Wave Life Sciences Ltd.

Wave Life Sciences Japan, Inc.

Chiralgen, Ltd.

The University of Tokyo

Mamoru Shimizu

Takeshi Wada

Chandra Vargeese

David Charles Donnell Butler

Pachamuthu Kandasamy

Gopal Reddy Bommineni

Genliang Lu

Naoki Iwamoto

Christopher P Hencken

Subramanian Marappan

Ilia Korboukh

Sethumadhavan Divakaramenon

Keith Andrew Bowman

Alvaro Andres Lanao

Snehlata Tripathi

Vincent Aduda

Stephany Michelle Standley

Mohammed Rowshon Alam

Kouichiro Arai

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.

Compounds, compositions and methods for synthesis

Among other things, the present disclosure provides technologies for oligonucleotide preparation, particularly chirally controlled oligonucleotide preparation, which technologies provide greatly improved crude purity and yield, and significantly reduce manufacturing costs.

Technologies for oligonucleotide preparation

To provide a chiral reagent or a salt thereof. The chiral reagent has following chemical formula (I). In the formula (I), Gand Gare independently a hydrogen atom, a nitro group (&#x2014;NO), a halogen atom, a cyano group (&#x2014;CN), a group of formula (II) or (III), or both Gand Gtaken together to form a group of formula (IV). 

Asymmetric auxiliary group

The disclosed and claimed compounds are chiral auxiliaries useful for efficiently producing a phosphorus atom-modified nucleic acid derivative with high stereoregularity. The disclosed and claimed compounds include those represented by the following formula (I) or formula (XI) for introducing the chiral auxiliaries. 

Chiral auxiliaries

Described herein are methods of syntheses of phosphorous atom-modified nucleic acids comprising chiral X-phosphonate moieties. The methods described herein provide backbone-modified nucleic acids in high diasteteomeric purity via an asymmetric reaction of an achiral molecule comprising a chemically stable H-phophonate moiety with a nucleoside/nucleotide.

Method for the synthesis of phosphorus atom modified nucleic acids

Described herein are methods of syntheses of phosphorous atom-modified nucleic acids comprising chiral X-phosphonate moieties. The methods described herein provide backbone-modified nucleic acids in high diasteteomeric purity via an asymmetric reaction of an achiral molecule comprising a chemically stable H-phosphonate moiety with a nucleoside/nucleotide.

A 2'-modified ribonucleoside having an alkoxymethyl protective group can be imparted with a high duplex-forming ability by introducing, as a substituent, a halogen atom into the protective group moiety. A modified form of RNA having a halogen-substituted alkoxymethyl protective group exhibits a high duplex-forming ability that is comparable to the duplex-forming ability of a 2&#x2032;-O-methyl modified nucleic acid.

2'-O-modified RNA

A protective group represented by the following general formula (I) (the oxygen atom attached with * represents oxygen atom of 2'-hydroxyl group of a ribonucleoside, a ribonucleotide or a derivative thereof; Rand Rboth represent hydrogen atom, or represent a halogen atom, a Calkyl group, or a Chalo-substituted alkyl group; Rand Rrepresent hydrogen atom, a halogen atom, a Calkyl group, or a Chalo-substituted alkyl group; and Rand Rrepresent a halogen atom, a Chalo-substituted alkyl group, cyano group, nitro group, or the like), which is stable under the reaction conditions of the nucleic acid synthetic cycles and has little steric hindrance, and can be removed under mild conditions using fluoride ions as a base. 

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Uruma, Japan

Mamoru Shimizu