Catalytic Cross-Metathesis Reactions That Afford E- and Z-Trisubstituted Alkenyl Bromides: Scope, Applications, and Mechanistic Insights

Abstract

Stereochemically defined trisubstituted alkenes with a bromide and a methyl group at a terminus can be readily and stereoretentively derivatized through catalytic cross-coupling, affording unsaturated fragments found in many bioactive natural products. A direct method for generating such entities would be by stereocontrolled catalytic cross-metathesis (CM). Such methods are scarce however. Here, we present a stereoretentive strategy for CM between tri-, Z- or E-di, or monosubstituted olefins and Z- or E-2-bromo-2-butene, affording an assortment of E- or Z-trisubstituted alkenyl bromides. The majority of the transformations were catalyzed by two Mo monoaryloxide pyrrolide (MAP) complexes, one purchasable and the other accessible by well-established protocols. Substrates, such as feedstock trisubstituted olefins, can be purchased; the alkenyl bromide reagents are commercially available or can be prepared in two steps in a multigram scale. The catalytic process can be used to generate products that contain polar moieties, such as an amine or an alcohol, or sterically hindered alkenes that are α- or β-branched. The utility of the approach is highlighted by a brief and stereocontrolled synthesis of an unsaturated fragment of phomactin A and a concise total synthesis of ambrein. An unexpected outcome of these investigations was the discovery of a new role for the presence of a small-molecule alkene in an olefin metathesis reaction. DFT studies indicate that this additive swiftly reacts with a short-lived Mo alkylidene and probably helps circumvent the formation of catalytically inactive square pyramidal metallacyclobutanes, enhancing the efficiency of a transformation.

Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation

“…While classic reactions for alkene synthesis, such as the Wittig 1 and Julia-Kocienski 2 methods, are reliably used to prepare disubstituted alkenes, challenges associated with forming highly substituted (i.e., tri-and tetrasubstituted) alkenes using these methods limit their broad applicability. Efforts to enable the synthesis of highly substituted alkenes have resulted in the development of catalytic strategies based on olefin metathesis 3 and crosscoupling. 4 As an alternative approach, transition-metal catalysis has been applied to the synthesis of alkenes via the hydroalkylation of alkynes (Figure 1A).…”

Taking Olefin Metathesis to the Limit: Stereocontrolled Synthesis of Trisubstituted Alkenes

“…With 6.0 mol % Z -hex-3-ene, the model reaction between a trisubstituted alkene and the Z - 25 proceeded smoothly (66% 37 ; Scheme a); this was largely expected. The surprise was that, unlike the reactions with trihalo-alkenes (see Scheme c–e), an additive was no longer needed for efficiency (more on this below).…”

“…A tri-, E-or Z-di-, or a monosubstituted olefin could serve as substrate, along with the same purchasable E-and Z-alkenyl bromides as before, but this time to be used in CM, not CC. With 6.0 mol % Z-hex-3-ene, the model reaction between a trisubstituted alkene and the Z-25 proceeded smoothly (66% 37; Scheme 15a); 37 this was largely expected. The surprise was that, unlike the reactions with trihalo-alkenes (see Scheme 12c− e), an additive was no longer needed for efficiency (more on this below).…”

“…Why would an alkene additive impact CM efficiency to such disparate degrees, insomuch that it is required for trihalo-alkenes (Schemes 12-13) but gives just a slight boost with alkenyl bromides (Scheme 15)? We sought help from the Liu group in Pittsburgh, 37 who confirmed that reaction of a neophylidene complex with a trisubstituted alkene is energetically more demanding than with the additive (Scheme 16a). This indicated that there must be another reason why Z-hex-3-ene facilitates CM with trihalo-alkenes.…”

An Anthracene-Thiolate-Ligated Ruthenium Complex: Computational Insights into Z-Stereoselective Cross Metathesis

“…Monoaryloxide chloride Mo-based catalysts also exhibited Z-selective CM reactions involving a series of olefins and Z-1,1,1,4,4,4-hexafluoro-2-butene in benzene at 22 °C . Furthermore, in the same context of the Mo-catalyzed CM framework, notable advances in the synthesis of Z-trisubstituted alkenes have been recently achieved by Hoveyda et al − …”