Enantioselective Protonation of Enolates and Enols

Fehr, Charles

doi:10.1002/anie.199625661

Cited by 285 publications

(77 citation statements)

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“…More recently, this strategy has been refined to instead generate a chiral Pd-enolate intermediate from allyl β-ketoester substrates (e.g., 104 and 107 , Figure 7c) in the hopes that chirality at the metal might impart improved stereocontrol in the protonation step and obviate the need for heterogeneous Pd catalysts. Stoltz and coworkers 69 found that the catalyst derived from Pd(OAc) 2 and phosphinooxazoline (PHOX) ligand 105 was capable of achieving enantioselective protonation in the presence of formic acid and molecular sieves (MS). High enantiomeric excesses were obtained for a range of cyclic ketone products including tetraloneand cyclohexanone-derived ketones (e.g., 106 and 109).…”

Section: Enantioselective Protonation By Means Of Chiral Brønsted Basementioning

confidence: 99%

“…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.…”

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Enantioselective Protonation

2008

Synfacts

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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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Section: Enantioselective Protonation By Means Of Chiral Brønsted Basementioning

confidence: 99%

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confidence: 99%

Enantioselective Protonation

2008

Synfacts

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“…The present asymmetric protonation reaction is unique in the term of catalytic amount of lithium. Generally in the asymmetric protonation reaction, stoichiometric amounts of metal enolate and chiral source are used, [62][63][64] and the use of the catalytic amount of lithium is a challenging task. 37,40,48,49,65,66) The reaction of methyl atropate 14 (R＝Ph) with 2e in the presence of 8 mol％ of 8 gave protonation product 15 (R＝Ph) in quantitative yield with 92％ ee.…”

Section: Stereochemistry Of Protonation Process 55)mentioning

confidence: 99%

Asymmetric Conjugate Addition of Arylthiols to Enoates and Its Application to Organic Synthesis of Biologically Potent Compounds

Nishimura

Tomioka

2003

ChemInform

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As a part of our studies aimed at asymmetric catalytic reactions by using an external chiral ligand, we have developed a catalytic asymmetric addition reaction of an arylthiol to a,b-unsaturated esters under the control of an external chiral ligand. The characteristic of our technology is a double activation of a thiol by lithiation and chelate formation with a chiral tridentate amino diether ligand, which simultaneously and eŠectively controls a stereochemistry of the reaction. One signiˆcant feature of an arylthiol is a bulky 2-substitution on aryl group, which enables the formation of a really reactive monomeric thiolate species. s-Cis conformation and capability of electron lone pair-diŠerentiating coordination of a carbonyl oxygen to lithium are structural requirements of the substrates for high enantioselectivity. The enantioselectivity came up to 97％ under the cited conditions. Asymmetric protonation of a transient enolate, generated by conjugate addition of a lithium thiolate to an enoate, was also realized. The stereochemistry of the protonation was controlled by the conformation of initially formed transient enolate in a 1,2-asymmetric induction manner. This technology enabled the asymmetric synthesis of (S)-naproxene. Stereoselective tandem C S and C C bond-forming reaction was developed as a logical extension by trapping the transient enolate intermediate with an aldehyde as a carbo-electrophile in the presence of phenylthiotrimethylsilane as an equilibrium-shift reagent. This tandem reaction was extended to a stereoselective cyclization of v-oxo-a,b-unsaturated esters initiated by a lithium thiolate. Stereoselectivity of both tandem inter-and intramolecular reaction is predictable by an allylic strain-controlled conformation model of the enolate, in which an approach of aldehyde takes place anti to C S bond through coordination of an aldehyde oxygen to lithium. Total synthesis of (-)-neplanocin A was achieved by using the tandem cyclization as a key tool for the direct construction of aˆve-membered carbocycle where every carbon is functionalized.

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“…[1][2][3][4][5][6] Over the past years, we contributed to this topic using various substrates and procedures. 7 With 2-methyl-2-benzyloxycarbonyl-1-indanone (KE) as the substrate, the procedure, studied in collaboration with Martens team, 8,9 involves a Pd-catalyzed hydrogenolysis in the presence of an unichiral 10 β-aminoalcohol (AH*) (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

On the mechanism of the domino reaction of 2-methyl-2-benzyloxycarbonyl-1-indanone mediated by palladium, hydrogen and aminoalcohols

Müller¹,

Hénin²,

Мuzart³

2014

Arkivoc

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Whereas the Pd-catalyzed hydrogenolysis of racemic 2-methyl-2-benzyloxycarbonyl-1-indanone in the presence of an unichiral (enantiopure) aminoalcohol leads to optically active 2-methylindanone, such a domino reaction using optically active 2-methyl-2-benzyloxycarbonyl-1-indanone and an achiral aminoalcohol affords racemic 2-methylindanone. According to these results, the ketone is obtained from the aminoalcohol-mediated protonation of an enolic species.

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Enantioselective Protonation of Enolates and Enols

Cited by 285 publications

References 121 publications

Enantioselective Protonation

Enantioselective Protonation

Asymmetric Conjugate Addition of Arylthiols to Enoates and Its Application to Organic Synthesis of Biologically Potent Compounds

On the mechanism of the domino reaction of 2-methyl-2-benzyloxycarbonyl-1-indanone mediated by palladium, hydrogen and aminoalcohols

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