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WO-2026092674-A1 - SYNTHESIS OF AIR-STABLE NEUTRAL SP2-SP3 DIBORON REAGENTS

WO2026092674A1WO 2026092674 A1WO2026092674 A1WO 2026092674A1WO-2026092674-A1

Abstract

Provided is the synthesis of 17 novel neutral sp2-sp3 diboron compounds. Diboron reagents are widely utilized as borylation agents for the incorporation of the boron moiety into organic molecules. The incorporation of boron into organic molecules has significant implications in biomedicine and material science. Boron-containing compounds are pivotal in drug design and the creation of novel materials with enhanced properties. The neutral sp2-sp3 diboron compounds are unsymmetrical diborylation agents. These reagents are expected to facilitate the exploration of novel borylation methodologies and potential synthetic applications.

Inventors

  • Lyu, Hairong
  • Sun, Weixuan
  • YANG, JUNJIE
  • LOU, Xiangyu
  • YE, Zhanqiang
  • TAO, HONGYI

Assignees

  • THE CHINESE UNIVERSITY OF HONG KONG

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241031

Claims (11)

  1. A neutral sp 2 -sp 3 diboron compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, and 17.
  2. The compound of claim 1, wherein 1-17 are sp 2 -sp 3 diboron derivatives.
  3. A pharmaceutical composition comprising the compound of claim 2, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier or excipient.
  4. The pharmaceutical composition of claim 3, wherein the composition comprises one or more sp 2 -sp 3 diboron derivatives selected from the group consisting of derivatives 1-17.
  5. A neutral sp 2 -sp 3 diboron compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of: 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, and 36, wherein LB is an N-heterocyclic carbene (NHC) selected from the group consisting of: 37, 38, 39, 40, 41, 42, 43, 44, and 45, or wherein LB is an N/P donor selected from the group consisting of: 46, and 47, where R 3 is H, methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl, benzyl, or aryl; where R 4 is isopropyl, cyclohexyl, aryl, or H; where R 5 is isopropyl, cyclohexyl, aryl, or H; where R 6 is -SO 2 Ar, benzyl, -COOMe, or -CONMe 2 ; where R 7 is methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl, benzyl, or aryl; where R 8 is methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl, benzyl, or aryl; where R 9 is methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl, benzyl, or aryl; where R 10 is methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl, benzyl, or aryl; where R 11 is C or N; and where R 12 is methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl, benzyl, or aryl.
  6. The compound of claim 5, wherein derivatives 22-47 are sp 2 -sp 3 diboron derivatives.
  7. A pharmaceutical composition comprising the compound of claim 6, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier or excipient.
  8. The pharmaceutical composition of claim 7, wherein the composition comprises one or more sp 2 -sp 3 diboron derivatives selected from the group consisting of derivatives 22-47.
  9. A method for synthesizing novel sp 2 -sp 3 diboron compounds, comprising: (a) performing a reaction of Lewis base with bis (pinacolato) diboron (B 2 pin 2 ) and tetrahydrofuran (THF) ; (b) performing an in-situ reduction with LiAlH 4 on the products of step (a) ; (c) obtaining the sp 2 -sp 3 diboron derivatives of formulas 1-5: 1, 2, 3, 4, and 5, wherein N-heterocyclic carbenes (NHCs) are used as the Lewis base, further comprising performing a reaction of Lewis base with trimethylamine, THF, and B 2 pin 2 to obtain sp 2 -sp 3 diboron derivative 6 of formula: 6, further comprising performing a reaction of Lewis base with triethylamine, THF, and B 2 pin 2 to obtain sp 2 -sp 3 diboron derivative 7 of formula: 7, further comprising performing a reaction of Lewis base with triphenylphosphine, THF and B 2 pin 2 to obtain sp 2 -sp 3 diboron derivative 8 of formula: 8, further comprising performing a reaction of Lewis base with triethylamine-coordinate diboron compound 7, 1, 3-dimesityl-imidazol-4, 5-dihydro-2-ylidene (SIMes carbene) , and THF to obtain diboron derivative 9 9, further comprising performing a reaction of Lewis base with triethylamine-coordinate diboron compound 7, a cyclic (alkyl) (amino) carbene (CAAC) , and THF to obtain diboron derivative 10: 10, further comprising performing a reaction of Lewis base with N-heterocyclic carbene, THF, a trialkylaluminum reagent and subsequently B 2 pin 2 to obtain sp 2 -sp 3 diboron derivatives 11-17: 11, 12, 13, 14, 15, 16, and 17, wherein the trialkylaluminum reagent replaces LiAlH 4 , wherein for diboron derivatives 11-17 the alkyl groups from aluminum agent are transferred to the sp 3 boron.
  10. A method for synthesizing bortezomib, comprising reacting reagent 3 with 3-methylbutyl N,N-bis (1-methylethyl) carbamate, sec-BuLi, and (+) -sparteine to obtain compound 18: 18, wherein compound 18 is further reacted with t BuOK, MeONH 2 , and toluene and subsequently with N-pyrazinoyl-L-phenylalanine, (1H-Benzotriazol-1-yloxy) (dimethylamino) -N, N-dimethylmethaniminium tetrafluoroborate (TBTU) , and diisopropylethylamine (DIPEA) to obtain masked-bortezomib (compound 19) : 19, wherein compound 19 is further reacted with THF and HCl to obtain bortezomib.
  11. A method for synthesizing masked-ixazomib, comprising reacting compound 18 of claim 10 with with t BuOK, MeONH 2 , and toluene and subsequently with 2- (2, 5-dichlorobenzamido)acetic acid, TBTU, and DIPEA to obtain masked-ixazomib.

Description

SYNTHESIS OF AIR-STABLE NEUTRAL SP2-SP3 DIBORON REAGENTS CROSS-REFERENCE TO RELATED APPLICATION The present application claims the benefit of U.S. Provisional Application Serial No. 63/714,184, filed October 31, 2024, which is hereby incorporated by reference herein in its entirety, including any figures, tables, or drawings. FIELD OF THE INVENTION The present invention pertains to a novel air-stable neutral sp2-sp3 unsymmetrical diboron compound that enables the transformation of both sp2 and sp3 boryl groups into substrates leading to unsymmetrical diborylation products. The differing electronic properties of the sp2 and sp3 boryl groups in these diborylated molecules allow for controlled stepwise carbon-boron (C-B) bond transformation reactions for introducing diverse functional groups into target molecules and enable the convenient synthesis of various bioisosteres of commercial medicines. BACKGROUND OF THE INVENTION The incorporation of boron into organic molecules has attracted increased research interest due to its applications in synthetic chemistry [1-9] , biomedicine [10-12] , and material science [13-16] . The design of these boron reagents is primarily according to three principles: (1) diverse reactivities with organic molecules, facilitating boron moieties introduction, (2) good stability and compatibility with various functional groups, and (3) well-controlled selectivity of the borylation reactions using these reagents. The past decades have witnessed the broad application of neutral sp2-sp2 diboron reagents, notably bis (pinacolato) diboron (B2pin2) [17] , which has triggered a variety of borylation reactions and corresponding synthetic applications. The diboron reagents has shown advantages comparing to traditional boron reagents, such as boron halides and boranes, which are sensitive to air/moisture with compromised practicability. However, the classic diboron reagents widely utilized in boron incorporation reactions are sp2-sp2 diboron, in which the two boron atoms are sp2 hybridized or three-coordinated. Most of them are symmetrical, such as B2pin2 and B2cat2. When they are used as diborylation reagents, two identical boryl groups are installed on substrates and need to be differentiated in the late-stage C-B bond transformation, which inhibits their further applications in synthesis. Although several unsymmetrical diboron reagents has been documented, such as Bpin-Bdan, the two sp2 boron moieties share similar electronic properties and reactivities, again making it challenging for late-stage differentiation (Figure 1) . In addition to sp2-sp2 diboron reagents, the unsymmetrical neutral sp2-sp3 diboron reagent represents a promising a new generation of borylation agents. Although several structures have been reported [18-22] , the use of neutral sp2-sp3 diboron as borylation reagent remains relatively underexplored (Figure 2) . Therefore, there is a growing need for the discovery and development of boron synthons or borylation reagents, which are the key to facilitate the incorporation of boron moieties into organic molecules._ BRIEF SUMMARY OF THE INVENTION The subject invention discloses novel sp2-sp3 diboron compounds and their derivatives. In certain embodiments, the neutral sp2-sp3 diboron compounds comprise unsymmetrical diborylation derivatives, which enable the transformation of both sp2 and sp3 boryl groups into substrates, leading to unsymmetrical diborylation products. The significant difference in the electron properties of the two boryl groups make them easily distinguishable in the downstream C-B bond transformations. In certain embodiments, through the reaction of the new reagents with substrates, both two boron moieties in the reagents can be transferred into the substrates. The differing electronic properties of the sp2 and sp3 boryl groups in these diborylated molecules allow for controlled stepwise carbon-boron (C-B) bond transformation reactions for introducting diverse functional groups into target molecules. In certain embodiments, the sp2-sp3 diboron compound of the subject invention is air-stable. In further embodiments, the sp2-sp3 diboron compound can be purified via column chromatography. In certain embodiments, the compound comprises a pharmaceutically acceptable salt thereof. In certain embodiments, the fresh diboron reagents enable the convenient synthesis of various bioisosteres of commercial medicines. In certain embodiments, disclosed herein is a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates sp2-sp2 diboron reagents. Figure 2 illustrates unsymmetrical neutral sp2-sp3 diboron reagents. Figure 3 illustrates the synthesis of neutral sp2-sp3 diboron reagents 1-8a. aAll yields are isolated yields after silica gel chromatography. b1.0 equiv. of LiAlH4 was used. Figure 4 illustrates the sy