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

Abstract

Metrics & MoreArticle Recommendations * sı Supporting Information CONSPECTUS: In this Account, we share the story of the development of catalytic olefin metathesis processes that efficiently deliver a wide range of acyclic and macrocyclic E-or Ztrisubstituted alkenes. The tale starts with us unveiling, in collaboration with Richard Schrock and his team, the blueprint in 2009 for the design of kinetically controlled Z-selective olefin metathesis reactions. This paved the way for the development of Mo-, W-, and Ru-based catalysts and strategies for synthesizing countless linear and macrocyclic Z-olefins. Six years later, in 2015, we found that abundant Z-alkene feedstocks, such as oleic acid, can be directly transformed to high-value and more difficult-to-access alkenes through a cross-metathesis reaction promoted by a Rucatechothiolate complex that we had developed; the approach, later coined stereoretentive olefin metathesis, was extended to the synthesis of E-alkenes.It was all about disubstituted alkenes until when in 2017 we addressed the challenge of accessing stereodefined Z-and Etrisubstituted alkenes, key to medicine and materials research. These transformations can be most effectively catalyzed by Mo monoaryloxides pyrrolide (MAP) and chloride (MAC) complexes. A central aspect of the advance is the merging of olefin metathesis, which delivered trisubstituted alkenyl fluorides, chlorides, and bromides with cross-coupling. These catalytic and stereoretentive transformations can be used in various combinations, thereby enabling access to assorted Z-or E-trisubstituted alkene. Ensuing work led to the emergence of other transformations involving substrates that can be purchased with high stereoisomeric purity, notably E-and Z-trihalo alkenes. Trisubstituted olefins, Z or E, bearing a chemoselectively and stereoretentively alterable F,Cl-terminus or B(pin),Cl-terminus may, thus, be easily and reliably synthesized. Methods for stereoretentive preparation of other alkenyl bromide regioisomers and α,β-unsaturated carboxylic and thiol esters, nitriles, and acid fluorides followed, along with stereoretentive ring-closing metathesis reactions that afford macrocyclic trisubstituted olefins. Z-and E-Macrocyclic trisubstituted olefins, including those that contain little or no entropic support for cyclization (minimally functionalized) and/or are disfavored under substrate-controlled conditions, can now be synthesized. The utility of this latest chapter in the history of olefin metathesis has been highlighted by applications to the synthesis of several biologically active compounds, as well as their analogues, such as those marked by one or more site-specifically incorporated fluorine atoms or more active but higher energy and otherwise unobtainable conformers. The investigations discussed here, which represent every stereoretentive method that has been reported thus far for preparing a trisubstituted olefin, underscore the inimitable power of Mo-based catalysts. This Account also showcases a variety of mechanistic attr...

Synthesis of Z-gem-Cl,CF3-Substituted Alkenes by Stereoselective Cross-Metathesis and the Role of Disubstituted Mo Alkylidenes

“…We began by following the tenets of stereoretentive olefin metathesis (Scheme a), , namely that CM of alkenes 1 and purchasable 2a would afford gem -Cl,CF 3 -substituted 3a . A range of complexes were screened but none promoted CM (<2% 3a as judged by 1 H NMR analysis; Scheme b; see the Supporting Information for additional details).…”

“…However, this would likely be energetically prohibitive. Based on the previous studies, , we expected that reaction of Cl-substituted alkylidene Alkyd-2 with 1 to start a new cycle via syn - mcb-3 would not be problematic.…”

“…We will describe below the results of an investigation regarding the development of a cross-metathesis (CM) method for preparing Z -trisubstituted alkenes bearing a chloro and a trifluoromethyl terminus. Despite the involvement of a trisubstituted alkene, the optimal process turned out to be stereo selective and not stereoretentive, that is, unlike the approaches recently disclosed. , Equally notable is the new light shed on the chemistry of Cl,CF 3 -disubstituted Mo alkylidenes and their role in catalytic olefin metathesis . Information is scant regarding such organometallic entities, likely to be vital to the development of methods for synthesis of E - and Z -tetrasubstituted olefins …”

“…The importance of stereodefined organofluorine compounds aside, , we were keen on exploring the limits of olefin metathesis reactions involving two trisubstituted alkenes . We opted for stereodefined olefins bearing a gem -Cl,CF 3 -substituted terminus as products.…”

“…With the development of methods for synthesis of E - and Z -trisubstituted olefins (mainly by Mo catalysts) gaining steam, the role of disubstituted alkylidenes has come under scrutiny. In 2017, we reported a study aimed at the development of a stereoretentive CM method for synthesis of stereodefined trisubstituted olefins (Scheme b).…”