Enantioselective Trifunctionalization of Terminal Alkynes
Langxuan Yang1, M Cole Detels1, Gojko Lalic1
1Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.
This study introduces a novel palladium-catalyzed method for synthesizing highly substituted alkenes from terminal alkynes. The efficient trifunctionalization reaction yields tetrasubstituted alkenes with exceptional stereoselectivity, offering a new route to complex organic molecules.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Catalysis
Background:
- Stereoselective synthesis of alkenes is crucial in organic chemistry.
- Existing methods struggle with synthesizing highly substituted alkenes due to steric hindrance.
- Developing efficient and selective routes for complex alkenes remains a significant challenge.
Purpose of the Study:
- To develop a novel palladium-catalyzed trifunctionalization of terminal alkynes.
- To achieve efficient and stereoselective synthesis of tetrasubstituted alkenes.
- To explore the regiodivergent, diastereoselective, and enantioselective incorporation of allylic fragments.
Main Methods:
- Palladium-catalyzed reaction utilizing terminal alkynes, organoboranes, and allylic carbonates.
- Optimization of reaction conditions to control stereoselectivity.
- Analysis of reaction mechanism to understand catalyst control over selectivity.
Main Results:
- Successful synthesis of tetrasubstituted alkenes with high regioselectivity and diastereoselectivity.
- Demonstration of regiodivergent, diastereoselective, and enantioselective formation of 1,4-diene products.
- Evidence showing palladium catalyst dictates selectivity in both tetrasubstituted alkene formation and allylic substitution.
Conclusions:
- The developed palladium-catalyzed trifunctionalization is an effective method for synthesizing highly substituted alkenes.
- This approach provides access to a diverse range of complex 1,4-diene structures with controlled stereochemistry.
- The study highlights the catalyst's pivotal role in controlling the selectivity of the transformation.
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Alkylation of terminal alkynes with primary alkyl halides in the presence of a strong base like sodium amide is one of the common methods for the synthesis of longer carbon-chain alkynes. For example, treatment of 1-propyne with sodium amide followed by reaction with ethyl bromide yields 2-pentyne.
02:47Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
02:24Reduction of Alkynes to cis-Alkenes: Catalytic Hydrogenation
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02:38Electrophilic Addition to Alkynes: Halogenation
Halogenation is another class of electrophilic addition reactions where a halogen molecule gets added across a π bond. In alkynes, the presence of two π bonds allows for the addition of two equivalents of halogens (bromine or chlorine). The addition of the first halogen molecule forms a trans-dihaloalkene as the major product and the cis isomer as the minor product. Subsequent addition of the second equivalent yields the tetrahalide.
02:34Preparation of Alkynes: Dehydrohalogenation
Alkynes can be prepared by dehydrohalogenation of vicinal or geminal dihalides in the presence of a strong base like sodium amide in liquid ammonia. The reaction proceeds with the loss of two equivalents of hydrogen halide (HX) via two successive E2 elimination reactions.
02:40Alkynes to Aldehydes and Ketones: Acid-Catalyzed Hydration
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