Streamlined Catalytic Enantioselective Synthesis of α-Substituted β,γ-Unsaturated Ketones and Either of the Corresponding Tertiary Homoallylic Alcohol Diastereomers

Pozo, Juan del; Zhang, Shaochen; Romiti, Filippo; Xu, Shibo; Conger, R. P.; Hoveyda, Amir H.

doi:10.1021/jacs.0c08732

Cited by 32 publications

(4 citation statements)

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“…Most recently, elegant studies by Hoveyda disclosed a method for the synthesis of α‐quaternary ketones by addition into nitriles. Reactions proceed via ketimine intermediates that are hydrolyzed in situ to the corresponding ketones (Scheme 1A) [18] . Of note, the method is not limited to aryl‐substituted quaternary carbons; three dialkyl α‐quaternary ketones formed in high enantioselectivity are reported.…”

Section: Methodsmentioning

confidence: 99%

“…Reactions proceed via ketimine intermediates that are hydrolyzed in situ to the corresponding ketones (Scheme 1A). [18] Of note, the method is not limited to aryl-substituted quaternary carbons; three dialkyl α-quaternary ketones formed in high enantioselectivity are reported. Overall, these methods are efficient and afford ketone products in excellent stereoselectivity, however, the in situ nature of the reactions renders synthesis of various dialkyl-substituted (or diaryl) quaternary stereo-centers problematic.…”

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confidence: 99%

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A Catalytic Method for the Enantioselective Synthesis of α‐Quaternary Ketones, α‐Ketoesters and Aldehydes

et al. 2023

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A practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α-quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkylsubstituted ketone and aldehyde products in 25-94 % yield and 90 : 10 to > 99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

A Catalytic Method for the Enantioselective Synthesis of α‐Quaternary Ketones, α‐Ketoesters and Aldehydes

et al. 2023

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“…Organonitriles are robust, yet versatile, compounds . We reasoned that an E - or a Z -alkenyl nitrile may be obtained through CM with purchasable fumaronitrile ( E ) or easily accessible maleonitrile ( Z ) or a mixture thereof ( 45 ) .…”

Section: αβ-Unsaturated Nitriles Esters and Acid Fluoridesmentioning

confidence: 99%

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

Hoveyda,

Qin,

Sui

et al. 2023

Acc. Chem. Res.

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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...

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“…Hoveyda and co-workers found that using a chiral copper catalyst, the three-component coupling of allene, diboron, and nitrile furnished -substituted ,-unsaturated ketones in high regioselectivity and enantioselectivity after hydrolysis (Scheme 15). 22 Acyclic quaternary carbon stereocenters were constructed from 1,1-disubstituted allenes. Although a strong internal coordination of C=N to boron was observed in the NH-ketimine intermediate, the  stereocenter was not epimerized under the mild conditions.…”

Section: Scheme 14 Cu-catalyzed Boroacylation Of Allenesmentioning

confidence: 99%

Acyclic Quaternary Carbon Stereocenters through Transition-Metal-Catalyzed Enantioselective Functionalization of Unsaturated Hydrocarbons

Li¹,

Sun²

2022

Synthesis

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Acyclic quaternary carbon stereocenters occur frequently in natural products, bioactive molecules, and pharmaceutical compounds. Construction of a carbon stereogenic center attached to four different carbons with defined spatial arrangement is a daunting challenge in asymmetric catalysis. Significant efforts have been directed towards the stereoselective construction of such acyclic quaternary carbon stereocenters. In particular, catalytic generation of acyclic quaternary carbon stereocenters through functionalization of unsaturated hydrocarbons is an extremely attractive approach because unsaturated hydrocarbons are easily accessible both in industry and in organic synthesis. In this short review, we summarize the recent advances achieved in this research area, with the aim to inspire future development.1 Introduction2 Acyclic Quaternary Carbon Stereocenters through Functionalization of Allenes3 Acyclic Quaternary Carbon Stereocenters through Functionalization of Dienes4 Acyclic Quaternary Carbon Stereocenters through Functionalization of Mono-alkenes5 Acyclic Quaternary Carbon Stereocenters through Functionalization of Alkynes6 Summary and Outlook

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Streamlined Catalytic Enantioselective Synthesis of α-Substituted β,γ-Unsaturated Ketones and Either of the Corresponding Tertiary Homoallylic Alcohol Diastereomers

Cited by 32 publications

References 71 publications

A Catalytic Method for the Enantioselective Synthesis of α‐Quaternary Ketones, α‐Ketoesters and Aldehydes

A Catalytic Method for the Enantioselective Synthesis of α‐Quaternary Ketones, α‐Ketoesters and Aldehydes

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

Acyclic Quaternary Carbon Stereocenters through Transition-Metal-Catalyzed Enantioselective Functionalization of Unsaturated Hydrocarbons

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