Method for the synthesis of phosphorus atom modified nucleic acids
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/00
C07H-021/02
C07H-021/04
C07H-001/00
출원번호
US-0167583
(2016-05-27)
등록번호
US-9695211
(2017-07-04)
발명자
/ 주소
Wada, Takeshi
Shimizu, Mamoru
출원인 / 주소
WAVE LIFE SCIENCES JAPAN, INC.
대리인 / 주소
Choate, Hall & Stewart LLP
인용정보
피인용 횟수 :
8인용 특허 :
294
초록▼
Described herein are methods of syntheses of phosphorous atom-modified nucleic acids comprising chiral X-phosphonate moieties. The methods described herein provide backbone-modified nucleic acids in high diasteteomeric purity via an asymmetric reaction of an achiral molecule comprising a chemically
Described herein are methods of syntheses of phosphorous atom-modified nucleic acids comprising chiral X-phosphonate moieties. The methods described herein provide backbone-modified nucleic acids in high diasteteomeric purity via an asymmetric reaction of an achiral molecule comprising a chemically stable H-phosphonate moiety with a nucleoside/nucleotide.
대표청구항▼
1. A method for a synthesis of a nucleic acid comprising a chiral X-phosphonate moiety comprising: reacting a molecule comprising an achiral H-phosphonate moiety, a chiral reagent, and a nucleoside comprising a 5′-OH moiety to form a condensed intermediate; andconverting the condensed intermediate t
1. A method for a synthesis of a nucleic acid comprising a chiral X-phosphonate moiety comprising: reacting a molecule comprising an achiral H-phosphonate moiety, a chiral reagent, and a nucleoside comprising a 5′-OH moiety to form a condensed intermediate; andconverting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety; wherein:the nucleic acid comprising a chiral X-phosphonate moiety is a compound of Formula 1: wherein: R1 is —OH or —ORa;Ra is a blocking moiety;each instance of R2 is independently hydrogen, —OH, halogen, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, or —ORb;Y1 is —O—;Rb is a blocking moiety;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;each instance of X is independently —S−Z+;Z+ is an ammonium ion, alkylammonium ion, heteroaromatic iminium ion, or heterocyclic iminium ion, any of which is primary, secondary, tertiary or quaternary, or Z+ is a monovalent metal ion;R3 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; andn is an integer of 1 to about 200. 2. The method of claim 1, wherein the molecule comprising an achiral H-phosphonate moiety is a compound of Formula 2: wherein: R1 is —OH or —ORa;Ra is a blocking moiety;R2 is hydrogen, —OH, halogen, or —ORb;Rb is a blocking moiety;Ba independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase; andZ+ is an ammonium ion, alkylammonium ion, heteroaromatic iminium ion, or heterocyclic iminium ion, any of which is primary, secondary, tertiary or quaternary, or Z+ is a monovalent metal ion. 3. The method of claim 2, wherein the chiral reagent is a compound of Formula 3: wherein: W1 is —NG5-;W2 is —O—;G1, G2, G3, G4, and G5 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetaryl, or aryl, or two of G1, G2, G3, G4, and G5 are G6 which are taken together to form a saturated, partially unsaturated or unsaturated carbocyclic or heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused, and wherein no more than four of G1, G2, G3, G4, and G5 are G6. 4. The method of claim 3, wherein the nucleoside comprising a 5′-OH moiety is a compound of Formula 4: wherein: each instance of R2 is independently hydrogen, halogen, or —ORb;Rb is a blocking moiety;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;m is an integer of 0 to n−1;OA is connected to a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid;J is O and D is H; or J is S, and D is a moiety of Formula A: wherein:W1 and W2 are independently NG5, O, or S;A is hydrogen, acyl, aryl, alkyl, aralkyl, or silyl moiety; andwherein G1, G2, G3, G4, and G5 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, or aryl, or two of G1, G2, G3, G4, and G5 are G6 which are taken together to form a saturated, partially unsaturated or unsaturated carbocyclic or heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused and wherein no more than four of G1, G2, G3, G4, and G5 are G6. 5. The method of claim 4, wherein the step of converting the condensed intermediate to a compound of Formula 1 comprises: capping the condensed intermediate and modifying the capped condensed intermediate to produce a compound of Formula 5: wherein: R1 is —OH or —ORa;Ra is a blocking moiety;each instance of R2 is independently hydrogen, —OH, halogen, or —ORb;Rb is a blocking moiety;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;each instance of J is S;v is an integer of 2 to n−1;OA is connected to a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid;A is an acyl, aryl, alkyl, aralkyl, or silyl moiety; andW1 and W2 are independently NG5, O, or S; andG1, G2, G3, G4, and G5 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, or aryl, or two of G1, G2, G3, G4, and G5 are G6 which are taken together to form a saturated, partially unsaturated or unsaturated carbocyclic or heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused and wherein no more than four of G1, G2, G3, G4, and G5 are G6. 6. The method of claim 5, wherein in each of formulae 3-5, G1, G2, and G3 are independently hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetaryl, or aryl, and G4 and G5 are taken together to form a saturated or partially unsaturated heteroatom-containing ring of up to about 20 ring atoms which is monocyclic or polycyclic, fused or unfused. 7. The method of claim 6, wherein G4 and G5 are taken together to form a saturated 5-membered saturated ring containing one nitrogen atom. 8. The method of claim 7, wherein one of G1 and G2 is alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetaryl, or aryl. 9. The method of claim 8, wherein the other of G1 and G2 is alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetaryl, or aryl. 10. The method of claim 8, wherein the other of G1 and G2 is hydrogen. 11. The method of claim 9, wherein G3 is hydrogen. 12. The method of claim 11, wherein the chiral reagent of formula 3 is 13. The method of claim 10, wherein G3 is hydrogen. 14. The method of claim 13, wherein the chiral reagent of formula 3 is 15. The method of claim 6, further comprising providing an activating reagent. 16. The method of claim 15, wherein the activating reagent is imidazole, 4,5-dicyanoimidazole (DCI), 4,5-dichloroimidazole, 1-phenylimidazolium triflate (PhIMT), benzimidazolium triflate (BIT), benztriazole, 3-nitro-1,2,4-triazole (NT), tetrazole, 5-ethylthiotetrazole, 5-(4-nitrophenyl)tetrazole, N-cyanomethylpyrrolidinium triflate (CMPT), N-cyanomethylpiperidinium triflate, or N-cyanomethyldimethylammonium triflate. 17. The method of claim 5, wherein Ra is substituted or unsubstituted trityl or substituted silyl. 18. The method of claim 17, wherein Rb is substituted or unsubstituted methyl ether. 19. The method of claim 18, wherein R3 is a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid. 20. The method of claim 5, wherein n is about 10 to about 200. 21. The method of claim 1, wherein at least one R2 is —OMe.
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