Β-keto Acid Derivatives Research Articles

Recent applications of dioxinone derivatives for macrocyclic natural product and terpenoid synthesis.

Dioxinone derivatives, a class of acetoacetate derivatives, have attracted widespread attention because of their multiple reactive sites, high reactivity, unique chemical properties, and potential synthetic applications. The dioxinone group is also stable under a wide range of reaction conditions, including strong acids, as well as a variety of transition-metal-catalysed processes, such as olefin metathesis and Pd-mediated cross-coupling. The inherent reactivity and diverse applications of dioxinones make them valuable reactive intermediates in organic synthesis. The conversion of dioxinones to acylketenes and their subsequent nucleophilic capture is also an excellent strategy for synthesising β-keto acid derivatives, which can be applied even in complex molecular synthesis. This review focuses on the recent advances in the application of dioxinones in synthetic method research and the total synthesis of natural products, highlighting the exceptional utility of these synthetic methodologies in the construction of macrocyclic cores and terpenoid skeletons. In particular, successful transformations of dioxinone fragments are discussed.

Synthesis of Complex Glycolates by Enantioconvergent Addition Reactions.

The unique role that stereochemistry plays in molecular recognition events continues to provide a driving force for synthesizing organic compounds in enantioenriched form. The tendency of enantioenriched organic compounds to revert to an entropically favored racemic state in the presence of viable racemization pathways (e.g., the enolization of stereogenic carbonyl derivatives) can sometimes interfere with this objective; however, beginning with Noyori's foundational disclosure of a dynamic kinetic transfer hydrogenation, the ability to channel racemic, configurationally labile starting materials through stereoconvergent reaction pathways has been recognized as a powerful strategy in asymmetric synthesis. Proton transfer, retro-aldol, retro-Michael, reversible redox events, and other processes that can be deleterious to asymmetric synthesis are exploitable in enantioconvergent reactions using chiral small molecules and enzymes as asymmetric catalysts. Enantioselective reduction of configurationally labile carbonyl derivatives bearing a C-H acidic chiral center are particularly common. Because facile racemization is vital to stereocontrol in these transformations, hydrogenations of β-dicarbonyls are commonplace, while less activated substrates have been used less commonly. Our entry into enantioconvergent catalysis evolved from a long-standing interest in the synthesis of complex glycolates and began with the development of a general Noyori-type transfer hydrogenation of α-keto esters. Key innovations in this work include the identification of a new terphenylsulfonamide-Ru(II) complex, which displays unusual preference toward reduction of α-keto esters, and the observation that α-keto esters racemize under mildly basic conditions. This work was extended to the dynamic kinetic hydrogenation of racemic acyl phosphonates. Moreover, the recent recognition that the mechanistic paradigm underlying enantioconvergent hydrogenation chemistry can be extended to diverse carbon-centered nucleophiles has led to advances in the art. Our lab has developed a number of enantioconvergent tertiary alcohol syntheses. In the context of carbon-centered nucleophiles, we have focused on the use of α-keto esters; however, in the latter part of this Account, we will briefly describe our nascent efforts to develop dynamic kinetic additions of carbon-centered nucleophiles to β-oxo acid derivatives. While the enantioconvergent hydrogenation of β-keto acid derivatives is carried out on 100-ton scale annually, non-hydrogenative transformations of these compounds constitute an underexplored subclass of enantioconvergent reactions. With regard to future prospects, a trend toward transformations that afford increasing levels of molecular complexity is apparent. It can be expected that the burgeoning field of asymmetric 1,2-addition chemistry will further drive this chemistry to encompass a wider array of enantioconvergent additions. Additionally, the continued exploration of these chemistries in the context of less conventional electrophiles, as well as identifying novel or overlooked modes of racemization, holds considerable potential.

Grinding assisted, column chromatography free decarboxylative carbon-carbon bond formation: Greener synthesis of 3, 3-disubstituted oxindoles

The decarboxylative carbon-carbon bond formation reaction of β-ketoacid derivatives with isatylidene malononitrile derivatives catalyzed by DBU afford adducts in excellent yield. The desired product can be easily isolated using simple filtration method without performing any column chromatography. The decarboxylative adduct was further subjected to reductive-cyclization to obtain biologically important spirooxindoles in 89% yield.

A Decennary Journey towards the Efficient Asymmetric Hydrogenation of Highly Functionalized Ketones

Around 2006, our group launched a long-term project on the asymmetric hydrogenation of functionalized ketones by using ruthenium complexes with SunPhos ligands. In this review, we recount the burgeoning and blossoming of this project. At the outset, we attempted some benchmark reactions with an array of monofunctionalized ketones, including α- and β-keto esters/amides, β-keto sulfones, phosphonates, and α-hydroxy ketones. For α-keto esters and amides, we discovered that CeCl3 •7H2 O was an efficient additive for both activity and enantioselectivity. The element iodine was found to be a valid additive for β-keto sulfones. β,γ-Unsaturated α-keto acids and esters were also hydrogenated to the saturated chiral blocks with good enantioselectivity and a high turnover number. For the α-substituted β-keto esters and phosphonates, exceptionally high stereoselectivity was achieved through dynamic kinetic resolution. Based on these incipient successes, we diverted to bifunctionalized ketone substrates, such as γ-heteroatom-substituted β-keto esters and δ-ketal-β-keto esters. For the δ-ketal-β-keto esters, CaCO3 was added to stabilize the δ-ketal groups, which ensured the formation of δ-ketal-β-hydroxy esters in good yields and high ee values. More interestingly, γ-halo-γ,δ-unsaturated-β-keto esters were hydrogenated to afford highly enantiopure chiral allyl alcohols under mild and neutral conditions. The distance effect of the directing groups was investigated in β-, γ-, and δ-keto amides; the last two were hydrogenated with the Ru-SunPhos-diamine system. To implement the pinpoint recognition of two carbonyl groups in similar chemical propinquity, we compared the reaction rates of different β-keto acid derivatives. THF was found to be a helpful coordinative solvent to control the chemo- and enantioselectivity for more challenging polycarbonyl substrates, such as 3-oxo glutaric acid derivatives, β,δ-diketo carboxamides, and γ-heteroatom-substituted β-diketones. The effects of solvents and heteroatoms in these substrates were also studied. Applications of these hydrogenation reactions were also exemplified by the employment of the products for important pharmaceutical syntheses.

Ruthenium‐Catalyzed Asymmetric Hydrogenation of 3‐Oxoglutaric Acid Derivatives: A Study of Unconventional Solvent and Substituent Effects

A series of 3-oxoglutaric acid derivatives have been hydrogenated in different solvents in the presence of [RuCl(benzene)(S)-SunPhos]Cl (SunPhos = (2,2,2',2'-tetramethyl-[4,4'-bibenzo[d][1,3]dioxole]-5,5'-diyl)bis(diphenylphosphine)). Unlike simple β-keto acid derivatives, these advanced analogues can be readily hydrogenated in uncommon solvents such as THF, CH(2)Cl(2), acetone, and dioxane with high enantioselectivities. Two possible catalytic cycles have been proposed to explain the different reactivities of these 1,3,5-tricarbonyl substrates in the tested solvents. The C-2 and C-4 substituents had notable but irregular influence on the reactivity and enantioselectivity of the reactions. More pronounced solvent effects were observed: the ee values increased from around 20% in EtOH or THF to 90% in acetone. Inversion of the product configuration was observed when the solvent was changed from EtOH to THF or acetone, and a mixed solvent system can lead to better enantioselectivity than a single solvent.

ChemInform Abstract: Synthesis of 1,3-Dioxin-4-ones Having a Trifluoromethyl Group at the 5- Position: Versatile Building Blocks for Trifluoromethylated Compounds.

The reaction of 5-iodo-1,3-dioxin-4-ones with trifluoromethyl iodide in the presence of copper powder in hexamethylphosphoric triamide affords the title compounds, which can be converted either to α-trifluoromethylated β-keto acid derivatives or to uracil or oxazine derivatives bearing a trifluoromethyl group.

ケテン化学の新展開 α‐オキソケテンの合成と反応

α-Oxoketenes are currently of major interest in synthetic and mechanistic studies. They are most conveniently generated by thermal fragmentation of 1, 3-dioxin-4-ones or acylated Meldrum's acids under a mild heating. Meldrum's acid itself also generates carboxyketene through the tautomeric 6-hydroxydioxinone under mild heating. The fragmentation of dioxinones to α-oxoketenes is of much interest from mechanistic viewpoint, because the transition structure of the ring opening is almost planner as recently revealed by ab initio calculations. α-Oxoketenes thus generated serve as powerful acylating reagents of nucleophiles to produce β-keto acid derivatives. They also serve as hetero-dienes in 4+2 cycloadditions to produce heterocyclic compounds. In addition, use of dioxinones provides ready access to hydroxylated or aminated ketenes. Intramolecular trappings of these ketenes afford lactones or lactams including macrocyclic compounds. Intramolecular dimerization of bis (oxoketene) tethered to origomethylene unit efficiently produces a series of new cyclophanes.

Enantiomerically enriched preparation of enolizable β-keto amides. Diastereoselective α-acylation and subsequent aminolysis of 2-acyl-3-phenyl- l-menthopyrazoles

After deprotonation with LDA, 2-acyl-3-phenyl- l-menthopyrazoles ( 13) were diastereomerically α-acylated to give N-(3-phenyl- l-menthopyrazolyl) β-keto amides ( 14–19). The subsequent amides were converted into the corresponding N-alkyl amides ( 21–24) retaining their enantiomeric enrichment on the α-position. These are the first examples of enolizable β-keto acid derivatives having only one chiral center at α-position. These chiral β-keto amides were surprisingly stable in dry benzene and their optical asymmetries were almost retained for two weeks at room temperature without any epimerization.

Synthesis of 1,3-dioxin-4-ones having a trifluoromethyl group at the 5-position: versatile building blocks for trifluoromethylated compounds

The reaction of 5-iodo-1,3-dioxin-4-ones with trifluoromethyl iodide in the presence of copper powder in hexamethylphosphoric triamide affords the title compounds, which can be converted either to α-trifluoromethylated β-keto acid derivatives or to uracil or oxazine derivatives bearing a trifluoromethyl group.

The reaction of β-dicarbonyl compounds with trifluoromethylsulphenyl chloride. Part I. CF 3S-substituted esters, anilides of β-keto acids, and their Schiff bases: Synthesis and stability.

The reactions of the β-keto acid derivatives with trifluoromethylsulphenyl chloride were carried out to give the α-SCF 3 substituted esters, anilides, and their Schiff bases of acetyl- and benzoylacetic acids. Ethyl esters of α-(trifluoromethylthio)acetoacetic and α-(trifluoromethylthio)benzoylacetic acids heated in dimethylsulphoxide/water solution give trifluoromethylthioacetone and ω-(trifluoromethylthio)acetophenone respectively, whereas with potassium hydroxide solution they form trifluoromethylthioacetic acid in a good yield.

Synthesis of pyrazofurin and its analogues

Pyrazofurin and its analogues have been synthesized from ribosyl β-keto acid derivatives, which can be readily prepared by Wittig reaction of the protected D-ribose with phosphoranes.