Synthesis of<i>t</i>-Butyl 3-Oxoalkanoates by Acylation of<i>t</i>-Butyl Lithioacetate with Alkyl Carboxylates

Ohta, Shunsaku; Shimabayashi, Akihiro; Hayakawa, Satoshi; Sumino, Motoshige; Okamoto, Masao

doi:10.1055/s-1985-31099

Cited by 21 publications

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“…The lithium tert-butoxide additive was crucial to ensure rapid deprotonation of product 14, thus preventing the addition of a second equivalent of the lithium enolate 12. 9 The trapping of the sodium enolate of β-ketoester 14 with Comins reagent (2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine, 15 , Scheme 2) gave the vinyl triflate 10 in 82% yield with high Z-alkene selectivity (Z:E, >20:1). 10 Early in our studies, we relied on the use of a copper-catalyzed N-vinylation of pyrroles for the synthesis of the requisite βpyrrolyl enoates.…”

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confidence: 99%

Enantioselective Total Synthesis of Tricyclic Myrmicarin Alkaloids

Movassaghi

Ondrus

2005

Org. Lett.

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An enantioselective gram-scale synthesis of a key dihydroindolizine intermediate for the preparation of myrmicarin alkaloids is described. Key transformations in this convergent approach include a stereospecific palladium-catalyzed N-vinylation of a pyrrole with a vinyl triflate, a copper-catalyzed enantioselective conjugate reduction of a β-pyrrolyl enoate, and a regioselective Friedel-Crafts reaction. The synthesis of optically active and isomerically pure samples of (4aR)-myrmicarins 215A, 215B, and 217 in addition to their respective C4a-epimers is presented. The myrmicarins are a family of structurally fascinating alkaloids isolated from the poison gland secretions of the African ant species Myrmicaria opaciventris (Figure 1). 1 Despite significant isolation and purification challenges due to air and temperature sensitivity, elegant spectroscopic studies have revealed their molecular structures. 2 The pyrroloindolizine core of myrmicarins 215A (1), 215B (2), and 217 (3) is a common structural motif within many of these alkaloids. Within the family, only the absolute stereochemistry of myrmicarin 237A (4) has been secured through an enantioselective synthesis. 1a,3 Interestingly, the conversion of an unsaturated derivative of 4 to myrmicarin 217 (3) suggests the possible biogenesis of other myrmicarins from simpler indolizine derivatives. 1b,4 The synthesis of (R)-myrmicarin 217 (3) and (R)-myrmicarin 215 as a mixture of olefin isomers has been reported starting with D-glutamic acid. 5 The intriguing molecular structures of these poisonous alkaloids combined with challenges associated with their sensitivity provide an exciting arena to test and discover new methodologies for organic synthesis. Herein we describe a convergent synthesis of all naturally occurring tricyclic myrmicarin alkaloids employing an efficient approach to a pivotal optically active dihydroindolizine intermediate. The first preparation of isomerically pure samples of myrmicarins 215A and 215B is discussed. Key steps of the synthesis include an efficient palladium-catalyzed fragment coupling reaction, a copper catalyzed asymmetric conjugate reduction and a regioselective Friedel-Crafts reaction. We envisioned utilization of the optically active dihydroindolizine 7 as a key intermediate for the preparation of myrmicarin alkaloids (Scheme 1). A regioselective Friedel-Crafts reaction of the pyrrole ring (C7a-alkylation) upon Brönsted-acid activation of the dimethoxyacetal 8 and elimination of methanol was expected to afford the bicyclic vinyl pyrrole 7. We planned to use a metal-catalyzed enantioselective conjugate reduction of the β-pyrrolyl enoate 9 to introduce the C4a-stereochemistry. 6,7 A convergent synthesis of the pyrrolylenoate 9 was envisioned via a metal-catalyzed union of pyrrole 11 and readily available Z-vinyl triflate 10 (Scheme 1). The synthesis of the required β-pyrrolylenoate 9 began with the Claisen condensation of the lithium enolate 12 and methyl 4-(dimethoxy)-butyrate (13) 8 to give the β-ketoester 14 (Scheme 2). The lit...

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Enantioselective Total Synthesis of Tricyclic Myrmicarin Alkaloids

Movassaghi

Ondrus

2005

Org. Lett.

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“…Usually, the autocondensation side reaction can be avoided by using the sterically hindered tertbutyl acetate. [32,37,38] However, as the resulting tert-butyl ester is sensitive to acidic conditions, the orthogonality of the protections would not be preserved. Thus, we considered the use of another sterically hindered acetate, that is, 1,1-dimethylallyl acetate (2b); the resulting 1,1-dimethylallyl ester could be selectively deprotected under mild conditions with a palladium catalyst.…”

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confidence: 99%

Cross‐Claisen Condensation of N‐Fmoc‐Amino Acids – A Short Route to Heterocyclic γ‐Amino Acids

et al. 2015

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4‐Amino(methyl)‐1,3‐thiazole‐5‐carboxylic acids (ATCs) are a new class of constrained heterocyclic γ‐amino acids built around a thiazole ring; these compounds are valuable as design mimics of the secondary structures of proteins such as helices, β‐sheets, turns, and β‐hairpins. We report herein a short and versatile chemical route to orthogonally protected ATCs. The synthesis is centered on cross‐Claisen condensations between N‐Fmoc‐amino acids and sterically hindered 1,1‐dimethylallyl acetate. The optimized conditions are compatible with aliphatic, aromatic, acidic, and basic amino acids. The resulting N‐Fmoc‐β‐keto ester intermediates were engaged in a two‐step process to give ATCs in 45–90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ‐carbon atom or on the thiazole core of the γ‐amino acids.

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“…We hypothesized that an ester enolate might react in a smooth manner with strong electrophile acid chloride, if proper conditions have maintained to slow down the side reactions such as, self‐Claisen condensation and O ‐alkylation. However, there have been very few reports on the application of cross‐Claisen condensation between different esters [8] or between esters and acid chlorides, and some successful results were also been reported in the reactions using hydroxyl esters [9]. A nucleophilic reaction of an ester enolate with acid imidazolide has been widely used to synthesis β‐keto esters [10], but it would rather be expensive to use imidazolide or active ester in an industrial setting.…”

Section: Resultsmentioning

confidence: 99%

A novel route to 4‐oxy/thio substituted‐1H‐pyrazol‐5(4H)‐ones via efficient cross‐Claisen condensation

Ragavan

Vijayakumar

2010

Journal of Heterocyclic Chem

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Abstractα‐Oxy/thio substituted β‐keto esters were synthesized through an efficient cross‐Claisen condensation of oxy/thio substituted acetic acid ethyl esters with acid chlorides, which in turn converted in situ into 4‐oxy/thio substituted‐1H‐pyrazol‐5(4H)‐ones by the addition of hydrazine and its derivatives. This method has been found to be extremely fast, general, and useful toward the synthesis of inaccessible pyrazolones and synthetically demanding 4‐oxy/thio substituted pyrazolones. J. Heterocyclic Chem., (2011).

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Synthesis oft-Butyl 3-Oxoalkanoates by Acylation oft-Butyl Lithioacetate with Alkyl Carboxylates

Cited by 21 publications

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Enantioselective Total Synthesis of Tricyclic Myrmicarin Alkaloids

Enantioselective Total Synthesis of Tricyclic Myrmicarin Alkaloids

Cross‐Claisen Condensation of N‐Fmoc‐Amino Acids – A Short Route to Heterocyclic γ‐Amino Acids

A novel route to 4‐oxy/thio substituted‐1H‐pyrazol‐5(4H)‐ones via efficient cross‐Claisen condensation

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