Intermolecular Enyne Research Articles

Palladium-Catalyzed Asymmetric Sequential Hydroamination of 1,3-Enynes: Enantioselective Syntheses of Chiral Imidazolidinones.

Pd-catalyzed sequential hydroamination of readily available 1,3-enynes is reported. The redox-neutral process provides an efficient route to synthesize a broad scope of imidazolidinones, thiadiazolidines, and imidazolidines. Asymmetric sequential hydroamination generates a series of synthetically valuable, enantioenriched imidazolidinones. Mechanistic studies revealed that the transformation occurred via an intermolecular enyne hydroamination pathway to give an allene intermediate. Subsequent intramolecular hydroamination of the allene intermediate proceeded under the Curtin-Hammett principle to provide enantioenriched imidazolidinone products.

A Selenide Catalyst for the Activation of Alkenes through Se⋅⋅⋅π Bonding.

Chalcogen bonding catalysis with divalent chalcogenides required using heteroatoms as electron donors to give reactivity, while the activation of hydrocarbons such as alkenes by this concept remains an unresolved challenge. Herein, we discovered a powerful selenide catalyst that showed unprecedented capability in the activation of alkenes. The Se⋅⋅⋅π interactions were capable of catalyzing a broad range of transformations, including intermolecular cyclization and coupling reactions. Significantly, the Se⋅⋅⋅π bonding activation mode can be exploited to achieve intermolecular enyne cyclizations and controlled cross-coupling of triple alkenes. The activation of alkenes by divalent selenides opens up a new avenue for supramolecular catalysis.

A Selenide Catalyst for the Activation of Alkenes through Se⋅⋅⋅π Bonding

AbstractChalcogen bonding catalysis with divalent chalcogenides required using heteroatoms as electron donors to give reactivity, while the activation of hydrocarbons such as alkenes by this concept remains an unresolved challenge. Herein, we discovered a powerful selenide catalyst that showed unprecedented capability in the activation of alkenes. The Se⋅⋅⋅π interactions were capable of catalyzing a broad range of transformations, including intermolecular cyclization and coupling reactions. Significantly, the Se⋅⋅⋅π bonding activation mode can be exploited to achieve intermolecular enyne cyclizations and controlled cross‐coupling of triple alkenes. The activation of alkenes by divalent selenides opens up a new avenue for supramolecular catalysis.

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules.

This account surveys the current progress on the application of intra- and intermolecular enyne metathesis as main key steps in the synthesis of challenging structural motifs and stereochemistries found in bioactive compounds. Special emphasis is placed on ruthenium catalysts as promoters of enyne metathesis to build the desired 1,3-dienic units. The advantageous association of this approach with name reactions like Grignard, Wittig, Diels–Alder, Suzuki–Miyaura, Heck cross-coupling, etc. is illustrated. Examples unveil the generality of such tandem reactions in providing not only the intricate structures of known, in vivo effective substances but also for designing chemically modified analogs as valid alternatives for further therapeutic agents.

An Atom-Economic and Stereospecific Access to Trisubstituted Olefins through Enyne Cross Metathesis Followed by 1,4-Hydrogenation

The combination of intermolecular enyne cross metathesis and subsequent 1,4-hydrogenation opens a stereocontrolled and atom-economic access to trisubstituted olefins. By investigating different combinations of functionalized alkyne and alkene substrates, we found that the outcome (yield, E/Z ratio) of the Grubbs II-catalyzed enyne cross-metathesis step depends on the substrate’s structure, the amount of the alkene (used in excess), and the (optional) presence of ethylene. In any case, the 1,4-hydrogenation, catalyzed by 1,2-di­methoxybenzene-Cr(CO)3, proceeds stereospecifically to yield exclusively the E-products from both the E- and Z-1,3-diene intermediates obtained by metathesis. A rather broad scope and functional group compatibility of the method is demonstrated by means of 15 examples.

Reproductive Regulating Pheromones of Queen Ant: A Short and Versatile Synthesis of 3,11-Dimethylheptacosane

Social behavior of insects always fascinates human beings as they appear to maintain good order and communication in the society. Insects have developed sophisticated chemical communication systems using their pheromones for the purpose. Among the pheromones, cuticular wax is used to recognize group members from non-members. In ants, there have been identified close to 1,000 cuticular hydrocarbons (CHCs) and the composition of CHCs of cuticles works for the discrimination between their friends and foes. Some species of ants are known to use cuticular wax of the dead ants in other colonies to disguise their identity when they invade other colonies. It was known that the antennae of ants recognize the composition of the CHCs but the exact mechanism of this recognition has not been well studied. The CHCs on the cuticles are also used to distinguish the queen ant from other fertile ants. Queen ants produce 3,11dimethylated linear hydrocarbons longer than C26 (Figure 1). Interestingly, only the odd numbered carbon chains ranging from 27 to 33 are found in insect society. These CHCs are also coated on the eggs of the queen but do not exist on those of other ants, which allow ants to distinguish those eggs and destroy the latter by eating to control their social hierarchy. We became interested in the recognition mechanism of the different composition of CHCs and the effect of the disruption of CHC composition on the social behavior of ants. For these studies, we need to devise a versatile synthetic route to these branched hydrocarbons. Herein, we report the first synthesis of 3,11-dimethylheptacosane (1) through a short and versatile synthetic route. The synthetic analysis of 3,11-dimethylheptacosane (1) shows that intermolecular enyne metathesis can allow to introduce two methyl group on the chain and the overall chain length could be controlled by using an alkyne with proper chain length (Scheme 1). Two methyl groups of 1 can be obtained from two conjugated dienes of 2. These two diene fragments, 3 and 4, can be prepared through enyne metathesis of tosylated butynol 6 with proper olefin. This synthesis would not require any protecting group and allows that alkyne 5 could be replaced by other alkynes with different chain length for the synthesis of all possible CHC pheromones. The synthesis started from 3-butynol to produce the corresponding tosylate 6. The alkyne 6 was treated with the second generation Grubbs catalyst (Grubbs II) under ethylene atmosphere to produce diene 3. Since allyl bromide was not

Cobalt-catalyzed regio- and stereoselective intermolecular enyne coupling: an efficient route to 1,3-diene derivatives

The reaction of alkynes with vinyl arenes or vinyl trimethyl silane in the presence of a cobalt(II) complex, Zn and ZnI(2) in CH(2)Cl(2) at rt to 50 degrees C provides 1,3-dienes in good to excellent yields.

Total Synthesis and Biological Evaluation of Amphidinolide V and Analogues

The awesome power of metathesis is illustrated by a concise synthesis of the extremely scarce marine natural product amphidinolide V, which hinges on a sequence of ring-closing alkyne metathesis followed by intermolecular enyne metathesis with ethylene (see scheme). As a complete set of conceivable stereoisomers was prepared, the constitution and absolute configuration of this macrolide could be established and first insights into structure-activity relationships governing its cytotoxicity were obtained.A sequence of ring-closing alkyne metathesis followed by an intermolecular enyne metathesis of the resulting cycloalkyne with ethene was used to forge the macrocyclic skeleton and to set the vicinal exo-methylene branches characteristic for the cytotoxic marine natural product amphidinolide V (1). Comparison of the synthetic material with an authentic sample of this extremely scarce metabolite isolated from a dinoflagellate of the Amphidinium sp. eliminated any doubts about its structure and allowed the absolute configuration of amphidinolide V to be determined as 8R,9S,10S,13R. Moreover, the flexibility inherent to the underlying synthesis blueprint also opened access to a comprehensive set of diastereomers of 1 as well as to synthetic analogues differing from the natural lead in the lipophilic chains appended to the macrocyclic core. This set of designed analogues gave first insights into structure-activity relationships, which revealed that the stereostructure of the macrolactone is a highly critical parameter, whereas the examined alterations of the side chain did not diminish the cytotoxicity of the compounds to any notable extent.

A New Versatile Strategy for C‐Aryl Glycosides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

A New Versatile Strategy for C-Aryl Glycosides

A versatile strategy involving a sequential intermolecular enyne metathesis of C-alkynyl glycosides with ethylene, Diels-Alder, and aromatization reactions is successfully developed to provide a range of C-aryl glycosides. [reaction: see text]

Highly Potent Vitamin D Receptor Antagonists: Design, Synthesis, and Biological Evaluation

Vitamin D receptor (VDR) antagonists have attracted significant levels of interest because of their potential utility in the treatment of Paget's disease, which is known as the most flagrant example of disordered bone remodeling and the second most common bone disease after osteoporosis in Anglo-Saxons. Recent studies on Paget's disease suggested a specific increase in osteoclasts' sensitivity to the differentiation activity of active vitamin D(3) as the principal mechanism for abnormal bone formation. We set out to conduct a structure-activity relationship study on the first VDR antagonists, TEI-9647 and TEI-9648 (25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone), with the goal of improved VDR antagonistic activity. Given that both potent agonists and antagonists must have high affinity for the VDR, we hoped that our accumulated knowledge in the field of VDR agonists would help us identify potent antagonists. First 2alpha-modified TEI-9647 analogues were synthesized, and then 24-substitution to stabilize the lactone structure under physiological conditions was investigated. Finally, 2alpha-modified 24-methyl-, 24,24-dimethyl-, and 24,24-ethano-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone analogues were synthesized. The synthesis of the 24,24-ethano-TEI lactone was accomplished through Ru-catalyzed intermolecular enyne metathesis of the alkynone CD-ring side chain with ethylene to give a dienone, followed by regioselective cyclopropanation. It was found that 2alpha,24,24-trimethyl-TEI-9647 (39) possessed an antagonistic activity (IC(50)=0.093 nM) approximately 90 times that of the original TEI-9647 (IC(50)=8.3 nM).

Synthesis of 24,24-Ethanovitamin D3 Lactones Using Ruthenium-Catalyzed Intermolecular Enyne Metathesis: Potent Vitamin D Receptor Antagonists

Novel vitamin D receptor antagonists, 24,24-ethanovitamin D 3 -26,23-lactones 6 and 7 and their 2a-functionalized analogues 6a-c and 7a-c were synthesized and their biological activities were evaluated. The triene structure of vitamin D 3 was constructed using Pd-catalyzed alkenylative cyclization of A-ring precursor enynes 12 and 12a-c with the CD-ring bromo-olefin counterpart having 24,24-ethano-a-methylene-y-lactone on the side chain (21 or 22). The CD-ring precursors 21 and 22 were efficiently synthesized via Ru-catalyzed intermolecular enyne metathesis of 15 with ethylene to give dienone 17 followed by cyclopropanation. The VDR antagonistic activity of the newly designed vitamin D 3 lactones 6 and 7 increased to 2.8 times that of TEI-9647 (2) in a HL-60 cell differentiation evaluating system. Moreover, introduction of three substituents, that is, a methyl (6a and 7a), a 3-hydroxypropyl (6b and 7b), or a 3-hydroxypropoxyl group (6c and 7c) into the C2a position of 6 and 7, resulted in marked enhancement, up to 19 times, of the antagonistic activity toward VDR.

Mechanism of Enyne Metathesis Catalyzed by Grubbs Ruthenium−Carbene Complexes: A DFT Study

The complete catalytic cycle of the reaction of alkenes and alkynes to dienes by Grubbs ruthenium carbene complexes has been modeled at the B3LYP/LACV3P**+//B3LYP/LACVP level of theory. The core structures of the substrates and the catalyst were used as models, namely, ethene, ethyne, hept-1-en-6-yne, (Me(3)P)(2)Cl(2)Ru=CH(2), and [C(2)H(4)(NMe)(2)C](Me(3)P)Cl(2)Ru=CH(2). Insight into the electronically most preferred mechanistic pathways was gained for both intermolecular as well as for intramolecular enyne metathesis. Alkene metathesis is predicted to proceed fast and reversible, while the insertion of the alkyne substrate is slower, irreversible, and kinetically regioselectivity determining. Ruthenacyclobut-2-ene structures do not exist as local minima in the catalytic cycle. Instead, vinylcarbene complexes are formed directly. The alkyne insertion step and the cycloreversion of 2-vinyl ruthenacyclobutanes feature comparable predicted overall barriers in intermolecular enyne metathesis. For intramolecular enyne metathesis, a noncyclic alkene fragment of the enyne substrate is first incorporated into the Grubbs catalyst by an alkene metathesis reaction. The subsequent insertion of the alkyne fragment then proceeds intramolecularly. Alkene association, cycloaddition, and cycloreversion to the diene product complex close the catalytic cycle. Rate enhancement by an ethene atmosphere (Mori's conditions) originates from a constantly higher overall alkene concentration that is necessary for the rate-limiting [2 + 2] cycloreversion step to the diene product complex.

Equilibrium Control in Enyne Metathesis: Crossover Studies and the Kinetic Reactivity of (E,Z)-1,3-Disubstituted-1,3-Dienes

The stereoselectivity of diene bond formation in the ruthenium-carbene mediated intermolecular enyne metathesis was studied. Initial reaction between an alkyne and 1-hexene gave mixtures of E- and Z-isomers in the newly formed 1,3-diene. However, over time the mixtures equilibrated to form mostly the diene of the E-configuration. To evaluate individual reactivity of the E- and Z-dienes, they were independently synthesized. The E-diene was found to be kinetically-stable under nominal metathesis conditions while the Z-diene isomerized to the E-isomer. The Z-isomeric dienes were found to react with other alkenes to produce a new diene of E-configuration. A secondary metathesis mechanism involving ruthenium alkylidene intermediates was invoked to explain the dynamic stereochemistry observed in this study.

Cross Enyne Metathesis of para-Substituted Styrenes: A Kinetic Study of Enyne Metathesis

[Reaction: see text] The intermolecular enyne metathesis between alkynes and styrene derivatives was developed to study electronic effects in enyne metathesis. A Hammett plot for the overall reaction, catalyst initiation and vinyl carbene turnover was determined with the second generation Grubbs ruthenium carbene catalyst.

Ring Synthesis by Stereoselective, Methylene‐Free Enyne Cross Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Ring synthesis by stereoselective, methylene-free enyne cross metathesis.

Tandem enyne metathesis between 1-alkynes and 1,5-cyclooctadiene or all-cis-1,4-polybutadiene resulted in a direct, one-step ring synthesis of cyclohexadienes by methylene-free metathesis. The use of methylene-free metathesis conditions provided apparent Z-selectivity in the intermolecular enyne metathesis step.

Ethylene‐Promoted Intermolecular Enyne Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cycloheptadiene Ring Synthesis by Tandem Intermolecular Enyne Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enyne Metathesis: A Catalytic, Cross-Selective Diene Synthesis

Methods for the synthesis of 1,3-dienes by intermolecular enyne metathesis are described. A brief overview of enyne metathesis is provided with a discussion of the scope and limitations with respect to reactants and catalyst. The surge of recent interest in metathesis generally and the cross enyne metathesis specifically, has closely matched the development of the functional group-tolerant Grubbs’ carbene catalysts.