HK1242331B - Asymmetric auxiliary group - Google Patents

Description

Asymmetric auxiliary groups

This application is a divisional application of the invention patent application "Asymmetric Auxiliary Group" with application number 201380037512.9 filed on July 12, 2013.

Technical Field

The present invention relates to chiral reagents for the synthesis of stereocontrolled phosphorus-modified oligonucleotide derivatives.

Background Art

Japanese Patent JP2005-89441A discloses a method for producing nucleotide derivatives called the oxazaphospholidine method. However, this method has a low monomer separation rate and requires a special, non-commercially available end-capping agent. The monomers obtained later do not have chemical stability. In addition, the separation rate of oligonucleotide derivatives is not high. The low yield of oligonucleotide derivatives is believed to be caused by degradation reactions during the deprotection step.

International Publication No. WO2010/064146 discloses a method for producing nucleotide derivatives. The disclosed method requires a special, non-commercially available end-capping agent. Furthermore, the isolation rate of the oligonucleotide derivatives is low. This low yield is believed to be caused by degradation reactions during the deprotection step. This tendency becomes more pronounced as the length of the oligonucleotide derivative increases.

International Publication No. WO2012/039448 discloses an asymmetric auxiliary group for producing stereocontrolled phosphorus-modified oligonucleotide derivatives.

Reference List

Patent Literature

[Patent Document 1] JP 2005-89441 A Patent Document 1

[Patent Document 2] WO2010/064146 A Patent Document 2

[Patent Document 3] WO2012/039448 A Patent Document 3

Summary of the Invention

The first aspect of the present invention relates to a chiral reagent or a salt thereof. The chiral reagent has the following chemical formula (I):

In formula (I), ^G1 and ^G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II), (III) or (V), or ^G1 and ^G2 are combined to form a group of formula (IV).

In formula (II), G ²¹ to G ²³ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or a C _1-3 alkyl group.

In formula (III), G ³¹ to G ³³ are independently C _1-4 alkyl, C _6-14 aryl, C _1-4 alkoxy, C _7-14 aralkyl, C _1-4 alkyl C _6-14 aryl, C _1-4 alkoxy C _6-14 aryl or C _6-14 aryl C _1-4 alkyl.

In formula (IV), G ⁴¹ to G ⁴⁶ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or a C _1-3 alkyl group.

In formula (V), G ⁵¹ to G ⁵³ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a C _1-3 alkyl group or a C _1-3 alkoxy group.

^G3 and ^G4 are independently hydrogen, _C1-3 alkyl, _C6-14 aryl, or ^G3 and ^G4 together with the NH portion in formula (I) are combined to form a heteroatom-containing ring containing 3 to 16 carbon atoms.

As a preferred embodiment, the chiral reagent has the following chemical formula (I').

In formula (I'), ^G1 and ^G2 are the same as described above. That is, ^G1 and ^G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II) or formula (III), or ^G1 and ^G2 are combined to form a group of formula (IV).

As a preferred embodiment, the chiral reagent has the chemical formula (I') and ^G1 and ^G2 are each a group of the formula (II), wherein ^G21 to ^G23 are independently hydrogen, nitro, halogen, cyano or _C1-3 alkyl.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 and ^G2 are each a group of the formula (II), and ^G21 to ^G23 are each a hydrogen atom.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 is a hydrogen atom, ^G2 is a group of formula (II), and ^G21 to ^G23 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or a _C1-3 alkyl group.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 is a hydrogen atom, ^G2 is a group of formula (II), ^G21 and ^G22 are each a hydrogen atom, and ^G23 is a nitro group.

As a preferred embodiment, the chiral reagent has the chemical formula (I') and ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C1-4 alkyl, C6-14 aryl, _C7-14 arylalkyl, _{C1-4 alkylC6-14} aryl, _{C1-4 alkoxyC6-14} aryl or _{C6-14 arylC1-4 alkyl} .

As a preferred embodiment, the chiral reagent has the chemical formula (I') and ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 arylalkyl, _{C1-4 alkylC6} aryl, _C1-4 alkoxyC6-14 aryl or _{C6 arylC1-4 alkyl} .

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. Examples of _C1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C1-4 alkyl groups.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C6 aryl groups, and ^G32 is _C1-4 alkyl groups.

As a preferred embodiment, the chiral reagent has the chemical formula (I') and ^G1 and ^G2 are combined to form a group of formula (IV), and ^G41 to ^G46 are independently hydrogen, nitro, halogen, cyano or _C1-4 alkyl.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), and ^G1 and ^G2 are combined to form a group of formula (IV), wherein ^G41 to ^G46 are each a hydrogen atom.

In a preferred embodiment, the chiral reagent has the chemical formula (I'), wherein ^G1 is a hydrogen atom, and ^G2 is a group of formula (V). Furthermore, ^G51 - ^G53 are each independently a hydrogen atom, a nitro group, a methyl group, or a methoxy group. In a more preferred embodiment, ^G1 is a hydrogen atom, and ^G2 is a group of formula (V), wherein ^G51 and ^G52 are each a hydrogen atom, and ^G53 is a 4-methyl group.

As a preferred embodiment, the chiral reagent is selected from 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-fluoren-9-yl)((S)-pyrrolidin-2-yl)methanol (XI-a)

(S)-2-p-Toluenesulfonyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a)

(R)-2-p-Toluenesulfonyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b)

The second aspect of the present invention relates to a nucleoside 3'-phosphoramidite derivative represented by formula (Va) or (Vb).

In formulae (Va) and (Vb), G ¹ to G ⁴ are the same as described above, G ⁵ is a protective group for a hydroxyl group, and Bs is a group selected from the groups represented by the following formulae (VI) to (XI) or derivatives thereof.

Examples of Bs are adenine, thymine, cytosine, guanine, uracil, 5-methylcytosine, or derivatives thereof.

^R2 is hydrogen, -OH, -SH, ^-NRdRd , ^-N3 , halogen, alkyl, alkenyl, alkynyl, alkyl- ^Y1- , alkenyl- ^Y1- , alkynyl- ^Y1- , aryl _- ^Y1- , heteroaryl- ^Y1- , -ORb or ^-SRb , wherein ^Rb is a blocking ^moiety .

Y ¹ is O, NR ^d , S or Se.

R ^d is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, -P(O)( ^Re ) ₂ , or -HP(O)( ^Re ).

R ^{e is} independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y ² —, alkenyl-Y ² —, alkynyl-Y ² —, aryl-Y ² —, or heteroaryl-Y ² —, or the cation Na ⁺ , Li ⁺ or K ⁺ .

^Y2 is O, ^NRd or S.

R ³ is a group represented by -CH ₂ -, -(CH ₂ ) ₂ -, -CH ₂ NH-, or -CH ₂ N(CH ₃ )-.

Examples of G ⁵ are trityl, 4-monomethoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 9-phenylxanthin-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthin-9-yl (MOX).

In a preferred embodiment of the second aspect, the nucleoside 3'-phosphoramidite derivative is represented by formula (VA') or (Vb').

In formulae (VA') and (Vb'), G ¹ , G ² , G ⁵ , Bs, R ² and R ³ are the same as described above.

The third aspect of the present invention relates to a method for synthesizing stereocontrolled phosphorus-modified oligonucleotide derivatives.

The first step is to react a molecule comprising an achiral H-phosphonate moiety with a first activating agent and a chiral reagent or a salt thereof to form a monomer. The chiral reagent has a chemical formula (I) or (I'), and the monomer can be represented by formula (Va), (Vb), (Va'), or (Vb'). The monomer reacts with a second activating agent and a nucleoside to form a condensation intermediate. The next step is to convert the condensation intermediate into a nucleic acid comprising a chiral X-phosphonate moiety.

According to the method of the present invention, stable and commercially available materials can be used as starting materials. Achiral starting materials can be used to produce stereocontrolled phosphorus-modified oligonucleotide derivatives.

As shown in one example, the method of the present invention does not lead to degradation during the deprotection step. In addition, the method does not require special blocking agents to produce phosphorus-modified oligonucleotide derivatives.

A fourth aspect of the present invention relates to a method for synthesizing stereocontrolled phosphorus atom-modified oligonucleotide derivatives by using chiral monomers.

The first step is to react a nucleoside 3'-phosphoramidite derivative represented by formula (Va), (Vb), (Va') or (Vb') with a second activating agent and a nucleoside to form a condensation intermediate. The second step is to convert the condensation intermediate into a nucleic acid containing a chiral X phosphonate moiety.

[Incorporated by reference]

All publications and patent applications disclosed herein are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a UPLC profile of oligonucleotide derivatives produced by using monomers of 4b.

FIG2 is a UPLC profile of oligonucleotide derivatives produced by using monomer 25.

DETAILED DESCRIPTION

The term "nucleic acid" includes: polyribonucleotides or oligoribonucleotides (RNA), and polydeoxyribonucleotides or oligodeoxyribonucleotides (DNA); RNA or DNA derived from N- or C-glycosides of nucleobases and/or modified nucleobases; nucleic acids derived from sugars and/or modified sugars; nucleic acids derived from phosphate bridges and/or modified phosphorus atom bridges. The term includes nucleic acids containing any combination of nucleobases, modified nucleobases, sugars, modified sugars, phosphate bridges, or modified phosphorus atom bridges. Examples of the term "nucleic acid" include, but are not limited to, nucleic acids containing ribose moieties, nucleic acids containing deoxyribose moieties, nucleic acids containing both ribose and deoxyribose moieties, and nucleic acids containing ribose and modified ribose moieties. The prefix "poly" refers to nucleic acids containing about 1 to 10,000 nucleotide monomer units, and wherein the prefix "oligo" refers to nucleic acids containing about 1 to 200 nucleotide monomer units.

The term "nucleobase" refers to the portion of a nucleic acid that participates in hydrogen bonding that binds one nucleic acid strand to another complementary strand in a sequence-specific manner. The most common naturally occurring nucleobases are adenine (A), guanine (G), uracil (U), cytosine (C), 5-methylcytosine, and thymine (T).

The term "modified nucleobase" refers to a moiety that can replace a nucleobase. The modified nucleobase mimics the spatial arrangement, electronic properties, or other physicochemical properties of the nucleobase while retaining the hydrogen bonding properties that bind one nucleic acid strand to another in a sequence-specific manner. The modified nucleobase can pair with all five naturally occurring bases (uracil, thymine, adenine, cytosine, or guanine) without substantially affecting melting behavior, recognition by intracellular enzymes, or activity of the oligonucleotide duplex.

The term "nucleoside" refers to a moiety wherein a nucleobase or modified nucleobase is covalently bound to a sugar or modified sugar.

The term "sugar" refers to monosaccharides in closed and/or open form. Sugars include, but are not limited to, ribose, deoxyribose, pentofuranoses, pentopyranoses, and hexopyranose moieties.

The term "modified sugar" refers to a moiety that can replace a sugar and mimic the spatial arrangement, electronic properties, or other physicochemical properties of a sugar.

The term "nucleotide" refers to a moiety wherein a nucleobase or modified nucleobase is covalently linked to a sugar or modified sugar, and the sugar or modified sugar is covalently linked to a phosphate group or a modified phosphorus atom.

The term "chiral reagent" refers to a compound that is chiral or enantiopure and can be used to induce asymmetry in nucleic acid synthesis.

The term "chiral ligand" or "chiral auxiliary" refers to a moiety that is chirally or enantiomerically pure and controls the stereochemical outcome of a reaction.

In the context of condensation reactions, the term "activating agent" refers to an agent that activates a less reactive site and makes it more susceptible to attack by a nucleophile.

The term "blocking moiety" refers to a group of moieties that temporarily shield the reactivity of a functional group. The functional group can then be unshielded by removing the blocking moiety.

The terms "boronating agent", "sulfur electrophile" and "selenium electrophile" refer to compounds that can be used to introduce BH ₃ , S and Se groups, respectively, to modify phosphorus atoms during the modification step.

The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

The term "solid support" refers to any support that enables the synthesis of nucleic acids to be produced in large quantities and can be reused as needed. As used herein, the term refers to a polymer that is insoluble in the medium used in the reaction steps used to synthesize nucleic acids and is derivatized to include reactive groups.

The term "linking moiety" refers to any moiety optionally positioned between a terminal nucleoside and a solid support or between a terminal nucleoside and another nucleoside, nucleotide, or nucleic acid.

As used herein, "treat," "treat," "treat," or "alleviate," or "improve," are used interchangeably herein. These terms refer to an approach for obtaining a beneficial or desired effect, including but not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit means eradication or amelioration of the underlying disease being treated. Additionally, a therapeutic benefit may be obtained by eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that, while the patient may still be suffering from the underlying disease, an improvement in symptoms is observed. For prophylactic benefit, the composition may be administered to a patient at risk for a particular disease, or may be administered to a patient who, although he or she may not have been diagnosed with the disease, is reported to be experiencing one or more of the physiological symptoms of the disease.

As used herein, the term "therapeutic effect" includes the above-mentioned therapeutic benefits and/or prophylactic benefits. The prophylactic benefits include delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl portion can be a saturated alkyl group (meaning it does not contain any unsaturated units, such as carbon-carbon double bonds or carbon-carbon triple bonds), or the alkyl portion can be an unsaturated alkyl group (meaning it contains at least one unsaturated unit). Whether saturated or unsaturated, the alkyl portion can be branched, straight chain, or include cyclic portions. The point of attachment of the alkyl group is at a carbon atom that is not part of a ring.

The "alkyl" moiety may contain 1 to 10 carbon atoms (although this definition also covers the term "alkyl" in the absence of a specified numerical range, whenever a numerical range such as "1 to 10" appears herein, it refers to each integer within the given range; for example, "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms). Alkyl groups include both branched and straight-chain alkyl groups. The alkyl groups of the compounds described herein may be designated as " _C1 - _C6 alkyl" or similar designations. By way of example only, " _C1 - _C6 alkyl" means that there are one, two, three, four, five, or six carbon atoms in the alkyl chain, that is, the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but should not be limited in any way to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, allyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like. In one aspect of the present invention, the alkyl group is a C ₁ -C ₆ alkyl group.

_C1-3 alkyl refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms. Examples of _C1-3 alkyl are methyl, ethyl, propyl, and isopropyl. _C1-4 alkyl refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of _C1-4 alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl rings are formed by five, six, seven, eight, nine, or more carbon atoms. Aryl groups can be substituted or unsubstituted. In one aspect of the invention, an aryl group is a phenyl or naphthyl group. Depending on its structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). In one aspect of the invention, an aryl group is a _C6 - _C10 aryl group.

The C _6-14 aryl group refers to an aryl group having 6 to 14 carbon atoms. Examples of the C _6-14 aryl group are phenyl, biphenyl, naphthyl, anthracenyl, indanyl, phthalimide, naphthimidyl, phenanthridinyl, and tetrahydronaphthyl.

The term "aralkyl" refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl and the like, all of which may be optionally substituted.

"Acyl moiety" refers to an alkyl-(C=O), aryl-(C=O), or aralkyl-(C=O) group. The acyl moiety may have an intermediate portion (Y) inserted between the carbonyl and alkyl groups, which is an oxy, amino, thiol, or selenoyl group. For example, the acyl group may be an alkyl-Y-(C=O), aryl-Y-(C=O), or aralkyl-Y-(C=O).

An "alkenyl" group is a straight chain, branched chain, or cyclic hydrocarbon group containing at least one carbon-carbon double bond. An alkenyl group may be substituted.

An "alkynyl" group is a straight chain, branched chain, or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. An alkynyl group may be substituted.

An "alkoxy" group refers to an alkyl group attached to an oxygen, ie, an (alkyl)-O- group, wherein alkyl is as defined herein. Examples include methoxy ( _-OCH3 ) or _ethoxy ( _-OCH2CH3 ) groups.

An "alkenyloxy" group refers to an alkenyl group attached to an oxygen, ie, an (alkenyl)-O- group, where alkenyl is as defined herein.

An "alkynyloxy" group refers to an alkynyl group attached to an oxygen, ie, an (alkynyl)-O- group, where alkynyl is as defined herein.

An "aryloxy" group refers to an aryl group attached to an oxygen, ie, an (aryl)-O- group, wherein the aryl group is as defined herein. Examples include a _phenoxy ( _-OC6H5 ) group.

The term "alkylselenyl" refers to an alkyl group having attached thereto a substituted seleno group, ie, an (alkyl)-Se- group, wherein alkyl is as defined herein.

The term "alkenylselenyl" refers to an alkenyl group having a substituted seleno group attached thereto, ie, a (alkenyl)-Se- group, wherein alkenyl is as defined herein.

The term "alkynylselenyl" refers to an alkynyl group having a substituted selenyl group attached thereto, ie, a (alkynyl)-Se- group, wherein alkynyl is as defined herein.

The term "alkylthio" refers to an alkyl group attached to a bridging sulfur atom, i.e., an (alkyl)-S- group, wherein alkyl is as defined herein. For example, alkylthio is methylthio and the like.

The term "alkenylthio" refers to an alkenyl group attached to a bridging sulfur atom, ie, an (alkenyl)-S- group, wherein alkenyl is as defined herein.

The term "alkynylthio" refers to an alkynyl group attached to a bridging sulfur atom, ie, an (alkynyl)-S- group, wherein alkynyl is as defined herein.

The term "alkylamino" refers to an amino group substituted with at least one alkyl group, ie, -NH(alkyl) or -N(alkyl) ₂ , wherein alkyl is as defined herein.

The term "enamino" refers to an amino group substituted with at least one alkenyl group, such as -NH(alkenyl) or -N(alkenyl) ₂ , wherein alkenyl is as defined herein.

The term "alkynylamino" refers to an amino group substituted with at least one alkynyl group, such as -NH(alkynyl) or -N(alkynyl) ₂ , wherein alkynyl is as defined herein.

The term "halogen" is meant to include fluorine, chlorine, bromine and iodine.

"Fluorophore" refers to a molecule that emits light of a different wavelength when excited by light of a selected wavelength. Fluorophores include, but are not limited to, indolyl, fluorescein, tetramethylrhodamine, Texas Red, boron dipyrrole fluoride (BODIPY), 5-(2-aminoethylamino)-1-naphthalenesulfonic acid (EDANS), coumarin, and Lucifer Yellow.

"Ammonium ion" refers to a positively charged polyatomic cation of the chemical formula _NH4 ⁺ .

"Alkylammonium ion" refers to an ammonium ion in which at least one hydrogen atom is replaced by an alkyl group, wherein alkyl is as defined herein. Examples include triethylammonium ion and N,N-diisopropylethylammonium ion.

"Iminium ion" has the general structure _R2C = _NR2 ⁺ . The R group refers to alkyl, alkenyl, alkynyl, or aryl as defined herein. "Heteroaromatic iminium ion" refers to an iminium ion in which the nitrogen and the R group to which it is attached form a heteroaromatic ring. "Heterocyclic iminium ion" refers to an iminium ion in which the nitrogen and the R group to which it is attached form a heterocyclic ring.

Unless otherwise specifically indicated herein, the term "amino" or "amine" refers to an -N( ^Rh ) ₂ radical group, wherein each ^Rh is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl. When the -N( ^Rh ) ₂ group has two non-hydrogen ^Rh , they can be combined with the nitrogen atom to form a four-, five-, six-, or seven-membered ring. For example, -N( ^Rh ) ₂ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Any one or more of hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilane, ^-ORi , -SRi, -OC(O)Ri, -N(Ri), ^-C (O) _Ri , -C(O) ^ORi , -OC(O) ^N ( ^Ri ) _, -C(O)N( ^Ri ), -N(Ri)C( ^O )OR ^, -N( ^Ri )C( ^O ) ^Ri , -N( ^Ri )C(O) _N ( ^Ri ₎ , N(R ⁱ )C(NR ⁱ )N(R ⁱ ) ₂ , -N(R ⁱ )S(O) _t R ⁱ (wherein t is 1 or 2), -S(O), or -S(O) _t N(R ⁱ ) ₂ (wherein t is 1 or 2), wherein each R ⁱ is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

As used herein, "carbamate" refers to a moiety attached to an amino group containing the formula -C(O)OR, where R is an alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl group. Examples include, but are not limited to, Boc (tert-butyl-OC(O)-), CBz (benzyl-OC(O)-), Teoc ((CH ₃ ) ₃ SiCH 2 CH 2 OC(O)-), alloc (allyl-OC(O)-), or Fmoc (9-fluorenylmethyl-OC(O)-) groups.

As used herein, "substituted silyl" refers to a moiety having the formula _R3Si- . Examples include, but are not limited to, TBDMS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilyl), or TMS (trimethylsilyl).

The term "mercapto" refers to a -SH group and includes substituted mercapto groups, i.e., -SR ^J groups, where each R ^J is independently substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclic group as defined herein.

The first aspect of the present invention relates to a chiral reagent or a salt thereof. The chiral reagent has the following chemical formula (I). The term "chiral reagent" refers to a chemical composition used to produce a stereocontrolled phosphorus-modified nucleotide or oligonucleotide derivative. The chiral reagent reacts with the nucleotide to form a chiral intermediate.

In formula (I), ^G1 and ^G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II), (III) or (V), or ^G1 and ^G2 are combined to form a group of formula (IV).

In formula (II), G ²¹ to G ²³ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or a C _1-3 alkyl group. A preferred example of G ²¹ to G ²³ is a hydrogen atom.

In formula (III), G ³¹ to G ³³ are independently C _1-4 alkyl, C _6-14 aryl, C _1-4 alkoxy, C _7-14 aralkyl, C _1-4 alkyl C _6-14 aryl, C _1-4 alkoxy C _6-14 aryl or C _6-14 aryl C _1-4 alkyl.

Examples of C _1-4 alkyl C _6-14 aryl groups are methylphenyl and ethylphenyl. Examples of C _1-4 alkoxy C _6-14 aryl groups are methoxyphenyl and ethoxyphenyl. Examples of C _6-14 aryl C _1-4 alkyl groups are benzyl and phenethyl. Preferred examples of G ³¹ to G ³³ are independently methyl and phenyl.

In formula (IV), G ⁴¹ to G ⁴⁶ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or a C _1-3 alkyl group. A preferred example of ^{G 41} to G ⁴⁶ is a hydrogen atom.

In formula (V), G ⁵¹ to G ⁵³ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a C _1-3 alkyl group or a C _1-3 alkoxy group.

^G3 and ^G4 are independently a hydrogen atom, a _C1-3 alkyl group, a _C6-14 aryl group, or ^G3 and ^G4 are combined to form a heteroatom-containing ring containing 3 to 16 carbon atoms. A preferred example of ^G3 and ^G4 is that ^G3 and ^G4 are combined to form a heteroatom-containing ring containing 3 to 16 carbon atoms with the NH portion in formula (I).

As a preferred embodiment, the chiral reagent has the following chemical formula (I').

In formula (I'), ^G1 and ^G2 are the same as described above, and ^G1 and ^G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II) or (III), or ^G1 and ^G2 are combined to form a group of formula (IV).

As a preferred embodiment, the chiral reagent has the chemical formula (I'), and ^G1 and ^G2 are each a group of formula (II), wherein ^G21 to ^G23 are independently hydrogen, nitro, halogen, cyano or _C1-3 alkyl.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 and ^G2 are each a group of formula (II), and ^G21 to ^G23 are each a hydrogen atom.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 is a hydrogen atom, ^G2 is a group of formula (II), and ^G21 to ^G23 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or a _C1-3 alkyl group.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), wherein ^G1 is a hydrogen atom, ^G2 is a group of formula (II), ^G21 and ^G22 are each a hydrogen atom, and ^G23 is a nitro group ( _-NO2 ).

As a preferred embodiment, the chiral reagent has the chemical formula (I'), and ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 arylalkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14} aryl or _{C6-14 arylC1-4 alkyl} .

As a preferred embodiment, the chiral reagent has the chemical formula (I'), and ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 arylalkyl, _{C1-4 alkylC6} aryl, _{C1-4 alkoxyC6} aryl or C6 _{arylC1-4 alkyl} .

As a preferred embodiment, the chiral reagent has the chemical formula (I'), wherein ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl (phenyl). Examples of _C1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 is a hydrogen atom, ^G2 is a group of formula (III), and ^G31 to ^G33 are independently _C1-4 alkyl groups.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), ^G1 is a hydrogen atom, ^G2 is a group of formula (III), ^G31 and ^G33 are _C6 aryl (phenyl), and ^G32 is a _C1-2 alkyl.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), and ^G1 and ^G22 together form a group of formula (IV), and ^G41 to ^G46 are independently hydrogen atom, nitro group, halogen atom, cyano group or _C1-3 alkyl group.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), and ^G1 and ^G2 together form a group of formula (IV), wherein ^G41 to ^G46 are each a hydrogen atom.

As a preferred embodiment, the chiral reagent has the chemical formula (I'), wherein ^G1 is a hydrogen atom, and ^G2 is a group of formula (V). Furthermore, ^G51 to ^G53 are each independently a hydrogen atom, a nitro group, a methyl group, or a methoxy group. As a more preferred embodiment, ^G1 is a hydrogen atom, ^G2 is a group of formula (V), wherein ^G51 and ^G52 are each a hydrogen atom, and ^G53 is a 4-methyl group.

As a preferred embodiment, the chiral reagent is selected from one of 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 (Va)

(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-fluoren-9-yl)((S)-pyrrolidin-2-yl)methanol (XI-a)

(S)-2-p-Toluenesulfonyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a)

(R)-2-p-Toluenesulfonyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b)

Chiral reagents react with nucleic acids or modified nucleic acids to generate asymmetric auxiliary groups. Nucleoside 3'-phosphoramidite derivatives are obtained by reacting chiral reagents with nucleic acids or modified nucleic acids, which are intermediates for producing stereocontrolled phosphorus-modified oligonucleotide derivatives.

A second aspect of the present invention relates to nucleoside 3'-phosphoramidite derivatives represented by formula (Va) or (Vb). Compounds of formula (Va) and (Vb) are referred to as monomers for synthesizing oligonucleotide derivatives. These compounds are also referred to as oxazaphospholidine monomers. The sugar moieties of the compounds represented by formula (Vb) are referred to as BNA and LNA (when R ³ is methylene).

In formulae (Va) and (Vb), G ¹ to G ⁴ are the same as described above, G ⁵ is a protective group for a hydroxyl group, and Bs is selected from the groups represented by formulae (VI) to (XI) or their derivatives.

Examples of Bs are adenine, thymine, cytosine, guanine, uracil, 5-methylcytosine, or derivatives thereof.

R ² is hydrogen, —OH, —SH, —NR ^d R ^d , —N ₃ , halogen, alkyl, alkenyl, alkynyl, alkyl-Y ¹ —, alkenyl-Y ¹ —, alkynyl-Y ¹ —, aryl-Y ¹ —, heteroaryl-Y ¹ —, —OR ^b , or —SR ^b , wherein R ^b is a blocking moiety.

Y ¹ is O, NR ^d , S or Se.

R ^d is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, -P(O)( ^Re ) ₂ , or -HP(O)( ^Re ).

R ^e is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y ² —, alkenyl-Y ² —, alkynyl-Y ² —, aryl-Y ² —, or heteroaryl-Y ² —, or the cation Na ⁺ , Li ⁺ , or K ⁺ .

^Y2 is O, ^NRd or S.

Preferred examples of the alkyl group are C _1-10 alkyl groups, preferred examples of the alkenyl group are C _2-10 alkenyl groups, preferred examples of the alkynyl group are C _2-10 alkynyl groups, preferred examples of the aryl group are C _6-14 aryl groups, and preferred examples of the heteroaryl group are C _6-14 heteroaryl groups.

R ³ is a group represented by -CH ₂ -, -(CH ₂ ) ₂ -, -CH ₂ NH-, or -CH ₂ N(CH ₃ )-.

Examples of G ⁵ are trityl, 4-monomethoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 9-phenylxanthin-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthin-9-yl (MOX).

Bs is adenine, thymine, cytosine, guanine or a derivative thereof. Bs is a nucleobase or a modified nucleobase. Examples of the derivative are disclosed in JP2005-89441A and are represented by the following formula.

In the above formula, ^R8 to ^R10 are each independently _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C1 aryloxy. Preferred examples of ^R8 are methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. Preferred examples of ^R9 and ^R10 are _C1-4 alkyl.

As a preferred embodiment of the second aspect, the nucleoside 3'-phosphoramidite derivative is represented by formula (VA') or (Vb').

In formulae (Va') and (Vb'), ^G1 , ^G2 , ^G5 , Bs, ^R2 and ^R3 are the same as described above. Nucleoside 3'-phosphoramidite derivatives are chiral monomers used to produce stereocontrolled phosphorus-modified nucleotides and oligonucleotide derivatives.

Preferred embodiments of nucleoside 3'-phosphoramidite derivatives are 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. These formulas are described in the Examples section.

DMTr represents a 4,4′-dimethoxytrityl group, and TOM represents a triisopropylsilyloxymethyl group.

For example, Japanese Patent JP2005-89441A discloses an example of using a nucleoside 3'-phosphoramidite derivative. As disclosed therein, the chain of an oligonucleotide derivative can be extended by repeating the steps of a condensation reaction and a deprotection reaction.

The formula of the oligonucleotide derivative is shown as formula (X).

In formula (X), X represents sulfur (=S), C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aralkyl or C ₆ -C ₁₀ aryloxialkyl. Preferably, X represents sulfur (=S). "n" is an integer representing or "n" can be preferably, preferably, and more preferably

A third aspect of the present invention relates to a method for synthesizing stereocontrolled phosphorus-modified oligonucleotide derivatives. The first step is to react a molecule comprising an achiral H-phosphonate moiety with a first activator and a chiral reagent or a salt thereof to form a monomer. The chiral reagent has a chemical formula (I) or (I'), and the monomer can be represented by formula (Va), (Vb), (Va') or (Vb'). The monomer reacts with a second activator and a nucleoside to form a condensation intermediate. The next step is to convert the condensation intermediate into a nucleic acid comprising a chiral X-phosphonate moiety. The method is primarily based on the disclosure of International Publication No. WO2010/064146 pamphlet. That is, the basic steps are disclosed as Path A and Path B therein. The chiral reagent of the present invention is used in the method.

The first illustration involves the synthesis of chiral oligonucleotides.

Activation step

The achiral H-phosphonate moiety is treated with a first activator to form a first intermediate. In one embodiment, the first activator is added to the reaction mixture during the condensation step. The use of the first activator depends on the reaction conditions, such as the solvent used for the reaction. Examples of the first activator are phosgene, trichloromethyl chloroformate, bis(trichloromethyl)carbonate (BTC), oxalyl chloride, _Ph3PCl2 , (PhO) _3PCl2 , N,N'-bis( _{2 -} oxo-3-oxazolidinyl)phosphinyl chloride (BopCl), 1,3-dimethyl-2-(3-nitro-1,2,4-triazol-1-yl)-2-pyrrolidin-1-yl-1,3,2-diazaphosphacyclopentane hexafluorophosphate (MNTP), or 3-nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP).

Examples of achiral H-phosphonate moieties are the compounds shown in the above diagrams. DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene. ^{H +} DBU can be, for example, an ammonium ion, an alkylammonium ion, a heteroiminium ion, or a heterocyclic iminium ion, any of which is a primary, secondary, tertiary, or quaternary, or a monovalent metal ion.

Chiral reagent reaction

After the first activation step, the activated achiral H-phosphonate moiety reacts with a chiral reagent represented by formula (I) or (I') to form a chiral intermediate of formula (Va), (Vb), (Va') or (Vb').

Stereospecific condensation steps

The chiral intermediate of formula Va ((Vb), (Va') or (Vb')) is treated with a second activating agent and a nucleoside to form a condensed intermediate. The nucleoside can be solidified. Examples of the second activating agent are 4,5-dicyanoimidazole (DCI), 4,5-dichloroimidazole, 1-phenylimidazolium trifluoromethanesulfonate (PhIMT), benzimidazole trifluoromethanesulfonate (BIT), benzotriazole, 3-nitro-1,2,4-triazole (NT), tetrazole, 5-ethylthiotetrazole (ETT), 5-benzylmercaptotetrazole (BTT), 5-(4-nitrophenyl)tetrazole, N-cyanomethylpyrrolidinium trifluoromethanesulfonate (CMPT), N-cyanomethylpiperidinium trifluoromethanesulfonate, and N-cyanomethyldimethylammonium trifluoromethanesulfonate. The chiral intermediate of Formula Va ((Vb), (Va'), or (Vb')) can be isolated as a monomer. Typically, the chiral intermediate of Formula Va ((Vb), (Va'), or (Vb')) is not isolated and reacts with a nucleoside or modified nucleoside in the same pot to provide a chiral phosphate compound, i.e., a condensation intermediate. In other embodiments, when the method is performed by solid phase synthesis, the solid support containing the compound can be filtered from byproducts, impurities, and/or reagents.

End-capping step

If the final nucleic acid is larger than a dimer, the unreacted -OH groups are capped with a blocking moiety, and the chiral auxiliary of the compound can also be capped with a blocking moiety to form a capped condensation intermediate. If the final nucleic acid is a dimer, no capping step is required.

Modification steps

The compound is modified by reacting with an electrophilic reagent. The blocked condensation intermediate can undergo a modification step. In some embodiments of the present method, the modification step is performed by using a sulfur electrophilic reagent, a selenium electrophilic reagent, or a boronating agent. Preferred embodiments of the modification step are an oxidation step and a sulfurization step.

In some embodiments of the present methods, the sulfur electrophile is a compound having one of the following formulae:

S ₈ (Formula B), Z ¹ -SSZ ² or Z ¹ -SVZ ² .

Z ¹ and Z ² are independently alkyl, aminoalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, acyl, amide, imide or thiocarbonyl, or Z ¹ and Z ² are combined to form a substituted or unsubstituted three- to eight-membered alicyclic or heterocyclic ring; V is SO ₂ , O or NR ^f ; R ^f is hydrogen, alkyl, alkenyl, alkynyl or aryl.

In some embodiments of the present methods, the sulfur electrophile is a compound having the following formula A, B, C, D, E, or F:

In some embodiments of the present methods, the selenium electrophile is a compound having one of the following formulae:

Se (Formula G), Z ³ -Se-Se-Z ⁴ or Z ³ -Se-VZ ⁴

Z ³ and Z ⁴ are independently alkyl, aminoalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, acyl, amide, imide or thiocarbonyl, or Z ³ and Z ⁴ are combined to form a substituted or unsubstituted three- to eight-membered alicyclic or heterocyclic ring; V is SO ₂ , O or NR ^f ; R ^f is hydrogen, alkyl, alkenyl, alkynyl or aryl.

In some embodiments of the present methods, the selenium electrophile is a compound having the following formula G, H, I, J, K, or L:

In some embodiments of the present method, the boronating agent is borane-N,N-diisopropylethylamine (BH ₃ DIPEA), borane-pyridine (BH ₃ Py), borane-2-chloropyridine (BH ₃ CPy), borane-aniline (BH ₃ An), borane-tetrahydrofuran (BH ₃ THF) or borane-dimethyl sulfide (BH ₃ Me ₂ S).

In some embodiments of the present method, the modification step is an oxidation step. For example, Japanese Patent JP2010-265304A and International Publication No. WO2010/064146 disclose such an oxidation step.

Chain extension cycle and deprotection step

The blocked condensation intermediate is unblocked by removing the blocking moiety at the 5' end of the growing nucleic acid chain, thereby providing a compound. The compound can optionally re-enter the chain extension cycle to form a condensation intermediate, a blocked condensation intermediate, a modified blocked condensation intermediate, and a 5'-end deprotected modified blocked intermediate. After at least one chain extension cycle, the 5'-end deprotected modified blocked intermediate is further unblocked by removing chiral auxiliary ligands and other protecting groups, such as protecting groups for nucleobases, modified nucleobases, sugars, and modified sugars, thereby providing a nucleic acid. In other embodiments, the nucleoside containing a 5'-OH moiety is an intermediate derived from a previous chain extension cycle as described herein. In still other embodiments, the nucleoside containing a 5'-OH moiety is an intermediate derived from other known nucleic acid synthesis methods. In embodiments utilizing a solid support, the phosphorus atom-modified nucleic acid is subsequently cleaved from the solid support. In certain embodiments, the nucleic acid is left attached to the solid support for purification purposes and cleaved from the solid support during a subsequent purification process.

According to the method of the present invention, stable and commercially available materials can be used as starting materials. It is possible to produce stereocontrolled phosphorus-modified oligonucleotide derivatives by using achiral starting materials.

As shown in one example, the method of the present invention does not lead to degradation during the deprotection step. In addition, the method does not require special blocking agents to produce phosphorus-modified oligonucleotide derivatives.

A fourth aspect of the present invention relates to a method for synthesizing stereocontrolled phosphorus-modified oligonucleotide derivatives using chiral monomers. The first step involves reacting a nucleoside 3'-phosphoramidite derivative represented by formula (Va), (Vb), (Va'), or (Vb') with a second activating agent and a nucleoside to form a condensation intermediate. The second step is converting the condensation intermediate into a nucleic acid containing a chiral X-phosphonate moiety.

The second scheme relates to a reaction for synthesizing a chiral oligonucleotide by using a monomer represented by formula Va ((Vb), (Va') or (Vb')). The second scheme is based on the method disclosed in Japanese Patent JP2005-89441A.

The specific conditions in the above diagram are similar to those in the first diagram. The starting materials of Formula Va (Vb), particularly those of Formula Va' (or Vb'), are chemically stable. As shown in one example, the method of the present invention does not result in degradation during the deprotection step. Furthermore, the method does not require special end-capping agents to produce phosphorus-modified oligonucleotide derivatives.

The mechanism used to remove the additive is shown in the figure below:

In the above diagram, Nu represents the nucleophile. The above mechanism is believed to be different from the mechanism previously used for the removal of auxiliary agents.

Example

abbreviation

ac: acetyl

bz: benzoyl

CSO：(1S)-(+)-10-Camphorsulfonazine

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

DCA: dichloroacetic acid

DCM: _{dichloromethane} , _CH2Cl2

DMTr: 4,4'-dimethoxytrityl

Tr: trityl

MeIm: N-methylimidazole

NIS: N-iodosuccinimide

PAC: Phenoxyacetyl

Ph: phenyl

PhIMT: N-phenylimidazole trifluoromethanesulfonic acid

POS: 3-phenyl-1,2,4-dithiazolin-5-one

TBS: tert-butyldimethylsilyl

TBDPS: tert-butyldiphenylsilyl

TOM: triisopropylsiloxymethyl

TFA: trifluoroacetic acid

Example 1

(S)-1-Triphenylmethylpyrrolidine-2-carbaldehyde (I-a)

Compound I-a was synthesized from L-proline according to the procedure described in the literature (Guga, P. Curr. Top. Med. Chem. 2007, 7, 695-713.).

Example 2

(R)-1-Triphenylmethylpyrrolidine-2-carbaldehyde (I-b)

Compound I-b was synthesized from D-proline in a manner similar to the synthesis of compound I-a.

Example 3

(S)-2-(Methyldiphenylsilyl)-1-((S)-1-tritylpyrrolidin-1-yl)ethanol (II-a)

A tetrahydrofuran solution of methyldiphenylsilylmethylmagnesium chloride was prepared from chloromethyldiphenylmethylsilane (4.02 g, 16.3 mmol) and magnesium (402 mg, 16.3 mmol) in tetrahydrofuran (14 mL). A solution of Ia (2.79 g, 8.14 mmol) in tetrahydrofuran (30 mL) was added to the tetrahydrofuran solution of methyldiphenylsilylmethylmagnesium chloride under ice-cooling. After stirring under ice-cooling for 1.5 hours, the mixture was warmed to room temperature and stirred for a further 30 minutes. A saturated aqueous _NH₄Cl solution (100 mL) was added to the reaction mixture at 0°C, and the mixture was extracted three times with diethyl ether (100 mL). The combined extracts were dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel to yield II-a (3.91 g, 87%) as a colorless foam.

¹ H NMR (300MHz, CDCl ₃ )δ7.48-7.08(25H,m),4.33-4.23(1H,m),3.16-2.89(3H,m),2.84(1H,brs),1.70-1.54(1H,m),1.35(1H,dd,J＝14 .7,6.3Hz),1.10(1H,dd,J＝14.7,8.1Hz),1.18-1.05(1H,m),1.04-0.90(1H,m),0.34(3H,s),-0.17--0.36(1H,m).

Example 4

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

Dissolve II-a (3.91 g, 7.06 mmol) in 3% DCA in DCM (70 mL) and stir at room temperature for 10 minutes. 1M NaOH (200 mL) is added to the mixture, and the mixture is extracted three times with DCM (100 mL). The combined extracts are dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure. The residue is chromatographed on silica gel to yield III-a (1.99 g, 90%) as a pale yellow oil.

¹ H NMR (300MHz, CDCl ₃ )δ7.57-7.52(5H,m),7.38-7.33(5H,m),3.77(1H,ddd,J＝8.9,5.4,3.5Hz),3.01(1H,dt,J＝7.4,3.6Hz),2.97-2.79 (2H,m),2.27(2H,brs),1.76-1.53(4H,m),1.38(1H,dd,J＝15.0,9.0Hz),1.24(1H,dd,J＝15.0,5.4Hz),0.65(3H,s); ¹³ CNMR (100.4MHz, CDCl ₃ )δ137.4,137.1,134.6,134.5,129.1,127.8,69.5,64.1,47.0,25.8,24.0,19.6,-3.4. MALDI TOF-MS m/z: calcd for C ₁₉ H ₂₆ NOSi[M+H] ⁺ 312.18, found 312.06.

Example 5

(R)-2-(Methyldiphenylsilyl)-1-(R)-1-tritylpyrrolidin-2-yl)ethanol (II-b)

In a similar manner to obtain compound II-a, using I-b instead of I-a, compound II-b is obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.48-7.12(25H,m),4.33-4.24(1H,m),3.16-2.89(3H,m),2.86(1H,brs),1.69-1.52(1H,m),1.35(1H,dd,J＝14 .4,6.0Hz),1.10(1H,dd,J＝14.4,8.4Hz),1.18-1.05(1H,m),1.03-0.89(1H,m),0.33(3H,s),-0.19--0.39(1H,m); ¹³ C NMR (75.5MHz, CDCl ₃ )δ144.5,137.5,136.8,134.6,134.3,129.8,129.0,127.8,127.7,127.4,126.1,77.9,71.7,65.1,53.5,25.0,24.8,19.6,-4.0. MALDI TOF-MS m/z: C ₃₈ H ₄₀ NOSi [M+H] ⁺ calcd. 554.29, found 554.09.

Example 6

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

In a similar manner to obtain compound III-a, using II-b instead of II-a, compound III-b is obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.58-7.52(5H,m),7.38-7.33(5H,m),3.78(1H,ddd,J＝9.0,5.1,3.6Hz),3.00(1H,dt,J＝7.4,3.3Hz),2.97-2.78 (2H,m),2.19(2H,brs),1.76-1.53(4H,m),1.38(1H,dd,J＝14.6,9.0Hz),1.24(1H,dd,J＝14.6,5.1Hz),0.66(3H,s); ¹³ CNMR (75.5MHz, CDCl ₃ )δ137.5,137.1,134.5,134.4,129.0,127.7,69.2,64.2,46.9,25.8,24.0,19.7,-3.4. MALDI TOF-MS m/z: calcd for C ₁₉ H ₂₆ NOSi[M+H] ⁺ 312.18, found 312.09.

Example 7

(S)-2-(Trimethylsilyl)-1-(S)-1-tritylpyrrolidin-2-yl)ethanol (IV-a)

In a similar manner to that for obtaining compound II-a, using "chloromethyltrimethylsilane" instead of "chloromethyldiphenylmethylsilane", compound IV-a was obtained.

^1H NMR (300 MHz, CDCl ₃ ) δ 7.58-7.51 (5H, m), 7.31-7.14 (10H, m), 4.13 (1H, dt, J=7.5, 3.0 Hz), 3.39-3.31 (1H, m), 3.20-2.99 (2H, m), 2.84 (1H, s), 1.74-1.57 (1H, m), 1.29-1.10 (2H, m), 0.74 (1H, dd, J=14.4, 7.2 Hz), 0.46 (1H, dd, J=14.4, 7.2 Hz), -0.15 (9H, s). MALDI TOF-MS m/z: Calcd. for C ₂₈ H ₃₆ NOSi [M+H] ⁺ 430.26, found 430.09.

Example 8

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

In a similar manner to obtain compound III-a, using IV-a instead of II-a, compound V-a is obtained.

¹ H NMR (300MHz, CDCl ₃ )δ3.76(1H,ddd,J＝8.8,5.7,3.3Hz),3.08(1H,dt,J＝7.8,3.3Hz),3.02-2.87(2H,m),2.48(2H,b rs),1.81-1.58(4H,m),0.83(1H,dd,J＝14.7,8.7Hz),0.68(1H,dd,J＝14.7,6.0Hz),0.05(9H,s); ¹³ C NMR (75.5MHz, CDCl ₃ ) δ 69.6, 64.3, 46.9, 25.8, 23.9, 22.0, -0.8. MALDI TOF-MS m/z: Calcd. for C ₉ H ₂₂ NOSi [M+H] ⁺ 188.15, found 188.00.

Example 9

(R)-2,2-Diphenyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (VI-a)

n-Butyllithium n-BuLi (1.67 M in hexane, 24 mL, 40 mmol) was added dropwise to a solution of diphenylmethane (6.7 mL, 40 mmol) in tetrahydrofuran (36 mL) at room temperature and stirred for 1 hour. A solution of Ia (3.41 g, 10 mmol) in anhydrous tetrahydrofuran (40 mL), repeatedly co-evaporated with toluene, was slowly added to the mixture at 0°C and stirred for 45 minutes. Saturated aqueous _NH₄Cl (100 mL) and diethyl ether (100 mL) were then added, the organic layer separated, and the aqueous layer extracted with diethyl ether (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield VI-a (1.41 g, 28%) as a white foam.

¹ H NMR (300MHz, CDCl ₃ )δ7.45-7.01(23H,m),6.67-6.61(2H,m),4.80(1H,d,J＝10.8Hz),3.63(1H,d,J＝10.8Hz),3.36-3.27(1H,m) ,3.23-3.09(1H,m),3.02-2.89(1H,m),2.66(1H,s),1.90-1.75(1H,m),1.32-1.04(2H,m),0--0.18(1H,m).

Example 10

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

In a similar manner to obtain compound III-a, using VI-a instead of II-a, compound VII-a is obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.44-7.38(2H,m),7.33-7.14(8H,m),4.46(1H,dd,J＝9.9,3.3Hz),3.91(1H,d,J =9.9Hz),3.02-2.88(2H,m),2.81-2.69(1H,m),2.52(2H,brs),1.88-1.56(4H,m); ¹³ C NMR (75.5MHz, CDCl ₃ )d 142.3, 142.0, 128.6, 128.5, 128.4, 128.2, 126.5, 126.4, 73.5, 60.1, 55.8, 46.6, 25.8, 23.4. MALDI TOF-MS m/z: Calcd. for C ₁₈ H ₂₂ NO [M+H] ⁺ 268.17, found 268.06.

Example 11

(S)-2,2-Diphenyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (VI-b)

In a similar manner to compound VI-a, compound VI-b was obtained by using I-b instead of I-a.

¹ H NMR (300MHz, CDCl ₃ )δ7.44-7.37(6H,m),7.30-7.01(17H,m),6.66-6.61(2H,m),4.80(1H,d,J＝10.8Hz),3.63(1H,d,J＝10.8Hz),3.36-3.2 8(1H,m),3.22-3.09(1H,m),3.01-2.89(1H,m),2.66(1H,s),1.90-1.75(1H,m),1.29-1.04(2H,m),0.00--0.19(1H,m); ¹³ C NMR (75.5MHz, CDCl ₃ )d 144.2, 142.9, 141.6, 130.0, 128.5, 128.4, 127.9, 127.8, 127.4, 126.4, 126.2, 77.9, 75.9, 61.9, 55.4, 53.4, 24.7, 24.5. MALDI TOF-MS m/z: Calcd. for C ₃₇ H ₃₆ NO [M+H] ⁺ 510.28, found 510.11.

Example 12

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

In a similar manner to obtain compound VII-a, using VI-b instead of VI-a, compound VII-b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.45-7.14(10H,m),4.45(1H,dd,J＝9.9,3.3Hz),3.91(1H,d,J＝9.9Hz) ,3.00-2.89(2H,m),2.82-2.71(1H,m),2.40(2H,brs),1.87-1.55(4H,m); ¹³ C NMR (75.5MHz, CDCl ₃ ) δ 142.3, 142.0, 128.5, 128.3, 128.1, 126.3, 126.2, 73.4, 60.1, 55.9, 46.5, 25.8, 23.5. MALDI TOF-MS m/z: Calcd _. for _C18H22NO [M+H] ⁺ 268.17, found 268.03.

Example 13

(R)-2-(4-Nitrophenyl)-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (VIII-a)

In a similar manner to obtaining compound VI-a, using "4-nitrobenzyl chloride" instead of "diphenylmethane" to obtain compound VIII-a.

¹ H NMR (300MHz, CDCl ₃ )δ8.09-8.03(2H,m),7.49-7.43(6H,m),7.28-7.09(11H,m),4.23(1H, ddd,J＝8.3,5.6,3.0Hz),3.43-3.33(1H,m),3.23-3.11(1H,m),3.07-2. 96(1H,m),2.83(1H,brs),2.74(1H,dd,J＝13.8,8.4Hz),2.49(1H,dd,J＝13.8,5.1Hz),1.83-1.67(1H,m),1.41-1.17(2H,m),0.27-0.08(1H,m); ^13C NMR (75.5 MHz, CDCl ₃ ) δ 147.3, 146.3, 144.3, 129.8, 129.6, 127.5, 126.3, 123.4, 77.9, 74.8, 63.5, 53.2, 39.5, 25.0, 24.9. MALDITOF-MS m/z: Calcd. for C ₃₁ H ₃₁ N ₂ O ₃ [M+H] ⁺ 479.23, found 479.08.

Example 14

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

In a similar manner to obtain compound VII-a, using VIII-a instead of VI-a, compound IX-a was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (2H, d, J = 8.7 Hz), 7.42 (2H, d, J = 8.7 Hz), 3.86-3.79 (1H, m), 3.16-3.07 (1H, m), 2.99-2.68 (6H, m), 1.84-1.68 (4H, m); ¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 147.4, 146.2, 129.9, 123.2, 72.4, 62.0, 46.6, 40.4, 25.7, 24.4. MALDI TOF-MS m/z: Calcd. for C ₁₂ H ₁₇ N ₂ O ₃ [M+H] ⁺ 237.12, found 237.01.

Example 15

(S)-2-(4-Nitrophenyl)-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (VIII-b)

In a similar manner to obtain compound VIII-a, using I-b instead of I-a, compound VIII-b is obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.09-8.04(2H,m),7.49-7.43(6H,m),7.28-7.09(11H,m),4.22(1H, ddd,J＝8.4,5.6,3.0Hz),3.43-3.33(1H,m),3.24-3.10(1H,m),3.08-2. 94(1H,m),2.81(1H,brs),2.75(1H,dd,J＝14.0,8.1Hz),2.49(1H,dd,J＝14.0,5.1Hz),1.81-1.67(1H,m),1.40-1.16(2H,m),0.26-0.09(1H,m); ^13C NMR (75.5 MHz, CDCl ₃ ) δ 147.3, 144.3, 129.8, 129.6, 129.4, 126.3, 123.5, 77.9, 74.8, 63.5, 53.2, 39.5, 25.0, 24.9. MALDITOF-MS m/z: Calcd. for C ₃₁ H ₃₁ N ₂ O ₃ [M+H] ⁺ 479.23, found 479.08.

Example 16

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

In a similar manner to obtain compound IX-a, using VIII-b instead of VIII-a, compound IX-b was obtained.

¹ H NMR (300MHz, CDCl ₃ )d 8.19-8.13(2H,m),7.45-7.39(2H,m),3.83(1H,ddd,J＝7.7,5.4,3.9Hz),3.14(1H,dt,J＝7.7,3. 9Hz),3.01-2.87(2H,m),2.83(1H,d,J＝3.3Hz),2.81(1H,s),2.62(2H,brs),1.79-1.72(4H,m); ¹³ C NMR (75.5MHz, CDCl ₃ ) δ147.3,146.5,130.0,123.5,72.7,61.7,46.7,40.1,25.8,24.2.MALDI TOF-MS m/z: _{Calcd. for C12H17N2O3 [ M} +H] ⁺ _237.12 , found 237.02.

Example 17

(R)-(9H-fluoren-9-yl)((S)-1-tritylpyrrolidin-2-yl)methanol (X-a)

In a similar manner to obtain compound VI-a, using fluorene instead of diphenylmethane, compound X-a is obtained.

¹ H NMR (300 MHz, CDCl ₃ )δ7.70(1H,d,J＝7.5Hz),7.66(1H,d,J＝7.8Hz),7.55(2H,d,J＝7.5Hz),7.44- 7.09(18H,m),6.87-6.62(1H,m),4.55-4.48(1H,m),4.06(1H,d,J＝7.5Hz),3. 43-3.34(1H,m),3.18-3.06(1H,m),2.98-2.88(1H,m),2.85(1H,brs),1.42-1 .24(1H,m),1.18-1.04(1H,m),0.53-0.39(1H,m),-0.02--0.20(1H,m); MALDI TOF-MS m/z: calcd. for C ₃₇ H ₃₄ NO [M+H] ⁺ 508.26, found 508.12.

Example 18

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

In a similar manner to obtain compound III-a, using X-a instead of II-a, compound XI-a is obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.76(2H,d,J＝7.5Hz),7.68(2H,t,J＝8.0Hz),7.43-7.35(2H,m),7.34-7.25(2H,m),4.28(1H,d,J＝6.3Hz),4.03(1H,dd,J＝6. MALDI TOF-MS m/z: C ₁₈ H ₂₀ NO[M+H] ⁺ Calculated value 266.15, measured value 266.04.

Example 19

(S)-2-(p-Toluenesulfonyl)-1-(S)-1-tritylpyrrolidin-2-yl)ethanol (XII-a)

In a similar manner to obtain compound II-a, using chloromethyl p-toluenesulfone instead of chloromethyldiphenylmethylsilane, compound XII-a was obtained.

¹ H NMR (600MHz, CDCl ₃ )d 7.66(2H,d,J＝8.4Hz),7.48-7.44(6H,m),7.35(2H,d,J＝7.2Hz),7.21-7.13(9H,m),4.39-4.36(1H,m),3.33(1H,s),3.24-3.20(1H, m),3.19-3.10(2H,m),2.98-2.92(2H,m),2.49(3H,s),1.55-1.49(1H,m),1.33-1.26(1H,m),1.12-1.04(1H,m),0.22-0.14(1H,m); ¹³ C NMR (150.9MHz, CDCl ₃ )δ144.6,144.5,136.3,129.9,129.5,128.1,127.5,126.2,78.0,69.1,63.9,60.2,52.6,25.5,24.7,21.7.

Example 20

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

In a similar manner to obtain compound III-a, using XII-a instead of II-a, compound XIII-a is obtained.

¹ H NMR (600MHz, CDCl ₃ )δ7.82(2H,d,J＝8.4Hz),7.37(2H,d,J＝8.4Hz),4.01(1H,ddd,J＝12.0,5.1,3.0Hz),3.32(1H,dd,J＝14.4,3.0Hz),3.25(1H,dd,J＝ 14.4,9.0Hz),3.16(1H,dt,J=7.8,5.1Hz),2.90-2.82(2H,m),2.46(3H,s),2.04(2H,brs),1.78-1.63(3H,m),1.62-1.55(1H,m); ¹³ C NMR (150.9MHz, CDCl ₃ )δ144.5,136.7,129.7,127.7,67.4,61.8,60.1,46.7,25.7,21.4 _{. MALDI} TOF-MS m/z: calcd for _C13H20NO3S [M+H] ⁺ 270.12, found 270.04.

Example 21

(R)-2-p-Toluenesulfonyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XII-b)

In a similar manner to obtain compound XII-a, using I-b instead of I-a, compound XII-b is obtained.

¹ H NMR (600MHz, CDCl ₃ )δ7.66(2H,d,J＝8.4Hz),7.47-7.44(6H,m),7.35(2H,d,J＝7.8Hz),7.21-7.13(9H,m),4.37(1H,dt,J＝8.6,2.4Hz),3.33(1H,s),3.23-3.2 0(1H,m),3.19-3.12(2H,m),2.98-2.92(2H,m),2.49(3H,s),1.56-1.49(1H,m),1.32-1.26(1H,m),1.11-1.03(1H,m),0.23-0.15(1H,m); ¹³ C NMR (150.9MHz, CDCl ₃ ) δ144.6,144.5,136.3,129.9,129.6,128.1,127.6,126.2,78.0,69.1,63.9,60.2,52.6,25.5,24.7,21.7.

Example 22

(R)-2-p-Toluenesulfonyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b)

In a similar manner to obtain compound XIII-a, using XII-b instead of XII-a, compound XIII-b is obtained.

¹ H NMR (600MHz, CDCl ₃ )δ7.82(2H,d,J＝8.4Hz),7.37(2H,d,J＝8.4Hz),4.01(1H,ddd,J＝9.0,5.1,3.0Hz),3.32(1H,dd,J＝14.4,3.0Hz),3.25(1H,dd,J＝ 14.4,9.0Hz),3.17(1H,dt,J＝7.2,5.1Hz),2.89-2.83(2H,m),2.46(3H,s),2.04(2H,brs),1.79-1.64(3H,m),1.62-1.55(1H,m); ¹³ CNMR (150.9MHz, CDCl ₃ )δ144.8,136.6,129.8,127.9,67.7,61.8,60.1,46.8,25.9,25.8,21.6 _. MALDI TOF-MS m/z: calcd _{for C13H20NO3S} [M+H] ⁺ 270.12, found 270.05.

Example 23

Oxazolidinone monomer 3a

III-a (560 mg, 1.80 mmol) was dried by repeated co-evaporation with dry toluene and dissolved in dry ether (0.90 mL) under argon. N-methylmorpholine (400 μL, 3.60 mmol) was added to this solution, and the resulting solution was added dropwise to a solution of _PCl₃ (160 μL, 1.80 mmol) in anhydrous ether (0.90 mL) at 0°C under argon with stirring. The mixture was then warmed to room temperature and stirred for 30 minutes. The resulting N-methylmorpholine hydrochloride was removed by filtration under nitrogen, and the filtrate was concentrated to dryness under reduced pressure to yield a crude 2-chloro-1,3,2-oxazolidinone derivative. The crude material was dissolved in freshly distilled tetrahydrofuran (3.6 mL) to prepare a 0.5 M solution and used without further purification to synthesize the nucleoside 3'-O-oxazolidinone.

5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine (636 mg, 0.84 mmol) was dried by repeated co-evaporation with dry toluene and dissolved in freshly distilled tetrahydrofuran (2.5 mL) under argon. Triethylamine (0.58 mL, 4.2 mmol) was added and the mixture was cooled to -78°C. A 0.5 M solution of the corresponding crude 2-chloro-1,3,2-oxazolidinone derivative in freshly distilled tetrahydrofuran (3.6 mL, 1.80 mmol) was added dropwise via syringe and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous NaHCO ₃ (70 mL) and chloroform (70 mL) were then added and the organic layer was separated and washed with saturated aqueous NaHCO ₃ (2 x 70 mL). The combined aqueous layers were back-extracted with CHCl ₃ (70 mL). The organic layers were combined and purified by _{chromatography} on a saturated silica gel column. _4, dried, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column to give 3a (829 mg, 90%) as a white foam.

¹ H NMR (300MHz, CDCl ₃ )d 8.77(1H,brs),7.99(1H,s),7.54-6.98(24H,m),6.81-6.73(4H,m),6.35(1H,dd,J＝8.0,6.3H z),4.89-4.73(4H,m),4.68(2H,brs),4.05-3.98(1H,m),3.75(6H,s),3.62-3.46(1H,m),3.4 1-3.20(3H,m),3.18-3.04(1H,m),3.08(2H,t,J＝6.6Hz),2.58-2.36(2H,m),1.94-1.59(2H,m ),1.56(1H,dd,J＝15.0,8.7Hz),1.43(1H,dd,J＝15.0,5.7Hz),1.33-1.16(2H,m),0.62(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ153.5 (1P, s).

Example 24

Oxazolidinone monomer 3b

In a similar manner to obtain compound 3a, using III-b instead of III-a, compound 3b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.80(1H,brs),7.96(1H,s),7.54-6.96(24H,m),6.79-6.71(4H,m),6.19(1H,t, J＝6.6Hz),4.90-4.73(4H,m),4.66(2H,brs),4.16-4.08(1H,m),3.76(6H,s),3.60- 3.36(2H,m),3.29(1H,d,J＝3.9Hz),3.27-3.12(2H,m),3.09(2H,t,J＝6.6Hz),2.59- 2.46(1H,m),2.07-1.97(1H,m),1.94-1.41(5H,m),1.36-1.18(1H,m),0.65(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ157.1 (1P, s).

Example 25

Oxazolidinone monomer 1a

In a similar manner to compound 3a, using 5'-O-(DMTr)-6-N-(benzoyl)adenosine instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine, compound 1a was obtained.

¹ H NMR (600MHz, CDCl ₃ )δ8.71(1H,s),8.12(1H,s),8.04(2H,d,J＝7.8Hz),7.62-7.15(23H,m),6.80-6.75(4H,m),6.37(1H,dd,J＝7.8,6.0Hz),4.94-4. 88(1H,m),4.80(1H,ddd,J＝12.0,6.0,5.4Hz),4.07-4.04(1H,m),3.76(6H,s),3.58-3.49(1H,m),3.41-3.34(1H,m),3.33(1H,d d,J＝10.8,4.8Hz),3.25(1H,dd,J＝10.8,4.8Hz),3.13-3.06(1H,m),2.66-2.58(1H,m),2.40-2.35(1H,m),1.91-1.84(1H,m),1. 73-1.66(1H,m),1.56(1H,dd,J＝15.0,9.0Hz),1.44(1H,dd,J＝15.0,5.4Hz),1.47-1.41(1H,m),1.30-1.23(1H,m),0.63(3H,s); ³¹ P NMR (243.0MHz, CDCl ₃ ) δ151.8 (1P, s).

Example 26

Oxazolidinone monomer 1b

In a similar manner to obtain compound 1a, using III-b instead of III-a, compound 1b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ9.06(1H,brs),8.76(1H,s),8.12(1H,s),8.07-7.99(2H,m),7.64-7.14(22H,m),6.83-6 .75(4H,m),6.25(1H,t,J＝6.6Hz),4.86-4.75(2H,m),4.20-4.15(1H,m),3.77(6H,s),3.61 -3.38(2H,m),3.36(1H,dd,J＝10.2,4.2Hz),3.27(1H,dd,J＝10.2,4.2Hz),3.27-3.13(1H,m ),2.71-2.59(1H,m),2.12-2.01(1H,m),1.94-1.42(5H,m),1.36-1.20(1H,m),0.67(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ157.3 (1P, s).

Example 27

Oxazolidinone monomer 2a

In a similar manner to compound 3a, using 5'-O-(DMTr)-4-N-(isobutyryl)cytidine instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine, compound 2a was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.33(1H,brs),8.17(1H,d,J＝7.5Hz),7.52-7.22(19H,m),7.07(1H,d,J＝7.5Hz),6 .88-6.81(4H,m),6.20(1H,t,J＝6.2Hz),4.81-4.64(2H,m),3.93-3.87(1H,m),3.79(6 H,s),3.59-3.43(1H,m),3.39-3.29(3H,m),3.16-3.02(1H,m),2.69-2.52(2H,m),2.1 2-2.00(1H,m),1.91-1.50(3H,m),1.47-1.32(2H,m),1.27-1.16(7H,m),0.60(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ154.8 (1P, s).

Example 28

Oxazolidinone monomer 2b

In a similar manner to obtain compound 2a, using III- instead of III-a, compound 2b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.33(1H,d,J＝7.5Hz),8.23(1H,brs),7.57-7.22(19H,m),7.12(1H,d,J＝7.5Hz),6.88- 6.81(4H,m),6.15(1H,dd,J＝6.6,4.2Hz),4.82-4.63(2H,m),4.03-3.97(1H,m),3.80(6H, s),3.55-3.26(4H,m),3.19-3.05(1H,m),2.59(1H,quintet,J＝6.9Hz),2.39-2.27(1H,m) ,2.21-2.10(1H,m),1.90-1.56(3H,m),1.50-1.32(2H,m),1.26-1.17(7H,m),0.66(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ157.2 (1P, s).

Example 29

Oxazolidinone monomer 4a

In a similar manner to compound 3a, using 5'-O-(DMTr)thymidine instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine, compound 4a was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.58-7.23(21H,m),6.86-6.79(4H,m),6.35(1H,dd,J＝8.1,5.7Hz),4.79-4.67(2H,m),3.83-3 .78(1H,m),3.78(6H,s),3.59-3.43(1H,m),3.34(1H,dd,J＝10.5,2.4Hz),3.35-3.24(1H,m),3.20 (1H,dd,J＝10.5,2.4Hz),3.16-3.02(1H,m),2.36-2.26(1H,m),2.15-2.02(1H,m),1.92-1.77(1H, m),1.74-1.59(1H,m),1.52(1H,dd,J＝14.7,9.0Hz),1.40(3H,s),1.45-1.15(3H,m),0.60(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ153.7 (1P, s).

Example 30

Oxazolidinone monomer 4b

In a similar manner to obtain compound 4a, using III-b instead of III-a, compound 4b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.46(1H,brs),7.59-7.20(20H,m),6.86-6.79(4H,m),6.26(1H,t,J＝6.8Hz),4.78-4 .65(2H,m),4.01-3.95(1H,m),3.78(6H,s),3.55-3.40(1H,m),3.42(1H,dd,J＝10.5,2.7 Hz),3.40-3.28(1H,m),3.22(1H,dd,J＝10.5,3.0Hz),3.19-3.06(1H,m),2.16-1.95(2H ,m),1.90-1.54(3H,m),1.49-1.35(1H,m),1.43(3H,s),1.34-1.17(2H,m),0.67(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ156.2 (1P, s).

Example 31

Oxazolidinone monomer 5a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-methyl-6-N-(benzoyl)adenosine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 5a.

¹ H NMR (300MHz, CDCl ₃ )δ8.66(1H,s),8.13(1H,s),8.03(2H,d,J＝7.2Hz),7.64-7.16(23H,m), 6.79(4H,d,J＝8.7Hz),6.08(1H,d,J＝6.3Hz),4.91-4.81(1H,m),4.77-4. 69(1H,m),4.64-4.57(1H,m),4.15-4.10(1H,m),3.76(6H,s),3.60-3.23 (4H,m),3.35(3H,s),3.14-3.00(1H,m),1.90-1.19(6H,m),0.62(3H,s); ^31P NMR (121.5MHz, CDCl ₃ ) δ155.8 (1P, s).

Example 32

Oxazolidinone monomer 5b

In a similar manner to obtain compound 5a, using III-b instead of III-a, compound 5b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ9.12(1H,brs),8.73(1H,s),8.24(1H,s),8.07-8.01(2H,m),7.62-7.17(22H,m),6.83-6.77(4H,m),6.12(1H,d,J＝4.8Hz),4.84-4.73(2H, m),4.43(1H,t,J=4.8Hz),4.25-4.19(1H,m),3.77(6H,s),3.55-3.20( 4H,m),3.28(3H,s),3.16-3.03(1H,m),1.90-1.17(6H,m),0.65(3H,s); ^31P NMR (121.5MHz, CDCl ₃ ) δ155.0 (1P, s).

Example 33

Oxazolidinone monomer 6a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-methyl-4-N-(isobutyryl)cytidine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to give compound 6a.

¹ H NMR (300MHz, CDCl ₃ )δ8.49(1H,d,J＝7.2Hz),7.58-7.20(19H,m),6.96(1H,d,J＝7.2Hz),6.90-6.82(4H,m),5.98(1 H,s),4.84(1H,dd,J＝13.1,7.5Hz),4.59(1H,dt,J＝8.3,4.5Hz),4.19-4.13(1H,m),3.79(6H,s) ,3.78-3.72(1H,m),3.63-3.40(3H,m),3.55(3H,s),3.36-3.24(1H,m),3.09-2.95(1H,m),2.5 9(1H,septet,J＝6.9Hz),1.85-1.53(5H,m),1.48-1.37(1H,m),1.24-1.17(6H,m),0.59(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ155.2 (1P, s).

Example 34

Oxazolidinone monomer 6b

In a similar manner to obtain compound 6a, using III-b instead of III-a, compound 6b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.62(1H,d,J＝7.5Hz),7.57-7.23(19H,m),7.02(1H,d,J＝7.5Hz),6.89-6.81(4H,m) ,5.92(1H,s),4.90(1H,dt,J＝9.0,5.7Hz),4.61(1H,dt,J＝8.7,4.8Hz),4.25-4.17(1H ,m),3.81(6H,s),3.67(1H,d,J＝4.5Hz),3.62-3.25(4H,m),3.38(3H,s),3.16-3.02(1 H,m),2.58(1H,septet,J＝6.9Hz),1.87-1.40(6H,m),1.26-1.14(6H,m),0.64(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ158.2 (1P, s).

Example 35

Oxazolidinone monomer 7a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-methyl-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 7a.

¹ H NMR (300MHz, CDCl ₃ )δ8.67(1H,brs),8.01(1H,s),7.56-7.16(24H,m),6.83-6.74(4H,m),6.08(1H,d,J＝6.9Hz), 4.85-4.76(1H,m),4.84(2H,t,J＝6.6Hz),4.65-4.56(1H,m),4.59(2H,brs),4.48(1H,dd,J＝6. 6,5.1Hz),4.09-4.05(1H,m),3.75(6H,s),3.60-3.42(2H,m),3.40-3.26(2H,m),3.35(3H,s) ,3.18-3.05(1H,m),3.08(2H,t,J＝6.6Hz),1.89-1.49(3H,m),1.48-1.16(3H,m),0.59(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ156.9 (1P, s).

Example 36

Oxazolidinone monomer 7b

In a similar manner to obtain compound 7a, using III-b instead of III-a, compound 7b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.74(1H,brs),8.09(1H,s),7.56-6.94(24H,m),6.84-6.71(4H,m),6.09(1H,d, J＝4.8Hz),4.83-4.70(2H,m),4.83(2H,t,J＝6.6Hz),4.63(2H,brs),4.35(1H,t,J＝ 5.0Hz),4.23-4.16(1H,m),3.75(6H,s),3.58-3.19(4H,m),3.32(3H,s),3.16-3.0 4(1H,m),3.07(2H,t,J＝6.6Hz),1.90-1.55(3H,m),1.48-1.15(3H,m),0.64(3H,s); ³¹ PNMR(121.5MHz,CDCl ₃ )δ154.6(1P,s).

Example 37

Oxazolidinone monomer 8a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-(methyl)uridine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to give compound 8a.

¹ H NMR (300MHz, CDCl ₃ )δ7.91(1H,d,J＝7.8Hz),7.58-7.20(19H,m),6.88-6.80(4H,m),5.96(1H,d,J＝3 .3Hz),5.19(1H,d,J=7.8Hz),4.88-4.78(1H,m),4.66-4.57(1H,m),4.03-3.95( 1H,m),3.90-3.74(1H,m),3.78(6H,s),3.77-3.71(1H,m),3.58-3.29(2H,m),3. 45(3H,s),3.13-2.82(2H,m),1.88-1.53(3H,m),1.49-1.16(3H,m),0.60(3H,s); ³¹ PNMR(121.5MHz,CDCl ₃ )δ155.3(1P,s).

Example 38

Oxazolidinone monomer 8b

In a similar manner to obtain compound 8a, using III-b instead of III-a, compound 8b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.10(1H,d,J＝8.4Hz),7.58-7.20(19H,m),6.87-6.79(4H,m),5.89(1H,d,J＝1.5Hz ),5.21(1H,d,J=8.4Hz),4.92-4.82(1H,m),4.73-4.63(1H,m),4.15-4.08(1H,m),3. 89-3.73(1H,m),3.78(6H,s),3.66-3.62(1H,m),3.57-3.27(2H,m),3.30(3H,s),3.1 7-2.82(2H,m),1.89-1.55(3H,m),1.55-1.40(1H,m),1.35-1.15(2H,m),0.66(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ157.5 (1P, s).

Example 39

Oxazolidinone monomer 9a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-deoxy-2'-fluoro-6-N-(benzoyl)adenosine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6O-(cyanoethyl)guanosine to give compound 9a.

¹ H NMR (300MHz, CDCl ₃ )δ8.64(1H,s),8.14(1H,s),8.06-8.01(2H,m),7.63-7.07(23H,m),6.78-6.70(4H,m),6.12(1H,dd,J＝18.0,2.4Hz),5.24-5.01(2H,m),4. 94-4.84(1H,m),4.17-4.06(1H,m),3.73(6H,s),3.55-3.40(3H,m),3 .30-3.22(1H,m),3.03-2.88(1H,m),1.92-1.19(6H,m),0.62(3H,s); ^31P NMR (121.5MHz, CDCl ₃ ) δ150.5 (1P, d, J = 7.7Hz).

Example 40

Oxazolidinone monomer 9b

In a similar manner to obtain compound 9a, using III-b instead of III-a, compound 9b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ9.07(1H,brs),8.80(1H,s),8.24(1H,s),8.08-8.01(2H,m),7.66-7.15(22H,m),6.81-6.75(4H,m),6.14(1H,dd,J ＝18.0,1.8Hz),5.16-4.91(3H,m),4.28-4.21(1H,m),3.76(6H,s),3.57-3.11(5H,m),1.82-1.16(6H,m),0.65(3H,s); ³¹ PNMR (121.5MHz, CDCl ₃ ) δ157.8 (1P, d, J = 5.6Hz).

Example 41

Oxazolidinone monomer 10a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-deoxy-2'-fluoro-4-N-(isobutyl)cytidine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 10a.

¹ H NMR (300MHz, CDCl ₃ )δ8.66(1H,brs),8.41(1H,d,J＝7.5Hz),7.55-7.20(19H,m),7.01(1H,d,J＝7.5Hz),6.89-6.81(4H,m ),6.06(1H,d,J＝15.9Hz),4.85(1H,dd,J＝51.4,3.9Hz),4.84(1H,dd,J＝12.9,7.5Hz),4.77-4.59(1H ,m),4.15-4.08(1H,m),3.79(6H,s),3.63-3.29(4H,m),3.10-2.96(1H,m),2.65(1H,septet,J＝6.9H z),1.85-1.53(3H,m),1.48-1.17(3H,m),1.21(3H,d,J＝4.8Hz),1.19(3H,d,J＝4.8Hz),0.59(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ155.5 (1P, d, J = 6.6Hz).

Example 42

Oxazolidinone monomer 10b

In a similar manner to obtain compound 10a, using III-b instead of III-a, compound 10b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.53(1H,d,J＝7.5Hz),7.57-7.23(20H,m),7.10(1H,d,J＝7.5Hz),6.89-6.81(4H,m), 6.10(1H,d,J＝15.9Hz),5.00-4.92(1H,m),4.84(1H,dd,J＝51.5,3.3Hz),4.75-4.58(1H, m),4.24(1H,d,J＝9.3Hz),3.81(6H,s),3.65-3.39(3H,m),3.32-3.06(2H,m),2.59(1H,s eptet,J＝6.9Hz),1.88-1.53(4H,m),1.49-1.34(2H,m),1.27-1.18(6H,m),0.65(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ159.0 (1P, d, J = 4.4).

Example 43

Oxazolidinone monomer 11a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-deoxy-2'-fluoro-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 11a.

¹ H NMR (300MHz, CDCl ₃ )δ8.74(1H,brs),8.03(1H,s),7.55-6.94(24H,m),6.80-6.69(4H,m),6.21(1H,dd ,J＝14.9,3.6Hz),5.34(1H,dt,J＝52.3,3.6Hz),5.01-4.75(2H,m),4.84(1H,t,J＝6. 6Hz),4.62(2H,brs),4.15-4.07(1H,m),3.73(6H,s),3.59-3.29(4H,m),3.15-3.0 0(1H,m),3.07(2H,t,J＝6.6Hz),1.90-1.49(3H,m),1.47-1.12(3H,m),0.58(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ155.6 (1P, d, J = 10.9Hz).

Example 44

Oxazolidinone monomer 11b

In a similar manner to obtain compound 11a, using III-b instead of III-a, compound 11b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.81(1H,brs),8.06(1H,s),7.55-6.95(24H,m),6.77-6.69(4H,m),6.0 6(1H,d,J＝17.1Hz),5.24-5.08(1H,m),5.04-4.80(2H,m),4.87(1H,t,J＝6 .6Hz),4.62(2H,brs),4.25-4.19(1H,m),3.73(6H,s),3.58-3.02(5H,m), 3.10(2H,t,J＝6.6Hz),1.90-1.56(3H,m),1.50-1.15(3H,m),0.63(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ158.0 (1P, d, J = 4.4Hz).

Example 45

Oxazolidinone monomer 12a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-deoxy-2'-fluorouridine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to give compound 12a.

¹ H NMR (300MHz, CDCl ₃ )δ7.85(1H,d,J＝8.1Hz),7.58-7.20(19H,m),6.87-6.79(4H,m),5.98(1H,d,J＝16.5Hz),5.23(1H,d,J＝8.1Hz),4.86-4.61(3H,m),3.99(1H,d, J＝6.9Hz),3.76(6H,d,J＝3.0Hz),3.56-3.34(4H,m),3.10-2.96(1H,m) ,1.88-1.74(1H,m),1.72-1.52(2H,m),1.48-1.16(3H,m),0.61(3H,s); ^31P NMR (121.5MHz, CDCl ₃ ) δ154.3 (1P, d, J = 8.9Hz).

Example 46

Oxazolidinone monomer 12b

In a similar manner to obtain compound 12a, using III-b instead of III-a, compound 12b was obtained.

¹ H NMR (300 MHz, CDCl ₃ )δ8.01(1H,d,J=8.4Hz),7.58-7.20(19H,m),6.87-6.79(4H,m),6.03(1H,d ,J＝16.2Hz),5.29(1H,d,J＝8.4Hz),4.96(1H,dd,J＝13.1,7.5Hz),4.80-4.54 (2H,m),4.15(1H,d,J＝9.0Hz),3.78(6H,s),3.61-3.39(3H,m),3.37-3.25(1 H,m),3.23-3.09(1H,m),1.91-1.56(3H,m),1.51-1.13(3H,m),0.66(3H,s); ^31P NMR (121.5MHz, CDCl ₃ ) δ158.9 (1P, d, J = 4.4Hz).

Example 47

Oxazolidinone monomer 13a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-TOM-6-N-(acetyl)adenosine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to give compound 13a.

¹ H NMR (300MHz, CDCl ₃ )δ8.82(1H,brs),8.49(1H,s),8.10(1H,s),7.58-7.17(19H,m),6.83-6.73(4H, m),6.11(1H,d,J＝6.6Hz),5.15(1H,dd,J＝6.6,5.4Hz),4.98-4.77(4H,m),4.18-4 .11(1H,m),3.76(6H,s),3.59-3.25(4H,m),3.16-3.02(1H,m),2.62(3H,s),1.9 1-1.53(3H,m),1.49-1.18(3H,m),0.96-0.80(3H,m),0.90(18H,s),0.62(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ156.7 (1P, s).

Example 48

Oxazolidinone monomer 13b

In a similar manner to obtain compound 13a, using III-b instead of III-a, compound 13b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.56(1H,brs),8.55(1H,s),8.13(1H,s),7.57-7.17(19H,m),6.82-6.73(4H,m),6.16(1H,d ,J＝5.7Hz),5.06(1H,t,J＝5.6Hz),4.93(1H,d,J＝5.1Hz),4.83(1H,d,J＝5.1Hz),4.81-4.69(2H, m),4.27-4.19(1H,m),3.76(6H,s),3.55-3.40(2H,m),3.33-3.16(2H,m),3.12-2.97(1H,m),2. 63(3H,s),1.88-1.52(3H,m),1.45-1.16(3H,m),0.91-0.79(3H,m),0.86(18H,s),0.64(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ 154.8 (1P, s).

Example 49

Oxazolidinone monomer 14a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-TOM-4-N-(acetyl)cytidine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 14a.

¹ H NMR (300MHz, CDCl ₃ )δ10.04(1H,brs),8.30(1H,d,J＝7.5Hz),7.51-7.21(19H,m),6.99(1H,d,J＝7.5Hz),6.89-6. 81(4H,m),6.12(1H,d,J＝3.3Hz),5.07(1H,d,J＝4.8Hz),5.05(1H,d,J＝4.8Hz),4.84-4.75(1H, m),4.62-4.52(1H,m),4.31-4.25(1H,m),4.08-4.01(1H,m),3.78(6H,d,J＝3.0Hz),3.55-3.2 3(4H,m),3.10-2.96(1H,m),2.24(3H,s),1.84-1.49(3H,m),1.46-0.96(24H,m),0.58(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ156.5 (1P, s).

Example 50

Oxazolidinone monomer 14b

In a similar manner to obtain compound 14a, using III-b instead of III-a, compound 14b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ10.19(1H,brs),8.46(1H,d,J＝7.5Hz),7.54-7.23(19H,m),7.01(1H,d,J＝7.5Hz),6.88- 6.79(4H,m),6.19(1H,d,J＝1.8Hz),5.11(1H,d,J＝4.8Hz),5.07(1H,d,J＝4.8Hz),4.81-4.71 (1H,m),4.60-4.51(1H,m),4.26-4.18(2H,m),3.79(6H,s),3.63-3.55(1H,m),3.48-3.28( 2H,m),3.21-2.94(2H,m),2.26(3H,s),1.81-1.49(3H,m),1.43-0.96(24H,m),0.62(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ156.4 (1P, s).

Example 51

Oxazolidinone monomer 15a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-TOM-2-N-(acetyl)guanosine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 15a.

¹ H NMR (300MHz, CDCl ₃ )δ7.70(1H,s),7.63-7.13(21H,m),6.84-6.76(4H,m),5.77(1H,d,J＝8.4Hz),5.41-5.33(1H,m),4.90(2H,s),4.78-4.68(2H,m),3 .86(1H,brs),3.75(3H,s),3.74(3H,s),3.56-3.41(2H,m),3.32-2.90(3H,m),1.92-1.10(9H,m),0.97-0.87(21H,m),0.52(3H,s); ^31P NMR (121.5MHz, CDCl ₃ )δ158.1(1P,s).

Example 52

Oxazolidinone monomer 15b

In a similar manner to obtain compound 15a, using III-b instead of III-a, compound 15b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.77(1H,s),7.56-7.15(21H,m),6.82-6.75(4H,m),5.86(1H,d,J＝7.5Hz),5. 26-5.17(1H,m),4.95(1H,d,J＝5.4Hz),4.85(1H,d,J＝5.4Hz),4.78-4.71(1H,m), 4.59-4.49(1H,m),4.10-4.05(1H,m),3.74(6H,s),3.52-3.37(2H,m),3.30-3.1 8(1H,m),3.11-2.85(2H,m),1.85-1.15(9H,m),0.93-0.84(21H,m),0.62(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ152.3 (1P, s).

Example 53

Oxazolidinone monomer 16a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-TOM-uridine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to give compound 16a.

¹ H NMR (300MHz, CDCl ₃ )δ7.76(1H,d,J＝8.1Hz),7.55-7.18(20H,m),6.88-6.80(4H,m),6.11(1H,d,J＝6.0Hz),5.32(1H,d,J＝8.1Hz ),4.99(1H,d,J＝5.1Hz),4.93(1H,d,J＝5.1Hz),4.84-4.75(1H,m),4.54-4.46(1H,m),4.38(1H,t,J＝5.7Hz) ,3.87-3.83(1H,m),3.78(3H,s),3.77(3H,s),3.56-3.42(1H,m),3.39-3.28(1H,m),3.36(1H,dd,J＝11.0,2 .7Hz),3.25(1H,dd,J＝11.0,2.7Hz),3.16-3.03(1H,m),1.88-1.12(6H,m),1.08-0.97(21H,m),0.59(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ156.6 (1P, s).

Example 54

Oxazolidinone monomer 16b

In a similar manner to obtain compound 16a, using III-b instead of III-a, compound 16b was obtained.

¹ H NMR (600MHz, CDCl ₃ )δ7.87(1H,d,J=7.8Hz),7.52-7.48(4H,m),7.38-7.21(16H,m),6.83-6 .79(4H,m),6.14(1H,d,J＝4.8Hz),5.33(1H,d,J＝7.8Hz),4.99(1H,d,J＝ 5.4Hz), 4.89 (1H, d, J = 5.4Hz), 4.67 (1H, dd, J = 13.8, 7.2Hz), 4.52 (1H, dt, J = 10.4, 4.8Hz), 4.31 (1H, t, J = 4.8Hz), 4.06-4.03 (1H, m), 3.78 (3H, s) ,3.77(3H,s),3.47(1H,dd,J＝10.4,2.4Hz),3.47-3.39(1H,m),3.22-3. 17(2H,m),3.00(1H,ddd,J＝19.5,10.4,4.8Hz),1.82-1.74(1H,m),1.68- 1.58(1H,m),1.56(1H,dd,J＝14.4,8.4Hz),1.38(1H,dd,J＝14.4,7.2Hz) ,1.31-1.25(1H,m),1.26-1.17(1H,m),1.08-0.98(21H,m),0.63(3H,s); ³¹ PNMR(243.0MHz,CDCl ₃ )δ154.3(1P,s).

Example 55

Oxazolidinone monomer 17a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O,4'-C-methylene-6-N-(benzoyl)adenosine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 17a.

¹ H NMR (300MHz, CDCl ₃ )δ9.10(1H,brs),8.76(1H,s),8.32(1H,s),8.04(2H,d,J＝7.2Hz),7.64-7.18(22H,m),6.84(4H,d,J＝8.7Hz),6.10(1H,s),4.76(1H,d J＝6.9Hz),4.58(1H,s),4.61-4.51(1H,m),3.91(1H,d,J＝7.8Hz),3.77(1H,d,J＝7.8Hz),3.75(6H,s), 3.50(1H,s),3.47-3.33(1H,m),3.31-3.19(1H,m),3.03-2.88(1H,m),1.84-1.09(6H,m),0.51(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ152.9 (1P, s).

Example 56

Oxazolidinone monomer 17b

In a similar manner to obtain compound 17a, using III-b instead of III-a, compound 17b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.81(1H,s),8.30(1H,s),8.07-8.00(2H,m),7.64-7.17(22H,m),6.86-6.79(4H,m),6.12(1H,s),4.81-4.72(1H,m),4.62(1H,d J＝7.2Hz),4.57(1H,s),3.94(1H,d,J＝7.8Hz),3.89(1H,d,J＝7.8Hz),3.77(6H,s),3.48(2H,s),3.46- 3.32(1H,m),3.24-3.13(1H,m),3.10-2.97(1H,m),1.84-1.49(3H,m),1.42-1.09(3H,m),0.58(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ157.3 (1P, s).

Example 57

Oxazolidinone monomer 18a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O,4'-C-methylene-4-N-(isobutyl)-5-methylcytidine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 18a.

¹ H NMR (300MHz, CDCl ₃ )δ7.88(1H,brs),7.58-7.18(20H,m),6.88-6.80(4H,m),5.65(1H,s),4.69-4.60(1H,m),4.52(1 H,d,J＝6.6Hz),4.49(1H,s),3.81-3.74(1H,m),3.75(3H,s),3.73(3H,s),3.64(1H,d,J＝8.1Hz),3 .56(1H,d,J＝11.1Hz),3.53(1H,d,J＝8.1Hz),3.46(1H,d,J＝11.1Hz),3.56-3.40(1H,m),3.32-3. 20(1H,m),3.14-3.00(1H,m),1.85-1.12(6H,m),1.60(3H,s),1.19(6H,d,J＝6.9Hz),0.55(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ155.9 (1P, s).

Example 58

Oxazolidinone monomer 18b

In a similar manner to obtain compound 18a, using III-b instead of III-a, compound 18b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.86(1H,brs),7.56-7.19(20H,m),6.88-6.79(4H,m),5.69(1H,s),4.86-4.76(1H,m),4.46(1H ,s),4.45(1H,d,J＝7.5Hz),3.80-3.75(1H,m),3.79(6H,s),3.74(1H,d,J＝8.1Hz),3.69(1H,d,J＝8. 1Hz),3.51(1H,d,J＝11.1Hz),3.44-3.30(1H,m),3.39(1H,d,J＝11.1Hz),3.29-3.17(1H,m),3.11-2 .97(1H,m),1.86-1.52(3H,m),1.64(3H,s),1.45-1.10(3H,m),1.21(6H,d,J＝6.6Hz),0.62(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ158.2 (1P, s).

Example 59

Oxazolidinone monomer 19a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O,4'-C-methylene-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to obtain compound 19a.

¹ H NMR (300MHz, CDCl ₃ )δ8.71(1H,brs),8.16(1H,s),7.50-7.17(21H,m),7.09-7.01(3H,m),6.86-6.79(4H,m),6.03(1H ,s),4.84(2H,t,J＝6.6Hz),4.72(2H,s),4.68(1H,d,J＝7.2Hz),4.55-4.46(1H,m),4.50(1H,s),3. 90(1H,d,J＝7.8Hz), 3.77(1H,d,J＝7.8Hz), 3.75(6H,s), 3.51(1H,d,J＝10.8Hz), 3.47(1H,d,J＝10. 8Hz),3.45-3.21(2H,m),3.08(2H,t,J＝6.6Hz),3.03-2.89(1H,m),1.80-1.08(6H,m),0.47(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ153.2 (1P, s).

Example 60

Oxazolidinone monomer 19b

In a similar manner to obtain compound 19a, using III-b instead of III-a, compound 19b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.86(1H,brs),8.13(1H,s),7.55-7.17(21H,m),7.08-6.98(3H,m),6.95-6.78(4H,m),6.01(1H, s),4.86(2H,t,J＝6.6Hz),4.82-4.73(1H,m),4.70(2H,s),4.64(1H,d,J＝7.5Hz),4.49(1H,s),3.94 (1H,d,J＝7.8Hz),3.89(1H,d,J＝7.8Hz),3.77(6H,s),3.46(2H,s),3.45-3.30(1H,m),3.24-3.12(1 H,m),3.09(2H,t,J＝6.6Hz),3.09-2.96(1H,m),1.81-1.50(3H,m),1.41-1.06(3H,m),0.58(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ157.4 (1P, s).

Example 61

Oxazolidinone monomer 20a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O,4'-C-methylene-5-methyluridine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to give compound 20a.

¹ H NMR (300MHz, CDCl ₃ )δ7.71(1H,d,J＝0.9Hz),7.50-7.17(20H,m),6.87-6.80(4H,m),5.61(1H,s),4.69-4.60(1H,m) ,4.55(1H,d,J＝6.9Hz),4.41(1H,s),3.74(3H,s),3.73(3H,s),3.64(1H,d,J＝7.8Hz),3.55(1H, d,J＝7.8Hz),3.53(1H,d,J＝10.8Hz),3.46(1H,d,J＝10.8Hz),3.56-3.42(1H,m),3.35-3.24(1H, m),3.13-3.00(1H,m),1.85-1.45(3H,m),1.55(3H,d,J＝0.9Hz),1.41-1.12(3H,m),0.56(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ155.1 (1P, s).

Example 62

Oxazolidinone monomer 20b

In a similar manner to obtain compound 20a, using III-b instead of III-a, compound 20b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.69(1H,s),7.56-7.19(20H,m),6.88-6.79(4H,m),5.66(1H,s),4.87-4.77(1H,m), 4.47(1H,d,J＝7.8Hz), 4.40(1H,s), 3.78(6H,s), 3.74(1H,d,J＝7.8Hz), 3.68(1H,d,J＝7. 8Hz),3.50(1H,d,J＝10.8Hz),3.46-3.32(1H,m),3.39(1H,d,J＝10.8Hz),3.30-3.19(1H ,m),3.12-2.98(1H,m),1.85-1.56(3H,m),1.59(3H,s),1.46-1.12(3H,m),0.63(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ )d 158.1 (1P, s).

Example 63

Oxazolidinone monomer 21a

In a similar manner to compound 3a, 5'-O-(DMTr)-2'-O-methoxyethyl-5-methyluridine was used instead of 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine to give compound 21a.

¹ H NMR (300MHz, CDCl ₃ )δ7.62-7.18(21H,m),6.84(4H,d,J＝8.7Hz),6.07(1H,d,J＝5.7Hz),4.86-4.76(1H,m),4.63-4.54(1H,m),4.20(1H,t,J＝5.4Hz),3.95-3.8 9(1H,m),3.78(6H,s),3.78-3.71(2H,m),3.60-3.48(2H,m),3.44-3. 02(5H,m),3.31(3H,s),1.88-1.15(6H,m),1.35(3H,s),0.58(3H,s); ^31P NMR(121.5MHz,CDCl ₃ )d 156.3(1P,s).

Example 64

Oxazolidinone monomer 21b

In a similar manner to obtain compound 21a, using III-b instead of III-a, compound 21b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.71(1H,d,J＝1.2Hz),7.55-7.22(20H,m),6.86-6.78(4H,m),5.99(1H,d,J＝3.9Hz),4. 78-4.62(2H,m),4.13-4.08(1H,m),4.07-4.02(1H,m),3.77(6H,s),3.77-3.70(1H,m),3. 65-3.56(1H,m),3.52-3.36(4H,m),3.33-3.14(2H,m),3.29(3H,s),3.08-2.94(1H,m),1. 86-1.72(1H,m),1.71-1.55(2H,m),1.30(3H,d,J＝1.2Hz),1.47-1.16(3H,m)0.64(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ155.6 (1P, s).

Example 65

Oxazolidinone monomer 22a

In a similar manner to obtain compound 4a, using VII-a instead of III-a, compound 22a was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.57(1H,d,J＝0.9Hz),7.37-6.94(20H,m),6.87-6.78(4H,m),6.48(1H,dd,J＝8.6,5.7Hz),5.42(1H ,dd,J＝11.0,5.1Hz),4.81-4.71(1H,m),4.02(1H,d,J＝11.0Hz),3.83(1H,d,J＝2.1Hz),3.79(6H,s),3. 61-3.41(2H,m),3.24-3.09(1H,m),3.16(1H,dd,J＝10.8,2.4Hz),3.02(1H,dd,J＝10.8,2.4Hz),2.54- 2.44(1H,m),2.34-2.22(1H,m),1.94-1.79(1H,m),1.74-1.56(1H,m),1.38(3H,s),1.38-1.28(2H,m); ³¹ PNMR(121.5MHz,CDCl ₃ )δ160.9(1P,s).

Example 66

Oxazolidinone monomer 22b

In a similar manner to obtain compound 22a, using VII-b instead of VII-a, compound 22b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ7.57(1H,d,J＝1.5Hz),7.43-7.11(20H,m),6.85-6.78(4H,m),6.48(1H,dd,J＝7.5, 5.7Hz),5.58(1H,dd,J＝11.4,5.1Hz),4.82-4.73(1H,m),4.17-4.02(2H,m),3.78(6H, s),3.56-3.40(3H,m),3.32(1H,dd,J＝10.7,2.4Hz),3.22-3.07(1H,m),2.26-2.04(2 H,m),1.95-1.81(1H,m),1.74-1.56(1H,m),1.40(3H,d,J＝1.5Hz),1.44-1.34(2H,m); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ162.2 (1P, s).

Example 67

Oxazolidinone monomer 23a

In a similar manner to obtain compound 4a, using IX-a instead of III-a, compound 23a was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ9.22(1H,brs),8.05-7.99(2H,m),7.52(1H,d,J＝1.2Hz),7.41-7.19(11H,m),6.87-6 .79(4H,m),6.37(1H,dd,J＝8.4,5.7Hz),4.88-4.75(2H,m),3.86-3.80(1H,m),3.79(6H ,s),3.64-3.49(2H,m),3.27-3.12(3H,m),2.97(2H,d,J＝6.6Hz),2.51-2.41(1H,m),2. 33-2.20(1H,m),2.03-1.75(2H,m),1.72-1.59(1H,m),1.46-1.36(1H,m),1.40(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ157.5 (1P, s).

Example 68

Oxazolidinone monomer 23b

In a similar manner to obtain compound 23a, using IX-b instead of IX-a, compound 23b was obtained.

¹ H NMR (300MHz, CDCl ₃ )δ8.67(1H,brs),8.18-8.11(2H,m),7.57(1H,d,J＝1.2Hz),7.47-7.22(11H,m),6.86-6.79(4H,m ),6.29(1H,t,J＝6.6Hz),4.87(1H,dt,J＝7.5,5.7Hz),4.80-4.72(1H,m),4.11-4.05(1H,m),3.79( 6H,s),3.67-3.47(2H,m),3.43(1H,dd,J＝10.8,2.7Hz),3.27(1H,dd,J＝10.8,2.4Hz),3.25-3.13 (1H,m),3.07-2.99(2H,m),2.19-2.12(2H,m),2.03-1.62(3H,m),1.46-1.30(1H,m),1.41(3H,s); ³¹ P NMR (121.5MHz, CDCl ₃ ) δ158.1 (1P, s).

Example 69

Oxazolidinone monomer 24a

In a similar manner to obtain compound 4a, using XIII-a instead of III-a, compound 24a was obtained.

¹ H NMR (600MHz, CDCl ₃ )δ7.76(2H,d,J＝9.0Hz),7.62(1H,d,J＝1.2Hz),7.40(2H,d,J＝7.2Hz),7.32-7.23(10H,m),6.85(4H,d,J＝8.4Hz),6.4 1(1H,dd,J＝8.4,5.4Hz),4.94(1H,dd,J＝12.3,5.4Hz),4.84-4.79(1H,m),4.03-4.01(1H,m),3.79(6H,s),3.59-3.53 (1H,m),3.52-3.44(2H,m),3.41(1H,dd,J＝14.7,7.2Hz),3.37-3.30(2H,m),3.13(1H,ddd,J＝19.3,10.3,4.1Hz),2.5 0-2.44(1H,m),2.39(3H,s),2.35-2.29(1H,m),1.91-1.72(2H,m),1.64-1.59(1H,m),1.40(3H,s),1.12-1.05(1H,m); ³¹ P NMR (243.0MHz, CDCl ₃ ) δ154.2 (1P, s).

General steps for synthesizing chiral oligonucleotides:

Automated solid-phase synthesis of chiral oligonucleotides was performed according to the cycle shown in Table 1. After synthesis, the resin was treated with 25% aqueous NH ₃ solution (1 mL) at 55°C for 12 hours. The mixture was cooled to room temperature, and the resin was removed by membrane filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in H ₂ O (3 mL) and analyzed by RP-UPLC-MS using a linear gradient elution (0-50%/30 minutes) of acetonitrile in 0.1 M triethylammonium acetate buffer (pH = 7.0) at a column temperature of 50°C and a flow rate of 0.3 mL/min.

Table 1

Comparative Example 1

Oligonucleotides were produced using the compound 25, which represents a conventional monomer. FIG2 shows a graph of the products obtained by Comparative Example 1.

analyze

The monomers in the examples are chemically stable, and the separation rates of the monomers are all over 80%, which is higher than the separation rate of conventional methods.

We synthesized oligonucleotide derivatives using the chiral reagents in the above-described embodiments based on the second general step and the monomers in the above-described embodiments based on the first general step. As shown in Figure 2, conventional monomers can result in incomplete deprotection products, by-products, and failed sequences. On the other hand, as shown in Figure 1, even if failed sequences are generated, the method of the present invention hardly results in incomplete deprotection products and by-products. As can be seen, the method of the present invention can reduce incomplete deprotection products and by-products. Because the present invention can reduce undesirable products, it is easy to separate the target oligonucleotide derivatives.

Claims (216)

1. A chiral reagent or a salt thereof, wherein the chiral reagent has the following chemical formula (I'): Wherein, ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). Wherein, G ³¹ to G ³³ are independently C _1-4 alkyl, C _1-4 alkoxy, C _6-14 aryl, C _7-14 aralkyl, C _1-4 alkyl C _6-14 aryl, C _1-4 alkoxy C _6-14 aryl or C _6-14 aryl C _1-4 alkyl. 2. The chiral reagent or its salt according to claim 1, wherein ^G1 is a hydrogen atom. 3. The chiral reagent or a salt thereof according to any one of claims 1-2, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 _aryl , _{C1-4 alkoxyC6-14} aryl, or _{C6-14 arylC1-4} alkyl. 4. The chiral reagent or a salt thereof according to any one of claims 1-2, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl- _C6 aryl, _C1-4 alkoxy- _C6 aryl, or C6 aryl _{-C1-4 alkyl} . 5. The chiral reagent or a salt thereof according to any one of claims 1-2, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 6. The chiral reagent or a salt thereof according to any one of claims 1-2, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 7. The chiral reagent or a salt thereof according to any one of claims 1-2, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are independently _C6 aryl, and ^G32 is _C1-4 alkyl. 8. The chiral reagent or a salt thereof according to claim 7, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 9. The chiral reagent or its salt according to claim 1, wherein the chiral reagent is (S)-2-(methyldiphenylsilane)-1-((S)-pyrrolidine-2-yl)ethanol. 10. The chiral reagent or a salt thereof according to claim 1, wherein the chiral reagent is (R)-2-(methyldiphenylsilane)-1-((R)-1-pyrrolidine-2-yl)ethanol. 11. The chiral reagent or a salt thereof according to claim 1, wherein the chiral reagent is (S)-2-(trimethylsilane)-1-((S)-1-pyrrolidine-2-yl)ethanol. 12. A nucleoside 3'-phosphoramide derivative, wherein the nucleoside 3'-phosphoramide derivative is represented by the formula (Va') or (Vb'), Wherein ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). Wherein G ³¹ to G ³³ are independently _C1-4 alkyl, _C1-4 alkoxy, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkyl- _C6-14 aryl, _C1-4 alkoxy- _C6-14 aryl, or _C6-14 aryl- _C1-4 alkyl. ^G5 is a protecting group for the hydroxyl group. ^R2 is hydrogen, -OH, -SH, ^-NRdRd , ^-N3 , halogen, _C1-10 alkyl, _C1-10 alkyl- ^Y1- , or _C6-14 aryl _- ^Y1- . ^Y1 is O, ^Rd is hydrogen. The ^R3 is a group represented by _-CH2- , -( _CH2 ) _2- , _-CH2NH- , or _-CH2N ( _CH3 )-, and The Bs are groups selected from those groups or their derivatives represented by formulas (VI) to (XI): 13. The nucleoside 3'-phosphoramide derivative according to claim 12, wherein the nucleoside 3'-phosphoramide derivative is represented by formula (Va'): 14. The nucleoside 3'-phosphoramide derivative according to claim 13, wherein ^G1 is a hydrogen atom. 15. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl, _{C6-14 aryl} , _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14} aryl, or _{C6-14 arylC1-4} alkyl. 16. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl- _C6 aryl, _C1-4 alkoxy- _C6 aryl, or _C6 aryl- _C1-4 alkyl. 17. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 18. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 19. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl and ^G28 is _C1-4 alkyl. 20. The nucleoside 3'-phosphoramide derivative of claim 19, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 21. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^R2 is hydrogen. 22. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^R2 is a halogen. 23. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^R2 is _C6-14 aryl- ^Y1- . 24. The nucleoside 3'-phosphoramide derivative according to claim 14, wherein ^R2 is a _C1-10 alkyl- ^Y1- . 25. The nucleoside 3'-phosphoramide derivative according to any one of claims 12-24, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 26. The nucleoside 3'-phosphoramide derivative according to claim 25, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 27. The nucleoside 3'-phosphoramide derivative according to any one of claims 12-24 and 26, wherein Bs is adenine, thymine, cytosine, guanine or a derivative thereof. 28. The nucleoside 3'-phosphoramide derivative according to claim 27, wherein Bs is selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 29. The nucleoside 3'-phosphoramide derivative according to claim 28, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, or phenoxymethyl. 30. The nucleoside 3'-phosphoramide derivative according to claim 28 or 29, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 31. The nucleoside 3'-phosphoramide derivative according to claim 12, wherein the nucleoside 3'-phosphoramide derivative is represented by formula (Vb'): 32. The nucleoside 3'-phosphoramide derivative according to claim 31, wherein ^G1 is a hydrogen atom. 33. The nucleoside 3'-phosphoramide derivative according to claim 32, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl, _{C6-14 aryl} , _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14} aryl or _{C6-14 arylC1-4} alkyl. 34. The nucleoside 3'-phosphoramide derivative according to claim 32, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl- _C6 aryl, _C1-4 alkoxy- _C6 aryl, or _C6 aryl- _C1-4 alkyl. 35. The nucleoside 3'-phosphoramide derivative according to claim 32, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 36. The nucleoside 3'-phosphoramide derivative according to claim 32, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 37. The nucleoside 3'-phosphoramide derivative according to claim 32, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl and ^G32 is _C1-4 alkyl. 38. The nucleoside 3'-phosphoramide derivative according to claim 37, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 39. The nucleoside 3'-phosphoramide derivative according to any one of claims 31-38, wherein ^R3 is _-CH2- . 40. The nucleoside 3'-phosphoramide derivative according to any one of claims 31-38, wherein ^R3 is -( _CH2 ) _2- . 41. The nucleoside 3'-phosphoramide derivative according to any one of claims 31-38, wherein ^R3 is _-CH2NH- . 42. The nucleoside 3'-phosphoramide derivative according to any one of claims 31-38, wherein ^R3 is _-CH2N ( _CH3 )-. 43. The nucleoside 3'-phosphoramide derivative according to any one of claims 31-38, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 44. The nucleoside 3'-phosphoramide derivative according to claim 43, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 45. The nucleoside 3'-phosphoramide derivative according to any one of claims 31-38 and 44, wherein Bs is adenine, thymine, cytosine, guanine or a derivative thereof. 46. The nucleoside 3'-phosphoramide derivative according to claim 45, wherein Bs is selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 47. The nucleoside 3'-phosphoramide derivative according to claim 46, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, or phenoxymethyl. 48. The nucleoside 3'-phosphoramide derivative according to claim 46 or 47, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 49. A nucleoside 3'-phosphoramide derivative, which is selected from the following compounds: Wherein DMTr represents 4,4'-dimethoxytriphenylmethyl. 50. A method for synthesizing stereocontrolled phosphorus-modified oligonucleotide derivatives, comprising providing a chiral reagent or a salt thereof, said chiral reagent having the following chemical formula (I’): Wherein ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). G ³¹ to G ³³ are independently C _1-4 alkyl, C _1-4 alkoxy, C _6-14 aryl, C _7-14 aralkyl, C _1-4 alkyl C _6-14 aryl, C _1-4 alkoxy C _6-14 aryl, or C _6-14 aryl C _1-4 alkyl. 51. A method for synthesizing stereo-controlled phosphorus-modified oligonucleotide derivatives, wherein the method comprises the following steps: A molecule containing a non-chiral H-phosphonate moiety reacts with a chiral reagent or its salt to generate a monomer of a nucleoside 3'-phosphamide derivative; Monomers react with nucleosides to form condensation intermediates; and The condensation intermediate is converted into a nucleic acid containing a chiral X-phosphonate moiety. Wherein, ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). Wherein, G ³¹ to G ³³ are independently C _1-4 alkyl, C _1-4 alkoxy, C _6-14 aryl, C _7-14 aralkyl, C _1-4 alkyl C _6-14 aryl, C _1-4 alkoxy C _6-14 aryl or C _6-14 aryl C _1-4 alkyl. 52. The method according to any one of claims 50-51, wherein ^G1 is a hydrogen atom. 53. The method according to claim 52, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14 aryl} or _{C6-14 arylC1-4} alkyl. 54. The method according to claim 52, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl- _C6 aryl, _C1-4 alkoxy- _C6 aryl or _C6 aryl- _C1-4 alkyl. 55. The method according to claim 52, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 56. The method according to claim 52, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 57. The method according to claim 52, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl and ^G32 is _C1-4 alkyl. 58. The method according to claim 57, wherein ^G2 is a group of formula (III), and wherein the _C1-4 alkyl group is methyl. 59. The method according to claim 50 or 51, wherein the chiral reagent is (S)-2-(methyldiphenylsilane)-1-((S)-pyrrolidine-2-yl)ethanol. 60. The method according to claim 50 or 51, wherein the chiral reagent is (R)-2-(methyldiphenylsilane)-1-((R)-1-pyrrolidine-2-yl)ethanol. 61. The method according to claim 50 or 51, wherein the chiral reagent is (S)-2-(trimethylsilane)-1-((S)-1-pyrrolidine-2-yl)ethanol. 62. A method for synthesizing stereo-controlled phosphorus-modified oligonucleotide derivatives, wherein the method comprises the following steps: Nucleoside 3'-phosphamide derivatives represented by formula (Va') or (Vb') react with an activator and a nucleoside to generate a condensation intermediate; and the condensation intermediate is converted into a nucleic acid containing a chiral X-phosphonate moiety. Wherein ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). Wherein G ³¹ to G ³³ are independently C _1-4 alkyl, C _1-4 alkoxy, C _6-14 aryl, C _7-14 aralkyl, C _1-4 alkyl-C _6-14 aryl, C _1-4 alkoxy-C _6-14 aryl, or C _6-14 aryl-C _1-4 alkyl. ^G5 is a protecting group for the hydroxyl group. ^R2 is hydrogen, -OH, -SH, ^-NRdRd , ^-N3 , halogen, _C1-10 alkyl, _C1-10 alkyl- ^Y1- , or _C6-14 aryl _- ^Y1- . ^Y1 is O, ^Rd represents a hydrogen atom. ^R3 is a group represented by _-CH2- , -( _CH2 ) _2- , _-CH2NH- or _-CH2N ( _CH3 )-, and Bs is a group selected from the groups or derivatives thereof represented by the following formulas (VI) to (XI): 63. The method according to claim 62, wherein the nucleoside 3'-phosphoramide derivative is represented by formula (Va'): 64. The method for synthesis according to claim 63, wherein ^G1 is a hydrogen atom. 65. The method according to claim 64, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14 aryl} or _{C6-14 arylC1-4} alkyl. 66. The method according to claim 64, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl-C6 aryl, _C1-4 alkoxy- _C6 aryl or _C6 aryl _{-C1-4 alkyl} . 67. The method according to claim 64, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 68. The method according to claim 64, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 69. The method according to claim 64, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl and ^G32 is _C1-4 alkyl. 70. The method according to claim 69, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 71. The method of claim 64, wherein ^R2 is hydrogen. 72. The method of claim 64, wherein ^R2 is a halogen. 73. The method of claim 64, wherein ^R2 is _C6-14 aryl- ^Y1- . 74. The method of claim 64, wherein ^R2 is a _C1-10 alkyl- ^Y1- . 75. The method according to any one of claims 62-74, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 76. The method of claim 75, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 77. The method according to any one of claims 62-74 and 76, wherein Bs is adenine, thymine, cytosine, guanine, or a derivative thereof. 78. The method of claim 77, wherein Bs is selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 79. The method of claim 78, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. 80. The method according to claim 78 or 79, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 81. The method according to claim 62, wherein the nucleoside 3'-phosphoramide derivative is represented by formula (Vb'): 82. The method according to claim 81, wherein ^G1 is a hydrogen atom. 83. The method according to claim 82, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14 aryl} or _{C6-14 arylC1-4} alkyl. 84. The method according to claim 82, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl- _C6 aryl, _C1-4 alkoxy- _C6 aryl or _C6 aryl- _C1-4 alkyl. 85. The method according to claim 82, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 86. The method according to claim 82, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 87. The method according to claim 82, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl and ^G32 is _C1-4 alkyl. 88. The method of claim 87, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 89. The method according to any one of claims 81-88, wherein ^R3 is _-CH2- . 90. The method according to any one of claims 81-88, wherein ^R3 is -( _CH2 )2-. 91. The method according to any one of claims 81-88, wherein ^R3 is _-CH2NH- . 92. The method according to any one of claims 81-88, wherein ^R3 is _-CH2N ( _CH3 )-. 93. The method according to any one of claims 81-88, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 94. The method of claim 93, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 95. The method according to any one of claims 81-88 and 94, wherein Bs is adenine, thymine, cytosine, guanine, or a derivative thereof. 96. The method of claim 95, wherein Bs is selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 97. The method of claim 96, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. 98. The method according to claim 96 or 97, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 99. A method for synthesizing stereo-controlled phosphorus-modified oligonucleotide derivatives, wherein the method comprises the following steps: A nucleoside 3'-phosphoramide derivative is reacted with an activator and a nucleoside to generate a condensation intermediate; and the condensation intermediate is converted into a nucleic acid containing a chiral X-phosphonate moiety, wherein the nucleoside 3'-phosphoramide derivative is a compound selected from the following: Wherein DMTr represents 4,4'-dimethoxytriphenylmethyl. 100. A compound formed by reacting a nucleoside 3'-phosphoramide derivative with an activator and a nucleoside, wherein the nucleoside 3'-phosphoramide derivative has a structure of formula (Va') or (Vb'): Wherein ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). Wherein G ³¹ to G ³³ are independently C _1-4 alkyl, C _1-4 alkoxy, C _6-14 aryl, C _7-14 aralkyl, C _1-4 alkyl-C _6-14 aryl, C _1-4 alkoxy-C _6-14 aryl, or C _6-14 aryl-C _1-4 alkyl. ^G5 is a protecting group for the hydroxyl group. ^R2 is hydrogen, -OH, -SH, ^-NRdRd , ^-N3 , halogen, _C1-10 alkyl, _C1-10 alkyl- ^Y1- , or _C6-14 aryl _- ^Y1- . ^Y1 is O, ^Rd represents a hydrogen atom. ^R3 is a group represented by _-CH2- , -( _CH2 ) _2- , _-CH2NH- , or _-CH2N ( _CH3 )-, and Bs is a group selected from the groups or derivatives thereof represented by the following formulas (VI) to (XI): 101. The compound according to claim 100, wherein the nucleoside 3'-phosphoramide derivative is represented by formula (Va'): 102. The compound according to claim 101, wherein ^G1 is a hydrogen atom. 103. The compound according to claim 102, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14 aryl} or _{C6-14 arylC1-4} alkyl. 104. The compound according to claim 102, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl- _C6 aryl, _C1-4 alkoxy- _C6 aryl or _C6 aryl- _C1-4 alkyl. 105. The compound according to claim 102, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 106. The compound according to claim 102, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 107. The compound according to claim 102, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl, and ^G32 is _C1-4 alkyl. 108. The compound according to claim 107, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 109. The compound of claim 108, wherein G ³¹ and G ³³ are phenyl. 110. The compound according to claim 102, wherein ^R2 is hydrogen. 111. The compound according to claim 102, wherein ^R2 is a halogen. 112. The compound according to claim 102, wherein ^R2 is _C6-14 aryl- ^Y1- . 113. The compound according to claim 102, wherein ^R2 is a _C1-10 alkyl- ^Y1- . 114. The compound according to any one of claims 100-113, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 115. The compound according to claim 114, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 116. The compound according to any one of claims 100-113 and 115, wherein Bs is adenine, thymine, cytosine, guanine, or a derivative thereof. 117. The compound according to claim 116, wherein Bs is selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 118. The compound of claim 117, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. 119. The compound according to claim 117 or 118, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 120. The compound according to claim 100, wherein the nucleoside 3'-phosphoramide derivative is represented by formula (Vb'): 121. The compound according to claim 120, wherein ^G1 is a hydrogen atom. 122. The compound according to claim 121, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14 aryl} or _{C6-14 arylC1-4} alkyl. 123. The compound according to claim 121, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl- _C6 aryl, _C1-4 alkoxy- _C6 aryl or _C6 aryl- _C1-4 alkyl. 124. The compound according to claim 121, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 125. The compound according to claim 121, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 126. The compound according to claim 121, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl and ^G32 is _C1-4 alkyl. 127. The compound according to claim 126, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 128. The compound of claim 127, wherein G ³¹ and G ³³ are phenyl. 129. The compound according to any one of claims 120-128, wherein ^R3 is _-CH2- . 130. The compound according to any one of claims 120-128, wherein ^R3 is -( _CH2 ) _2- . 131. The compound according to any one of claims 120-128, wherein ^R3 is _-CH2NH- . 132. The compound according to any one of claims 120-128, wherein ^R3 is _-CH2N ( _CH3 )-. 133. The compound according to any one of claims 120-128, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 134. The compound according to claim 133, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 135. The compound according to any one of claims 120-128, wherein Bs is adenine, thymine, cytosine, guanine, or a derivative thereof. 136. The compound according to claim 135, wherein Bs is selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 137. The compound of claim 136, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. 138. The compound according to claim 136 or 137, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 139. The compound of claim 135, wherein the nucleoside 3'-phosphoramide derivative reacts with an activator and a nucleoside located on a solid support. 140. An oligonucleotide having the following structure on a solid support: in: Wherein ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). Wherein G ³¹ to G ³³ are independently C _1-4 alkyl, C _1-4 alkoxy, C _6-14 aryl, C _7-14 aralkyl, C _1-4 alkyl-C _6-14 aryl, C _1-4 alkoxy-C _6-14 aryl, or C _6-14 aryl-C _1-4 alkyl. ^G3 and ^G4 , together with their spacer atoms, form a pyrrolidinyl ring. ^G5 is a protecting group for the hydroxyl group. ^R2 is hydrogen, -OH, -SH, ^-NRdRd , ^-N3 , halogen, _C1-10 alkyl, _C1-10 alkyl- ^Y1- , or _C6-14 aryl _- ^Y1- . ^Y1 is O, ^Rd represents a hydrogen atom. Each Bs is independently a group selected from the groups or their derivatives represented by the following formulas (VI) to (XI): 141. The oligonucleotide of claim 140, wherein ^G1 is a hydrogen atom. 142. The oligonucleotide according to claim 141, wherein ^G2 is a group of formula ( _III ), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14} aryl, or _{C6-14 arylC1-4} alkyl. 143. The oligonucleotide according to claim 141, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl-C6 aryl, _C1-4 alkoxy- _C6 aryl or _C6 aryl _{-C1-4 alkyl} . 144. The oligonucleotide according to claim 141, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 145. The oligonucleotide according to claim 141, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 146. The oligonucleotide according to claim 141, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl and ^G32 is _C1-4 alkyl. 147. The oligonucleotide of claim 146, wherein ^G2 is a group of formula (III), and wherein the _C1-4 alkyl group is methyl. 148. The oligonucleotide of claim 147, wherein ^G2 is a group of formula (III), and wherein ^G31 and ^G33 are phenyl groups. 149. The oligonucleotide of claim 141, wherein ^R2 is hydrogen. 150. The oligonucleotide of claim 141, wherein ^R2 is a halogen. 151. The oligonucleotide of claim 141, wherein ^R2 is _C6-14 aryl- ^Y1- . 152. The oligonucleotide of claim 141, wherein ^R2 is a _C1-10 alkyl- ^Y1- . 153. The oligonucleotide according to any one of claims 140-152, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 154. The oligonucleotide of claim 153, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 155. The oligonucleotide according to any one of claims 140-152 and 154, wherein Bs is independently adenine, thymine, cytosine, guanine, or a derivative thereof. 156. The oligonucleotide of claim 155, wherein each Bs is independently selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 157. The oligonucleotide of claim 156, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. 158. The oligonucleotide according to claim 156 or 157, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 159. An oligonucleotide having the following structure on a solid support: in: Wherein ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). Wherein G ³¹ to G ³³ are independently C _1-4 alkyl, C _1-4 alkoxy, C _6-14 aryl, C _7-14 aralkyl, C _1-4 alkyl-C _6-14 aryl, C _1-4 alkoxy-C _6-14 aryl, or C _6-14 aryl-C _1-4 alkyl. ^G3 and ^G4 , together with their spacer atoms, form a pyrrolidinyl ring. ^G5 is a protecting group for the hydroxyl group. X is O or S. ^R2 is hydrogen, -OH, -SH, ^-NRdRd , ^-N3 , halogen, _C1-10 alkyl, _C1-10 alkyl- ^Y1- , or _C6-14 aryl _- ^Y1- . ^Y1 is O, ^Rd represents a hydrogen atom. Each Bs is independently a group selected from the groups or their derivatives represented by the following formulas (VI) to (XI): 160. The oligonucleotide of claim 159, wherein X is S. 161. The oligonucleotide of claim 159, wherein X is O. 162. The oligonucleotide of claim 160, wherein ^G1 is a hydrogen atom. 163. The oligonucleotide according to claim 160, wherein ^G2 is a group of formula ( _III ), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14} aryl, or _{C6-14 arylC1-4} alkyl. 164. The oligonucleotide according to claim 160, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl-C6 aryl, _C1-4 alkoxy- _C6 aryl, or _{C6 aryl} - _C1-4 alkyl. 165. The oligonucleotide according to claim 160, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 166. The oligonucleotide according to claim 160, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 167. The oligonucleotide according to claim 160, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl groups and ^G32 is a _C1-4 alkyl group. 168. The oligonucleotide of claim 167, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 169. The oligonucleotide of claim 168, wherein ^G2 is a group of formula (III), and wherein ^G31 and ^G33 are phenyl groups. 170. The oligonucleotide of claim 160, wherein ^R2 is hydrogen. 171. The oligonucleotide of claim 160, wherein ^R2 is a halogen. 172. The oligonucleotide of claim 160, wherein ^R2 is _C6-14 aryl- ^Y1- . 173. The oligonucleotide of claim 160, wherein ^R2 is a _C1-10 alkyl- ^Y1- . 174. The oligonucleotide according to any one of claims 159-173, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 175. The oligonucleotide of claim 174, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 176. The oligonucleotide according to any one of claims 159-173 and 175, wherein Bs is independently adenine, thymine, cytosine, guanine, or a derivative thereof. 177. The oligonucleotide of claim 176, wherein each Bs is independently selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 178. The oligonucleotide of claim 177, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. 179. The oligonucleotide of claim 177 or 178, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 180. An oligonucleotide having the following structure on a solid support: in: Wherein ^G1 and ^G2 are independently hydrogen atoms or groups of formula (III), provided that at least one of ^G1 and ^G2 is a group of formula (III). Wherein G ³¹ to G ³³ are independently C _1-4 alkyl, C _1-4 alkoxy, C _6-14 aryl, C _7-14 aralkyl, C _1-4 alkyl-C _6-14 aryl, C _1-4 alkoxy-C _6-14 aryl, or C _6-14 aryl-C _1-4 alkyl. ^G3 and ^G4 , together with their spacer atoms, form a pyrrolidinyl ring. ^G5 is a protecting group for the hydroxyl group. X is O or S. n is 1-150, ^R2 is hydrogen, -OH, -SH, ^-NRdRd , ^-N3 , halogen, _C1-10 alkyl, _C1-10 alkyl- ^Y1- , or _C6-14 aryl _- ^Y1- . ^Y1 is O, ^Rd represents a hydrogen atom. Each Bs is independently a group selected from the groups or their derivatives represented by the following formulas (VI) to (XI): 181. The oligonucleotide of claim 180, wherein X is S. 182. The oligonucleotide of claim 180, wherein X is O. 183. The oligonucleotide of claim 181, wherein n is 2-100. 184. The oligonucleotide of claim 181, wherein n is 10-100. 185. The oligonucleotide of claim 181, wherein n is 10-50. 186. The oligonucleotide of claim 181, wherein n is 15-30. 187. The oligonucleotide of claim 181, wherein ^G1 is a hydrogen atom. 188. The oligonucleotide according to claim 181, wherein ^G2 is a group of formula ( _III ), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6-14 aryl, _C7-14 aralkyl, _C1-4 alkylC6-14 aryl, _{C1-4 alkoxyC6-14} aryl, or _{C6-14 arylC1-4} alkyl. 189. The oligonucleotide according to claim 181, wherein ^G2 is a group of formula (III), wherein ^G31 to ^G33 are independently _C1-4 alkyl, _C6 aryl, _C7-10 aralkyl, _C1-4 alkyl-C6 aryl, _C1-4 alkoxy- _C6 aryl or _C6 aryl _{-C1-4 alkyl} . 190. The oligonucleotide according to claim 181, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl or _C6 aryl. 191. The oligonucleotide according to claim 181, wherein ^G2 is a group of formula (III), and wherein ^G31 to ^G33 are independently _C1-4 alkyl groups. 192. The oligonucleotide according to claim 181, wherein ^G2 is a group of formula (III), wherein ^G31 and ^G33 are _C6 aryl and ^G32 is _C1-4 alkyl. 193. The oligonucleotide of claim 192, wherein ^G2 is a group of formula (III), and wherein _C1-4 alkyl is methyl. 194. The oligonucleotide of claim 193, wherein ^G2 is a group of formula (III), and wherein ^G31 and ^G33 are phenyl groups. 195. The oligonucleotide of claim 181, wherein ^R2 is hydrogen. 196. The oligonucleotide of claim 181, wherein ^R2 is a halogen. 197. The oligonucleotide of claim 181, wherein ^R2 is _C6-14 aryl- ^Y1- . 198. The oligonucleotide of claim 181, wherein ^R2 is a _C1-10 alkyl- ^Y1- . 199. The oligonucleotide according to any one of claims 180-198, wherein ^G5 is triphenylmethyl, 4-monomethoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 9-phenylxanthine-9-yl or 9-(p-methoxyphenyl)xanthine-9-yl. 200. The oligonucleotide of claim 199, wherein ^G5 is 4,4'-dimethoxytriphenylmethyl. 201. The oligonucleotide according to any one of claims 180-198 and 200, wherein Bs is independently adenine, thymine, cytosine, guanine, or a derivative thereof. 202. The oligonucleotide of claim 201, wherein each Bs is independently selected from: Each of ^R8 to ^R10 is independently a _C1-10 alkyl, _C6 - _C10 aryl, _C6 - _C10 aralkyl, or _C6 - _C10 aryloxyalkyl. 203. The oligonucleotide of claim 202, wherein ^R8 is methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. 204. The oligonucleotide according to claim 202 or 203, wherein ^R9 and ^R10 are _C1-4 alkyl groups. 205. The method according to any one of claims 50-51 and 53-58, wherein the product is an oligonucleotide according to any one of claims 140-152, 154, 156 and 157. 206. The method according to any one of claims 50-51 and 53-58, wherein the product is an oligonucleotide according to any one of claims 159-173, 175, 177 and 178. 207. The method according to any one of claims 50-51 and 53-58, wherein the product is an oligonucleotide according to any one of claims 180-198, 200, 202 and 203. 208. The method according to any one of claims 62-74, 76, 78 and 79, wherein the product is an oligonucleotide according to any one of claims 140-152, 154, 156 and 157. 209. The method according to any one of claims 62-74, 76, 78 and 79, wherein the product is an oligonucleotide according to any one of claims 159-173, 175, 177 and 178. 210. The method according to any one of claims 62-74, 76, 78 and 79, wherein the product is an oligonucleotide according to any one of claims 180-198, 200, 202 and 203. 211. The oligonucleotide according to any one of claims 140-152, 154, 156 and 157, prepared by any one of claims 50-51 and 53-58. 212. The oligonucleotide of any one of claims 159-173, 175, 177 and 178, prepared by any one of claims 50-51 and 53-58. 213. The oligonucleotide according to any one of claims 180-198, 200, 202 and 203, prepared by any one of claims 50-51 and 53-58. 214. The oligonucleotide according to any one of claims 140-152, 154, 156 and 157, prepared by the method according to any one of claims 62-74, 76, 78 and 79. 215. The oligonucleotide according to any one of claims 159-173, 175, 177 and 178, prepared by any one of claims 62-74, 76, 78 and 79. 216. The oligonucleotide according to any one of claims 180-198, 200, 202 and 203, prepared by any one of claims 62-74, 76, 78 and 79.