Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-Hydrogenation of 1,4-Dienes

Abstract

The control of site selectivity in asymmetric mono-hydrogenation of dienes or polyenes remains largely underdeveloped. Herein, we present a highly efficient desymmetrization of 1,4-dienes via iridium-catalyzed site- and enantioselective hydrogenation. This methodology demonstrates the first iridium-catalyzed hydrogenative desymmetriation of meso dienes and provides a concise approach to the installation of two vicinal stereogenic centers adjacent to an alkene. High isolated yields (up to 96 %) and excellent diastereo- and enantioselectivities (up to 99:1 d.r. and 99 % ee) were obtained for a series of divinyl carbinol and divinyl carbinamide substrates. DFT calculations reveal that an interaction between the hydroxy oxygen and the reacting hydride is responsible for the stereoselectivity of the desymmetrization of the divinyl carbinol. Based on the calculated energy profiles, a model that simulates product distribution over time was applied to show an intuitive kinetics of this process. The usefulness of the methodology was demonstrated by the synthesis of the key intermediates of natural products zaragozic acid A and (+)-invictolide.

Keywords: 1,4-diene; asymmetric hydrogenation; iridium catalysis; site selectivity.

Figure 1

a) Strategies for site‐selectivity control in asymmetric mono‐hydrogenation of dienes. b) Ir‐catalyzed hydrogenative desymmetrization of 1,4‐dienes.

Figure 2

Selected examples of natural products and bioactive compounds containing an allylic alcohol or allylic amide bearing two contiguous chiral centers adjacent to an alkene.

Figure 3

Proposed hydrogenation mechanism.

Figure 4

Free energy profile for a) the first hydrogenation; b) the second hydrogenation.

Scheme 1

Hydrogenative desymmetrization process.

Figure 5

Kinetic modeling based on the calculated energy. Concentration in percent of total reactant and product concentration and time in 10⁻⁵ seconds.

Scheme 2

Gram scale desymmetrization and application in the synthesis of the alkyl side chain fragment of zaragozic acid A.

Scheme 3

Synthesis of γ‐butyrolactones via a sequential desymmetrization and tandem hydrogenation and lactonization process: Formal total synthesis of (+)‐invictolide. Reaction conditions: a) 0.5 mol % Ir cat., 10 mol % K₂CO₃, 3 bar H₂, toluene, r.t. 30 min; b) O₃, then DMS, CH₂Cl₂/MeOH 4:1; c) benzene, reflux, 24 h; d) 4‐nitrobenzoic acid, DTBAD, PPh₃, THF; e) K₂CO₃, MeOH, r.t., 1 h; f) 1.0 mol % Ir cat., 3 bar H₂, toluene, r.t. 1 h.