Development of Novel Phosphine- and Copper-Catalyzed Alkyne Functionalization Methods

Abstract

Organoboron compounds find immense application in organic synthesis and medicinal chemistry. The activation of boron-carbon bonds has enabled the formation of carbon-nitrogen, carbon-oxygen, carbon-sulfur, carbon-hydrogen, and carbon-carbon bonds, making them highly valuable precursors to complex molecules. Unlike many other organometallic reagents used in cross-coupling reactions, organoboron compounds display notable stability and low toxicity, further cementing their value in pharmaceutical science and agrochemical production. Furthermore, medicinal chemists have leveraged the electrophilic character of boron for the development of reversible covalent inhibitors. Five of these compounds have received approval for clinical usage by the Food and Drug Administration (FDA) for various indications. These applications underpin the value of novel reactions that selectively forge carbon-boron bonds. 1,3-Enynes are highly unsaturated substrates that present significant challenges for selective functionalization. Herein, we describe a synthetic protocol for installing a boronic ester (Bpin) into 1,3-enynes with excellent chemo-, regio-, and stereoselectivity. Utilizing a copper catalyst and pinacolborane (HBpin), the boronic ester was delivered to the internal alkyne carbon, a selectivity which had only been previously achieved with the use of directing groups. Both (Z)- and (E)-1,3-enynes are tolerated without isomerization of the alkene, highlighting that (Z,Z)- and (Z,E)-2-boryl-1,3-dienes are accessible with our methodology. The 2-boryl-1,3-diene products were further derivatized into useful functional groups, highlighting their synthetic utility. In a follow-up study, the mechanistic intricacies of the previously disclosed hydroboration reaction were investigated. A kinetic analysis revealed that the 1,3-enyne has first-order kinetics, HBpin has zeroth-order kinetics, and the catalyst (CuOAc and Xantphos) has a positive fractional rate order. These results indicate that hydrocupration (copper-hydride insertion into the alkyne) is rate-limiting and important for governing the observed selectivity. A positive fractional rate order in the catalyst suggests that the copper-hydride catalyst is in rapid equilibrium with an off-cycle complex that is catalytically incompetent. 11B NMR studies involving copper(I) acetate, Xantphos, and HBpin revealed a new peak in the 11B NMR spectra (8.9 ppm), which may be the off-cycle complex. DFT calculations indicate that a cyclic CuHBpinOAc species serves as the off-cycle complex, which is consistent with our experimental data. DFT calculations also corroborated that hydrocupration was rate-limiting and that the transition state leading to internal alkyne borylation was the most energetically accessible. Finally, we developed a mild and convenient approach for the synthesis of α,β-dehydroamino acids using an inexpensive trialkyl phosphine catalyst. α,β-dehydroamino acids are non-canonical amino acids that contain unsaturation between the α- and β-sidechain carbons. This motif appears in many bioactive natural products and the FDA-approved dehydropeptidase inhibitor Cilastatin. The synthesis of α,β-dehydroamino acids has been heavily explored, but most previously established syntheses result in N-protected dehydroamino acids, which have very limited application in the synthesis of complex α,β-dehydroamino acids. The problem arises when attempting to deprotect the N-terminus, resulting in a primary enamine which tautomerizes into the corresponding imine before hydrolyzing into the α-keto ester. To circumvent this issue, we report a straightforward synthetic method that couples complex amides to alkynoates directly, negating any requirement for N-terminal deprotection at the unsaturated amino acid. The reaction relies on a substoichiometric amount of n-tributylphosphine, an inexpensive commodity. Several dehydroamino acid-containing dipeptides were accessed using our method, without epimerization of the chiral center. The α,β-dehydroamino acids were chemically modified into two natural products, one of which (scutianene M) had never been synthesized before.