Enantioselective Nazarov Reactions through Catalytic Asymmetric Proton Transfer

Liang, Guangxin; Trauner, Dirk

doi:10.1021/ja0476664

Cited by 197 publications

(75 citation statements)

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“…The synthetic applications of the Nazarov reaction in its original form have in the past been hampered by the harsh reaction conditions required (usually strong acids and high temperatures) and poor regioisomeric control. However, the abundance of five-membered carbocycles among natural products has inspired much research into the Nazarov reaction and these problems are nowadays solved by the use of Lewis acids as cyclization initiators, [8][9][10][11][12][13][14] procedures called "directed Nazarov cyclization" [15][16][17][18][19] and the "interrupted Nazarov reaction", [20][21][22][23][24] and the use of a variety of divinyl Abstract: Density functional theory (DFT) has been used to define the energy profiles of the Nazarov reaction involving cyclic systems. The calculations were carried out at the B3LYP/6-311G** level of theory and the solvent (dichloromethane) contribution was estimated by using the recently developed SM5.43R solvation model.…”

Section: Introductionmentioning

confidence: 99%

Density Functional Studies on the Nazarov Reaction Involving Cyclic Systems

Cavalli

Masetti

Recanatini

et al. 2006

Chemistry A European J

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Density functional theory (DFT) has been used to define the energy profiles of the Nazarov reaction involving cyclic systems. The calculations were carried out at the B3LYP/6-311G** level of theory and the solvent (dichloromethane) contribution was estimated by using the recently developed SM5.43R solvation model. DFT calculations were first carried out to determine the energy profiles associated with the electrocyclization reactions of 3-hydroxy- and 3-ethoxypentadienyl cations in which one of the double bonds is embedded in O-heterocyclic and carbocyclic systems. In particular, the effects on the reaction rate of modifications to the substrate, as well as the presence of the heteroatom in the cycle, have been investigated. The torquoselectivity of the electrocyclization reaction was then explored with substituted O-heterocycles to understand the factors that control the stereochemical outcome of the process that preferentially provides 2,5-trans-disubstituted products. These DFT-based results rationally explain most of the experimental observations related to the Nazarov reaction of the substrates herein investigated and could be useful in the rational interpretation, and likely in the prediction, of the outcome of Nazarov reactions involving other cyclic systems.

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Section: Introductionmentioning

confidence: 99%

Density Functional Studies on the Nazarov Reaction Involving Cyclic Systems

Cavalli

Masetti

Recanatini

et al. 2006

Chemistry A European J

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“…[3] The first examples were achieved when the groups of Trauner and Aggarwal discovered chiral Lewis acid catalyzed enantioselective Nazarov 4p electrocyclizations. [4,5] In the meantime, Trauner and Bergman have also established the feasibility of catalysis of certain 6p electrocyclizations. [6] In connection with a different project, we speculated on the potential for asymmetric catalysis of the rearrangement of a,b-unsaturated hydrazones into the corresponding potentially biologically active pyrazolines.…”

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confidence: 99%

A Catalytic Asymmetric 6 π Electrocyclization: Enantioselective Synthesis of 2‐Pyrazolines

2009

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“…This demonstrated that enantioselective protonation could occur at a site distant from the chiral catalyst. (Reduced to 45%) 64 developed a scandium-catalyzed cascade Nazarov cyclization/ enolate protonation sequence to access cyclopentenones. b) Stoltz and coworkers 69,73 employed a chiral palladium complex to effect decarboxylative protonation reactions from allyl β-ketoester substrates (e.g., 104 and 107).…”

Section: Resultsmentioning

confidence: 99%

Enantioselective Protonation

2008

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Enantioselective protonation is a common process in biosynthetic sequences. The decarboxylase and esterase enzymes that effect this valuable transformation are able to control both the steric environment around the proton acceptor (typically an enolate) and the proton donor (typically a thiol). Recently, several chemical methods to achieve enantioselective protonation have been developed by exploiting various means of enantiocontrol in different mechanisms. These laboratory transformations have proven useful for the preparation of a number of valuable organic compounds.A fundamental method to generate a tertiary carbon stereocenter is to deliver a proton to a carbanion intermediate. However, enantioselective transfer of a proton presents unusual challenges, specifically, manipulating a very small atom and avoiding product racemization at a particularly labile stereocenter. As a result, the conditions for a successful enantioselective protonation protocol may be very specific to a certain substrate class. Tertiary carbon stereocenters are extremely common in valuable biologically active natural products, and thus the need for synthetically useful enantioselective methods to form these stereocenters is vital. 1In this review, we discuss several strategic approaches to enantioselective protonation. Emphasis has been placed on recently developed methods and their accompanying mechanisms in order to update the most recent prior reviews on this topic. 2,3,4,5,6,7,8 Each method relies on particular stereochemical control elements based on the mechanism of the protonation transformation. Appreciation of these controlling elements may lead to improved methods for preparing valuable chiral materials for a variety of synthetic applications. Important Factors in Achieving Enantioselective ProtonationSeveral of the most important practical features of enantioselective protonation were enumerated in Fehr's 1996 review. 2 Principal among these is the fact that enantioselective protonations are necessarily kinetic processes since under thermodynamic control racemate would be formed. Accordingly, it is often necessary to match the pK a of the proton donor and the product to prevent racemization before product isolation. It is unfortunate that the same anion stabilizing groups (e.g., ketones) that make protonations relatively easy to achieve also impart a degree of instability in the product. This has led some researchers to explore hydrogen atom transfer reactions in lieu of Brønsted acid-mediated protonations (see the subsection Enantioselective Hydrogen Atom Transfer below).Correspondence should be addressed to B.M.S. stoltz@caltech.edu. The authors declare no competing financial interests. NIH Public Access Author ManuscriptNat Chem. Author manuscript; available in PMC 2010 April 27. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn addition to the obvious challenges of product stability under the reaction conditions, the rapid rate of proton exchange in solution often leads to significant l...

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Enantioselective Nazarov Reactions through Catalytic Asymmetric Proton Transfer

Abstract: The development of catalytic asymmetric Nazarov reactions that require only 10 mol % of chiral Lewis acid and proceed with ee's between 72% and 97% is described.

Cited by 197 publications

References 12 publications

Density Functional Studies on the Nazarov Reaction Involving Cyclic Systems

Density Functional Studies on the Nazarov Reaction Involving Cyclic Systems

A Catalytic Asymmetric 6 π Electrocyclization: Enantioselective Synthesis of 2‐Pyrazolines

Enantioselective Protonation

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