Chiral Glycolate Equivalents for the Asymmetric Synthesis of α-Hydroxycarbonyl Compounds

Ley, Steven V.; Sheppard, Tom D.; Myers, R. M.; Chorghade, Mukund S.

doi:10.1246/bcsj.80.1451

Cited by 40 publications

(9 citation statements)

References 126 publications

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“…New methods to produce the glycolic acid moiety continue to be important in the creation of small molecule building blocks 1. γ,δ-Unsaturated glycolic acid derivatives represent a functional group-rich subset of substituted α-hydroxy acids with significant potential for further elaboration.…”

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confidence: 99%

Synthesis of γ,δ-Unsaturated Glycolic Acids via Sequenced Brook and Ireland−Claisen Rearrangements

Schmitt

Johnson

2010

Org. Lett.

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Organozinc, magnesium, and lithium nucleophiles initiate a Brook/Ireland-Claisen rearrangement sequence of allylic silyl glyoxylates resulting in formation of γ,δ-unsaturated α-silyloxy acids.New methods to produce the glycolic acid moiety continue to be important in the creation of small molecule building blocks. 1 γ,δ-Unsaturated glycolic acid derivatives represent a functional group-rich subset of substituted α-hydroxy acids with significant potential for further elaboration. The preparation of such compounds may be achieved via Ireland-Claisen rearrangement of allyl glycolate esters. 2 While the standard Ireland-Claisen rearrangement is performed by sequential enolization and silylation of allylic esters, alternative approaches to the requisite silyl ketene acetal have been reported. Methods include 1,4-addition to enoates, 3 silylene transfer followed by 6π-electrocyclization, 4 or by Rh-catalyzed reduction of enoates. 5 These methods allow for the generation of chiral products from achiral starting materials; however, a method that introduces multiple α-substituents in a single-pot process could potentially allow more rapid buildup of molecular complexity. An assessment of other Grignard reagents revealed that MeMgBr had potential as an effective nucleophile as it cleanly added to cinnamyl silyl glyoxylate 1a at 0 °C. In this case, Brook rearrangement did not occur below room temperature. When the reaction was allowed to warm, only decomposition was observed. Silyl ketene acetal formation was then attempted by addition of MeMgBr at 0 °C followed by warming to room temperature and addition of TMSCl; however, this also resulted in decomposition. Given that no TMS incorporation had occurred, we turned to TMSOTf, which induced the desired Ireland-Claisen rearrangement and provided the γ,δ-unsaturated glycolic acid 7 in 55% yield ( Organozinc nucleophiles were also found to be effective. ZnEt 2 serves as an efficient hydride donor, triggering the sequential Brook and Ireland-Claisen rearrangements, to afford the glycolic acid in 69% yield with good diastereoselectivity (Table 1, entry 5). The reduction of α-ketoesters with ZnEt 2 or EtMgBr has been previously reported; however, it is typically a minor byproduct to ethyl addition. 9 Allyl zinc bromide and allenyl zinc bromide were useful triggers as well (Table 1, entries 6-10).Substituted allylic zinc nucleophiles were also competent initiators. Methallyl zinc bromide provided the desired products with slightly diminished diastereoselectivity relative to allyl zinc bromide (Table 1, entries 11-12). The reaction was also tolerant of crotyl-and cinnamylzinc reagents; however, products were obtained as a complex mixture of diastereomers (not shown). Notably, none of the organozinc nucleophiles required silyl ketene acetal formation, as the zinc enolate underwent [3,3]-rearrangement spontaneously. Geranyl silyl glyoxylate 20 underwent the title transformation when treated with allenyl or allylic zinc bromides, providing glycolic acid derivatives in moderat...

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confidence: 99%

Synthesis of γ,δ-Unsaturated Glycolic Acids via Sequenced Brook and Ireland−Claisen Rearrangements

Schmitt

Johnson

2010

Org. Lett.

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“…Certain aspects thereof were summarized in a 2007 review about asymmetric alkylations, aldol additions, and other transformations of chiral glycolic acid equivalents. 1 The present review is larger in scope and different in accent, focusing on simply diastereoselective aldol additions of glycolate (derivative) enolates. Most of those that we selected utilize an achiral aldehyde.…”

Section: Organization Of This Reviewmentioning

confidence: 99%

“…The acylsilane 17 is reduced and the Mg alkoxide 18 is oxidized. The α-silylated alkoxide 20 results, which proceeds to give the glycolate enolate 22 by a [1,2]-Brook rearrangement, plus the aldehyde 21. These components allow for a terminating aldol addition to ensue.…”

Section: Tablementioning

confidence: 99%

Stereoselective Aldol Additions of Glycolic Acid and Its Derivatives

Engesser¹,

Brückner²

2019

Synthesis

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This review gives a comprehensive overview of aldol additions of glycolic acid derivatives to achiral aldehydes and acetals affording α,β-dihydroxycarboxylic acids or derivatives thereof. The focus is on simple diastereoselectivity. A selection of related aldol additions is also presented: aldol additions of glycolic acid derivatives to ketones with two different substituents and aldol additions of α-substituted glycolic acid derivatives.1 Introduction1.1 Organization of this Review1.2 Outside the Scope of this Review: Aldol Additions Giving α,β-Dihydroxyaldehydes and α,β-Dihydroxyketones Diastereoselectively1.3 Non-Aldol Routes to Diastereomerically Pure α,β-Dihydroxycarboxylic Acid Derivatives2 Aldol Additions of Glycolic Acid (Derivative) Enolates to Aldehydes2.1 Aldol Additions of Glycolate Enolates (‘Glycolic Acid Dianions’)2.2 Aldol Additions of Glycolic Ester Enolates2.3 Aldol Additions of Glycolic Thioester Enolates2.4 Aldol Additions of Glycolimide Enolates2.5 Aldol Additions of Glycolamide Enolates2.6 Mukaiyama Aldol Additions of Silyl Ketene Acetals of Glycolic Esters and Thioesters2.7 Aldol Additions of Glycoloyl Chlorides via Acyl Ammonium Enolates3 Aldol-Providing Substitutions of Glycolimide Enolates in Acetals4 Additions Related to Aldol Additions of Glycolic Acid Derivative Enolates to Aldehydes4.1 Selected Simply Diastereoselective Aldol Additions of Enolates of Glycolic Acid Derivatives to Ketones with Two Different Substituents4.2 Simply Diastereoselective Aldol Additions of Enolates of Glycolic Acid Derivatives with a Methyl Substituent at C-α (Lactic Acid Derivatives)5 Conclusion

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“…Due to their synthetic interest, several methods have been developed for the synthesis of such compounds. 2 Among them, the asymmetric aldol reaction 3 is the most attractive and straightforward method to accomplish this synthetic goal. Although the use of enantioselective catalytic methods to perform this transformation would be desirable, 4 the stereoselective synthesis of natural products relies mostly on chiral auxiliary based methods.…”

Section: Catalystmentioning

confidence: 99%

Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantioselective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction

et al. 2014

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N-Tosyl-(S a)-binam-L-prolinamide is an efficient catalyst for the aqueous aldol reaction between ketones and glyoxylic acid, as the monohydrate or as an aqueous solution, or a 50% toluene solution of ethyl glyoxylate. These reactions led to the formation of chiral α-hydroxy-γ-keto carboxylic acids and esters in high levels of diastereo-and enantioselectivities (up to 97% ee), providing mainly anti aldol products. Only cyclopentanone and cyclohexane-1,4-dione afforded an almost 1:1 mixture of the syn/anti-diastereoisomers; however, the reaction between 4-phenylcyclohexanone and ethyl glyoxylate gave the corresponding syn,syn-product as the major diastereoisomer.

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Chiral Glycolate Equivalents for the Asymmetric Synthesis of α-Hydroxycarbonyl Compounds

Abstract: Chiral glycolic acid equivalents are used extensively for the enantioselective synthesis of α-hydroxycarbonyl compounds. Their efficacy in enolate reactions and their utility in synthetic applications are discussed, highlighting the relevance of these methods to natural product synthesis.

Cited by 40 publications

References 126 publications

Synthesis of γ,δ-Unsaturated Glycolic Acids via Sequenced Brook and Ireland−Claisen Rearrangements

Synthesis of γ,δ-Unsaturated Glycolic Acids via Sequenced Brook and Ireland−Claisen Rearrangements

Stereoselective Aldol Additions of Glycolic Acid and Its Derivatives

Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantioselective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction

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Chiral Glycolate Equivalents for the Asymmetric Synthesis of α-Hydroxycarbonyl Compounds

Cited by 40 publications

References 126 publications

Synthesis of γ,δ-Unsaturated Glycolic Acids via Sequenced Brook and Ireland−Claisen Rearrangements

Synthesis of γ,δ-Unsaturated Glycolic Acids via Sequenced Brook and Ireland−Claisen Rearrangements

Stereoselective Aldol Additions of Glycolic Acid and Its Derivatives

Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantio­selective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction

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Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantioselective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction