699 results about "Stereoselectivity" patented technology

The invention provides a carbonyl reductase mutant. The carbonyl reductase mutant is obtained by performing single-point mutation or multi-point combined mutation on the 17th site, the 40th site and the 64th site of an amino acid sequence as shown in SEQ ID NO.1. The invention also provides a coding gene, a recombinant vector containing the coding gene, a co-expression engineering bacterium and an application of the co-expression engineering bacterium. Compared with a wild type enzyme, the carbonyl reductase mutant has high activity and high stereoselectivity, the enzyme activity can reach more than two times that of the wild type enzyme, the catalytic efficiency on a substrate precursor ketone is remarkably improved, the yield of a statin drug intermediate and chiral alcohol synthesized by an enzyme method of the carbonyl reductase mutant is remarkably improved, and the yield of a rosuvastatin intermediate (3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R, 3R) is remarkably improved. The highest yields of the (3R, 5R)-6-chloro-3, 5-dihydroxyhexanoic acid tert-butyl ester and the atorvastatin intermediate (3R, 5R)-6-cyano-3, 5-dihydroxyhexanoic acid tert-butyl ester reach 99% and 97.6% respectively, e.e. Is larger than 99%, and the method has high industrial application value.

The invention discloses a preparation method of a pyrazolone amino-acid ester derivative. The pyrazolone amino-acid ester derivative is obtained through three-component cascade reaction by taking pyrazolone imine, a pentafluorophenylacetate derivative and alcohol as reactants and chiral isothiourea as a catalyst. According to the invention, challenges of competitive side reactions between a plurality of reaction substrates and intermediates and stereoselectivity control are overcome, the application range of the substrate combination of the existing system is broken through, and synthesis of a series of pyrazolone amino-acid ester derivatives is realized in a green and efficient manner. According to the method disclosed by the invention, substrate preassembly is not needed, transition metal catalysis is not needed, raw materials and the catalyst are cheap and easy to obtain, reaction conditions are mild, and the substrate application range is wide. In addition, the invention also provides a new way for introducing the medicine bioactive molecules into the synthesis of the pyrazolone amino-acid ester compound.

The invention discloses a haloalkane dehalogenase mutant and an application thereof in degradation of 1, 2, 3-tribromopropane, haloalkane dehalogenase DhaA31 coded by dhaA gene of a Rhodococcus rhodococcus NCIMB 13064 strain is modified to obtain the haloalkane dehalogenase mutant F168W / I246C, the haloalkane dehalogenase mutant has high degradation efficiency on haloalkane pollutant 1, 2, 3-tribromopropane, and the haloalkane dehalogenase mutant has high degradation efficiency on haloalkane pollutant 1, 2, 3-tribromopropane under the condition of water phase normal temperature. The degradation rate of the alkyl halide dehalogenase mutant to 10 mM of 1, 2, 3-tribromopropane within 1 h reaches 100%, and the degradation rate of the alkyl halide dehalogenase mutant to 10 mM of 1, 2, 3-tribromopropane reaches 100%. The haloalkane dehalogenase mutant has high stereoselectivity on (R)-2, 3-dibromo-1-propanol, and the e.r. Value of the haloalkane dehalogenase mutant reaches 6: 94. The haloalkane dehalogenase mutant provided by the invention has high catalytic efficiency and high stereoselectivity, is beneficial to recognition and further degradation of downstream enzymes, and has a good application prospect in bioremediation of emerging haloalkane pollutants.

The invention provides a dihydropyrimidinase mutant, a related product of the dihydropyrimidinase mutant and application of the dihydropyrimidinase mutant in production of a medical intermediate (R)-3-(carbamylmethyl)-5-methylhexanoic acid or an analogue of the (R)-3-(carbamylmethyl)-5-methylhexanoic acid. It is found for the first time that wild type dihydropyrimidinase shown in SEQ ID NO: 1 and a dihydropyrimidinase mutant modified by the wild type dihydropyrimidinase can effectively catalyze a substrate to generate a medical intermediate (R)-3-(carbamylmethyl)-5-methylhexanoic acid; particularly, compared with wild type dihydropyrimidinase, the dihydropyrimidinase mutant has the advantages that the dihydropyrimidinase activity is remarkably improved, the organic solvent tolerance and the high-temperature tolerance are relatively high, and the stereoselectivity of a product obtained by catalysis of the dihydropyrimidinase mutant is relatively high; therefore, the (R)-3-(carbamylmethyl)-5-methylhexanoic acid or the analogue thereof can be produced at lower cost and higher efficiency, and the method has higher industrial value.

The invention belongs to the technical field of biological catalysis, and particularly relates to four R-transaminase and application thereof in asymmetric synthesis of chiral N-heterocyclic amine active drug intermediates. The amino acid sequences of the R-transaminase disclosed by the invention are shown as SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5 and SEQ ID NO. 7. Four kinds of R-transaminase are obtained through gene mining and screening, and recombinant escherichia coli is constructed and expressed by adopting a gene engineering technology. The obtained R-transaminase can be used for synthesizing chiral drug intermediates (R)-3-amino-N-Boc-pyrrole (1b) and (R)-3-amino-N-Boc-piperidine (2b) with high stereoselectivity, and has a good application prospect.

The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.

The invention discloses a dihydrodaidzein reductase mutant and application of the dihydrodaidzein reductase mutant in synthesis of (3S, 4R)-tetrahydrodaidzein, and belongs to the technical field of biology. According to the mutant, wild-type dihydrodaidzein reductase DHDR is taken as a parent, single-point mutation or combined mutation is carried out, and a DHDR mutant is obtained; the parent site of the single point mutation is one of the 120th site, the 122nd site, the 170th site, the 178th site, the 214th site, the 219th site, the 220th site or the 220th site; the combined mutation adopts two modes: one mode is that a single-point mutation DHDR mutant is taken as a parent, mutation is carried out, and a combined mutation mutant I is obtained; and 2, taking the DHDR combined mutation mutant I as a parent, and performing mutation to obtain a combined mutation mutant II. The DHDR mutant disclosed by the invention is used for synthesizing (3S, 4R)-tetrahydrodaidzein by reducing dihydrodaidzein, and asymmetric reduction with high activity and high stereoselectivity can be realized.

The invention discloses an aldehyde reductase mutant and application thereof in synthesis of a dexmethylphenidate hydrochloride intermediate, and belongs to the field of molecular biology and enzyme engineering. The aldehyde reductase mutant, polynucleotide for coding the mutant, and the recombinant expression vector can express the aldehyde reductase mutant and are used for constructing a recombinant cell or a recombinant strain for expressing the aldehyde reductase mutant. The provided aldehyde reductase mutant can catalyze 2-phenyl-2-((R)-piperidine-2)-acetaldehyde into (R)-2-phenyl-2-((R)-piperidine-2)-1-ethanol, especially improves the stereoselectivity of (R)-2-phenyl-2-((R)-piperidine-2)-1-ethanol, solves the problems of strict conditions, complex reaction and high cost in the existing synthesis method, and has a wide application prospect in the field of synthesis of (R)-2-phenyl-2-((R)-piperidine-2)-1-ethanol. Wide application prospects are realized.

The invention discloses a carbonyl reductase mutant as well as a preparation method and application thereof, and belongs to the technical field of gene engineering and enzyme engineering. According to the invention, wild-type carbonyl reductase of Stachybotrys chlorohallonata is taken as an evolution template, and a plurality of mutants with catalytic activity, thermal stability and substrate spectrum obviously superior to those of the wild-type carbonyl reductase are obtained through an enzyme engineering technology. The carbonyl reductase mutant can catalyze various prochiral carbonyl compounds to obtain chiral alcohol with high stereoselectivity (ee is greater than 99%). The carbonyl reductase mutant provides a novel, efficient and environment-friendly technical route for industrial production of chiral alcohol products, and has very high industrial application potential.

The present application relates to imine reductases useful in the synthesis of high optical purity amines, and specifically provides engineered polypeptides having improved imine reductase activity and / or stereoselectivity compared to wild-type sequences, and further, to the synthesis of high optical purity amines. The invention provides a fusion protein of the engineered polypeptide, a polynucleotide, a nucleic acid construct, an expression vector, a host cell, a composition and a method for catalytically synthesizing chiral amine by using the engineered polypeptide.

The invention belongs to the technical field of biological catalysis, and particularly relates to application of R-transaminase and a mutant thereof in asymmetric synthesis of chiral amine compounds. The amino acid sequence of the R-transaminase is as shown in SEQ ID NO. 1. The amino acid sequences of the R-transaminase mutants are respectively shown as SEQ ID NO: 2 (G66L), 3 (F127A), 4 (F127M), 5 (G66L / F127M), 6 (G66L / F127A), 7 (G66L / F127M / L160I) and 8 (G66L / H67N / F127M / L160I). The recombinant transaminase mutant obtained by the invention has the advantages of high catalytic activity, strict stereoselectivity, mild reaction conditions and the like for various cyclic ketone and N-heterocyclic ketone compounds.

The invention provides a method for constructing planar chiral [2, 2] paracyclophane by cobalt-catalyzed asymmetric carbon-hydrogen bond activation-kinetic resolution, which comprises the following steps: by using a cobalt catalyst, a chiral ligand and an additive, taking a graphite felt electrode as an anode and taking a platinum sheet electrode as a cathode, carrying out racemization on [2, 2] paracyclophane under the condition of direct-current electrolysis, so as to obtain the planar chiral paracyclophane. The preparation method comprises the following steps: carrying out asymmetric carbon-hydrogen bond dehydrogenation coupling / kinetic resolution on 2, 2] paracyclophane formamide and aryl acid, and after the reaction is finished, carrying out corresponding post-treatment to obtain planar chiral [2, 2] paracyclophane formamide and planar chiral oxopara-[2, 2] paracyclophane; according to the method, electrochemical synthesis of planar chiral oxara-[2, 2] paracyclophane is realized through a method for catalyzing asymmetric carbon-hydrogen bond activation by virtue of a crustal high-yield transition metal, a reaction substrate is wide in universality and excellent in stereoselectivity, and a product and a split and recycled raw material can have an excellent ee value (up to gt; 99% ee) and a splitting factor (up to 1057).

The invention discloses an enzyme catalytic synthesis method of a luliconazole chiral intermediate, which comprises the following steps: adding a recombinant escherichia coli wet cell for expressing alcohol dehydrogenase, a recombinant escherichia coli wet cell for expressing formate dehydrogenase, a buffer solution, a substrate, a cosolvent, ammonium formate and a coenzyme into a reaction container, reacting at 25-35 DEG C for 2-24 hours, extracting, separating, and carrying out rotary evaporation, thereby obtaining the luliconazole chiral intermediate. The luliconazole chiral intermediate is obtained; the substrate is 2, 2 ', 4'-trichloroacetophenone; the alcohol dehydrogenase is a mutant of AKR3. The method is mild in reaction condition, environmentally friendly, high in regioselectivity and stereoselectivity, high in conversion rate, high in chiral purity, small in enzyme dosage, low in preparation cost and suitable for industrial production.

The invention discloses a benzaldehyde lyase derived from Pseudomonas fluorescens, a mutant of the benzaldehyde lyase, and an application of the benzaldehyde lyase and the mutant of the benzaldehyde lyase as a catalyst in catalysis of chiral amino alcohol. The invention further discloses a preparation method of the benzaldehyde lyase and the mutant of the benzaldehyde lyase. The benzaldehyde lyase disclosed by the invention has the advantages of high reactivity, high stereoselectivity, wide substrate range and the like, the yield is as high as 99%, the ee value is as high as 99%, low-cost production is favorably realized, and the benzaldehyde lyase has an industrial application prospect.

A pharmaceutical composition comprises a GPCR agonist fusion protein in which a GPCR agonist peptide is covalently coupled to albumin via a linker in a manner that is resistant to a retro-Michael addition. Advantageously, compositions presented herein avoid decoupling of the agonist form the albumin while retaining the agonist in a steric relationship to the albumin that allows for effective binding and activation of the GPCR while also enabling gp60-mediated transcytosis and FcRn-mediated albumin recycling. These properties enable ultra-low dosages for the GPCR agonist fusion protein to give a therapeutic effect while substantially reducing or even entirely avoiding adverse effects otherwise commonly associated with unbound agonists. Such retro-Michael resistant composition is generally achieved by conformational modification of the albumin, resulting in stereoselective coupling of the linker to the albumin.

A pharmaceutical composition comprises a GPCR agonist fusion protein wherein the GPCR agonist peptide is covalently conjugated to an albumin via a linker in a manner that is resistant to a reverse Michael addition. Advantageously, the compositions presented herein avoid uncoupling of the agonist to the albumin while maintaining the agonist and the albumin in a spatial relationship that allows efficient binding and activation of the GPCR while also enabling gp60-mediated endocytosis transport and FcRn-mediated albumin recirculation. These characteristics enable ultra-low doses of GPCR agonist fusion proteins to produce therapeutic effects while significantly reducing or even completely avoiding side effects that would otherwise be typically associated with unbound agonists. Such reverse Michael resistant compositions are typically achieved by conformationally modifying an albumin, resulting in a stereoselective coupling of a linker to the albumin.

The application discloses a method for preparing a CGRP receptor antagonistic intermediate, and belongs to the field of synthesis of medical intermediates. Compound 1 is used as a raw material, reacts with hydroxylamine hydrochloride in an organic solvent to generate an intermediate 2, and then reacts in the presence of a reducing agent to obtain a remikiren intermediate 3. The application is characterized in that a large steric hindrance silicon group is used as the R substituent in the compound 1, so that high stereoselectivity is ensured in the reduction reaction. The key intermediate obtained by using the method has high chiral purity, and the operation is simple, so that the industrial production of the product in the later stage can be realized.

The invention discloses ethanol dehydrogenase, recombinant genetically engineered bacteria and application of the ethanol dehydrogenase in asymmetric reduction of prochiral carbonyl compounds, the ethanol dehydrogenase has good biological performance, heterologous expression in Escherichia coli engineering bacteria is achieved, intracellular coenzyme can be directly utilized when whole cells are adopted as a catalyst, and the catalyst has a good application prospect. Zero addition of the coenzyme is realized, the enzyme has the advantages of high activity, high stereoselectivity, wider substrate spectrum and the like, prochiral ketone compounds can be greenly and efficiently catalyzed to be converted into corresponding chiral alcohols, and the problems of low conversion rate, low yield, low e.e. Value, complex reaction process, more byproducts and the like in a traditional chemical method are solved. The ethanol dehydrogenase has good tolerance to isopropanol, and the isopropanol can be used as a hydrogen source to realize the circulation of coenzyme. And the byproduct acetone generated by the enzyme catalytic reaction and the isopropanol remaining in the reaction can be separated and recovered by a technical means, so that the production cost is greatly reduced.

The invention discloses application of double enzymes in one-step preparation of L-selenium methyl selenocysteine, and belongs to the technical field of biochemical engineering. In the method, racemic N-acetyl selenium methyl selenocysteine is used, and the L-selenium methyl selenocysteine with high optical purity is prepared in a green and efficient manner through co-catalysis of stereoselective L amino acid acylase and N-acetyl amino acid racemase. The catalyst is prepared through fermentation by adopting a one-bacterium two-enzyme method. Synchronous racemization and selective hydrolysis are realized by a one-step method, the theoretical conversion rate is 100%, the actual conversion rate is 95%, and the product is e.egt; the concentration of the substrate is 8%.

The invention belongs to the field of chemical synthesis, and particularly relates to four acinetobacter baumannii cell wall oligosaccharide fragments as well as a synthesis method and application thereof. Four acinetobacter baumannii core oligosaccharide fragments are synthesized by adopting a divergent synthesis strategy, compounds 1-3 take orthogonally protected alpha-(2-> 5)-Kdo-Kdo disaccharide as key precursors, protecting groups at different sites are selectively removed, glycosyl is introduced through a stereoselective glycosylation reaction, and thus a target molecular skeleton is constructed. The method disclosed by the invention and the four finally prepared acinetobacter baumannii core oligosaccharide fragments have huge industrial application potential.

The invention belongs to the technical field of organic synthesis and medicinal chemistry, and discloses a total synthesis method of rhododendron heteroterpenin Rhododaurines A-C. The total synthesis method comprises the following steps: carrying out allyl stereoselective addition on a compound 3 and a compound 5 in a toluene solvent under the conditions of catalysis of n-butyllithium and low temperature of-78 DEG C, and constructing a chiral center to obtain a compound 6; removing a methoxy methyl (MOM) protecting group from the compound 6 under an acidic condition, cyclizing, and reacting to generate rhododaurine C (7); the rhododaurine C (7) is subjected to intramolecular [4 + 2] cycloaddition and oxidation reaction in the illumination and oxygen atmosphere of 300-385 nm, and rhododaurine B (8) and an epoxy epimer epinedodaurine B (9) are obtained; and carrying out protonation and rearrangement on the epidodaurine B (9) by virtue of acid catalysis cyclic ether, so as to generate the rhododaurine A (10). The method can overcome the defects that the content of rhododendron miscellaneous terpenoids Rhododaurines A-C in nature is extremely low, and large-scale extraction is difficult.

The invention relates to a method for preparing (S)-chiral amine through asymmetric catalysis of imine reductase, and belongs to the technical field of biological pharmacy. Comprising the following steps that imine reductase catalyzes imine to be subjected to a reductive hydrogenation reaction under the conditions of coenzyme and a coenzyme regeneration system, and the (S)-chiral amine compound is generated. According to the method, imine reductase is utilized to catalyze imine asymmetric reduction to prepare the innovative drug (S)-chiral amine compound, and compared with a traditional chemical synthesis method, the method has the advantages of being high in reaction efficiency, good in stereoselectivity, mild in reaction condition, environmentally friendly and the like, and is a method meeting the green production requirement.

The invention discloses a nitrilase mutant and application of the nitrilase mutant in synthesis of a brivaracetam chiral intermediate, and provides an efficient (R)-3-cyanohexanoic acid nitrilase synthesis process by constructing the nitrilase mutant with improved catalytic activity and stereoselectivity. The requirement of industrially synthesizing the brivaracetam key chiral intermediate is met, and a foundation is laid for industrial production of brivaracetam synthesized by a chemical-enzyme method.

The invention belongs to the technical field of asymmetric catalysis, and discloses a chiral phosphine nitrogen-nitrogen tridentate ligand based on a ferrocene skeleton as well as a preparation method and application of the chiral phosphine nitrogen-nitrogen tridentate ligand. The structural formula of the ligand is shown as (I) or an enantiomer (II) of the ligand. The preparation method comprises the steps of acylation reaction, oxazoline ring construction, aldehyde group introduction, reductive amination and the like, and application in asymmetric hydrogenation reaction, such as asymmetric hydrogenation of aryl ketone. The ligand has a plurality of chiral factors, simultaneously has a potential hydrogen bond donor, forms secondary interaction with a substrate in an asymmetric catalytic reaction, can further stabilize a reaction transition state, is an efficient novel chiral P, N, N-ligand, has the advantages of high reaction activity, good stereoselectivity, wide substrate range and the like, and has a wide application prospect. # imgabs0 #

The invention discloses a tryptophan synthetase trp B modified gene and a preparation method of 6-fluoro-L-tryptophan, belongs to the technical field of gene modification and amino acid synthesis, and provides a tryptophan synthetase trp B gene subjected to mutation modification, and the nucleotide sequence of the tryptophan synthetase trp B gene is shown as SEQ ID NO.1. After gene modification, substrate molecules can enter the channel more easily. After gene modification, a channel of an active center of tryptophan synthetase is more beneficial to entering of substrates 6-fluoroindole and L-serine, and the yield of 6-fluoro-L-tryptophan is increased. According to the method, a specific strain containing tryptophan synthetase is adopted, tryptophan synthetase can be efficiently expressed by culturing in an optimized culture medium, so that the 6-fluoro-L-tryptophan synthesized by an enzymic method has relatively high catalytic rate and conversion rate, the molar conversion rate of L-serine reaches 86.5% or above, the reaction conditions of the enzymic method synthesis are mild, the enzyme stereoselectivity is strong, the catalytic efficiency is high, and the method is suitable for industrial production. The method is suitable for industrial production.

The invention provides a preparation method of sitafloxacin intermediate 5-benzyl-7 (S)-tertiary butyl carbonyl amino-5-azaspiro [2, 4] heptane, which comprises the following steps: carrying out condensation reaction on 5-benzyl-4, 7-dioxo-5-azaspiro [2, 4] heptane serving as an initial raw material and (S)-tertiary butyl sulfinamide to obtain imine, reducing the imine and reducing amide under the action of a reducing agent to obtain 5-benzyl-7 (S)-tertiary butyl carbonyl amino-5-azaspiro [2, 4] heptane. And removing tert-butyl sulfinyl from the obtained reduction product under an acidic condition, and finally, carrying out protection by tert-butyloxycarboryl to obtain the 5-benzyl-7 (S)-tert-butyl carbonyl amino-5-azaspiro [2, 4] heptane. The synthesis method provided by the invention is simple and convenient to operate, mild in reaction condition, relatively short in production period, good in stereoselectivity and more suitable for industrial production, and the obtained product has high yield and optical purity.

The invention provides immobilized ketoreductase, an immobilization method and application of the immobilized ketoreductase in preparation of a key intermediate of bentonatate, the amino acid sequence of the ketoreductase is as shown in SEQ ID NO.2, preferably a ketoreductase mutant is as shown in SEQ ID NO.16, and the immobilized ketoreductase comprises resin and corresponding ketoreductase. The ketoreductase mutant and the immobilized ketoreductase prepared from the ketoreductase mutant are very high in enzyme activity during ketoreduction reaction, and when the ketoreductase mutant is used for preparing a key intermediate of bentonamate, a solvent is pure water, so that the ketoreductase mutant and the immobilized ketoreductase prepared from the ketoreductase mutant are environment-friendly. The immobilized transaminase is high in conversion rate, good in stereoselectivity, good in stability, reusable and simpler to operate, so that the production cost is reduced, and industrial production is facilitated.

The invention discloses an olefin reductase, a coding gene, a carrier, an engineering bacterium and an application of the olefin reductase. An olefin reductase SeER mutant is obtained by carrying out single-point or multi-site site-directed mutagenesis or site-directed saturation mutagenesis on the 38th site, the 117th site, the 248th site, the 293th site and the 373th site of an amino acid sequence shown in SEQ ID NO.2. The invention provides a series of novel olefin reductase SeER mutants capable of efficiently, stereocomplementarily reducing an olefin compound to prepare a chiral compound, chiral GABA derivative drugs such as phenibuterol, baclofen, tolybuterol, pregabalin and the like are successfully synthesized through a chemical-enzyme coupling method, and compared with an existing method, the novel olefin reductase SeER mutants have the advantages that the novel olefin reductase SeER mutants can be used for efficiently and stereocomplementarily reducing the olefin compound to prepare the chiral compound; the strain disclosed by the invention can flexibly regulate and control the configuration of a product, and is high in stereoselectivity and conversion rate.

The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a chiral synthesis method of spiro [cyclopenta [c] carbazole-1, 1 '-isoindoline]-3'-ketone compounds. The compound synthesized by the invention has an isoindolinone skeleton and a carbazole active fragment at the same time. The carbazole compound and the isoindolinone compound are successfully combined in a cyclization mode for the first time, and the chiral compound can be prepared. The invention provides a synthesis method of a chiral spiro [cyclopenta [c] carbazole-1, 1 '-isoindoline]-3'-ketone compound, which has the advantages of mild reaction conditions, green and environment-friendly catalyst, easiness in operation, few synthesis steps, easiness in purification and separation of products, capability of obtaining higher yield and high stereoselectivity, easiness in amplification of reaction, high yield, high yield and high yield, and is suitable for large-scale production of the chiral spiro [cyclopenta [c] carbazole-1, 1 '-isoindoline]-3'-ketone compound. And the method has a wide application prospect.

To provide a novel stereoselective method for producing a cyclic dinucleotide derivative that can be used for an antibody-immunostimulator conjugate, and a production intermediate thereof, and to provide methods for producing a cyclic dinucleotide-linker and antibody-immunostimulator conjugate using the production method.SOLUTION: The present invention relates to a method that makes it possible to produce, in large amounts and with high yield, a cyclic dinucleotide derivative having a desired steric configuration, by using an optically active phosphitylation agent twice, during coupling and cyclization.SELECTED DRAWING: None