Asymmetric auxiliary group

Abstract

Abstract To provide a chiral reagent or a salt thereof. The chiral reagent has following chemical formula (I). In the formula (I), G1 and G2 are inde pendently a hydrogen atom, a nitro group (-NO 2), a halogen atom, a cyano group (-CN), a group of formula (II) or (III), or both G1 and G2 taken together to form a group of formula (IV). HO HN-G4 H G2 G(I2 Abstract 20 Mar 2023 2023201700 H (I) G³ G¹ G²

Description

Description Title of Invention: ASYMMETRIC AUXILIARY GROUP FIELD OF THE INVENTION The present invention is directed to a chiral reagent that is used to synthesize stereo- controlled phosphorus atom-modified oligonucleotide derivatives. BACKGROUND OF THE INVENTION JP 2005-89441 A discloses a method for producing a derivative of nucleotides called an oxazaphospholidine method. However, the isolate yield of the monomers is low and the method requires special capping agents that are not commercially available. Further obtained monomers are chemically unstable. Furthermore, the isolate yields of oligonucleotide derivatives are not high. It is thought that the low yield of oligonu- cleotide derivatives is caused by the degradation reactions under the de-protection steps. WO02010 / 064146 pamphlet discloses a method for producing a derivative of nu- cleotides. The method disclosed therein requires special capping agents that are not commercially available. Furthermore, the isolate yields of oligonucleotide derivatives are not high. The low yield is thought to be caused by the degradation reactions under the de-protection steps. This tendency becomes strongly apparent when the length of oligonucleotide derivatives becomes long. ‘W02012 / 039448 pamphlet discloses Asymmetric auxiliary group which is used to produce stereocontrolled phosphorus atom-modified oligonucleotide derivatives. Citation List Patent Literature [Patent Literature 1] JP 2005-89441 A [Patent Literature 2] W02010 / 064146 A [Patent Literature 3] W02012 / 039448 A SUMMARY OF THE INVENTION The first Aspect of the Invention relates to a chiral reagent or a salt thereof. The chiral reagent has following chemical formula (I). HO HN—G* \ a I) ~ G3 H 1 G2 In the formula (I), G' and G? are independently a hydrogen atom, a nitro group (-NO, ), a halogen atom, a cyano group (-CN), a group of formula (II), (III) or (V), or both G! and G2? taken together to form a group of formula (IV). a?! == (1) Nu cB 2 G22 In the formula (II), G? to G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group. a3 LSi—@G32 (ID) G3 In the formula (IIT), G3! to G3 are independently C, alkyl group, Ce.14 aryl group C4 alkoxy group, C.,4 aralkyl group, C,.4 alkyl Ce 4 aryl group, C,.4 alkoxy Cs.4 aryl group, or Ce.14 aryl C,.4 alkyl group. cM av) ary r 5” vo 44 In the formula (IV), G* to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.2 alkyl group. a5? 0 =|=\ (V) —8— 7 { lew" Je In the formula (V), G*! to G are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, C,.; alkyl group or C,.; alkyloxy group. G? and G* are independently a hydrogen atom, C,.; alkyl group, Cs. aryl group, or both G3 and G* taken together to form a heteroatom-containing ring that has 3 to 16 carbon atoms, together with the NH moiety in formula (I). A preferred embodiment is that the chiral reagent has following chemical formula {[T). HO HN— A a oN mm H oT, G? In the formula (I'), G! and G? are same as above. Namely, G' and G2 are inde- pendently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II) or (III), or both G! and G? taken together to form a group of formula (IV). A preferred embodiment is that the chiral reagent has chemical formula (I') and each of G! and G? is a group of formula (II), wherein G?! to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and each of G! and G2 is a group of formula (I) and each of G2 to G23 is a hydrogen atom A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G2 is a group of formula (II), and G*' to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.5 alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G? is a group of formula (II), each of G?! and G2? is a hydrogen atom and G2 is a nitro group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom and G2 is a group of formula (III), and G3! to G* are independently C 1-4 alkyl group, Ce.,4 aryl group, C.14 aralkyl group, Cy, alkyl Cs, aryl group, Cy, alkoxy Cse.14 aryl group, or Cg.14 aryl C,., alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom and G2 is a group of formula (III), and G3! to G* are independently C 14 alkyl group, Cs aryl group, Cs. aralkyl group, C,, alkyl Cs aryl group, C, alkoxy C ¢ aryl group, or Cg aryl C, alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G? is a group of formula (III), and G* to G* are independently C,4 alkyl group or Cs aryl group. Examples of C,.4 alkyl group are methyl group, ethyl group, n-propyl group, iso-propyl group, n-buthyl group and tert-buthyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G2 is a group of formula (IIT), and G* to G* are independently C,. alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G2 is a group of formula (III), and G*' and G* are Cg aryl group and G*» is C,4 alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! and G? taken together to form a group of formula (IV), and G* to G* are inde- pendently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,., alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! and G? taken together to form a group of formula (IV), wherein each of G* to G% is a hydrogen atom. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom and G2 is a group of formula (V). Further each of G*! to G*2 is inde- pendently a hydrogen atom, a nitro group, a methyl group, or a methoxy group. More preferred embodiment is that G! is a hydrogen atom and G? is a group of formula (V), wherein each of G* and G** is a hydrogen atom and G* is a 4-methyl group. A preferred embodiment is that the chiral reagent is selected from one of I1I-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-ylethanol (III-a) (R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (III-b) (S)-2-(Trimethylsilyl)-1-((S)-1-pyrrolidin-2-yl)ethanol (V-a) (R)-2,2-Diphenyl-1-((S)-pyrrolidin-2-yl)ethanol (VII-a) (S)-2,2-Diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (VII-b) (R)-2-(4-Nitrophenyl)-1-((S)-pyrrolidin-2-yl)ethanol (IX-a) (S)-2-(4-Nitrophenyl)- 1-((R)-pyrrolidin-2-yl)ethanol (IX-b) (R)-(9H-Fluororen-9-y1)((S)-pyrrolidin-2-yl)methanol (XI-a) (S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a) (R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b) The second aspect of the invention relates to a nucleoside 3'-phosphoramidite derivative which is represented by formula (Va) or (Vb). Go— Bs GS0— Bs oy 5 ne ~J RY Oo 0d oO he (ve) To P p oo” Sn—gt or nat es 7 hy pi H +1 G2 ° cd H i g G2 In the formula (Va) and (Vb), G! to G* are same as above, G° is a protective group of the hydroxyl group, and Bs is a group selected from the groups represented by following formula (VI) to (XI) or derivatives thereof. oO NH, NH, 2 ol Tn Yn 0 C1 LA N x / 3 LC (VD) (VID) (VII) oO [e] NHo Mn Wr HsC. Lr Cr A 4 PN WNP No No (IX) (X) (XD Examples of Bs are an adenine, a thymine, a cytosine, a guanine, an uracil, a 5-methylcytosine or derivative thereof. R?is hydrogen, -OH, -SH, -NR¢R¢, -Nj, halogen, alkyl, alkenyl, alkynyl, alkyl-Y'-, alkenyl-Y'!-, alkynyl-Y!-, aryl-Y!-, heteroaryl-Y!-, -OR®, or -SR®, wherein R® is a blocking moiety. Y!is O, NR¢, S, or Se. R¢ is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, -P(O)(R®),, or -HP(O)(R¢). Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2-, alkenyl-Y2-, alkynyl-Y2-, aryl-Y?-, or heteroaryl-Y2, or a cation which is Na+, Li*, or K*. Y2is O, NR¢, or S. R3 is a group represented by -CH,-, -(CH,),-, -CH,NH-, or -CH,N(CH)-. Examples of G* are trityl, 4-monomethoxytrityl, 4,4'-dimethoxytrityl, 4,4' 4"-trimethoxytrityl, 9-phenylxanthin-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthin-9-yl (MOX). A preferred embodiment of the second aspect is that the nucleoside 3'-phosphoramidite derivative is represented by formula (Va') or (Vb'). GSO— Bs GSO— Bs oy 1 he FNS —: | | R2 oO R2 oO a] RY 0 0b (Va) 0 (Vb) | P or NN } a 7 1 = | P. o NN— A / H 1 ( he H 1 G2 In the formula (Va') and (Vb'), G1, G2, G5, Bs, R?, and R?are same as above. The third aspect of the invention relates to a method for synthesis of a stereo- controlled phosphorus atom-modified oligonucleotide derivative. First step is a step of reacting a molecule comprising an achiral H-phosphonate moiety, the first activating reagent and a chiral reagent or a salt thereof to form a monomer. The chiral reagent has chemical formula (I) or (I) and the monomer may be represented by fomura (Va), (Vb), (Va'), or (Vb'). The monomer reacts with the second activating reagent and a nucleoside to form a condensed intermediate. Next step is a step of converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety. Based on the present method, it is possible to use stable and commercially available materials as starting materials, It is possible to produce stereocontrolled phosphorus atom-modified oligonucleotide derivatives using an achiral starting material. As shown in a working example, the method of the present invention does not cause degradations under de-protection steps. Further the method does not require special capping agents to produce phosphorus atom-modified oligonucleotide derivatives. The fourth aspect of the invention relates to a method for synthesis of stereo- controlled phosphorus atom-modified oligonucleotide derivatives using a chiral monomer. The first step is reacting a nucleoside 3'-phosphoramidite derivative which is rep- resented by formula (Va), (Vb), (Va'), or (Vb') with the second activating reagent and a nucleoside to form a condensed intermediate. The second step is converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety. INCORPORATION BY REFERENCE All publications and patent applications disclosed herein in this specification are herein incorporated by reference in their entirety to the same extent as if each in- dividual publication or patent application was specifically and individually indicated to be incorporated by reference. Brief Description of Drawings [fig.1]Figure 1 is UPLC profile in producing oligonucleotide derivative using the monomer of 4b. [fig.2]Figure 2 is UPLC profile in producing oligonucleotide derivative using the monomer of 25. Best Mode for Carrying out the Invention The term "nucleic acid" encompasses poly- or oligo-ribonucleotides (RNA) and poly- or oligo-deoxyribonucleotides (DNA); RNA or DNA derived from N-glycosides or C-glycosides of nucleobases and / or modified nucleobases; nucleic acids derived from sugars and / or modified sugars; and nucleic acids derived from phosphate bridges and / or modified phosphorus-atom bridges. The term encompasses nucleic acids containing any combinations of nucleobases, modified nucleobases, sugars, modified sugars, phosphate bridges or modified phosphorus atom bridges. Examples include, and are not limited to, nucleic acids containing ribose moieties, the nucleic acids containing deoxyribose moieties, nucleic acids containing both ribose and deoxyribose moieties, nucleic acids containing ribose and modified ribose moieties. The prefix poly- refers to a nucleic acid containing about 1 to about 10,000 nucleotide monomer units and wherein the prefix oligo- refers to a nucleic acid containing about 1 to about 200 nucleotide monomer units. The term "nucleobase” refers to the parts of nucleic acids that are involved in the 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 some other physicochemical property of the nucleobase and retains the property of hydrogen-bonding that binds one nucleic acid strand to another in a sequence specific manner. A modified nucleobase can pair with all of the five naturally occurring bases (uracil, thymine, adenine, cytosine, or guanine) without substantially affecting the melting behaviour, recognition by intracellular enzymes or activity of the oligonu- cleotide duplex. The term "nucleoside" refers to a moiety wherein a nucleobase or a modified nu- cleobase is covalently bound to a sugar or modified sugar. The term "sugar" refers to a monosaccharide in closed and / or open form. Sugars include, but are not limited to, ribose, deoxyribose, pentofuranose, pentopyranose, and hexopyranose moieties. The term "modified sugar" refers to a moiety that can replace a sugar. The modified sugar mimics the spatial arrangement, electronic properties, or some other physico- chemical property of a sugar, The term "nucleotide" refers to a moiety wherein a nucleobase or a modified nu- cleobase 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 moiety. The term "chiral reagent" refers to a compound that is chiral or enantiopure and can be used for asymmetric induction in nucleic acid synthesis. The term "chiral ligand" or "chiral auxiliary" refers to a moiety that is chiral or enantiopure and controls the stereochemical outcome of a reaction. In a condensation reaction, the term "activating reagent" refers to a reagent that activates a less reactive site and renders it more susceptible to attack by a nucleophile. The term "blocking moiety" refers to a group that transiently masks the reactivity of a functional group. The functional group can be subsequently unmasked by removal of the blocking moiety. The terms "boronating agents”, "sulfur electrophiles”, "selenium electrophiles” refer to compounds that are useful in the modifying step used to introduce BH, S, and Se groups, respectively, for modification at the phosphorus atom. The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. The term "solid support” refers to any support which enables synthetic mass production of nucleic acids and can be reutilized at need. As used herein, the term refers to a polymer that is insoluble in the media employed in the reaction steps performed to synthesize nucleic acids, and is derivatized to comprise reactive groups. The term "linking moiety" refers to any moiety optionally positioned between the terminal nucleoside and the solid support or between the terminal nucleoside and another nucleoside, nucleotide, or nucleic acid. As used herein, "treatment" or "treating," or "palliating” or "ameliorating" are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the un- derlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a saturated alkyl group (which means that it does not contain any units of unsaturation, e.g. carbon-carbon double bonds or carbon-carbon triple bonds) or the alkyl moiety may be an unsaturated alkyl group (which means that it contains at least one unit of un- saturation). The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or include a cyclic portion. The point of attachment of an alkyl is at a carbon atom that is not part of a ring. The "alkyl" moiety may have 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., "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, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). Alkyl includes both branched and straight chain alkyl groups. The alkyl group of the compounds described herein may be designated as "C,-Cs alkyl" or similar designations. By way of example only, " C,-C alkyl" indicates that there are one, two, three, four, five, or six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, allyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. In one aspect, an alkyl is a C,-Cg alkyl. C,.; alkyl group means straight or branched alkyl group that has 1 to 3 carbon atoms. Examples of C,.5 alkyl group are methyl, ethyl, propyl and isopropyl. C,., alkyl group means straight or branched alkyl group that has 1 to 4 carbon atoms. Examples of C, 4 alkyl group are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. As used herein, the term "aryl" refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings are formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups are a substituted or unsubstituted. In one aspect, an aryl is a phenyl or a naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). In one aspect, an aryl is a C¢-Cyparyl. Ce.14 aryl group means aryl group that has 6 to 14 carbon atoms. The examples of C 6.14 aryl group are phenyl, biphenyl, naphthyl, anthracyl, indanyl, phthalimidyl, naph- thimidyl, 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. An "acyl moiety" refers to an alkyl(C=0), aryl(C=0), or aralkyl(C=0) group. An acyl moiety can have an intervening moiety (Y) that is oxy, amino, thio, or seleno between the carbonyl and the hydrocarbon group. For example, an acyl group can be alkyl-Y-(C=0), aryl-Y-(C=0) or aralkyl-Y-(C=0). "Alkenyl" groups are straight chain, branch chain, and cyclic hydrocarbon groups containing at least one carbon-carbon double bond. Alkenyl groups can be substituted. "Alkynyl" groups are straight chain, branch chain, and cyclic hydrocarbon groups containing at least one carbon-carbon triple bond. Alkynyl groups can be substituted. An "alkoxy" group refers to an alklyl group linked to oxygen i.e. (alkyl)-O- group, where alkyl is as defined herein. Examples include methoxy (-OCHs) or ethoxy (-OCH ,CH,) groups. An "alkenyloxy" group refers to an alkenyl group linked to oxygen i.e. (alkenyl)-O- group, where alkenyl is as defined herein. An "alkynyloxy" group refers to an alkynyl group linked to oxygen i.e. (alkynyl)-O- group, where alkynyl is as defined herein. An "aryloxy" group refers to an aryl group linked to oxygen i.e. (aryl)-O- group, where the aryl is as defined herein. An example includes phenoxy (-OC¢Hs) group. The term "alkylseleno” refers to an alkyl group having a substituted seleno group attached thereto i.e. (alkyl)-Se- group, wherein alkyl is defined herein. The term "alkenylseleno" refers to an alkenyl group having a substituted seleno group attached thereto i.e. (alkenyl)-Se- group, wherein alkenyl is defined herein. The term "alkynylseleno” refers to an alkynyl group having a substituted seleno group attached thereto i.e. (alkynyl)-Se- group, wherein alkenyl is defined herein. The term "alkylthio" refers to an alkyl group attached to a bridging sulfur atom i.e. (alkyl)-S- group, wherein alkyl is defined herein. For example, an alkylthio is a methylthio and the like. The term "alkenylthio" refers to an alkenyl group attached to a bridging sulfur atom i.e. (alkenyl)-S- group, wherein alkenyl is defined herein. The term "alkynylthio” refers to an alkynyl group attached to a bridging sulfur atom i.e. (alkynyl)-S- group, wherein alkenyl is defined herein. The term "alkylamino" refers to an amino group subsituted with at least one alkyl group i.e. -NH(alkyl) or -N(alkyl),, wherein alkyl is defined herein. The term "alkenylamino" refers to an amino group subsituted with at least one alkenyl group i.e. -NH(alkenyl) or -N(alkenyl),, wherein alkenyl is defined herein. The term "alkynylamino" refers to an amino group subsituted with at least one alkynyl group i.e. -NH(alkynyl) or -N(alkynyl),, wherein alkynyl is defined herein. The term "halogen" is intended to include fluorine, chlorine, bromine and iodine. A "fluorescent group” refers to a molecule that, when excited with light having a selected wavelength, emits light of a different wavelength. Fluorescent groups include, but are not limited to, indole groups, fluorescein, tetramethylrhodamine, Texas Red, BODIPY, 5-[(2-aminoethyl)amino]napthalene-1-sulfonic acid (EDANS), coumarin and Lucifer yellow, An "ammonium ion" is a positively charged polyatomic cation of the chemical formula NH,*. An "alkylammonium ion" is an ammonium ion that has at least one of its hydrogen atoms replaced by an alkyl group, wherein alkyl is defined herein. Examples include triethylammonium ion, N,N-diisopropylethylammonium ion. An "iminium ion" has the general structure R,C=NR,*. The R groups refer to alkyl, alkenyl, alkynyl, aryl groups as defined herein. A "heteroaromatic iminium ion" refers to an imminium ion where the nitrogen and its attached R groups form a het- eroaromatic ring. A "heterocyclic iminium ion" refers to an imminium ion where the nitrogen and its attached R groups form a heterocyclic ring. The terms "amino" or "amine" refers to a -N(R"), radical group, where each Rb is in- dependently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a -N(R¥®), group has two R® other than hydrogen they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -N(R®), is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. Any one or more of the hydrogen, alkyl, fluoroalkyl, carbocyclyl, car- bocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or het- eroarylalkyl are optionally substituted by one or more substituents which inde- pendently are alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluo- romethoxy, nitro, trimethylsilyl, -OR}, -SR}, -OC(O)R!, -N(R}),, -C(O)R}, -C(O)OR}, - OC(O)N(RY),, -C(O)N(Ri),, -N(RHC(O)OR, -N(R)HC(O)R}, - N(R)C(O)N(Ri),, N(R! YC(NRHN(RY),, -N(R)S(O).R! (where t is 1 or 2), -S(O), or -S(O)N(R¥), (where tis 1 or 2), where each Ri is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocy- clylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. "Carbamate" as used herein, refers to a moiety attached to an amino group which has the formula -C(O)OR where R is alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. Examples include but are not limited to Boc (tert-butyl-OC(O)-), CBz (benzyl-OC(O)-), Teoc (Me;SiCH,CH,0C(0)-), alloc (allyl-OC(O)-), or Fmoc (9-fluorenylmethyl-OC(O)-) group. "Substituted silyl" as used herein, refers to a moiety which has the formula RSi-. Examples include, but are not limited to, TBDMS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilyl) or TMS (trimethylsilyl) group. The term "thiol" refers to -SH groups, and include substituted thiol groups i.e. -SR’ groups, wherein R’ are each independently a substituted or unsubstituted alkyl, cy- cloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. The first aspect of the invention relates to a chiral reagent or a salt thereof. The chiral reagent has following chemical formula (I). The term "chiral reagent" is a chemical composition which is used to produce stereocontrolled phosphorus atom-modified nu- cleotide or oligonucleotide derivatives. The chiral reagent reacts with a nucleotide to form a chiral intermediate. HO HN—G?* ji a [0] Ng? H oT, G2 In the formula (I), G! and G? are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group (-CN), a group of formula (II), (IIT) or (V), or both G! and G2 taken together to form a group of formula (IV). a2! == {an Pr 2 G22 In the formula (II), G? to G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.3 alkyl group. Preferred examples of G2! to G2 are a hydrogen atom. fell Ldi—a2 am G33 In the formula (IIT), G*! to G* are independently C, alkyl group, Ce.4 aryl group C4 alkoxy group, C., aralkyl group, Cy, alkyl Cg, aryl group, C4 alkoxy Ce 4 aryl group, or C14 aryl C,., alkyl group. Examples of C,., alkyl Cy, aryl group are methylphenyl group, and ethylphenyl group. Examples of C,., alkoxy Cs, aryl group are a methoxyphenyl group and an ethoxyphenyl group. Examples of Cq.1 aryl C4 alkyl groups are a benzyl group and a phenylethyl group. Preferred examples of G* to G33 are independently a methyl group and a phenyl group. Gc av) he Fr 5” C 44 In the formula (IV), G* to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.3 alkyl group. Preferred examples of G*! to G* are a hydrogen atom. fed O == Vv) —S— \ / { = pa In the formula (V), G*! to G are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, C,., alkyl group or C,.5 alkyloxy group. G? and G* are independently a hydrogen atom, C, , alkyl group, Cs. aryl group, or both G* and G* taken together to form a heteroatom-containing ring that has 3 to 16 carbon atoms. Preferred examples of G* and G* are that taken together to form a heteroatom-containing ring that has 3 to 16 carbon atoms with NH moiety in the formula (I). A preferred embodiment is that the chiral reagent has following chemical formula {@). HO HN— A TH No {1 H oT, G2 In the formula (I'), G! and G? are same as above and G! and G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II) or (II), or both G! and G2? taken together to form a group of formula (IV). A preferred embodiment is that the chiral reagent has chemical formula (I') and each of G! and G? is a group of formula (II), wherein G?! to G? are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and each of G! and G2? is a group of formula (II) and each of G2! to G2? is a hydrogen atom. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G2 is a group of formula (II), and G*' to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.5 alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G? is a group of formula (II), each of G?! and G2? is a hydrogen atom and G2 is a nitro group (-NO,). A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom and G? is a group of formula (III), and G3 to G* are independently C 1.4 alkyl group, Ce.4 aryl group, Cs, aralkyl group, C,4 alkyl Ce, aryl group, Cy. alkoxy Cs.14 aryl group, or Cs.14 aryl C4 alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom and G? is a group of formula (III), and G* to G* are independently C 1.4 alkyl group, Cs aryl group, Cr.1 aralkyl group, Cy alkyl Cs aryl group, C,4 alkoxy C ¢ aryl group, or Cg aryl C, alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G? is a group of formula (III), and G* to G* are independently C,, alkyl group or Cs aryl group (a phenyl group). Examples of C,., alkyl group are methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group and tert-butyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G2 is a group of formula (IIT), and G*! to G** are independently C,. alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom, G? is a group of formula (III), and G* and G* are Cg aryl group (a phenyl group) and G32 is C,., alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G* and G? taken together to form a group of formula (IV), and G* to G* are inde- pendently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group. A preferred embodiment is that the chiral reagent has chemical formula (I') and G* and G2 taken together to form a group of formula (IV), wherein each of G* to G* is a hydrogen atom. A preferred embodiment is that the chiral reagent has chemical formula (I') and G! is a hydrogen atom and G2 is a group of formula (V). Further each of G*! to G*2 is inde- pendently a hydrogen atom, a nitro group, a methyl group, or a methoxy group. More preferred embodiment is that G! is a hydrogen atom and G? is a group of formula (V), wherein each of G* and G** is a hydrogen atom and G* is a 4-methyl group. A preferred embodiment is that the chiral reagent is selected from one of I1I-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-ylethanol (III-a) (R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (III-b) (S)-2-(Trimethylsilyl)-1-((S)-1-pyrrolidin-2-yl)ethanol (V-a) (R)-2,2-Diphenyl-1-((S)-pyrrolidin-2-yl)ethanol (VII-a) (S)-2,2-Diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (VII-b) (R)-2-(4-Nitrophenyl)-1-((S)-pyrrolidin-2-yl)ethanol (IX-a) (S)-2-(4-Nitrophenyl)-1-((R)-pyrrolidin-2-yl)ethanol (IX-b) (R)-(9H-Fluororen-9-y1)((S)-pyrrolidin-2-yl)methanol (XI-a) (S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a) (R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b) The chiral reagent reacts with a nucleic acid or modified nucleic acid to be an asymmetric auxiliary group. A nucleoside 3'-phosphoramidite derivative, which is an intermediate of manufacturing a stereocontrolled phosphorus atom-modified oligonu- cleotide derivative, is obtained by chiral reagent reacting with a nucleic acid or modified nucleic acid. The second aspect of the invention relates to a nucleoside 3'-phosphoramidite derivative which is represented by formula (Va) or (Vb). The compounds of formula (Va) and (Vb) are known as monomers that are used in synthesizing ologonucleotide derivatives. These compounds are also known as oxazaphospholidine monomers. The sugar moieties of the compounds represented by formula (Vb) are known as BNA and LNA (when R? is a methylene group). 5 5, Gfo— Bs G0— Bs yl Oo RR? oO 1 NO RY Ty OO 3. (Va) 0 (Vb) AS oo P —t 0” DN—a 7 “N—gt —-c i a J \ / H +L G2 ; G2 H od G2 In the formula (Va) and (Vb), G! to G* are same as above, G° is a protective group of the hydroxyl group, and Bs is a group selected from the groups represented by formula (VD) to (XI) or derivatives thereof. oO NH, NH, Tn NY yr N C LA hY 7 (VD (VID

[10] NH, oO Oo Tr Cn TO an No No (1X) X) (XD) Examples of Bs are an adenine, a thymine, a cytosine, a guanine, an uracil, a 5-methylcytosine, or derivative thereof. R2is hydrogen, -OH, -SH, -NR¢R¢, -Nj, halogen, alkyl, alkenyl, alkynyl, alkyl-Y'-, alkenyl-Y!-, alkynyl-Y!-, aryl-Y!-, heteroaryl-Y!-, -OR®, or -SR®, wherein R® is a blocking moiety. Y!is O, NR¢, S, or Se. R¢ is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, -P(Q)(R¢),, or -HP(O)(Re). Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2-, alkenyl-Y?2- . alkynyl-Y2-, aryl-Y2-, or heteroaryl-Y2, or a cation which is Na+, Li*, or K*. Y2is O, NR¢, or S. Preferred examples of alkyl are C,.;o alkyl group, preferred examples of alkenyl are C 210alkenyl, preferred examples of alkynyl are C, palkynyl, preferred examples of aryl are Cq.5aryl, and preferred examples of heteroaryl are Ce. heteroaryl. R? is a group represented by -CHy-, -(CH,),-, -CH,NH-, or -CH,N(CH)-. Examples of G* the 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 an adenine, a thymine, a cytosine, a guanine, or derivative thereof. Bs is a nu- cleobase or a modified nucleobase. The examples of the derivatives are that disclosed in JP 2005-89441 A and are represented as follows. I 1 HN RE o HN R® Oo HN it 1 I o vS ) Ny 0 PN | 0 oy TY H 0 R10 NZ R® NZ SN ! Ngo r Ngo I ; N N NZ IY TS 1) SN, | 0 RE AY | 0 oy 1 Re In the above formula, each of R® to R!? is independently C,.,o alkyl, C¢-Cjparyl, Cs-C raralkyl, or Cs-Cyoaryloxyalkyl. Preferred examples of R® are methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. Preferred examples of Rand R!° are C,., alkyl group. A preferred embodiment of the second aspect is that the nucleoside 3'-phosphoramidite derivative is represented by formula (Va') or (Vb). Gfo— Bs cSo— Bs | 1 = 1 - Pes" I | R2 oO Peed R3 S—~4b (Va) iH (Vb) PS SY P oo” “N— oF SN— TY ig a J \ / H. 1 { NS H. 1. G2 In the formula (Va') and (Vb), G!, G2, G%, Bs, R?, and R3 are same as above. The nu- cleoside 3'-phosphoramidite derivative is a chiral monomer which is used to produce stereocontrolled phosphorus atom-modified nucleotides and oligonucleotide derivatives. Preferred examples of the nucleoside 3'-phosphoramidite derivatives are represented by the formula la, 1b, 2a, 2b, 3a, 3b, 4a, 4b, Sa, 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 at the Experimental section. DMTr represents a 4,4'-dimethoxytrityl group and TOM represents a triisopropyl- siloxymethyl group. The examples of using the nucleoside 3'-phosphoramidite derivative are disclosed in, e.g., JP 2005-89441 A. By repeating steps of condensation and de-protection, it is possible to lengthen the chain of oligonucleotide derivatives as disclosed therein. Formula of such an oligonucleotide derivative is shown in formula (X). HO— Bs en | R2 (xX) EN SK 0— Bs | ] | RZ |g LL an In the formula (X), X represents sulfide (=S), C,.; alkyl, C,.; alkoxy, C,., alkylthio, Cs -Cyoaryl, Ce-Cyp aralkyl, or Cs-Cy aryloxialkyl. Preferably, X represents sulfide (=S). "n" is an integer that represents 1 to 150, 1 to 100, 1 to 50, or 1 to 30. "n" may be preferably 2 to 100, preferably 10 to 100, preferably 10 to 50, and more preferably 15 to 30. The third aspect of the invention relates to a method for synthesis of a stereo- controlled phosphorus atom-modified oligonucleotide derivative. First step is a step of reacting a molecule comprising an achiral H-phosphonate moiety, the first activating reagent and a chiral reagent or a salt thereof to form a monomer. The chiral reagent has chemical formula (I) or (I') and the monomer may be represented by fomura (Va), (Vb), (Va), or (Vb'). The monomer reacts with the second activating reagent and a nu- cleoside to form a condensed intermediate. Next step is a step of converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety. The method basically based on disclosure of WO 2010 / 064146 pamphlet. Namely, fundamental steps are disclosed as route A and route B therein. In the method the chiral reagent of the present invention is used. First Scheme relates to synthesis of Chiral Oligos. HO" Phan Np-H HO | o Bs oR wo 1) Activation 2) Chiral Reagent gory 0B 0,0 BR DS 9 Php [ 0 5 Bs y 1) Activation —7 on 2) Chiral Roagant 0 ® a A ne Qo N-G* Stereo Hope 7% 0” HO o. Bs Ne ud] Go 8s = / oR <7 2 wx [9] pO R’ ———————————= G'NH 0" 0 o Bs specific Condensation Ln &e % 1) capping oo Bs IO. G0; Bs 2 suliryzaton oy ot o no as 0 jalio: oxidation SOx 0 wo ceroen oY / deprotecion < ey —_— we GN Oo Bs —a LF Xp0 as —— rh og” 1 [5% 1) capping Goo 8 2) sulfuryzation ite] : of “O° : elo oxidation XpO R % —————— oN oto es I &@® o wm . Oo TN Os 0 2 XO o Bs HO RE h Chiral Oligos Activation Step An achiral H-phosphonate moiety is treated with the first activating reagent to form the first intermediate. In one embodiment, the first activating reagent is added to the reaction mixture during the condensation step. Use of the first activating reagent is dependent on reaction conditions such as solvents that are used for the reaction. Examples of the first activating reagent are phosgene, trichloromethyl chloroformate, bis(trichloromethyl)carbonate (BTC), oxalyl chloride, PhsPCl,, (PhO);PCl,, N,N'-bis(2-0x0-3-oxazolidinyl)phosphinic chloride (BopCl), 1,3-dimethyl-2-(3-nitro-1,2,4-triazol-1-y1)-2-pyrrolidin-1-yl-1,3,2-diazaphospholidiniu m hexafluorophosphate (MNTP), or 3-nitro-1,2,4-triazol- 1-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP). The example of achiral H-phosphonate moiety is a compound shown in the above Scheme. DBU represents 1,8-diazabicyclo[5.4.0Jundec-7-ene. H*DBU may be, for example, ammonium ion, alkylammonium ion, heteroaromatic iminium ion, or hete- rocyclic iminium ion, any of which is primary, secondary, tertiary or quaternary, or a monovalent metal ion. Reacting with Chiral Reagent After the first activation step, the activated achiral H-phosphonate moiety reacts with a chiral reagent, which is represented by formula (I) or (I'), to form a chiral in- termediate of formula (Va), (Vb), (Va), or (Vb". Stereospecific Condensation Step A chiral intermediate of Formula Va ((Vb), (Va), or (Vb") is treated with the second activating reagent and a nucleoside to form a condensed intermediate. The nucleoside may be solidified. Examples of the second activating reagent are 4,5-dicyanoimidazole (DCI), 4,5-dichloroimidazole, 1-phenylimidazolium triflate (PhIMT), benzimi- dazolium triflate (BIT), benztriazole, 3-nitro-1,2,4-triazole (NT), tetrazole, S-ethylthiotetrazole (ETT), 5-benzylthiotetrazole (BTT), 5-(4-nitrophenyl)tetrazole, N- cyanomethylpyrrolidinium triflate (CMPT), N-cyanomethylpiperidinium triflate, N- cyanomethyldimethylammonium triflate. A chiral intermediate of Formula Va (Vb), (Va), or (Vb") may be isolated as a monomer. Usually, the chiral intermediate of Va ((Vb), (Va'), or (Vb) is not isolated and undergoes a reaction in the same pot with a nucleoside or modified nucleoside to provide a chiral phosphite compound, a condensed intermediate. In other embodiments, when the method is performed via solid phase synthesis, the solid support comprising the compound is filtered away from side products, impurities, and / or reagents. Capping Step If the final nucleic acid is larger than a dimer, the unreacted -OH moiety is capped with a blocking group and the chiral auxiliary in the compound may also be capped with a blocking group to form a capped condensed intermediate. If the final nucleic acid is a dimer, then the capping step is not necessary. Modifying Step The compound is modified by reaction with an electrophile. The capped condensed intermediate may be executed modifying step. In some embodiments of the method, the modifying step is performed using a sulfur electrophile, a selenium electrophile or a boronating agent. The preferred examples of modifying steps are step of oxidation and sulfurization. In some embodiments of the method, the sulfur electrophile is a compound having one of the following formulas: S; (Formula B), Z!-S-S-Z2, or Z!-S-V-Z2. 71 and Z2 are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocy- cloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, acyl, amide, imide, or thiocarbonyl, or Z! and Z2 are taken together to form a 3 to 8 membered alicyclic or heterocyclic ring, which may be substituted or unsubstituted; V is SO,, O, or NRf; and Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl. In some embodiments of the method, the sulfur electrophile is a compound of following Formula A, B,C, D, E, or F: A SG g . F 7 & Formula A Formula B Formula C Formula D Formula E Formula F In some embodiments of the method, the selenium electrophile is a compound having one of the following formulas: Se (Formula G), Z3-Se-Se-Z4, or Z3-Se-V-Z* 73 and Z# are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cy- cloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, acyl, amide, imide, or thiocarbonyl, or Z* and Z* are taken together to form a 3 to 8 membered alicyclic or heterocyclic ring, which may be substituted or unsubstituted; V is SO,, S, O, or NR; and Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl. In some embodiments of the method, the selenium electrophile is a compound of Formula G,H, I,J, K, or L. wel KSeCN Sa Seg \ Sess CN Nd Ty, FormulaG ~~ FormulaH ~~ Formula] ~~ Formula] ~~ FormulaK Formula L In some embodiments of the method, the boronating agent is borane- N,N-diisopropylethylamine (BH; DIPEA), borane-pyridine (BH; Py), borane- 2-chloropyridine (BH; CPy), borane-aniline (BH; An), borane-tetrahydrofiirane (BH; THF), or borane-dimethylsulfide (BH: Me,S). In some embodiments of the method, the modifying step is oxidation step. Oxidation step is disclosed in, e.g., JP 2010-265304 A and W02010 / 064146. Chain Elongation Cycle and De-protection Step The capped condensed intermediate is deblocked to remove the blocking group at the 5'-end of the growing nucleic acid chain to provide a compound. The compound is op- tionally allowed to re-enter the chain elongation cycle to form a condensed in- termediate, a capped condensed intermediate, a modified capped condensed in- termediate, and a 5'-deprotected modified capped intermediate. Following at least one round of chain elongation cycle, the 5'-deprotected modified capped intermediate is further deblocked by removal of the chiral auxiliary ligand and other protecting groups, e.g., nucleobase, modified nucleobase, sugar and modified sugar protecting groups, to provide a nucleic acid. In other embodiments, the nucleoside comprising a 5'-OH moiety is an intermediate from a previous chain elongation cycle as described herein. In yet other embodiments, the nucleoside comprising a 5'-OH moiety is an in- termediate obtained from another known nucleic acid synthetic method. In em- bodiments where a solid support is used, the phosphorus-atom modified nucleic acid is then cleaved from the solid support. In certain embodiments, the nucleic acids is left attached on the solid support for purification purposes and then cleaved from the solid support following purification. Based on the present method, it is possible to use stable and commercially available materials as starting materials, It is possible to produce stereocontrolled phosphorus atom-modified oligonucleotide derivatives using an achiral starting material. As shown in a working example, the method of the present invention does not cause degradations under the de-protection steps. Further the method does not require special capping agents to produce phosphorus atom-modified oligonucleotide derivatives. The fourth aspect of the invention relates to a method for the synthesis of stereo- controlled phosphorus atom-modified oligonucleotide derivatives using a chiral monomer. The first step is reacting a nucleoside 3'-phosphoramidite derivative which is represented by formula (Va), (Vb), (Va), or (Vb") with the second activating reagent and a nucleoside to form a condensed intermediate. The second step is converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety. Second Scheme relates to synthesis of Chiral Oligos using a monomer of Formula Va ((VDb), (Va'), or (Vb")). The second Scheme based on the method disclosed in JP 2005-89441 A. THO “ed 0 + GO Bs 1 i 5 B: Phan ANH ~~ o ) capping TOT iil = < 7 2) sulfuryza — or MT 2 oR i 2 5 wl" oxidatior 2 — —————— ot oop OE o N-G* Stereospecific Condensation eh S 7 Ho @% o_ wr ey, Fak} o Hoo Bs SH Loy o_o 5 1) capping _ bg < 7 2) sulfuryzation MT 2 0 R? oe ——— ctw oon py Otdaon specific Condensation a) L 7 a § wm ~ hain elongation “pOx_o RY oon Chiral Oligos The detailed conditions of the above scheme are similar to that of the first scheme. The starting material of formula Va (Vb), especially of formula Va' (or Vb'), is chemically stable. As shown in a working example, the method of the present invention does not cause degradations under the de-protection steps. Further the method does not require special capping agents to produce phosphorus atom-modified oligonucleotide derivatives. Mechanism for the removal of auxiliaries is shown as follows: a % Bs “ Bs oy 3 | R2 | { 2 HN. + \ N° G4=N Bs =x ~NO— Bs No JJ 1 oo | cb ol 1 ad / Ce a! aN 4 1 | Os, 0 R? xX ee J a. i Se <7 Oo | 2 Y XpeS FR G in] 7 oO oJ’ e = H 2 Nu_f %, R In the above scheme, Nu stands for Nucleophile. The above mechanism is thought to be different from the previous mechanism for the removal of auxiliaries. Examples bbreviati ac: acetyl bz: benzoyl CSO: (1S)-(+)-(10-camphorsulfonyl)oxaziridine DBU: 1,8-diazabicyclo[5.4.0Jundec-7-ene DCA: dichloroacetic acid DCM: dichloromethane, CH,Cl, DMTr: 4,4'-dimethoxytrityl Tr: trityl, triphenylmethyl Melm: N-methylimidazole NIS: N-iodosuccinimide pac: phenoxyacetyl Ph: phenyl PhIMT: N-phenylimidazolium triflate POS: 3-phenyl-1,2,4-dithiazoline-5-one TBS: tert-butyldimethylsilyl TBDPS: tert-butyldiphenylsilyl TOM: triisopropylsiloxymethyl TFA: trifluoroacetic acid Example 1 (S)-1-Tritylpyrrolidin-2-carbaldehyde (I-a). o Tr HAN 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-Tritylpyrrolidin-2-carbaldehyde (I-b). o id on MN 1-b Compound I-b was synthesized from D-proline in a similar manner to compound I-a. Example 3 (S)-2-(Methyldiphenylsilyl)-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (IT-a). Tr N—, 7 ~~ 7 1I-a To a solution of methyldiphenylsilylmethyl magnesium chloride in THF prepared from chloromethyldiphenylmethylsilane (4.02 g, 16.3 mmol) and magnesium (402 mg, 16.3 mmol) in THF (14 mL) was added I-a (2.79 g, 8.14 mmol) in THF (30 mL) solution with ice cooling. After stirring for 1.5 h with ice cooling, the mixture warmed to room temperature and continued stirring for 30 min. Saturated aqueous NH,CI (100 mL) was added to the reaction mixture at 0 degrees C, and extraction was performed with diethylether (100 mL) for three times. The combined extract was dried over Na, SO, filtered and concentrated under reduced pressure. The residue was chro- matographed on silica gel afforded II-a as a colorless foam (3.91 g, 87%). 'H NMR (300 MHz, CDCL3) d 7.48-7.08 (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-ylethanol (III-a). HN— 1 NS 111-a II-a (3.91 g, 7.06 mmol) was dissolved in 3% DCA in DCM (70 mL), and stirred for 10 min at room temperature. To the mixture, IM NaOH (200 mL) was added, and ex- traction was performed with DCM (100 mL) for three times. The combined extract was dried over Na,SO,, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel afforded III-a as a light yellow oil (1.99 g, 90%). 'H NMR (300 MHz, CDCl3) d 7.57-7.52 (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, 5); *C NMR (100.4 MHz, CDCl;) d 137.4, 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,sHxNOSi [M+H]* 312.18, found 312.06. Example 5 (R)-2-(Methyldiphenylsilyl)-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (II-b). Tr HO N— a) Me—gi—®" Ph 11-h Compound II-b was obtained by using I-b instead of I-a in a similar manner to compound II-a. 'H NMR (300 MHz, CDCL,) d 7.48-7.12 (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); 13C NMR (75.5 MHz, CDCl) d 144.5, 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 Caled for CagH,oNOSi [M+H]* 554.29, found 554.09. Example 6 (R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (111-b). (R)-2-(Methyldiphe pn "NT —,, Mei" Ph T11.h 111-b Compound III-b was obtained by using II-b instead of II-a in a similar manner to compound I1I-a. 'H NMR (300 MHz, CDCls) d 7.58-7.52 (5H, m), 7.38-7.33 (5H, m), 3.78 (1H, ddd, 1=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, 5); *C NMR (75.5 MHz, CDCly) d 137.5, 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,sH,sNOSi [M+H]* 312.18, found 312.09. Example 7 (8)-2-(Trimethylsilyl)-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (IV-a). Tr N— J HO ~ \ “ ve Me—Si— Me IV-a Compound IV-a was obtained by using "chloromethyltrimethylsilane" instead of "chloromethyldiphenylmethylsilane" in a similar manner to compound II-a. 'H NMR (300 MHz, CDCl3) d 7.58-7.51 (5H, m), 7.31-7.14 (10H, m), 4.13 (1H, dt, J =7.5,3.0Hz), 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, 7.2Hz), 0.46 (1H, dd, J = 14.4, 7.2Hz), -0.15 (9H, 5). MALDI TOF-MS m / z Calcd for C3H3NOSi [M+H]* 430.26, found 430.09. Example 8 (8)-2-(Trimethylsilyl)-1-((S)-1-pyrrolidin-2-yl)ethanol (V-a). HN— if HO 5 \ NS Me Me~Si— Me V-a Compound V-a was obtained by using IV-a instead of II-a in a similar manner to compound III-a. 'H NMR (300 MHz, CDCls) d 3.76 (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, brs), 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); *C NMR (75.5 MHz, CDCl, )d 69.6, 64.3, 46.9, 25.8, 23.9, 22.0, -0.8. MALDI TOF-MS m / z Calcd for CsH,NOSi [M+H]* 188.15, found 188.00. Example 9 (R)-2,2-Diphenyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (VI-a). Tr N— ¥ HO \ NS ~ Ph Vi-a To a solution of diphenylmethane (6.7 mL, 40mmol) in anhydrous THF (36 mL), n- BuLi (1.67M solution of Hexane, 24mL, 40mmol) was added dropwise at room tem- perature and stirred for 1 h, To the mixture, I-a (3.41g, 10mmol), which was dried by repeated coevaporations with toluene, in anhydrous THF (40mL) was slowly added at 0 degrees C, and continued stirring for 45 min. A saturated NH.CI aqueous solution (100mL) and Et,0 (100mL) were then added, and the organic layer was separated and the aqueous layer was extracted with E,0 (2 x 100mL). The organic layer were combined, dried over Na,SO, filterd and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford VI-a (1.41g, 28%) as white foam. 1H NMR (300 MHz, CDCl) d 7.45-7.01 (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). HN— I] HQ 1 NS ™~ h VII-a Compound VII-a was obtained by using VI-a instead of II-a in a similar manner to compound I1I-a. 'H NMR (300 MHz, CDCl3) d 7.44-7.38 (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); *C NMR (75.5 MHz, CDCl;) 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,sH»,NO [M+H]* 268.17, found 268.06. Example 11 (5)-2,2-Diphenyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (VI-b). id N— } VI-b Compound VI-b was obtained by using I-b instead of I-a in a similar manner to compound VI-a, 'H NMR (300 MHz, CDCl) d 7.44-7.37 (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), 3.36-3.28 (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); 13C NMR (75.5 MHz, CDCl,) 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 C3;HyNO [M+H]* 510.28, found 510.11. Example 12 (5)-2,2-Diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (VII-b). HN— VII-b Compound VII-b was obtained by using VI-b instead of VI-a in a similar manner to compound VII-a. 'H NMR (300 MHz, CDCl,) d 7.45-7.14 (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); *C NMR (75.5 MHz, CDCly) d 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 C,sH, NO [M+H]* 268.17, found 268.03. Example 13 (R)-2-(4-Nitrophenyl)-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (VIII-a). Tr | N— HO 1 1 NS VIII-a Compound VIII-a was obtained by using "4-nitrobenzylchloride" instead of "diphenylmethane" in a similar manner to compound VI-a. 'H NMR (300 MHz, CDCl) d 8.09-8.03 (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); *C NMR (75.5 MHz, CDCl) d 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. MALDI TOF-MS m / z Calcd for C5, H;,N,0; [M+H]* 479.23, found 479.08. Example 14 (R)-2-(4-Nitropheny})-1-((S)-pyrrolidin-2-yl)ethanol (IX-a). HN— HO HN— > I1X-a Compound IX-a was obtained by using VIII-a instead of VI-a in a similar manner to compound VII-a. 'H NMR (300 MHz, CDCl3) d 8.15 (2H, d, J] = 8.7Hz), 7.42 (2H, d, ] = 8.7Hz), 3.86-3.79 (1H, m), 3.16-3.07 (1H, m), 2.99-2.68 (6H, m), 1.84-1.68 (4H, m); *C NMR (75.5 MHz, CDCly) d 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 Caled for C;,H;N,O5 [M+H]* 237.12, found 237.01. Example 15 (S5)-2-(4-NitrophenyD)-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (VIII-b). i HO N— ond y= “wr V1ii-b Compound VIII-b was obtained by using I-b instead of I-a in a similar manner to compound VIII-a. 'H NMR (300 MHz, CDCl) d 8.09-8.04 (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); *C NMR (75.5 MHz, CDCly) d 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. MALDI TOF-MS m / z Calcd for Cy HNO; [M+H]* 479.23, found 479.08. Example 16 (5)-2-(4-Nitrophenyl)-1-({R)-pyrrolidin-2-yl)ethanol (IX-b). HN— (5)-2-(4-Nitrophenyl)-1-(f HQ HN— oped Jr IX-b Compound IX-b was obtained by using VIII-b instead of VIII-a in a similar manner to compound IX-a. 'H NMR (300 MHz, CDCl) 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, 5), 2.62 (2H, brs), 1.79-1.72 (4H, m); *C NMR (75.5 MHz, CDCly) d 147.3, 146.5, 130.0, 123.5, 72.7, 61.7, 46.7, 40.1, 25.8, 24.2. MALDI TOF-MS m / z Caled for C,H,7N,0; [M+H]* 237.12, found 237.02. Example 17 (R)-(9H-Fluoren-9-yl)((S)-1-tritylpyrrolidin-2-yl) methanol (X-a). Tr N— gq HO \ NS 0) X-a Compound X-a was obtained by using "fluorene” instead of "diphenylmethane" in a similar manner to compound VI-a, 'H NMR (300 MHz, CDCls) d 7.70 (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 C3;Hy,NO [M+H]* 508.26, found 508.12. Example 18 (R)-(9H-Fluororen-9-yl)((S)-pyrrolidin-2-yl)methanol (XI-a). HN— ol HQ 1 NS OJ XI-a Compound XI-a was obtained by using X-a instead of I-a in a similar manner to compound III-a. 'H NMR (300 MHz, CDCl) d 7.76 (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 = 6.5, 4.2Hz), 3.19-3.11 (1H, m), 2.97-2.88 (1H, m), 2.86-2.76 (1H, m), 2.02 (2H, brs), 1.77-1.53 (3H, m), 1.38-1.23 (1H, m); MALDI TOF-MS m / z Calcd for C;sHNO [M+H]* 266.15, found 266.04. Example 19 (5)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (X1I-a). Tr N— HQ \ ! NS XII-a Compound XII-a was obtained by using "chloromethyl p-tolyl sulfone" instead of "chloromethyldiphenylmethylsilane" in a similar manner to compound II-a. 'H NMR (600 MHz, CDCls) 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, 5), 1.55-1.49 (1H, m), 1.33-1.26 (1H, m), 1.12-1.04 (1H, m), 0.22-0.14 (1H, m); *C NMR (150.9 MHz, CDCl,) d 144.6, 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, 31.7. Example 20 (S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a). HN— HQ \ ol NS ++ XIii-a Compound XIII-a was obtained by using XII-a instead of II-a in a similar manner to compound III-a. 'H NMR (600 MHz, CDCls) d 7.82 (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, ] = 14.4, 9.0Hz), 3.16 (1H, dt, ] = 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); '*C NMR (150.9 MHz, CDCl;) d 144.5, 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 C,3Hy NOS [M+H]* 270.12, found 270.04. Example 2 (R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XII-b). Ir HO N— 0 / = 4 XI1-b Compound XII-b was obtained by using I-b instead of I-a in a similar manner to compound XII-a. 'H NMR (600 MHz, CDCl3) d 7.66 (2H, d, J = 8.4Hz), 7.47-7.44 (6H, m), 7.35 (2H, d, J=1.8Hz), 7.21-7.13 (9H, m), 4.37 (1H, dt, ] = 8.6, 2.4Hz), 3.33 (1H, 5), 3.23-3.20 (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); *C NMR (150.9 MHz, CDCly) d 144.6, 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 21 (R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (X111-b). HN— (R)-2-Tosyl-1-((R)-1-trity o HQ HN— 4 = | XIII-b Compound XIII-b was obtained by using XII-b instead of XII-a in a similar manner to compound XIII-a. 'H NMR (600 MHz, CDCl3) d 7.82 (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, ] = 7.2, 5.1Hz), 2.89-2.83 (2H, m), 2.46 (3H, 5), 2.04 (2H, brs), 1.79-1.64 (3H, m), 1.62-1.55 (1H, m); °C NMR (150.9 MHz, CDCly) d 144.8, 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 CsHyNO5S [M+H]* 270.12, found 270.05. Example 22 Oxazaphospholidine monomer 3a. viaZapnospnoinaine monomer oa. oN CIS DMTIO— | NT? NAN OPh eo H 1 1! NS and dissolved in dry diethylether (0.90 mL) under argon. N-Methylmorpholine (400 mL, 3.60 mmol) was added to the solution, and the resultant solution was added dropwise to a solution of PCI; (160 mL, 1.80 mmol) in dry diethylether (0.90 mL) at 0 degrees C under argon with stirring. The mixture was then allowed to warm to room temperature and stirred for 30 min. The resultant N-methylmorpholine hydrochloride was removed by filtration under nitrogen, and the filtrate was concentrated to dryness under reduced pressure to afford crude 2-chloro-1,3,2-oxazaphospholidine derivative. The crude materials were dissolved in freshly distilled THF (3.6 mL) to make 0.5 M solutions, which were used to synthesize the nucleoside 3'-O-oxazaphospholidines without further purification. 5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine (636 mg, 0.84 mmol) was dried by repeated coevaporations with dry toluene, and dissolved in freshly distilled THF (2.5 mL) under argon, Et;N (0.58 mL, 4.2 mmol) was added, and the mixture was cooled to -78 degrees C. A 0.5 M solution of the corresponding crude 2-chloro-1,3,2-oxazaphospholidine derivative in freshly distilled THF (3.6 mL, 1.80 mmol) was added dropwise via a syringe, and the mixture was stirred for 15 min at room temperature, A saturated NaHCO; aqueous solution (70 mL) and CHCl; (70 mL) were then added, and the organic layer was separated and washed with saturated NaHCO; aqueous solutions (2 x 70 mL). The combined aqueous layers were back- extracted with CHCl; (70 mL). The organic layers were combined, dried over Na,SO,, filtered and concentrated under reduced pressure. The residue was purified by chro- matography on silica gel to afford 3a (829 mg, 90%) as a white foam. 1H NMR (300 MHz, CDCl;) d 8.77 (1H, brs), 7.99 (1H, 5), 7.54-6.98 (24H, m), 6.81-6.73 (4H, m), 6.35 (1H, dd, J = 8.0, 6.3Hz), 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), 3.41-3.20 (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); *P NMR (121.5 MHz, CDCl;) d 153.5 (1P, s). Example 23 Oxazaphospholidine monomer 3b. uxazapnosphoudaine monomer So. CN DMTrO: N PoP oy TR lo 4 F" Compound 3b was obtained by using III-b instead of III-a in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl) d 8.80 (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 (SH, m), 1.36-1.18 (1H, m), 0.65 (3H, 5); *P NMR (121.5 MHz, CDCls) d 157.1 (IP, s). Example 24 Oxazaphospholidine monomer 1a. DMTrO— 3 l o rE AN Q N= NS 4 Me—Si— 5 Compound la was obtained by using "5'-O-(DMTr)-6-N-(benzoyl)adenosine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (600 MHz, CDCls) d 8.71 (1H, s), 8.12 (1H, 5), 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, dd, 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); *P NMR (243.0 MHz, CDCl;) d 151.8 (1P, s). Example 25 Oxazaphospholidine monomer 1b. o 0 N ae J oy 7 ¢ i Pp 7] 1b Compound 1b was obtained by using III-b instead of III-a in a similar manner to compound la. 'H NMR (300 MHz, CDCl3) d 9.06 (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, 5); 'P NMR (121.5 MHz, CDCly) d 157.3 (IP, 5). Example 26 Oxazaphospholidine monomer 2a. 4 x Qo" N— \ 1 NT Ph Me—Si— bn Compound 2a was obtained by using "5'-O-(DMTr)-4-N-(isobutyryl)cytidine” instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl,) d 8.33 (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 (6H, 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), 2.12-2.00 (1H, m), 1.91-1.50 (3H, m), 1.47-1.32 (2H, m), 1.27-1.16 (7H, m), 0.60 (3H, s); *P NMR (121.5 MHz, CDCl,) d 154.8 (IP, s). Example 27 Oxazaphospholidine monomer 2b. DMTrO— 4 I P. TN q N Ph \__ / | ot, Me—si—" “ Ph compound 2a. 'H NMR (300 MHz, CDCly) d 8.33 (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, 5); ¥P NMR (121.5 MHz, CDCly) d 157.2 (IP, 5). Example 28 Oxazaphospholidine monomer 4a. JAaaLapiOspiondine mono 0 Cr DMTO— Ie 6 ¥ 1 o A TN q oN NS Ph Mg Gime Ph 4a Compound 4a was obtained by using "5'-O-(DMTr)thymidine" instead of "5'-0-(DMTTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl,) d 7.58-7.23 (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);* P NMR (121.5 MHz, CDCl, d 153.7 (1P, s). Example 29 Oxazaphospholidine monomer 4b. MOT oJ 4 4b Compound 4b was obtained by using III-b instead of III-a in a similar manner to compound 4a. 'H NMR (300 MHz, CDCl) d 8.46 (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, 2.7Hz), 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, 5), 1.34-1.17 (2H, m), 0.67 (3H, 5); *'P NMR (121.5 MHz, CDCls) d 156.2 (1P, s). Example 30 Oxazaphospholidine monomer 5a. oO 0 N € TT J pmTIO— J 7 6 OMe i P 7! 9 Of A ON q oN NS Ph Me—Si— L. 5a Compound 5a was obtained by using "5'-0-(DMTr)-2'-O-methyl-6-N-(benzoyl)adenosine" instead of "5'-0O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl) d 8.66 (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, 5), 3.14-3.00 (1H, m), 1.90-1.19 (6H, m), 0.62 (3H, 5); *P NMR (121.5 MHz, CDCl:) d 155.8 (1P, s). Example 31 Y )xazaphospholidine monomer 5b. o 0 N DMTrO eT Re 9 OMe P. oO N— Ph \ 7 ¥y P. Ph q “N — Metis" 2” Ph 5p Compound 5b was obtained by using III-b instead of III-a in a similar manner to compound Sa. 'H NMR (300 MHz, CDCls) d 9.12 (1H, brs), 8.73 (1H, 5), 8.24 (1H, 5), 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, 5), 3.16-3.03 (1H, m), 1.90-1.17 (6H, m), 0.65 (3H, 5); *'P NMR (121.5 MHz, CDCl,) d 155.0 (1P, s). Example 32 Oxazaphospholidine monomer 6a. oO wo 6a Compound 6a was obtained by using "5'-O-(DMTr)-2'-O-methyl-4-N-(isobutyryl)cytidine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl) d 8.49 (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 (1H, 5), 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, 5), 3.36-3.24 (1H, m), 3.09-2.95 (1H, m), 2.59 (1H, septet, ] = 6.9Hz), 1.85-1.53 (SH, m), 1.48-1.37 (1H, m), 1.24-1.17 (6H, m), 0.59 (3H, 5); P NMR (121.5 MHz, CDCl) d 155.2 (1P, s). Example 33 Oxazaphospholidine monomer 6b. 3 OMe ¥ - oN Th Ph VJ Medi” 5 6b Compound 6b was obtained by using III-b instead of III-a in a similar manner to compound 6a. 'H NMR (300 MHz, CDCl,) d 8.62 (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, 5), 3.67 (1H, d, J = 4.5Hz), 3.62-3.25 (4H, m), 3.38 (3H, 5), 3.16-3.02 (1H, m), 2.58 (1H, septet, J = 6.9Hz), 1.87-1.40 (6H, m), 1.26-1.14 (6H, m), 0.64 (3H, s);>'P NMR (121.5 MHz, CDCl;) d 158.2 (1P, s). Example 34 Oxazaphospholidine monomer 7a. DMTrO— H nospnoindinc monomer / a. oN N SB ’ 0. 0 — SAA I om (i B 4 OMe l Oo O ¥ Q" “N— \ / NS kh Me—Si— Ph manner to compound 3a. 'H NMR (300 MHz, CDCl) d 8.67 (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, 5);*'P NMR (121.5 MHz, CDCl, d 156.9 (1P, s). Example 35 Oxazaphospholidine monomer 7b. uXxazapnosphoidinc monomer / D. ACN ? C (AAJ DMTIO— $ EL Oph oJ H vo 3 OMe i 7b Compound 7b was obtained by using III-b instead of III-a in a similar manner to compound 7a. 'H NMR (300 MHz, CDCl3) d 8.74 (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, 5), 3.16-3.04 (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);*'P NMR (121.5 MHz, CDCly) d 154.6 (1P, s). Example 36 Oxazaphospholidine monomer 8a. JAadZapnipnoiainge mono 0 CY DMTIO— I o OMe ¥ DD 4g ¥ oe \ NS Ph Me—Si— bn 8a Compound 8a was obtained by using "5'-O-(DMTr)-2'-O-(methyl)uridine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl3) d 7.91 (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, 5), 3.13-2.82 (2H, m), 1.88-1.53 (3H, m), 1.49-1.16 (3H, m), 0.60 (3H, s);3P NMR (121.5 MHz, CDCl3) d 155.3 (1P, s). Example 37 Oxazaphospholidine menomer 8b. JAAL4 PHOSPHONG HC NGI Q Cx me oy 0 SMe x yo P AN TH Ph 7 | Me—gi—" Kd Ph 8b Compound 8b was obtained by using III-b instead of III-a in a similar manner to compound 8a. 'H NMR (300 MHz, CDCl.) d 8.10 (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, 5), 3.17-2.82 (2H, m), 1.89-1.55 (3H, m), 1.55-1.40 (1H, m), 1.35-1.15 (2H, m), 0.66 (3H, s);>'P NMR (121.5 MHz, CDCl;) d 157.5 (1P, s). Example 38 Oxazaphospholidine monomer 9a. DMTrO— 4 ¢ Oo F I AN qo NS Ph Me—Si— 5, 9a Compound 9a was obtained by using "5'-0-(DMTr)-2'-deoxy-2'-fluoro-6-N-(benzoyl)adenosine" instead of "5'-0-(DMTTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl3) d 8.64 (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, 5); *P NMR (121.5 MHz, CDCly)d 150.5 (1P,d, J =7.7Hz). Example 39 Dxazaphospholidine monomer 9b. o 0 N $0 ZZ PT 3 N 0 B 0 N— ro sN I N- Ph VJ Moin” 5 9b Compound 9b was obtained by using III-b instead of III-a in a similar manner to compound 9a. 'H NMR (300 MHz, CDCl3) d 9.07 (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):»P NMR (121.5 MHz, CDCl,) d 157.8 (IP, d, J = 5.6Hz). Example 40 Oxazaphospholidine monomer 10a. § t NS 10a Compound 10a was obtained by using "5'-O-(DMTr)-2'-deoxy-2'-fluoro-4-N-(isobutyryl)cytidine" instead of "5'-0-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine" in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl;) d 8.66 (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, 5), 3.63-3.29 (4H, m), 3.10-2.96 (1H, m), 2.65 (1H, septet, J = 6.9Hz), 1.85-1.53 (3H, m), 1.48-1.17 (3H, m), 1.21 (3H, d, J = 4.8Hz), 1.19 (3H, d, = 4.8Hz), 0.59 (3H, 5);*'P NMR (121.5 MHz, CDCl,) d 155.5 (1P, d, J = 6.6Hz). Example 41 Oxazaphospholidine monomer 10b. 4 Y r P Ph q ba | o , Me—si—" Bh 10b Compound 10b was obtained by using III-b instead of III-a in a similar manner to compound 10a. 'H NMR (300 MHz, CDCl;) d 8.53 (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, 5), 3.65-3.39 (3H, m), 3.32-3.06 (2H, m), 2.59 (1H, septet, J = 6.9Hz), 1.88-1.53 (4H, m), 1.49-1.34 (2H, m), 1.27-1.18 (6H, m), 0.65 (3H, 5); >'P NMR (121.5 MHz, CDCl3) d 159.0 (1P, d, J =4.4). Example 42 Oxazaphospholidine monomer 11a. Uxazaphospholidine monomer 11a. oN <1 DMTrO— < PSAP «> H ie 0 L ! NS Fh Me—Si— 5 11a Compound 11a was obtained by using "5'-0-(DMTTr)-2'-deoxy-2'-fluoro-2-N-(phenoxyacetyl)-6-O-(cyanoethyl) guanosine” instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl) d 8.74 (1H, brs), 8.03 (1H, s), 7.55-6.94 (24H, m), 6.80-6.69 (4H, m), 6.21 (1H, dd, ] = 14.9, 3.6Hz), 5.34 (1H, dt, ] = 52.3, 3.6Hz), 5.01-4.75 (2H, m), 4.84 (1H, 1, J = 6.6Hz), 4.62 (2H, brs), 4.15-4.07 (1H, m), 3.73 (6H, 5), 3.59-3.29 (4H, m), 3.15-3.00 (1H, m), 3.07 (2H, t, | = 6.6Hz), 1.90-1.49 (3H, m), 1.47-1.12 (3H, m), 0.58 (3H, 5); 'P NMR (121.5 MHz, CDCl;) d 155.6 (IP, d,] = 10.9Hz). Example 43 Oxazaphospholidine monomer 11b. uxazapnospnondine monomer 110. oN i DMTrO— N Py FP «> H a Sf 1 compound 11a. 'H NMR (300 MHz, CDCl) d 8.81 (1H, brs), 8.06 (1H, s), 7.55-6.95 (24H, m), 6.77-6.69 (4H, m), 6.06 (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, 5), 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);>'P NMR (121.5 MHz, CDCl,) d 158.0 (1P, d, J = 4.4Hz). Example 44 Oxazaphospholidine monomer 12a. JAdLaPHOPINOIULILC ROT 0 Cp PMO o Ie ot ¥ oD oO F g Qo N— \ 1 NS ph Me—Si— by 12a Compound 12a was obtained by using "5'-0-(DMTr)-2'-deoxy-2'-fluorouridine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl3) d 7.85 (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, ] = 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, 5); 'P NMR (121.5 MHz, CDCl) d 154.3 (1P, d, ] = 8.9Hz). Example 45 Oxazaphospholidine monomer 12b. 4 oO r 2 Ph q > 0", Me—si—" n / Ph 12b Compound 12b was obtained by using III-b instead of III-a in a similar manner to compound 12a. 'H NMR (300 MHz, CDCl) d 8.01 (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, 5), 3.61-3.39 (3H, m), 3.37-3.25 (1H, m), 3.23-3.09 (1H, m), 1.91-1.56 (3H, m), 1.51-1.13 (3H, m), 0.66 (3H, s);3'P NMR (121.5 MHz, CDCl,) d 158.9 (1P, d, ] = 4.4Hz). Example 46 Oxazaphospholidine monomer 13a. aliaita luau slatted nat dt ca a a 0 in 1] PTT J 7 $ OO 1 O_Os / Sa?” “si oo 7 ~~ ] 9 0 A oN qT MN NS ih Me—Si— bo 13a Compound 13a was obtained by using "5'-0-(DMTr)-2'-O-TOM-6-N-(acetyl)adenosine” instead of "5'-0-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl) d 8.82 (1H, brs), 8.49 (1H, s), 8.10 (1H, 5), 7.58-7.17 (19H, m), 6.83-6.73 (4H, m), 6.11 (1H, d, J = 6.6Hz), 5.15 (1H, dd, I = 6.6, 5.4Hz), 4.98-4.77 (4H, m), 4.18-4.11 (1H, m), 3.76 (6H, 5), 3.59-3.25 (4H, m), 3.16-3.02 (1H, m), 2.62 (3H, 5), 1.91-1.53 (3H, m), 1.49-1.18 (3H, m), 0.96-0.80 (3H, m), 0.90 (18H, s), 0.62 (3H, 5):3'P NMR (121.5 MHz, CDCl) d 156.7 (IP, s). Example 47 Oxazaphospholidine monomer 13b. vr Sy ws. Ne y ar, $0 9 OO OO! - XY TN oP N= Ph J |, Me—gi—" Ph 13b Compound 13b was obtained by using III-b instead of III-a in a similar manner to compound 13a. 'H NMR (300 MHz, CDCl) d 8.56 (1H, brs), 8.55 (1H, s), 8.13 (1H, 5), 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, 5); P NMR (121.5 MHz, CDCl, d 154.8 (1P, s). Example 48 Oxazaphospholidine monomer 14a. OToM l NS Ph Me—Si— bn 14a Compound 14a was obtained by using "5'-0O-(DMTr)-2'-O-TOM-4-N-(acetyl)cytidine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine" in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl3) d 10.04 (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), 3.55-3.23 (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);*' P NMR (121.5 MHz, CDCl, d 156.5 (1P, s). Example 49 Oxazaphospholidine monomer 14b. 5 OSdtom Oo O I 27, q N= Ph NJ Lo, Me—gi—" be 14b Compound 14b was obtained by using III-b instead of IlI-a in a similar manner to compound 14a. 'H NMR (300 MHz, CDCl3) d 10.19 (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, ] = 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, 5); *P NMR (121.5 MHz, CDCl) d 156.4 (1P, s). Example 50 Oxazaphospholidine monomer 15a. 0 SL o DMTrO— N PN «> H I S Strom 0 O 2 Q N— \ / NS Ph Me—Si— Ly 15a Compound 15a was obtained by using "5'-0-(DMTr)-2'-O-TOM-2-N-(acetyl)guanosine" instead of "5'-0-(DMTTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCly) d 7.70 (1H, 5), 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, 5), 3.74 (3H, 5), 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, 5); *'P NMR (121.5 MHz, CDCl;) d 158.1 (1P, s). Example 51 Oxazaphospholidine monomer 15b. uxazaphospnouain¢ monomer 13D 0 SL 0 DMTrO— N Pas - H | 1 a So Otom ! Compound 15b was obtained by using III-b instead of III-a in a similar manner to compound 15a. 'H NMR (300 MHz, CDCl3) d 7.77 (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), 3.30-3.18 (1H, m), 3.11-2.85 (2H, m), 1.85-1.15 (9H, m), 0.93-0.84 (21H, m), 0.62 (3H, 5);*'P NMR (121.5 MHz, CDCl) d 152.3 (1P, 5). Example 52 Oxazaphospholidine monomer 16a. JAaaza Pnospnofidiie mono 0 Cy oMTIO— J oO obrom ¥ Oo OO i oN qn NS 16a Compound 16a was obtained by using "5'-0-(DMTr)-2'-O-TOM-uridine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCLs) d 7.76 (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, ] = 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, | = 5.7Hz), 3.87-3.83 (1H, m), 3.78 (3H, 5), 3.77 (3H, 5), 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, 5); *'P NMR (121.5 MHz, CDCls) d 156.6 (1P, s). Example 53 Oxazaphospholidine monomer 16b. JAadZapnuspnolduc moo 0 Cr Durie _ ° Ie oO brom x yo P AN TN Ph \__ / Le Me-si—" "~ Ph 16b Compound 16b was obtained by using III-b instead of III-a in a similar manner to compound 16a. H NMR (600 MHz, CDCl;) d 7.87 (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, ] = 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, 5), 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); 3'P NMR (243.0 MHz, CDCl;) d 154.3 (1P, s). Example 54 Dxazaphospholidine monomer 17a. o 0 N ae DMTrO— J =. 2 of N= NS Ph Me—Si— L Compound 17a was obtained by using "5'-0-(DMTr)-2'-0,4'-C-methylene-6-N-(benzoyl)adenosine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCl3) d 9.10 (1H, brs), 8.76 (1H, s), 8.32 (1H, 5), 8.04 (2H, d, J =7.2Hz), 7.64-7.18 (22H, m), 6.84 (4H, d, J = 8.7Hz), 6.10 (1H, 5), 4.76 (1H,d J = 6.9Hz), 4.58 (1H, 5), 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, 5), 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); 'P NMR (121.5 MHz, CDCl;) d 152.9 (IP, s). Example 55 Oxazaphospholidine monomer 17b. DMTrO— = ro ON q MN Ph J Me—% a L 17b Compound 17b was obtained by using III-b instead of IlI-a in a similar manner to compound 17a. 'H NMR (300 MHz, CDCl) d 8.81 (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, ] = 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);*'P NMR (121.5 MHz, CDCl3) d 157.3 (1P, s). Example 56 Oxazaphospholidine monomer 18a. Ph \ 7 ie P. oN q oN NS Me—gi— Ly 18a Compound 18a was obtained by using "5'-0-(DMTr)-2'-0,4'-C-methylene-4-N-(isobutyryl)-5-methylcytidine" instead of "5'-0-(DMTTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCls) d 7.88 (1H, brs), 7.58-7.18 (20H, m), 6.88-6.80 (4H, m), 5.65 (1H, 5), 4.69-4.60 (1H, m), 4.52 (1H, d, J = 6.6Hz), 4.49 (1H, s), 3.81-3.74 (1H, m), 3.75 (3H, 5), 3.73 (3H, 5), 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);3'P NMR (121.5 MHz, CDCl3) d 155.9 (1P, s). Example 57 Oxazaphospholidine monomer 18b. l 18b Compound 18b was obtained by using III-b instead of III-a in a similar manner to compound 18a. 'H NMR (300 MHz, CDCl) d 7.86 (1H, brs), 7.56-7.19 (20H, m), 6.88-6.79 (4H, m), 5.69 (1H, 5), 4.86-4.76 (1H, m), 4.46 (1H, 5), 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, ] =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):*'P NMR (121.5 MHz, CDCl) d 158.2 (1P, s). Example 58 Ph VN 1 )xazaphospholidine monomer 19a. oN | NSN © DMTrO— $ Pp OP OJ H 5~0 i on Ph NV a ~N NS 1 Me—Si— Ph instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCls) d 8.71 (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);3P NMR (121.5 MHz, CDCl;) d 153.2 (1P, s). Example 59 1 Dxazaphospholidine monomer 19b. oN N xX ay J DMTrO— N Pn RP 7 7 ¥ oN 19b y oo oe Ph \ J Mogi” | Ph 1 Compound 19b was obtained by using III-b instead of III-a in a similar manner to compound 19a. 'H NMR (300 MHz, CDCl,) d 8.86 (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, | = 6.6Hz), 4.82-4.73 (1H, m), 4.70 (2H, s), 4.64 (1H, d, J = 7.5Hz), 4.49 (1H, 5), 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 (1H, 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);3'P NMR (121.5 MHz, CDCl;) d 157.4 (1P, s). Example 60 Oxazaphospholidine monomer 20a. 1 NS fh Me—8i— Lo 20a Compound 20a was obtained by using "5'-0-(DMTr)-2'-0,4'-C-methylene-5-methyluridine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCly) d 7.71 (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, 5), 3.74 (3H, s), 3.73 (3H, 5), 3.64 (1H, d, J = 7.8Hz), 3.55 (1H, d, J = 7.8Hz), 3.53 (IH, 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);*! P NMR (121.5 MHz, CDCl, d 155.1 (1P, s). Example 61 Oxazaphospholidine monomer 20b. vy P. Qo" N— i Ph Yt M 1 —, e—Si—" Kd Le 20b Compound 20b was obtained by using III-b instead of III-a in a similar manner to compound 20a. 'H NMR (300 MHz, CDCl3) d 7.69 (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, 5), 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, 5), 1.46-1.12 (3H, m), 0.63 (3H, s);*'P NMR (121.5 MHz, CDCl;) d 158.1 (1P, s). Example 62 Oxazaphospholidine monomer 21a. I Some 7 NS Ph Me—Si— bn 21a Compound 21a was obtained by using "5'-0O-(DMTr)-2'-O-methoxyethyl-5-methyluridine" instead of "5'-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a. 'H NMR (300 MHz, CDCls) d 7.62-7.18 (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), 3.95-3.89 (1H, m), 3.78 (6H, s), 3.78-3.71 (2H, m), 3.60-3.48 (2H, m), 3.44-3.02 (SH, m), 3.31 (3H, s), 1.88-1.15 (6H, m), 1.35 (3H, s), 0.58 (3H, s);3P NMR (121.5 MHz, CDCl) d 156.3 (1P, s). Example 63 Oxazaphospholidine monomer 21b. DMTroO— 4 Some ra 21b Compound 21b was obtained by using III-b instead of III-a in a similar manner to compound?21a. 'H NMR (300 MHz, CDCly) d 7.71 (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, 5), 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, 5); *'P NMR (121.5 MHz, CDCl,) d 155.6 (1P, s). Example 64 Oxazaphospholidine monomer 22a. UXd4Z4 PRosponainge mol Or MT ° aN ¢ ¥ oD o] ¥ oN od NS "™ h 22a Compound 22a was obtained by using VII-a instead of III-a in a similar manner to compound 4a. 'H NMR (300 MHz, CDCL,) d 7.57 (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, 5), 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); 3'P NMR (121.5 MHz, CDCl;) d 160.9 (1P, s). Example 65 Oxazaphospholidine monomer 22b. ¥ VaaZapiiosphnouaine AU oO Or DMTTrO- N 0 oy 1 Oo ¥ Do 22b Compound 22b was obtained by using VII-b instead of VII-a in a similar manner to compound 22a. 'H NMR (300 MHz, CDCl) d 7.57 (1H, d, ] = 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, ] = 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 (2H, m), 1.95-1.81 (1H, m), 1.74-1.56 (1H, m), 1.40 (3H, d,]=1.5Hz), 1.44-1.34 (2H, m); »P NMR (121.5 MHz, CDCl3) d 162.2 (1P, s). Example 66 Oxazaphospholidine monomer 23a. 3 : N q oN NS Compound 23a was obtained by using IX-a instead of III-a in a similar manner to compound 4a. 'H NMR (300 MHz, CDCl3) d 9.22 (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, 5); *'P NMR (121.5 MHz, CDCl;) d 157.5 (1P, s). Example 67 Oxazaphospholidine monomer 23b. PIES PpRYIAne monomer < Q Cr PMT 0) 6 x Oo A AN q N= 0; “OL > 1 No o , n 23b Compound 23b was obtained by using IX-b instead of IX-a in a similar manner to compound 23a. 'H NMR (300 MHz, CDCl) d 8.67 (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 =1.5,5.7Hz), 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);3'P NMR (121.5 MHz, CDCl,) d 158.1 (1P, s). Example 68 Oxazaphospholidine monomer 24a. DMTrO— l NS HH = / I 24a Compound 24a was obtained by using XIII-a instead of III-a in a similar manner to compound 4a. 'H NMR (600 MHz, CDCl3) d 7.76 (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), 6.41 (1H, dd, ] = 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, 5), 3.59-3.53 (1H, m), 3.52-3.44 (2H, m), 3.41 (1H, dd, ] = 14.7, 7.2Hz), 3.37-3.30 (2H, m), 3.13 (1H, ddd, J = 19.3, 10.3, 4.1Hz), 2.50-2.44 (1H, m), 2.39 (3H, 5), 2.35-2.29 (1H, m), 1.91-1.72 (2H, m), 1.64-1.59 (1H, m), 1.40 (3H, 5), 1.12-1.05 (1H, m): *P NMR (243.0 MHz, CDCL) d 154.2 (1P, 5). G f is of chrial-oligos: The automated solid-phase synthesis of chiral-oligos were performed according to the cycles shown in Table 1. After the synthesis, the resin was treated with a 25% NH; aqueous solution (1 mL) for 12 h at 55 degrees C. The mixture was cooled to room temperature and the resin was removed by membrane filtration. The filtrate was con- centrated to dryness under reduced pressure. The residue was dissolved in H,O (3 mL) and analyzed by RP-UPLC-MS with a linear gradient of acetonitrile (0-50% / 30 min) in 0.1 M triethylammonium acetate buffer (pH 7.0) at 50 degrees C at a rate of 0.3 mL / min. Table. 1 step operation reagents and solvent volume waiting detritylation 3% DCA / DCM 1.6 mL 20s 2 coupling 0.1M monomer / MeCN + IM 0.5 mL 5 min capping Ac,O / THF-pyridine + 16% / THF ~~ 0.5 mL 30s 4 oxidation / urization ~~ 0.5M CSOMeCN or 0.IM MeCN 0.5 mL 90s Comparison Example 1 0 Or DMTrO— No a 9 14 A or N— J pw” 25 The above Compound 25, which represents a conventional monomer, was used to produce oligos. Figure 2 shows a chart of products obtained through Comparison Example 1. Analysis The monomers of the working examples were chemically stable. The isolate yield of the monomers were more than 80 %, which was higher that of conventional method. ‘We synthesized oligonucleotide derivatives using the chiral reagents of the above working examples based on the second general procedure and monomers of the above working examples based on the first general procedure. As shown in Figure 2, the con- ventional monomer causes incomplete de-protection products, side products and failure sequences. On the other hand, the method of the invention causes little incomplete de- protection products and little side products even though it causes failure sequences as shown in Figure 1. It is obvious that the method of the invention can lessen the in- complete de-protection products and side products, It was easy to isolate the targeted oligonucleotide derivatives because the present invention can lessen undesirable

Claims

Claims

1. A chiral reagent or a salt thereof, the chiral reagent having following chemical formula (I), HN—G* i HO % [4)) N\, G3 H 1 G2 wherein G! and G? are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II), (III) or (V), or both G! and G? taken together to form a group of formula (IV), ferdl == (In 2X 2 ol wherein G to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.5 alkyl group, Gc 1 1 di—g® (HD) ls wherein G3! to G* are independently C,., alkyl group, C,.; alkoxy group, Cg.y4 aryl group, C;.4 aralkyl group, C,., alkyl Cq.14 aryl group, C 1.4 alkoxy Ce.14 aryl group, or Ce4 aryl C, alkyl group, (Iv) G4 ( G% Tw 2 2, 1 m~a3 G 5 2 44 wherein G* to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.5 alkyl group, G3 and G* are independently a hydrogen atom, C3 alkyl group, Ce.14 aryl group, or both G* and G* taken together to form a heteroatom- containing ring that has 3 to 16 carbon atoms, G51 0 =l= Vv) u —S——_ ) [ER wherein G5! to G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, C,.; alkyl group or C,.; alkyloxy group.

2. The chiral reagent or a salt thereof in accordance with claim 1, wherein the chiral reagent has following chemical formula (I'). HN— Er HO 1 No (I H ~d G2

3. The chiral reagent or a salt thereof in accordance with claim 2, wherein each of G! and G2 is a group of formula (II), wherein G2! to G2 are in- dependently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group.

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

5. The chiral reagent or a salt thereof in accordance with claim 2, wherein G! is a hydrogen atom, and G? is a group of formula (II), wherein G2! to G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group.

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

7. The chiral reagent or a salt thereof in accordance with claim 2, wherein G! is a hydrogen atom, and G2 is a group of formula (III), wherein G3! to G* are independently C,., alkyl group, C.14 aryl group, C,. 4 aralkyl group, C,.4 alkyl Cs.,4 aryl group, C,.4 alkoxy Ce.4 aryl group, or Ce.14 aryl C, alkyl group.

8. The chiral reagent or a salt thereof in accordance with claim 2, wherein G! is a hydrogen atom, and G? is a group of formula (III), wherein G3! to G3? are independently C,.4 alkyl group, Cs aryl group, Cs. aralkyl group, C,., alkyl Cs aryl group, C,., alkoxy Cs aryl group, or Cg aryl C,.4 alkyl group.

9. The chiral reagent or a salt thereof in accordance with claim 2, wherein G! is a hydrogen atom and G2 is a group of formula (IIT), wherein G* to G3 are independently C,., alkyl group, or Cg aryl group.

10. The chiral reagent or a salt thereof in accordance with claim 2, wherein G! is a hydrogen atom and G2 is a group of formula (III), wherein G3! to G* are independently C,., alkyl group.

11. The chiral reagent or a salt thereof in accordance with claim 2, wherein G! is a hydrogen atom and G2 is a group of formula (III), wherein G3! and G* are Cg aryl group and G32 is C,., alkyl group.

12. The chiral reagent or a salt thereof in accordance with claim 2, wherein G! and G? taken together to form a group of formula (IV), wherein G4 to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group.

13. The chiral reagent or a salt thereof in accordance with claim 2, wherein G! and G? taken together to form a group of formula (IV), wherein each of G¥ to G* is a hydrogen atom.

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

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

16. The chiral reagent or a salt thereof in accordance with claim 2, wherein the chiral reagent is represented by III-a, III-b, V-a, VII-a, VII-b, IX-a, IX-b, XI-a, XIII-a or XIII-b: (S)-2-(Methyldiphenylsilyl)-1-((S)-pyrrolidin-2-yl)ethanol (III-a) (R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (III-b) (S)-2-(Trimethylsilyl)-1-((S)- 1-pyrrolidin-2-yl)ethanol (V-a) (R)-2,2-Diphenyl-1-((S)-pyrrolidin-2-yl)ethanol (VII-a) (S)-2,2-Diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (VII-b) (R)-2-(4-Nitrophenyl)-1-((S)-pyrrolidin-2-yl)ethanol (IX-a) (S)-2-(4-Nitrophenyl)-1-((R)-pyrrolidin-2-yl)ethanol (IX-b) (R)-(9H-Fluororen-9-y1)((S)-pyrrolidin-2-yl)methanol (XI-a) (S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a) (R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b)

17. A nucleoside 3'-phosphoramidite derivative which is represented by formula (Va) or (Vb), Go Bs G50. a | Re, | R2 ody (Va) E) (Vb) i Nf Nes Ise” Ne > &' G6? ™ G? H 1 ao? wherein G! and G? are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II), (IIT) or (V), both G! and G? taken together to form a group of formula (IV), G21 == (an on Tn 52% 2 G22 wherein G to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.5 alkyl group, G31 1 di—g® (0) Ls wherein G* to G* are independently C,., alkyl group, C,.; alkoxy group, Ce. aryl group, Cs. aralkyl group, C,., alkyl Ce.1, aryl group, C 1.4 alkoxy Cg 4 aryl group, or Cg 4 aryl C, 4 alkyl group, (Iv) cH a G4 NT 1 dr G4. 5" 2 wherein G# to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group, G51 0 =l= Vv) u —S——_ ) [ER wherein G5! to G3 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, C,; alkyl group or C,.; alkyloxy group, G3 and G* are independently a hydrogen atom, C3 alkyl group, Ce.14 aryl group, or both G* and G* taken together to form a heteroatom- containing ring that has 3 to 16 carbon atoms. GS is a protective group of a hydroxyl group, R?is hydrogen, -OH, -SH, -NRR¢, -N;, halogen, alkyl, alkenyl, alkynyl, alkyl-Y'-, alkenyl-Y'-, alkynyl-Y'-, aryl-Y'-, heteroaryl-Y!-, OR?®, or -SR?, wherein R? is a blocking moiety, Y!is O, NRS, S, or Se, R¢ is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, sub- stituted silyl, carbamate, -P(O)(R¢),, or -HP(O)(R¢), Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2-, alkenyl-Y?2-, alkynyl-Y?-, aryl-Y?-, or heteroaryl-Y2-, or a cation which is Na+, Li+, or K*, Y2is QO, NR¢, or S, R? is a group represented by -CH,-, -(CH,),-, -CH,NH-, or -CH,N(CH; )-, and Bs is a group selected from the groups represented by following formula (VI) to (XI) or derivatives thereof. NH, NHz Ey ~ N (VD (VII) [o} NH, 1 2 Oo Lr ~ N NH;

18. The nucleoside 3'-phosphoramidite derivative in accordance with claim 17, wherein the nucleoside 3'-phosphoramidite derivative is represented by formula (Va') or (Vb'). Bs Tod i rR? fe} G%0 Bs ~~) RY | oo I 1 (Va) P. P. Id SN— 0” Sn— vd % H > { ~~ H. 1 G2?

19. The nucleoside 3'-phosphoramidite derivative in accordance with claim 17,wherein the nucleoside 3'-phosphoramidite derivative is represented by formula 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, Oa, 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. 1 y / gy ~N TO oY SN wi 9 BL NS l NS fo OMTIO— NZ Woe H A / pm Mo—Si® NS 57 ASN o_o | Hom A Or Po o J 4 I 3 ON 7 Nm ~N NH ro J é o TO No Ay anor JE ¢ SMe 5 $ on P, BE NS 10 N. SN a er 0. TL. A om ON Sie 9 bn PF, ] q a ~N oN N XN ¢ DMTIO ECE Som le 5 Xo oda Sve 4 on qe oN EY ° MrT _o N PA OP H 1 PQ Dh o N— o CY oro _o 9 Sve — 2 & AN , § ~N NH wo GE o bwe 4 Nm Nf ~~ 0 TO No Ay aon G0 § + A 1 | 5 F . 7A ~NS L oN MSN 0 ¢ DMTO: ELI Am os H Ll st A A NS CN MSN 0 DMTrO: SU oy UR Ll L NH SW ox bf NS NH me ox 9 4 o " a8 iin J § Sod Sol I go N\, SQN ~~ 0 HN A N. NN wn oJ § boa o_o N— LY Strom Strom 0 NH Pm SLA gh jE I. OTOM ~~ ¢ DMTrO: 4 (LA “7 H oO OToM PQ, Ph om amie? ur’ h o NH C Pm o Na 4 rom r 4 on A CN NS 0 Cy To o Je o brom 1 ~~ 20 N. DMTrO: $E N pH i ~N oN (LAI DMTIO: J io en 5 H ~~ A OF SN— Fr A om NS oN 2 i PP DMTrO: < PA oP 7 H Se Eb OF “Ne— 1 ~N by & qe ~~ 0 Cr Poo J 9 Oo sy A MM ~~ ~N d ON q Nm x NS d i ON. on 2 a Ol nS 23b ~N OF 24a wherein DMTr represents a 4,4'-dimethoxytrityl group and TOM represents a triisopropylsiloxymethyl group.

20. A method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives comprising steps of: reacting a molecule comprising an achiral H-phosphonate moiety, a chiral reagent or a salt thereof to form a monomer of a nucleoside 3'-phosphoramidite derivative, reacting the monomer and a nucleoside to form a condensed in- termediate; and converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety, wherein the chiral reagent has following chemical formula (I), HO HN—G% ™ (I) Ng? H = G2 wherein G' and G? are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II), (III) or (V), or both G! and G? taken together to form a group of formula (IV), a2! = un =u pray A G22 wherein G2! to G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C, ; alkyl group, a3! L.gi—GR2 wun dn wherein G3! to G* are independently C,., alkyl group or Cq.,4 aryl group, Cy. alkoxy group, Ce.14 aryl group, Cs.1, aralkyl group, C,4 alkyl Ce.14 aryl group, Cy. alkoxy Ce.14 aryl group, or Ce.14 aryl Cy.4 alkyl group, (Iv) G4 £ G . 5 2 44 wherein G# to G* are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C,.; alkyl group, G51 0 =l= Vv) u —S——_ ) [ER wherein G5! to G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, C,.5 alkyl group or C,.; alkyloxy group, and G? and G* are independently a hydrogen atom, C,.; alkyl group, Ce.14 aryl group, or both G® and G# taken together to form a heteroatom- containing ring that has 3 to 16 carbon atoms.

21. The method for synthesis of stereocontrolled phosphorus atom- modified oligonucleoside derivatives in accordance with claim 20, wherein the wherein the chiral reagent has following chemical formula IT). HO HN— TN No I H tL G2

22. The method for synthesis of a stereocontrolled phosphorus atom- modified oligonucleotide derivative in accordance with claim 20, wherein the chiral reagent is represented by III-a, III-b, V-a, VII-a, VII- b, IX-a, IX-b, XI-a, XIII-a and XIII-b: (S)-2-(Methyldiphenylsilyl)-1-((S)-pyrrolidin-2-yl)ethanol (III-a) (R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (III-b) (S)-2-(Trimethylsilyl)-1-((S)- 1-pyrrolidin-2-yl)ethanol (V-a) (R)-2,2-Diphenyl-1-((S)-pyrrolidin-2-yl)ethanol (VII-a) (S)-2,2-Diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (VII-b) (R)-2-(4-Nitrophenyl)-1-((S)-pyrrolidin-2-yl)ethanol (IX-a) (S)-2-(4-Nitrophenyl)-1-((R)-pyrrolidin-2-yl)ethanol (IX-b) (R)-(9H-Fluororen-9-y1)((S)-pyrrolidin-2-yl)methanol (XI-a) (S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a) (R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b)

23. A method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives comprising steps of: reacting a nucleoside 3'-phosphoramidite derivative which is rep- resented by formula (Va) or (Vb), with an activating reagent and a nu- cleoside to form a condensed intermediate; and converting the condensed intermediate to the nucleic acid comprising a chiral X- phosphonate moiety. GcSo— Bs GSo— cy | Res | R2 od (Va) I (Vb) 5 nN es Ns Nes > a a? S G3 H 1 G2?

24. The method for synthesis of stereocontrolled phosphorus atom- modified oligonucleotide derivatives in accordance with claim 23, wherein the nucleoside 3'-phosphoramidite derivative is represented by formula (Va") or (Vb). a0. Bs: is G50. - Bs Gfo— Bs ° > RY] | Ss R2 oo bow ! o Ne o” SN— x 4 7 H. or { NS H. 1 1,

25. The method for synthesis of stereocontrolled phosphorus atom- modified oligonucleotide derivatives in accordance with claim 23, wherein the nucleoside 3'-phosphoramidite derivative is represented by formula 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, Oa, Ob, 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, 1 2 / Te ~N 0 TO No Ay a GE 0 Bh NS 4 cN ora oMTIO— OW PA oP eo H 1 { AN N— LP NS GCN ae. 0 PTO a Ny Po 0) o AS: EN 0 9 9 A ’ ; T Ft ~~ 4 o TO N ) a0 DMTIO N=? oy ¢ Sve Po $ on qm NS o TO ae me o N=NN . A mm & Sie 9 PX ] q Pip ~N 5 Site oN N XN ¢ DMTIO ECE Som ey UA Xo oda Sve b on qe ~~ oN LY 3 PUTO 0 nN ENN H 3 PS Dh o N— o NH & o_o J od bue x 1 Oh N qn ~~ o Cy oo oo) ¢ me 6 A CN ~~ 0 TO Ne Ay wy J § 4 a 1 | 5 F . 7A ~NS L oN N. x ha TA FE ot P oN LA NS oN N x STN 9 DMTIO SC A orn eed Ll L bf A Ce “No NH me ox 9 4 We 20 Cl oe 0 7 § Oodl 1 OO . lad } § 4 Pon ; q rr ~N a win oJ 9 boy i PS Sa ~~ PN Jorn tom § br PS TN NS | Sd broom 0 J NH © v DMTIO ELIA oy YH A J Strom NS N NH / DMTIO erg ey VOR oh. hen SS dtom rom b & CN NS Oo Cr MO oy yo] ¢ brom ! NS 20 N. DMTrO: $2 N pC i NS 7 NS CN 5 o DMTIO S LA Horn o H —d A Ph 3 Me—Si NS 5h = ’ N © DMT / O S (A Hom < H — A oh a tari? “nr” h ~N 0 Cr Poo Na 9 Oo 9 NH are LE 9 "ON— “5 Lo $ T 2 ON. g SN nS 7 qn ~~ OF wherein DMTr represents a 4,4'-dimethoxytrityl group an represents a triisopropylsiloxymethyl group.

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