optionally repeating (1) to (4) until the desired oligonucleotide length is achieved;
wherein a coupling step comprises providing a compound of claim 1 for coupling.