Intramolecular Carbonyl-ene Reaction Research Articles

Bioinspired Total Synthesis of Hyperireflexolides A and B.

Hyperireflexolides A and B were synthesized in six steps via the dearomatization and fragmentation of a simple acylphloroglucinol starting material. The dearomatized acylphloroglucinol undergoes a sequence of oxidative radical cyclization, retro-Dieckmann fragmentation, stereodivergent intramolecular carbonyl-ene reactions, and final α-hydroxy-β-diketone rearrangements to give the target natural products. This sequence is based on a biosynthetic proposal that claims the hyperireflexolides as highly rearranged polycyclic polyprenylated acylphloroglucinols (PPAPs), which is supported by the structural revision of hyperireflexolide B.

(Z)-γ-Alkylidenebutenolide Synthesis through Au(I)-Catalyzed 1,3-Acyloxy Migration and the Carbonyl-Ene Reaction.

A bimetallic protocol has been developed to construct (Z)-γ-alkylidenebutenolide compounds from readily available propargyl α-ketoesters. It involves a gold-catalyzed 1,3-acyloxy migration of propargyl α-ketoesters and a carbonyl-ene cyclization of in situ generated allenyl esters. DFT calculations suggest that the copper salt might play dual roles as both chloride abstractor facilitating the generation of highly active gold catalyst and Lewis acid promoting the stepwise intramolecular carbonyl-ene reaction.

Stereoselective Construction of the Methylcyclopentane Core of Peditithins B-H with Five Continuous Stereocenters.

A stereoselective construction of the methylcyclopentane core (3) of jatrophane diterpenoids peditithins B-H was achieved in 14 steps from commercially available d-(+)-ribono-1,4-lactone (9). The linear 5-ene-heptanal derived from 9 was cyclized to the five-membered ring by an intramolecular carbonyl ene reaction, and five continuous stereocenters on 3 were stereoselectively introduced via a successive substrate-controlled manner, involving diastereoselective 1,4-addition, MoOPH-induced hydroxylation, and stereospecific epoxidation.

The Effect of Solvent-Substrate Noncovalent Interactions on the Diastereoselectivity in the Intramolecular Carbonyl-Ene and the Staudinger [2 + 2] Cycloaddition Reactions.

Noncovalent interactions (NCIs) have been identified as important contributing factors for determining selectivity in organic transformations. However, cases where NCIs between solvents and substrates are responsible for a major extent for determining selectivity are rare. The current computational study with density functional theory identifies two important transformations where this is the case: the intramolecular carbonyl-ene reaction and the Staudinger [2 + 2] cycloaddition reaction. In both cases, the role of explicit solvent molecules interacting noncovalently with the substrate has been taken into account. Calculations indicate that the diastereomeric ratio would be 95.0:5.0 for the formation of tricyclic tetrahydrofuran diastereomers via the intramolecular carbonyl-ene reaction and 94.0:6.0 for the formation of the triflone diastereomers via the Staudinger [2 + 2] cycloaddition reaction, which corroborates with the experiment. Interestingly, in both the cases, the calculations indicate that noninclusion of explicit solvent molecules would lead to only a small difference between the competing transition states, which leads to the conclusion that solvent-substrate NCIs are the major cause for diastereoselectivity in both the cases considered.

Effects of Chiral Ligands on the Asymmetric Carbonyl-Ene Reaction

The carbonyl-ene reaction is one of the most well-known reactions for C–C bond formation. Based on frontier molecular orbitals (FMO), carbonyl-ene reactions occur between the highest occupied molecular orbital (HOMO) of the ene compound bearing an active hydrogen atom at the allylic center and the lowest unoccupied molecular orbital (LUMO) of the electron-deficient enophile, which is a carbonyl compound. A high activation barrier enforces the concerted ene reaction rather than a Diels–Alder reaction at high temperature. Employing a catalytic system can eliminate defects in the ene reaction, and chiral catalysts promote the reaction under mild conditions to produce optically active compounds. In this account, we highlight investigations on the effects of various classes of chiral ligands on intermolecular and intramolecular carbonyl-ene reactions.1 Introduction2 Biaryl-Type Chiral Ligands3 C 1- and C 2-Symmetric Bis(oxazoline) Ligands4 Schiff Base Ligands5 N,N′-Dioxide Ligands6 Conclusions

Application of intramolecular carbonyl-ene reaction towards the synthesis of idarubicinone scaffold

Application of intramolecular carbonyl-ene reaction towards the synthesis of idarubicinone scaffold

Fe(BF4)2-Catalyzed Inter- and Intramolecular Carbonyl-Ene Reaction of Trifluoropyruvate

Inter- and intramolecular carbonyl-ene reactions have been developed using 5 mol% Fe(BF4)2 as catalyst, affording homoallylic alcohols in 36–87% isolated yields. This catalyst, prepared from FeCl2 and AgBF4, is the first FeII Lewis acid reported for the carbonyl-ene reaction using ethyl trifluoropyruvate. The method was successfully applied to the reaction of various 1,1-disubstituted alkenes with ethyl trifluoropyruvate and to the cyclization of citronellal.

Applications of [4+2] Anionic Annulation and Carbonyl-Ene Reaction in the Synthesis of Anthraquinones, Tetrahydroanthraquinones, and Pyranonaphthoquinones

Hexa-2,5-dienoates, susceptible to isomerization by acids and bases, are suitable for the [4+2] anionic annulation to give 3-(2-alkenyl)naphthoates in regiospecific manner. When combined with intramolecular carbonyl-ene reaction (ICE), the accessibility of the naphthoates culminates in a new synthesis of anthraquinones and diastereoselective synthesis of tetrahydroanthraquinones. This strategy has also resulted in a 3-step synthesis of dehydroherbarin from a 3-methallylnaphthoate.

Organocatalyzed Intramolecular Carbonyl-Ene Reactions.

An organocatalyzed intramolecular carbonyl-ene reaction was developed to produce carbocyclic and heterocyclic 5- and 6-membered rings from a citronellal-derived trifluoroketone and a variety of aldehydes. A phosphoramide derivative was found to promote the cyclization of the trifluoroketone, whereas a less acidic phosphoric acid proved to be a superior catalyst for the aldehyde substrates.

Intramolecular carbonyl-ene reactions in the synthesis of peri-oxygenated hydroaromatics

2-Methallyl aromatic aldehydes, synthesized by Suzuki coupling of 2-formylphenylboronic acids, are shown to provide cycloalkylidene ene products under acidic conditions. Susceptibility of the products to aromatization is manoeuvred by varying the reaction conditions and catalysts including binol-derived Brønsted acid catalysts. A peri-effect is identified as a controlling factor for the aromatizations. Several oxidative transformations of an ene product are carried out as model studies of hydroaromatic polyketide natural products.

ChemInform Abstract: Confined Acid‐Catalyzed Asymmetric Carbonyl—Ene Cyclization.

AbstractThis is the first organocatalytic asymmetric intramolecular carbonyl—ene reaction of olefinic aldehydes.

Enantioselective Total Synthesis of (+)-Steenkrotin A and Determination of Its Absolute Configuration.

The first enantioselective total synthesis of (+)-steenkrotin A has been achieved in 18 steps and 4.2 % overall yield. The key features of the strategy entail a Rh-catalyzed O-H bond insertion followed by an intramolecular carbonyl-ene reaction, two sequential SmI2 -mediated Ueno-Stork and ketyl-olefin cyclizations, and a cascade intramolecular aldol condensation/vinylogous retro-aldol/aldol process with inversion of the relative configuration at the C7 position. The absolute configuration of (+)-steenkrotin A was determined based on the stepwise construction of the stereocenters during the total synthesis.

Confined Acid-Catalyzed Asymmetric Carbonyl-Ene Cyclization.

A highly enantioselective Brønsted acid catalyzed intramolecular carbonyl-ene reaction of olefinic aldehydes has been developed. Using a confined imidodiphosphate catalyst, the reaction delivers diverse trans-3,4-disubstituted carbo- and heterocyclic five-membered rings in high yields and with good to excellent diastereo- and enantioselectivities. ESI-MS, NMR, and DFT mechanistic studies reveal that the reaction proceeds via a stepwise pathway involving a novel covalent intermediate.

ChemInform Abstract: Total Synthesis of Diterpenoid Steenkrotin A.

AbstractThe first symmetric synthesis of diterpenoid steenkrotin A is described.

Total synthesis of diterpenoid steenkrotin A.

A concise and diastereoselective total synthesis of the diterpenoid (±)-steenkrotin A is described for the first time. The strategy mainly features three key ring formations: 1) a rhodium-catalyzed O-H bond insertion followed by an intramolecular carbonyl-ene reaction to build up the tetrahydrofuran subunit; 2) sequential SmI2 -mediated Ueno-Stork and ketyl-olefin cyclizations to construct the [5,7] spirobicyclic skeleton; and 3) an intramolecular aldol condensation/vinylogous retro-aldol/aldol sequence to form the final six-membered ring with inversion of the relative configuration at the C7 position.

Catalytic intramolecular carbonyl–ene reaction with ketones: evidence for a retro–ene process

The ene and reverse ene-processes occur with ketones, as shown by control experiments and by ESI-MS analysis.

Highly stereoselective synthesis of cyclopentanes bearing four stereocentres by a rhodium carbene-initiated domino sequence.

Stereoselective synthesis of a cyclopentane nucleus by convergent annulations constitutes a significant challenge for synthetic chemists. Though a number of biologically relevant cyclopentane natural products are known, more often than not, the cyclopentane core is assembled in a stepwise fashion due to lack of efficient annulation strategies. Herein, we report the rhodium-catalyzed reactions of vinyldiazoacetates with (E)-1,3-disubstituted 2-butenols generate cyclopentanes, containing four new stereogenic centers with very high levels of stereoselectivity (99% ee, >97 : 3 dr). The reaction proceeds by a carbene–initiated domino sequence consisting of five distinct steps: rhodium–bound oxonium ylide formation, [2,3]-sigmatropic rearrangement, oxy-Cope rearrangement, enol–keto tautomerization, and finally an intramolecular carbonyl ene reaction. A systematic study is presented detailing how to control chirality transfer in each of the four stereo-defining steps of the cascade, consummating in the development of a highly stereoselective process.

Efficient synthesis of mibefradil analogues: an insight into in vitro stability.

This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2. Using this protocol, we could obtain 22 new mibefradil analogues 2, which were biologically tested for in vitro efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue 2aa containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of 1 was effective for improving in vitro stability, i.e., reducing CYP inhibition and metabolic degradation.

Toward the Total Synthesis of (±)-Andrastin C

An efficient approach to generate a fully functionalized cyclopenta[a]phenanthrene 34, the basic carbon framework of andrastin C (1c), is described. The present synthetic route features a stereoselective intramolecular Diels-Alder reaction of triene 12 and an intramolecular carbonyl ene reaction of 3-phenanthrenyl-2-(methoxymethoxy)propanal 31.

Enantioselective Total Synthesis of Marine Diterpenoid Clavulactone

The key steps in the synthesis of clavulactone are formation of an enantiopure cyclopentane precursor by epoxide rearrangement and intramolecular carbonyl-ene reaction, construction of the 3,4-dihydro-2H-pyran ring by intermolecular hetero-Diels-Alder reaction, closure of the eleven-membered ring, and finally generation of the lactone functionality by chemoselective allylic C(sp(3))-H oxidation.