Practical and Modular Construction of C(sp³)-Rich Alkyl Boron Compounds

Abstract

Alkyl boronic acids and esters play an important role in the synthesis of C(sp 3 ) rich medicines, agrochemicals, and other materials. This work describes a new type of transition-metal free mediated transformation to enable the construction of C(sp 3)-rich, and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage functionalization of scaffolds relevant to medicinal chemistry. The strategic significance of this approach, with alkyl boronic acid as a linchpin, is demonstrated through various downstream functionalizations of the alkyl boron compounds. This two-step concurrent cross-coupling approach, resembling formal and flexible alkyl-alkyl couplings, provides a general entry to previously synthetically challenging high Fsp 3 -containing drug-like scaffolds.File list (2) download file view on ChemRxiv Manuscript--Chemrxiv modified.pdf (794.17 KiB) download file view on ChemRxiv chemrxiv SI.pdf (14.12 MiB)

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…Significant contribution in the synthesis of saturated (hetero)aliphatic boronate building blocks by this approach was made by Aggarwal and co-workers; [118,119] an occasionally selected example of this chemistry (reactions of azetidine 13), is given in Scheme 12; [120] (xi) "strain release" organoboron chemistry based on (aza) bicyclo[1.1.0]butane 14 or [1.1.1]propellane ring system opening was also pursued mainly by Aggarwal group (an example is given in Scheme 13 [121] ); (xii) boron-retaining Barluenga-Valdés cross-coupling of sulfonyl hydrazines 15 is illustrated in Scheme 14. [122] The reaction proceeds via intermediate formation of diazoalkanes that can be used in similar transformations directly; [123] (xiii) modification of MIDA boronates. As it was mentioned above, MIDA protection is stable towards a number of standard reagents and conditions used in organic synthesis.…”

Catalytic, Undirected Borylation of Tertiary C–H Bonds in Bicyclo[1.1.1]pentanes and Bicyclo[2.1.1]hexanes

“…Cross-coupling with aryl electrophiles occurred under either metallaphotoredox conditions 40 to form the 3-aryl BCP 1f from the trifluoroborate 1c or by activation with t-BuLi followed by Pd-catalyzed coupling 41 to form the 3-aryl BCP 1g from boronic ester 1a. An intermolecular Barluenga−Valdés coupling 48 afforded 1e from boronic acid 1d, Zweifel olefination afforded the 3-vinyl BCP 11e from boronic ester 11a, heteroarylation afforded the 3-heteroaryl BCP 13c from boronic ester 13a, and Matteson homologation formed the homologated boronic ester 1h from boronic ester 1a. The 3-boryl BCPs also underwent reactions to form heteroatom-substituted BCPs.…”

Saturated Boronic Acids, Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

“…In 2020, Merchant, Qin, and co-authors discovered a new type of transition-metal-free mediated transformation enabling the synthesis of sp 3 -rich sterically hindered saturated boronates in a modular manner closely related to the Barluenga-Valdés reaction. [348] The method was based on the reaction of free boronic acids with generated in situ diazo compound leading to formal insertion of carbene into the CÀ B bond (Scheme 85; cf Scheme 31 [118] ). A broad generality and functional group tolerance of this approach has been confirmed for a huge variety of substrates, including applications for the late-stage functionalization and synthesis of compounds potentially relevant to early drug discovery.…”