Reduction Of Lactone Research Articles

En Route to Diastereopure Polycyclic γ‐Lactones by Iridium‐Catalyzed Hydride Transfer†

Comprehensive SummaryThe reductive lactonization strategy provides an efficient access to diastereoenriched polycyclic γ‐lactones. However, it is still a formidable challenge to develop an efficient and versatile protocol with excellent levels of diastereocontrol. Herein, we provide a highly diastereoselective and efficient route to diastereopure bi‐ and polycyclic γ‐lactones, by means of an iridium‐catalyzed hydride transfer strategy. This method features high levels of diastereocontrol, broad substrate scope, and high catalyst efficiency (S/C = up to 5000). Mechanistic studies suggest that the iridium hydride formation might be the rate‐determining step, and that the hydride transfer step be the diastereo‐determining step. The large steric hindrance of the iridium hydride species and intramolecular hydrogen bonding are critically key to the diastereocontrol of the hydride transfer process. From the perspectives of configurational analysis and Duniz angles of attack, the nature of diastereocontrol is well rationalized. A more general empirical rule based on facial selectivity analysis for explaining and predicting the stereochemistry is also proposed.

An irreversible paper-based profluorescent nitroxide probe for the selective detection of ascorbic acid.

Ascorbic acid (AA) or vitamin C plays multiple crucial roles, particularly as an antioxidant. This essentially biologically active molecule was selectively detected over other reductants by the synthesized profluorescent nitroxide probe ProN6via a switch-on method. After either a hydrogen atom or single electron transfer from AA to nitroxide, the resulting diamagnetic hydroxylamine was rapidly cyclized to form a fluorescent O-acylalkoxyamine. This cyclization prevented the reoxidation of the corresponding hydroxylamine to the nitroxide, leading to a high precision of detection. A kinetic fluorescence study indicated that ProN6 exhibited higher reactivity than ProN7. Density functional theory (DFT) calculations indicated that the Gibbs free energy of the AA-induced cascade reductive lactonization of ProN6 was lower than that of ProN5 and ProN7. The designed probe achieved the sensitive and specific detection of AA with detection limits of 77.9 nM and 195.9 μM in solution and on paper, respectively. The utilization of the probe as a paper-based fluorescent sensor demonstrated the good accuracy of the quantitative analysis of AA in commercial supplements.

Total syntheses of Ganoderma-derived meroterpenoids, (-)-oregonensin A, (-)-chizhine E, (-)-applanatumol U, and (-)-ent-fornicin A.

In this study, we report the total syntheses of Ganoderma-derived meroterpenoids, (-)-oregonensin A, (-)-chizhine E, (-)-applanatumol U, and (-)-ent-fornicin A. The 3-alkyl-5-aryl-γ-butenolide skeleton, a common motif of these meroterpenoids, was constructed through the enantioselective reductive lactonization of the γ-keto ester, alkylation, and sulfoxide-β-syn-elimination. This flexible approach enabled enantioselective access to these meroterpenoids with the longest linear sequence of 6-8 steps, and in 21-36% overall yield, respectively.

Total synthesis of the proposed structure of Anti-TMV active tabasesquiterpene A

The proposed structure of Tabasesquiterpene A, an illudalane type of sesquiterpene has been synthesized in twelve steps from 2-methoxy-4-methylbenzaldehyde in 40% overall yield. Triflic acid mediated intramolecular Freidel-Crafts acylation allows to develop the critical indanone moiety, a key intermediate of this synthesis. A careful ortho-selective formylation and subsequent Knoevenagel condensation to incorporate three carbon side chain, followed by reduction, formation of tricyclic lactone and DIBAL-H supported reduction of lactone to target were other key transformation involved. The NMR spectroscopic data of the synthetic sample differ from those of natural tabasesquiterpene A.

A Short Method for the Synthesis of Hydroxyoleic Acids

AbstractEnzymatic or microbiological oxidation of oleic acid can afford azelaic acid as a building block for bioplastics. However, during the oxidation, the formation of hydroxylated byproducts is observed. To better follow the oxidation reaction, the availability of reference compounds is of great importance. To this aim, the synthesis of a series of oleic acids hydroxylated at ω ‐ 1, ω ‐ 2, ω ‐ 3 positions is described without the use of protecting groups. The final products are obtained by partial lactone reduction to hydroxyaldehyde followed by Grignard addition, selective oxidation of the primary hydroxyl group, and Wittig reaction.

Development of the Large-Scale Synthesis of Tetrahydropyran Glycine, a Precursor to the HCV NS5A Inhibitor BMS-986097

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.

Total Synthesis and Structure Revision of (±)-Clavilactone D Through Selective Cyclization of an α,β-Dicarbonyl Peroxide.

The structure of (±)-clavilactone D was revised, and the synthesis was achieved in seven steps from a substituted benzaldehyde. The key step was the base-catalyzed cyclization of an α,β-carbonyl peroxide, which was obtained by an iron-catalyzed three-component reaction of a benzaldehyde, an alkene, and TBHP. NaBH4-mediated reductive lactonization of the resulting cis-dicarbonyl epoxide led to the α,β-epoxy-γ-butyrolactone skeleton highly stereoselectively. The synthesis provides a concise, reliable, and practical route to the revised structure of clavilactone D.

ChemInform Abstract: Gallium‐Catalyzed Reductive Lactonization of γ‐keto Acids with a Hydrosilane.

Described herein is the GaCl3-catalyzed lactonization of γ-keto carboxylic acids in the presence of PhSiH3 leading to the direct preparation of γ-lactone derivatives. This reducing system showed a relatively wide functional group tolerance.

Gallium-catalyzed reductive lactonization of γ-keto acids with a hydrosilane

Gallium chloride efficiently catalyzes cyclization of γ-keto carboxylic acids in the presence of PhSiH3 to produce the corresponding γ-lactone derivatives.

Synthesis and evaluation of antibacterial activity of (R)-2-methylheptyl isonicotinate, a putative naturally occurring bioactive agent.

A putative antibacterial and antifungal compound, (R)-2-methylheptyl isonicotinate, was synthesized via reductive lactone alkylation of (R)-4-methyldihydrofuran-2(3H)-one. Structural characterisation data as well as bioassay results (with Bacillus subtilis or Escherichia coli) contradict those previously reported.

ChemInform Abstract: “One‐Pot” Reductive Lactone Alkylation Provides a Concise Asymmetric Synthesis of Chiral Isoprenoid Targets.

AbstractNucleophilic addition‐ring opening of lactones followed by modified in situ Clemmensen reduction provides a short synthetic route to chiral isoprenoid targets (III).

“One-Pot” Reductive Lactone Alkylation Provides a Concise Asymmetric Synthesis of Chiral Isoprenoid Targets

An efficient method, based on nucleophilic addition to lactones followed by modified in situ Clemmensen reduction, provides a short synthetic route to chiral isoprenoid targets. The efficacy of this method has been exemplified through the synthesis of several targets including the commercial fragrance Rosaphen, the side chain of Zaragozic acid C, the cotton leaf sex pheromone, and the side chains of vitamin E.

Development of an additive-controlled, SmI2-mediated stereoselective sequence: Telescoped spirocyclisation, lactone reduction and Peterson elimination

Studies on SmI2-mediated spirocyclisation and lactone reduction culminate in a telescoped sequence in which additives are used to “switch on” individual steps mediated by the electron transfer reagent. The sequence involves the use of two activated SmI2 reagent systems and a silicon stereocontrol element that exerts complete diastereocontrol over the cyclisation and is removed during the final stage of the sequence by Peterson elimination. The approach allows functionalised cyclopentanols containing two vicinal quaternary stereocentres to be conveniently prepared from simple starting materials.

Uncovering the Importance of Proton Donors in TmI2‐Promoted Electron Transfer: Facile CN Bond Cleavage in Unactivated Amides

The amide bond is one of the most ubiquitious functional groups in chemistry and biology.1 To date, the majority of strategies to functionalize amide bonds have focused on activation of the carbonyl group towards nucleophilic addition,2 however only few examples of the selective activation of σ C–N bonds in amides have been reported. In this regard, the cleavage of a σ C−N bond in amides was achieved in several highly innovative but very specialized bridged lactams, in which one of the C−N bonds was sufficiently distorted from planarity (Figure 1 a).3 Functionalization of the C−N bond in electronically activated phthalimides has also been described.4 However, a general method for the activation of σ C−N bonds in amides is unknown despite its considerable potential to advance the synthetic application of amide linkages in chemistry and biology.

Uncovering the Importance of Proton Donors in TmI2‐Promoted Electron Transfer: Facile CN Bond Cleavage in Unactivated Amides

Uncovering the Importance of Proton Donors in TmI₂‐Promoted Electron Transfer: Facile CN Bond Cleavage in Unactivated Amides

Preparation of O-Methyl Substituted 2-Oxofuro- and 2-Oxopyrrolidinoindolines by Reductive Lactonization of Oxindol-3-Ylacetic Acids

A practical procedure for the preparation of O-methyl substituted 3a,8-dialkyl-2-oxofuroindolines is described. Reductive lactonization of the corresponding oxindol-3-ylacetic acids provides a route for the formation of this class of compounds. Further transformation of 2-oxofuroindolines into 2-oxopyrrolidinoindolines, and then to pyrrolidinoindolines demonstrates their versatility as key intermediates in natural products synthesis. The results of single-crystal X-ray crystallographic analyses are given for five of the studied compounds.

Synthetic Studies towards NG-121: Diastereoselective Synthesis of NG-121 Methyl Ether

Starting from unsymmetrically O-protected methyl 4-bromo-3,5-dihydroxybenzoate, a facile synthesis of the methyl ether of bioactive natural product NG-121 was accomplished in very good overall yield. The key steps were: Stille coupling reaction of the farnesyl unit with the electron-rich phenolic segment; hydroxy-directed selective epoxidation of the farnesyl chain along with concomitant phenol-driven intramolecular regio- and diastereoselective ring closure to the corresponding hydroxybenzopyran; and regioselective formylation followed by in situ reductive lactonization.

A general electron transfer reduction of lactones using SmI2–H2O

Herein we describe a strategy for the selective, electron transfer reduction of lactones of all ring sizes and topologies using SmI(2)-H(2)O and a Lewis base to tune the redox properties of the complex. The current protocol permits instantaneous reduction of lactones to the corresponding diols in excellent yields, under mild reaction conditions and with useful chemoselectivity. We demonstrate the broad utility of this transformation through the reduction of complex lactones and sensitive drug-like molecules. Sequential electron transfer reactions and syntheses of deuterated diols are also described.

Synthesis of Pyrrolidinoindolines from 2-(2-Oxo-3-indolyl)acetates: Scope and Limitations

A series of 1,3a,8-alkylpyrrolidinoindolines have been synthesized. The scope and limitations of the alkylation of starting methyl oxindol-3-acetates are explored employing electron-rich and electron-poor alkylating agents. Hydrolysis and reductive lactonization of the resulting carboxylic gamma-oxindolic acid derivatives proceeds with good yields to afford 2-oxofuroindolines providing ready access to the pyrrolidinoindoline derivatives.

Novel reaction in the chemistry of organoaluminum compounds

We previously reported on the synthesis of stereoisomerically pure O-isobutyl lactol I via low-temperature (–70°C) treatment of lactone II with 2 equiv (or more) of diisobutylaluminum hydride in methylene chloride and proposed a probable scheme of this reaction [1]. In the present communication we present new examples of synthesis of O-isobutyl derivatives III and IV from lactones V and VI, respectively, under analogous conditions. These examples demonstrate unusual behavior of diisobutylaluminum hydride in reactions with seven-membered lactones in methylene chloride. Low-temperature (–70°C) hydride reduction of lactones II, V, and VI in such solvents as toluene and tetrahydrofuran quantitatively afforded the corresponding lactols. Reduction of lactones V and VI (general procedure). A solution of 11.8 mmol of lactone V [2] or VI [3] in 20 ml of anhydrous methylene chloride was ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 3, pp. 472–473. © Pleiades Publishing, Ltd., 2011. Original Russian Text © G.Yu. Ishmuratov, V.A. Vydrina, M.P. Yakovleva, E.F. Valeeva, R.R. Muslukhov, G.A. Tolstikov, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 3, pp. 471–472.