Michael Cowley

Nature, Published online: 15 April 2025; doi:10.1038/d41586-025-01124-w

Nature, Published online: 15 April 2025; doi:10.1038/d41586-025-01126-8

Nature, Published online: 15 April 2025; doi:10.1038/d41586-025-01125-9

Nature, Published online: 15 April 2025; doi:10.1038/d41586-025-01204-x

A nickel-catalyzed group-exchange strategy has been developed for the direct conversion of aromatic lactones into cyclic hemiboronic acid bioisosteres. Scope evaluation and product derivatization experiments demonstrate broad functional-group compatibility and the synthetic value of this strategy. Furthermore, the application of this methodology to the rapid modification of lactone cores in bioactive molecules underscores its practical utility.

Abstract

Bioisosteric replacement is an important strategy in drug discovery and is commonly practiced in medicinal chemistry; however, the incorporation of bioisosteres typically requires laborious multistep de novo synthesis. The direct conversion of a functional group into its corresponding bioisostere is of particular significance in evaluating structure-property relationships. Herein, we report a functional-group-exchange strategy that enables the direct conversion of aromatic lactones, a prevalent motif in bioactive molecules, into their corresponding cyclic hemiboronic acid bioisosteres. Scope evaluation and product derivatization experiments demonstrate the synthetic value and broad functional-group compatibility of this strategy, while the application of this methodology to the rapid remodeling of chromenone cores in bioactive molecules highlights its utility.

Reactions of the dimeric alkaline earth hydrides, [(BDI)AeH]₂ (BDI=HC{(Me)CNDipp}₂; Dipp=2,6-i-Pr₂C₆H_3; Ae=Mg, Ca), with Ph₃GeH in the presence of THF provide H₂ and [(BDI)AeGePh₃(THF)]. Although the synthesis of the magnesium derivative is complicated by THF ring opening, the calcium reagent is a viable source of the triphenylgermanide nucleophile.

Abstract

The dimeric calcium and magnesium hydrides, [(BDI)AeH]₂ [BDI=HC{(Me)CNDipp}₂, Dipp=2,6-i-Pr₂C₆H₃; Ae=Mg or Ca] do not react with Ph₃GeH in non-coordinating solvent. Addition of THF, however, induces deprotonation and access to monomeric Ae-germanide complexes, [(BDI)Ae{GePh₃}(THF)], both of which have been structurally characterized. Although this process is facile when Ae=Ca, the analogous magnesium-based reaction requires heating to temperatures >100 °C, under which conditions germanide formation is complicated by THF ring opening and the generation of an alkaline earth germyl-C-terminated n-butoxide, [(BDI)Mg{μ₂-O(CH₂)₄GePh₃}]. Reactions of [(BDI)Ca{GePh₃}(THF)] with N,N′-di-isopropylcarbodiimide and benzophenone provide the respective germylamidinate and germylalkoxide derivatives, [(BDI)Ca{(i-PrN)₂CGePh₃}(THF)] and [(BDI)Ca{OC(GePh₃)Ph₂}(THF)], demonstrating its potential as a well-defined and soluble source of the [Ph₃Ge]⁻ anion in nucleophilic addition reactions.

Reactions of [(2,6-Dipp₂C₆H₃)Sn(μ-H)]₂ (Dipp=2,6-i-Pr₂C₆H₃) with [(BDI)AeH]₂ (BDI=HC{(Me)CNDipp}₂; Ae=Mg, Ca) provide heterobimetallic bis-μ₂-hydrido species, [[(BDI)Ae-μ-(H)₂-Sn(C₆H₃-2,6-Dipp₂)]. Although both compounds react with hex-1-ene to provide alkaline earth derivatives of tetravalent organostannides, the magnesium reagent promotes twofold addition of the alkene whereas the calcium-based reaction is arrested after a single hydrostannylation event.

Abstract

Reactions of a m-terphenylhydridostannylene with β-diketiminato magnesium and calcium hydrides provide bis-μ₂-hydrido species, the heterobimetallic constitutions of which are maintained after the addition of THF donor solvent. In both cases, reactions with hex-1-ene result in the formation of tetravalent organostannyl alkaline earth derivatives. Whereas the magnesium reagent undergoes facile twofold addition, the calcium-centered process is arrested after a single alkene reduction event. This contrasting behavior is assessed to result from the heavier alkaline earth element's ability to form a persistent polyhapto interaction with an arene substituent of the m-terphenyl ligand.

Abstract

Abstract