Decarboxylative alkenylation

Abstract

Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.

Figure 1. Development of Ni– and Fe–catalyzed decarboxylative alkenylation

a, Conventional route to sterol acetates (2a–c). b, Utilization of previously unavailable electrophiles in cross-coupling reactions. c, Decarboxylative alkenylation presents a potential solution. d, Optimization of decarboxylative alkenylation. ^a0.1 mmol. ^bYield by ¹H NMR with CH₂Br₂ internal standard. ^c0.25 mmol scale, isolated. ^d1.1 equiv. TCNHPI, 1.1 equiv. DIC, CH₂Cl₂ (0.2 M). ^e20 mol% [Ni] and L, 3.0 equiv. alkenylzinc. ^f10 mol% [Fe], 12 mol% dppbz, 1.5 equiv. dialkenylzinc. See Supporting Information for additional details.

Figure 2. Substrate scope of decarboxylative alkenylation

The carboxylic acid component is shown in blue and the alkenyl zinc reagent is shown in green. Cross-coupling using various alkenyl zinc reagents (a, b) and different primary (c), secondary and tertiary (d) acids evaluated. Yields refer to isolated yields of products after chromatography on SiO₂. ^a in situ activation. ^b 3 equiv. alkenylzinc. ^c alkenylzinc derived from commercial Grignard that exists as a mixture of olefin isomers. ^d 10 mol% Fe(acac)₃, 12 mol% dppbz, 1.5 equiv. dialkenylzinc. ^e 2 equiv. alkenylzinc, 2 equiv. MgBr₂·OEt₂. ^f MeCN as solvent. ^g 60 °C. ^h 20 mol% Ni/L, 3 equiv. alkenylzinc, 3 equiv. MgBr₂·OEt₂. ⁱ 20 mol% Ni/L, 5 equiv. alkenylzinc, 5 equiv. MgBr₂·OEt₂. ^j alkenylzinc derived from OBO-ester; see SI for work up details. ^k 3 equiv. alkenylzinc, 3 equiv. MgBr₂·OEt₂. ^l See SI for details regarding mol-scale reaction. ^m 4 equiv. alkenylzinc. ⁿ 4 equiv. alkenylzinc, 4 equiv. MgBr₂·OEt₂. ^o 10 mol% NiCl₂·glyme/4,4′-di-tBuBipy. ^p See SI for details regarding peptide substrates. ^q 20 mol% Ni/L, 5 equiv. alkenylzinc, NMP.

Figure 3. Total synthesis enabled by decarboxylative alkenylation

All decarboxylative alkenylations were performed with in situ activation of the carboxylic acid. See SI for full synthetic details and schemes (a–h). LLS = longest linear sequence. [H] = reduction.