Formation of γ-Lactones through CAN-Mediated Oxidative Cleavage of Hemiketals

Jacobine, Alexander M.; Lin, Weimin; Walls, Bethany; Zercher, Charles K.

doi:10.1021/jo801258h

Cited by 18 publications

(29 citation statements)

References 23 publications

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“…The potential for utilization of anhydrides in a tandem reaction process for the production of spirofused cyclic ketal cores was explored by treatment of methyl acetoacetate (11) with the Furukawa-modified carbenoid, 19 followed by exposure of the resulting organometallic intermediate to 3-methoxymaleic anhydride 20 (12, Scheme 3). While the 1 H NMR spectrum of the crude reaction mixture was challenging to interpret due to the equilibrium between hemiketal 13 and other isomeric forms, the 13 C NMR spectrum showed resonances consistent with hemiketals and ketals. The crude reaction mixture that contained hemiketal 13 was treated with dimethoxypropane in an effort to trap the spirofused ketal core as a product mixture suitable for chromatographic separation.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…For example, when β-keto ester 6 was subjected to a zinc carbenoid derived from diethylzinc and diiodomethane (R 1 = H), an organometallic intermediate 7 (Scheme 1) was generated. 13 Similar to the Reformatsky dimer, 14,15 intermediate 7 can be trapped with aldehydes or ketones to produce α-substituted aldol products ( 8a and 8b ). The regiospecific substitution at the α-position of a γ-keto substrate has been key to the synthesis of peptide isosteres 16 and natural products.…”

Section: Introductionmentioning

confidence: 99%

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Syntheses of Papyracillic Acids: Application of the Tandem Chain Extension–Acylation Reaction

Mazzone

Zercher

2012

J. Org. Chem.

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A synthetic approach to the papyracillic acid family of natural products has been developed. The spiroacetal core is rapidly assembled through an unprecedented zinc carbenoid-mediated tandem chain extension-acylation reaction. Subsequent functional group manipulation provided access to papyracillic acid B and 4-epi-papyracillic acid C. The successful preparation of these molecules resulted in the clarification of structural assignments of members of this family of natural products.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Syntheses of Papyracillic Acids: Application of the Tandem Chain Extension–Acylation Reaction

Mazzone

Zercher

2012

J. Org. Chem.

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“…18 By this approach β-keto imides were converted in one-pot to α-substituted γ-keto imides by the highly stereoselective zinc-mediated aldol reaction directed by chiral oxazolidinones. 19,20 Utilization of the TCEA reaction for stereoselective synthesis of α-substituted ketomethylene isosteres has been reported for proline as the stereodirecting element as well. 21 …”

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confidence: 99%

“…19–21 We protected the amine group of L-phenylalanine 1 sequentially with p -methoxybenzyl (PMB) and benzyloxycarbonyl (Cbz) (Scheme 1). The PMB group was introduced by reductive amination by treating 1 with p -anisaldehyde and sodium borohydride in succession.…”

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confidence: 99%

The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1

Thorn

Nielsen

Jakobsen

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-ψ[COCH2]-Ser(Bz)-Xaa-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived β-keto imides were stereoselectively converted to α-substituted γ-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (Ki-values <0.5 mM) for hPEPT1 by measuring the concentration dependent inhibition of apical [14C]Gly-Sar uptake in Caco-2 cells. Consequently, the ketomethylene replacement for the natural amide bond and α-side chain modifications appears to offer a promising strategy to modify tripeptidic structures while maintaining a high affinity for hPEPT1.

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“…During this transformation, no epimerization is observed. When 39 is treated with TFA in toluene at 110 °C for 48 h, chemoselective cleavage of the dimethylamide occurs to provide lactone 41 with three contiguous stereocenters in 72% yield.…”

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Enantio- and Diastereoselective Intermolecular Stetter Reaction of Glyoxamide and Alkylidene Ketoamides

2009

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A triazolinylidine carbene catalyzed intermolecular Stetter reaction of glyoxamide and alkylidene ketoamides has been developed. 1,4-dicarbonyl products are afforded in good to excellent yields, enantioselectivities and diastereoselectivities. Further derivatization of the products affords useful intermediates for organic synthesis.The Stetter reaction, 1 the N-heterocyclic carbene (NHC) catalyzed addition of aldehydes to Michael acceptors, is a prototypical example of the emerging class of catalyzed umpolung reactions. 2 Following a seminal early report by Enders and Teles, 3 we 4 and others 5 have extensively investigated the asymmetric intramolecular Stetter reaction. The asymmetric intermolecular Stetter, on the other hand, has remained a much more significant challenge. 6 In 2008, Enders reported an asymmetric intermolecular Stetter reaction of aromatic aldehydes and chalcones proceeding in good yield and modest modest selectivities. 7 Concurrently, we reported the enantioselective intermolecular Stetter reaction of glyoxamides 1 with alkylidene malonates 2 (eq 1). 8(1) Supporting Information Available Detailed experimental procedures and spectral data for all new compounds, nOe of 12, and X-ray structures of 11 and 22. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 July 2. A shortcoming of the use of alkylidene malonates 2 is the need for the second ester group. We considered that the use of alkylidene ketoacid derivatives would provide an opportunity to incorporate synthetically useful substituents on the second carbonyl (eq 2). However, the reaction would generate mixtures of diastereomers, a situation that could be rectified through the use of alkylidene ketoamides. We have already demonstrated that the protonation event in the asymmetric Stetter is highly diastereoselective 4d and it has been welldocumented that tertiary β-ketoamides, bearing a stereocenter between the carbonyls, are configurationally stable due to strong A 1,3 strain in the enolate. 9 Interestingly, catalytic asymmetric transformations that generate ketoamide stereocenters are surprisingly rare. 10

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Formation of γ-Lactones through CAN-Mediated Oxidative Cleavage of Hemiketals

Cited by 18 publications

References 23 publications

Syntheses of Papyracillic Acids: Application of the Tandem Chain Extension–Acylation Reaction

Syntheses of Papyracillic Acids: Application of the Tandem Chain Extension–Acylation Reaction

The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1

Enantio- and Diastereoselective Intermolecular Stetter Reaction of Glyoxamide and Alkylidene Ketoamides

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