Chiral Phosphine-Catalyzed Asymmetric Intermolecular -Addition of Oxygen Nucleophiles

William ReichardSURF 2014October 18, 2014Chiral Phosphine-Catalyzed Asymmetric Intermolecular -Addition of Oxygen Nucleophiles

Oxygen Nucleophiles in Intermolecular -Addition ReactionsAlcohol Nucleophiles

Carboxylate/Carboxylic Acid Nucleophiles

Trost, B. M. J. Am. Chem. Soc. 1994, 116, 10819.Lu, X. Synlett 1995, 645.

Alvarez-Ibarra, C. Tetrahedron Lett. 1999, 40, 8465.

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Oxygen Nucleophiles in Intramolecular Asymmetric -Addition Reactions

Chung, Y. K. Angew. Chem., Int. Ed. 2009, 48, 2225.

-Addition, -Addition, and Diene Formation-addition

-addition diene formation

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Other Strategies For Synthesizing -Hydroxy-Unsaturated Carbonyl Compounds Generating the Stereocenter to a Carbonyl

Brusse Tetrahedron 2000, 56, 2491.Zhong, Org. Lett. 2004, 6, 1637.Krawczyk Synthesis 2008, 20, 3299.

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Other Strategies For Synthesizing -Hydroxy-Unsaturated Carbonyl Compounds Asymmetric Functionalization of ,-Unsaturated Carbonyl Compounds

Tiecco, Chem. Eur. J. 2002, 8, 1118.Bruckner, Synlett 2001, 718.

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Other Strategies For Synthesizing -Hydroxy-Unsaturated Carbonyl Compounds Enantioselective Nucleophilic Additions to Aldehydes

Trost, Chem. Eur. J. 2012, 18, 16498.Wang, Org. Lett. 2007, 9, 2329.

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Advantages of phosphene -addition over other strategiesMakes use of few and easily synthesized reagents, while some other strategies make use of numerous reagents, some of which might not be easily accessible. Simple one step reactionCan simply set up the reaction and set aside to react overnight.Multi step reactions require more care and attentionRelatively mild conditionsReaction set up in nitrogen atmosphere, then left to react at room temperature.Some other strategies must be carried out in harsher conditions.

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Synthesis

Aromatic Heterocycle-Substituted AlkynoatesYield: 66%Yield:77%Yield:11%Product decomposed on silica, crude product was used in next step

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Synthesis

Aromatic Heterocycle-Substituted AlkynoatesYield:86%

Yield:69%Yield:92%Yield:87%Tosyl protecting group added in order to prevent decomposition

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Synthesis

Aromatic Heterocycle Substituted Alkynoates

Yield:31%Yield:65%Yield:89%Yield:7% +crude product

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Synthesis

Varying the EWG of the Alkynoate

Yield:67%No product formation observed for many similar reactions

Yield:74%Yield:19%Changed synthetic route

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Oxygen -Addition

Aromatic Heterocycle-Substituted Alkynoates

Yield: 69%ee: 94%Yield: