ASYMMETRIC AUXILIARY GROUP

• US 20150197540A1
• Filed: 07/12/2013
• Published: 07/16/2015
• Est. Priority Date: 07/13/2012
• Status: Active Grant

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: Chiralgen, Ltd.
• Inventors: Wada, Takeshi, Shimizu, Mamoru
• Granted Patent: US 9,598,458 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07B 53/00 Asymmetric syntheses
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07F 7/0812 comprising a heterocyclic ring
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/11 containing cyclic phosphate
• CPC Class Codes: C07H 19/207 the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
• CPC Class Codes: C07H 19/213 containing cyclic phosphate
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds

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).

Claims

1. A chiral reagent or a salt thereof, the chiral reagent having following chemical formula (I),

2. The chiral reagent or a salt thereof in accordance with claim 1, wherein the chiral reagent has following chemical formula (I′

).

3. The chiral reagent or a salt thereof in accordance with claim 2, wherein each of G¹ and G² is a group of formula (II), wherein G²¹ to G²³ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C_1-3 alkyl group.

4. The chiral reagent or a salt thereof in accordance with claim 2, wherein each of G¹ and G² is a group of formula (II), wherein each of G²¹ to G²³ is a hydrogen atom.

5. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom, and G² is a group of formula (II), wherein G²¹ to G²³ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C_1-3 alkyl group.

6. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (II), wherein each of G²¹ and G²² is a hydrogen atom and G²³ is a nitro group.

7. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom, and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group, C_6-14 aryl group, C_7-14 aralkyl group, C_1-4 alkyl C_6-14 aryl group, C_1-4 alkoxy C_6-14 aryl group, or C_6-14 aryl C_1-4 alkyl group.

8. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom, and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group, C₆ aryl group, C_7-10 aralkyl group, C_1-4 alkyl C₆ aryl group, C_1-4 alkoxy C₆ aryl group, or C₆ aryl C_1-4 alkyl group.

9. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group, or C₆ aryl group.

10. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group.

11. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ and G³³ are C₆ aryl group and G³² is C_1-4 alkyl group.

12. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ and G² taken together to form a group of formula (IV), wherein G⁴¹ to G⁴⁶ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C_1-3 alkyl group.

13. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ and G² taken together to form a group of formula (IV), wherein each of G⁴¹ to G⁴⁶ is a hydrogen atom.

14. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (V), wherein each of G⁵¹ to G⁵³ are independently a hydrogen atom, a nitro group, a methyl group, or a methoxy group.

15. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (V), wherein each of G⁵¹ and G⁵³ is a hydrogen atom and G⁵³ is a 4-methyl group.

16. The chiral reagent or a salt thereof in accordance with claim 2, wherein the chiral reagent is represented by III-a, III-b, V-a, VII-a, VII-b, IX-a, IX-b, XI-a, XIII-a or XIII-b:

(S)-2-(Methyldiphenylsilyl)-1-((S)-pyrrolidin-2-yl)ethanol (III-a)

(R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (III-b)

(S)-2-(Trimethylsilyl)-1-((S)-1-pyrrolidin-2-yl)ethanol (V-a)

(R)-2,2-Diphenyl-1-((S)-pyrrolidin-2-yl)ethanol (VII-a)

(S)-2,2-Diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (VII-b)

(R)-2-(4-Nitrophenyl)-1-((S)-pyrrolidin-2-yl)ethanol (IX-a)

(S)-2-(4-Nitrophenyl)-1-((R)-pyrrolidin-2-yl)ethanol (IX-b)

(R)-(9H-Fluororen-9-yl)((S)-pyrrolidin-2-yl)methanol (XI-a)

(S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a)

(R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b)

17. A nucleoside 3′

-phosphoramidite derivative which is represented by formula (Va) or (Vb),

18. The nucleoside 3′

-phosphoramidite derivative in accordance with claim 17, wherein the nucleoside 3′

-phosphoramidite derivative is represented by formula (Va′

) or (Vb′

).

19. The nucleoside 3′

-phosphoramidite derivative in accordance with claim 17, wherein the nucleoside 3′

-phosphoramidite derivative is represented by formula 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, 16b, 17a, 17b, 18a, 18b, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, 23b, or 24a.

20. A method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives comprising steps of:

reacting a molecule comprising an achiral H-phosphonate moiety, a chiral reagent or a salt thereof to form a monomer of a nucleoside 3′

-phosphoramidite derivative,

reacting the monomer and a nucleoside to form a condensed intermediate; and

converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety,

wherein the chiral reagent has following chemical formula (I),

21. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleoside derivatives in accordance with claim 20, wherein the wherein the chiral reagent has following chemical formula (I′

).

22. The method for synthesis of a stereocontrolled phosphorus atom-modified oligonucleotide derivative in accordance with claim 20, wherein the chiral reagent is represented by III-a, III-b, V-a, VII-a, VII-b, IX-a, IX-b, XI-a, XIII-a and XIII-b:

(S)-2-(Methyldiphenylsilyl)-1-((S)-pyrrolidin-2-yl)ethanol (III-a)

(R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (III-b)

(S)-2-(Trimethylsilyl)-1-((S)-1-pyrrolidin-2-yl)ethanol (V-a)

(R)-2,2-Diphenyl-1-((S)-pyrrolidin-2-yl)ethanol (VII-a)

(S)-2,2-Diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (VII-b)

(R)-2-(4-Nitrophenyl)-1-((S)-pyrrolidin-2-yl)ethanol (IX-a)

(S)-2-(4-Nitrophenyl)-1-((R)-pyrrolidin-2-yl)ethanol (IX-b)

(R)-(9H-Fluororen-9-yl)((S)-pyrrolidin-2-yl)methanol (XI-a)

(S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a)

(R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b)

23. A method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives comprising steps of:

reacting a nucleoside 3′

-phosphoramidite derivative which is represented by formula (Va) or (Vb), with an activating reagent and a nucleoside to form a condensed intermediate; and

converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety.

24. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 23, wherein the nucleoside 3′

-phosphoramidite derivative is represented by formula (Va′

) or (Vb′

).

25. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 23, wherein the nucleoside 3′

-phosphoramidite derivative is represented by formula 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, 16b, 17a, 17b, 18a, 18b, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, 23b, or 24a,