Six-membered Ring Lactones Research Articles

Fully Automatized Optimization of Ring-Opening Reactions in Lactone Derivatives via Two-Step Machine Learning.

Cyclization and cycloreversion of organic compounds are fundamental kinetic processes in the design of functional molecules, molecular machines, nanoscale sensors, and switches in the field of molecular and nanoelectronics. We present a fully automatic computational platform for the design of a class of five- and six-membered ring lactones by optimizing the ring-opening reaction rate. Starting from a minimal initial parent set, our algorithm generates iteratively cascades of pools of candidate lactone derivatives where optimization and down-selection are performed without human supervision. We employ the density functional theory combined with the transition state theory to elucidate the exact mechanism leading to the lactone ring-opening reaction. On the basis of the analysis of the reaction pathway and the frontier molecular orbitals, we identify a simple descriptor that can easily correlate with the reaction rate. Consequently, we can omit computationally expensive transition state calculations and deduce the reaction rate from simple ground-state and ionic calculations. To accelerate the platform, we use a data set of the order of 800 molecules to train machine learning models for the prediction of targeted chemical properties, reducing the computational time by a 90% factor. We developed an evolutionary algorithm capable of generating data sets 3 orders of magnitude larger than the initial parent set. Thus, we can explore a large domain of chemical space using minimal computational effort. Our entire platform is modular, and our current implementation for lactone can be further generalized to more complex systems via substitution of the quantum chemical and fingerprinting modules.

Substrate-Dependent Selectivity in Sc(OTf)3-Catalyzed Cyclization of Alkenoic Acids and N-Protected Alkenamides

Five- and six-membered ring lactones and lactams are ubiquitous frameworks in various natural and synthetic molecules and are key building blocks in organic synthesis. Catalytic addition of an O-H or N-H bond across an unactivated C–C double bond is an appealing approach to rapidly access such highly valuable N- and O-containing skeletons in a waste-free and 100% atom efficient process. Herein, we report, for the first time, the efficient and high-yield cyclization of δ/ε-alkenoic acids and N-protected δ-alkenamides catalyzedby practical and easily accessible Lewis acid scandium(III) triflate under thermal and microwave conditions. The selectivity outcome of the reaction of δ/ε-alkenoic acids was dependent on the substitution patterns of the backbone chain and alkene moiety, leading to the exclusive formation of either the corresponding γ/δ-lactones via an O-selective cyclization or the Friedel–Crafts-type product by C-selective cyclization. An uncommon and rarely disclosed O-selective cyclization occurred preferentially or exclusively when N-protected δ-alkenamides were engaged in the reaction. The atom selectivity of the cyclization was unambiguously confirmed by single crystal X-ray crystallography.

Synthesis and Biodegradation of Poly(l-lactide-co-β-propiolactone).

Although the copolymerizations of l-lactide (LA) with seven- or six-membered ring lactones have been extensively studied, the copolymerizations of LA with four-membered ring lactones have scarcely been reported. In this work, we studied the copolymerization of LA with β-propiolactone (PL) and the properties of the obtained copolymers. The copolymerization of LA with PL was carried out using trifluoromethanesulfonic acid as a catalyst and methanol as an initiator to produce poly(LA-co-PL) with Mn of ~50,000 and PL-content of 6–67 mol %. The Tg values of the copolymers were rapidly lowered with increasing PL-contents. The Tm and ΔHm of the copolymers gradually decreased with increasing PL-contents, indicating their decreased crystallinity. Biodegradation test of the copolymers in compost demonstrated their improved biodegradability in comparison with the homopolymer of LA.

Selectivity controlled by ligand tuning in the palladium-catalysed cyclocarbonylation: Synthesis of new γ and δ lactones from a natural sesquiterpene

The cyclocarbonylation of homoallylic alcohols, derived from α-atlantone, catalysed by [Pd(Cl2)L2]/SnCl2] system, afforded new γ and δ lactones as the main products with high selectivities. The regiochemical control depends on the nature of phosphines involved. Catalysts based on monophosphines with large cone angles such as tricyclohexyl phosphine produce the six-membered ring lactones with selectivities up to 80%, while diphosphines with wide bite angle such as xantphos are found to favor the five-membered ring lactones with up to 99% selectivity. Monocrystals of the γ and δ lactones suitable for X-ray diffraction analysis have been obtained and the stereochemistry of the lactones 5a,a′ and 6 have been elucidated. This study is the first example of an attractive catalytic transformation of one single natural sesquiterpene easily available from bio-renewable resources to obtain either γ- or δ-lactones.

The Mechanism of TBD-Catalyzed Ring-Opening Polymerization of Cyclic Esters

Triazabicyclodecene (TBD) has recently been shown to be an effective organocatalyst for the ring-opening polymerization (ROP) of cyclic esters. Using DFT methods, we have studied possible mechanisms of this reaction. Our studies explain not only the narrow polydispersity index (PDI) observed in the ROP of six-membered ring lactones, but also the surprising failure of the ROP for the more reactive butyrolactone.

Catalytic Barbier-type reactions of lactones and esters mediated by the Mischmetall/SmI 2(cat.) system or the Mischmetall/[SmI 2/NiI 2(cat′.)] (cat.) system

Barbier-type reactions using SmI 2 in catalytic amounts together with Mischmetall as a coreductant, involving lactones or esters and a variety of organic halides (allylic, benzylic and alkyl), have been performed. With alkyl halides and five- or six-membered ring lactones, catalytic quantities of nickel diiodide (with respect to SmI 2) must be added to achieve reactions. Thus, a ‘two-stage catalysis’ is carried out. Unexpectedly, it was found that with esters or an unstrained lactone the Mischmetall/SmI 2 (catalytic) system is more reactive than samarium diiodide in stoichiometric amounts. Tentative interpretations of the catalytic role of NiI 2 are proposed.

Stereochemistry Control in the Lewis Acid Mediated Lactonization Reaction of γ,δ-Epoxy-β-silyloxy Esters

ZnCl2-triggered lactonization reactions of γ,δ-epoxy-β-silyloxy esters with remote alkoxy groups (CH2)nOR (n = 2, 3), producing five- and/or six-membered ring lactones, have been investigated. Under such conditions, the regiochemistry of the reaction is governed by the cis or trans nature of the starting epoxy ester and also by its C(3) stereochemistry. An X-ray crystallographic structure of a γ-lactone (compound 24′) and a 13C NMR correlation for the C(4) carbon chemical shifts of all γ-lactones were obtained and used to determine the regioselectivity of the epoxide ring-opening. A mechanistic hypothesis, involving an oxocarbenium ion as a common intermediate, is presented in interpretation of the results.

Cationic palladium complex-catalyzed cyclocarbonylation of 3-butyn-1-ols

Cyclocarbonylation of 3-butyn-1-ols catalyzed by cationic palladium complexes has been studied. Six-membered ring lactones were produced preferentially in acetonitrile using cationic complexes coordinated by certain chelating diphosphines as catalyst. A triphenylphosphine-coordinated cationic palladium complex, on the other hand, effected the formation of five-membered α-alkylidene lactones exclusively in N, N-dimethylformamide. A mechanism involving a palladium hydride as active species has been presumed for the formation of six-membered ring lactones.

Palladium-catalysed conversion of alkenols into five- and six-membered ring lactones at room temperature and atmospheric pressure

Unsaturated alcohols react with carbon monoxide, oxygen, palladium chloride, copper(II) chloride, and hydrochloric acid in tetrahydrofuran to give lactones in 42–80% yield.

THE CARBONYL STRETCHING BANDS IN THE INFRARED SPECTRA OF UNSATURATED LACTONES

Certain types of unsaturated lactones exhibit two bands in the region of the spectrum associated with the C=O stretching vibrational mode. This is observed both in the infrared and Raman spectra.The infrared spectra of 23 simple saturated and unsaturated lactones have been examined in an attempt to determine the structural features with which this carbonyl band splitting is associated. It appears to be common to most unsaturated five- and six-membered ring lactones in which the double bond is conjugated with the carbonyl group, though one well-established exception has been observed. The relative intensities of the two bands are extremely sensitive to changes in the polarity of the solvent; they also vary reversibly with temperature but are independent of concentration.The splitting of the C=O stretching band is attributed to an intramolecular vibrational effect similar to that which occurs in cyclopentanone and in certain Δ2-cyclopentenone derivatives. Its possible dependence on Fermi resonance with the overtone of a lower lying fundamental vibration is discussed.Similar effects occur in other types of carbonyl compounds, such as benzoyl chloride and cyclic five-membered ring anhydrides, and care is needed to distinguish carbonyl band splitting of this kind from that associated with equilibria between conformational isomers.