Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki–Miyaura Coupling

Abstract

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki–Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of Pd(OAc)2/RuPhos catalytic system. Both the enol tosylation and Suzuki–Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either E- or Z-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki–Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species.

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities

“…The resulting enolates in poorly coordinating trialkylamines form mixed aggregates E -15 and Z -15 in proportions consistent with trapping experiments. 5 Adding THF converted the mixed aggregates to an ensemble of dimers dominated by homodimer E,E -2 . …”

“…9 Ketone 1 was prepared as described in a preceding paper. 5 Air- and moisture-sensitive materials were manipulated under argon using standard glovebox, vacuum line, and syringe techniques.…”

“…4 Our strategy, outlined in Scheme 1, was fraught with challenges, not the least of which was the requisite E -selective enolization en route to desired olefin E -4 . 5 …”

“…Indeed, 65:1 E/Z selectivity exceeded expectations. 5 In this paper, we describe the combination of spectroscopic, kinetic, and computational methods used to ascertain the origins of the low selectivities observed with LiHMDS/tetrahydrofuran (THF) and the high selectivities observed with LiHMDS/trialkylamine/toluene. …”

Stereo‐Defined Synthetic Route to (E)‐ and (Z)‐Tamoxifen Derived from(E)‐1‐Bromo‐2‐iodoalkenes.

“…The vinyl bromide 2 is a very useful intermediate in preparation of ( E )‐Tamoxifen; thus, 2 in 95% purity was provided to the chemical transformations as depicted in Scheme . As we expected, 2 undertook conventional Suzuki cross‐coupling to afford 4 in 83% yield with full retention of stereochemistry, which means the product 4 is practically single. The starting 5% of impurities in 2 didn't affect the single isomeric formation of 4 .…”