Stereoselective Synthesis of Trisubstituted Olefins by a Directed Allylic Substitution Strategy

Abstract

New methodology for the stereoselective synthesis of trisubstituted olefins is presented. The use of ortho-diphenylphosphanyl benzoate (o-DPPB) as a directing leaving group for copper-mediated allylic substitution with Grignard reagents allowed for the stereoselective construction of a wide range of E olefins, without the need for an adjacent electron-withdrawing group. Our modular three-step approach toward trisubstituted alkenes commenced with geminal α-methylene aldehydes. Addition of an organometallic reagent and introduction of the o-DPPB group by esterification was followed by the o-DPPB-directed copper-mediated allylic substitution with a Grignard reagent to furnish stereodefined trisubstituted olefins. Additionally, incorporation of a stereocenter from the chiral pool allowed the preparation of an enantiomerically pure olefin that bore three alkyl substituents in high E/Z selectivity.

Revised Mechanism for a Ruthenium-Catalyzed Coupling of Aldehyde and Terminal Alkyne

“…It is worth noting that trisubstituted alkenes are valuable synthetic intermediate and their regio- and stereoselective synthesis is generally accepted to be more challenging than that of mono- and disubstituted alkenes. 13,47…”

Catalytic Asymmetric Synthesis of Allylic Alcohols and Derivatives and their Applications in Organic Synthesis

“…Some of the various methods are highly efficient for the synthesis of allylic cyanohydrins in enantiopure form from a,b-unsaturated carbonyl compounds. [128,129] Shibasaki and co-workers have reported a formal total synthesis of fostriecin by a titanium-catalyzed cyanosilylation of ketones (Scheme 45). Both enzymatic and chemically catalyzed approaches have been studied and are summarized in many reviews.…”

“…This ester has been used as a key building block for the stereospecific construction of the major structural motifs of polyketides, such as tribulore and vittatalactone, by employing an o-DPPB-directed allylic substitution with Grignard-derived organocopper reagents (Scheme 44). [128,129] Shibasaki and co-workers have reported a formal total synthesis of fostriecin by a titanium-catalyzed cyanosilylation of ketones (Scheme 45). [130] Tertiary a-cyanoallylic alcohol The main advantage of this catalytic system is that the reaction can be performed on a 50 g scale, and 84 can be recovered by column chromatography on silica gel and used several times without any loss of activity.…”

Michael Addition Initiated Substrate- or Catalyst-Controlled Chemodivergent Three-Component Construction of Fused and Bridged Polycyclic Heterocycles

“…2-Benzylacrylaldehyde (8g) was prepared in one step from hydrocinnamaldehyde according to the literature. 22 Toluene and THF were dried using a M-Braun SPS-800 system. Petroleum ether (PE) refers to a hydrocarbon mixture with a boiling range of 40-60 °C.…”