Enyne Metathesis Research Articles

Synthesis of Carbocyclic Aromatic Compounds Using Ruthenium-Catalyzed Ring-Closing Enyne Metathesis

General synthetic methods of substituted carbocyclic aromatic compounds are reported. Ring-closing enyne metathesis (RCEM)/dehydration of 1,5-octadien-7-yn-4-ols 6 and RCEM/tautomerization of 1,5-octadien-7-yn-4-ones 7 furnished a wide variety of substituted styrenes 4 and 4-vinylphenols 8, respectively. Acyclic precursors 6 and 7 were readily prepared from beta-halo-alpha,beta-unsaturated aldehydes 9 or 3-halo-2-propene-1-ols 13 by utilizing combinations of the Sonogashira coupling, allylation, and the Dess-Martin oxidation. The RCEM/dehydration for the synthesis of 1,3,5-tris(1-phenylethenyl)benzene derivative 4r and the RCEM/RCM/dehydration for the synthesis of 1,1'-binaphthyl derivative 19a are also presented as applications of this method.

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.

ChemInform Abstract: Acceleration Effect of an Allylic Hydroxy Group on Ring‐Closing Enyne Metathesis of Terminal Alkynes: Scope, Application, and Mechanistic Insights.

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 of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Efficient Synthesis of 4‐Vinyl α,β‐Unsaturated γ‐Lactams by Ring‐Closing Enyne Metathesis Reactions.

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 of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enyne Metathesis/Brønsted Acid-Promoted Heterocyclization

The "one-pot" synthesis of nitrogen heterocycles and an oxygen heterocycle by enyne metathesis and in situ cyclization is reported.

A Convenient Approach to Polycyclic Derivatives with a cis‐Fused 2,6‐Dioxabicyclo[4.3.0]nonane System by the Sequence Ring‐Opening/Intramolecular Ring‐Closing Enyne Metathesis/Diels–Alder Reaction

Abstract7‐Oxanorbornene derivatives functionalized with alkyneappendages undergo intramolecular enyne metathesis reactions to give cis‐fused 2,6‐dioxabicyclo[4.3.0]nonane derivatives. These compounds have a diene functionality thatallows their reaction with dienophiles (N‐phenylmaleimide) to yield densely functionalized polycyclic compounds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Synthesis, Transformations, And Comparative Studies of Porphyryl Acrylic Acids and Their Homologues

The reactivity of porphyryl acrylates and their homologues was studied systematically and to establish their potential as building blocks for the synthesis of novel tetrapyrroles. A new synthetic approach for multifunctional porphyrins was developed using alpha,beta-unsaturated acyl porphyrins as versatile building blocks with yields of 44-95%. The reaction of acyl chlorides generated in situ with ethyl diazoacetate in the presence of PPh(3) led to the corresponding phosphazine, which was quickly self-transformed into a novel porphyrin beta-keto ester system in up to 78% yield. Comparative studies of the next homologue of acrylic porphyrins, i.e., those bearing an additional CH(2) group next to the double bond of the alpha,beta-unsaturated fragment, showed that these can undergo rearrangement reactions via vinylketenes to yield both regioisomers. Depending on the reaction conditions, this method gives regioselectively access to either a rearrangement product or the product of esterification reactions in yields of 81% or 57%, respectively. Enyne metathesis of novel propargyl esters with allyl porphyrins provided an easy access to 1,3-disubstituted butadienes in up to 76% yield.

Stereoselective Total Synthesis of (+)-Valienamine and (+)-4-epi-Valienamine via a Ring-Closing Enyne Metathesis Protocol

Stereoselective total synthesis of (+)-valienamine is reported utilizing Sharpless asymmetric dihydroxylation, diastereoselective Carreira alkynylation, and ring-closing enyne metathesis (RCEYM) as key steps from l-serine. A similar strategy is also reported for the first total synthesis of (+)-4-epi-valienamine.

Advanced approach to polycyclics by a synergistic combination of enyne metathesis and Diels–Alder reaction

Enyne metathesis (EM) has widely been used to prepare various synthetic and natural products. Further, a sequential use of EM and Diels-Alder (DA) reactions generates highly functionalized and intricate polycarbocycles and heterocyclic frameworks. In this critical review we describe the application of a unique combination of EM and DA reactions to prepare various amino acid derivatives, natural products and heterocycles. Some of the heterocyclic targets include cyclic peroxides, siloxanes and various nitrogen (or oxygen) containing compounds. Use of ethylene and cyclooctadiene (COD) for improving the yield of EM products are also discussed (69 references).

Synthesis of Five- and Six-Membered Heterocyclic Compounds by the Application of the Metathesis Reactions

This review describes the formation of five- and six-membered heterocyclic rings in various compounds by ring closing diene and enyne metathesis.

High-yielding synthesis of Nefopam analogues (functionalized benzoxazocines) by sequential one-pot cascade operations

An efficient amine-/ruthenium-catalyzed three-step process for the synthesis of Nefopam analogues was achieved through combinations of cascade enamine amination/iso-aromatization/allylation and diene or enyne metathesis as key steps starting from functionalized Hagemann's esters. In this communication, we discovered the application of ruthenium-catalysis on olefins containing free amines without in situ formation of salts.

閉環メタセシスを利用する置換芳香族化合物の合成

The demand for functionalized aromatic compounds is growing rapidly in many research fields. Therefore, the efficient synthesis of desired aromatic compounds is a critical issue in organic synthesis. In this account, we describe new synthetic approaches to versatile aromatic compounds, such as phenols, benzenes, 3-hydroxypyridines, and styrenes, by ring-closing olefin metathesis (RCM)/aromatization and ring-closing enyne metathesis (RCEM)/aromatization of acyclic precursors. The advantages in terms of simplicity, flexibility, and avoidance of the formation of regioisomers are proof of the versatility of this method for the synthesis of aromatic compounds.

“Click, Click, Cyclize”: A DOS Approach to Sultams Utilizing Vinyl Sulfonamide Linchpins

A diversity-oriented synthesis (DOS) strategy termed "Click, Click, Cyclize" is reported. This approach relies on functional group (FG) pairing between a vinyl sulfonamide and an array of functional groups to synthesize skeletally diverse sultams. Several FG pairing pathways on central tertiary vinyl sulfonamide linchpins have been developed including intramolecular Heck, aza-Michael, ring-closing enyne metathesis, Pauson-Khand, and chemoselective oxidation/Baylis-Hillman reactions.

Acceleration Effect of an Allylic Hydroxy Group on Ring‐Closing Enyne Metathesis of Terminal Alkynes: Scope, Application, and Mechanistic Insights

An interesting acceleration effect of an allylic hydroxy group on ring-closing enyne metathesis has been found. Ring-closing enyne metathesis of terminal alkynes possessing an allylic hydroxy group proceeded smoothly without the ethylene atmosphere generally necessary to promote the reaction. The synthesis of (+)-isofagomine with the aid of this efficient reaction has been demonstrated. Mechanistic studies of the acceleration effect were also carried out. Results of NMR studies suggested that the reaction proceeded via an "ene-then-yne" pathway. Kinetic studies indicated switching of the rate-determining step as a consequence of the presence of an allylic hydroxy group. These results suggest acceleration of the reentry step of Ru-carbene species by the allylic hydroxy group.

Initial Catalyst−Substrate Association Step in Enyne Metathesis Catalyzed by Grubbs Ruthenium Complex Probed by Time-Dependent Fluorescence Quenching

This communication introduces an FRET-based simple and efficient method for monitoring kinetics and thermodynamics of organic reactions and describes its application to studies on the initial catalyst−substrate association step in the enyne metathesis catalyzed by a Grubbs Ru complex to probe the reaction initiation on the alkyne versus the alkene. The kinetic and thermodynamic parameters of alkene and alkyne with the first generation Grubbs Ru complex, determined by the time-dependent fluorescence quenching of the dye-conjugated substrate by the Ru catalyst, strongly support the dominance of the reaction initiation on alkene over alkyne in the reaction both kinetically and thermodynamically.

Efficient synthesis of 4-vinyl α,β-unsaturated γ-lactams by ring-closing enyne metathesis reactions

The ring-closing enyne metathesis reaction of alkyl 2-substituted-2-( N-alkynyl acrylamido)esters using the first-generation Grubbs’ catalyst afforded five-membered lactams bearing a 1,3-diene moiety in high isolated yields. In the reaction process, the presence of ethylene gas is essential.

Highly Active Ammonium-Tagged Olefin-Metathesis Catalyst for Simplified Purification

When an 2-isopropoxy-substituted benzylidene ligand of a Hoveyda-type Ru-metathesis complex is modified by an additional 4-diethylamino group and treated wit PTSA it yields a highly active precatalyst suitable for RCM, cross metathesis, and enyne metathesis. The important property of this ammonium tagged Ru-complex is associated with the possibility of its easy removal by a simple filtration protocol.

A Rapid Access to New Fluorinated 1,3-Dienes and Benzylic Fluorides via Metathesis on Propargylic Fluorides

The cross enyne metathesis reaction of propargylic fluoride (+)-12 with ethylene affords the enantioenriched 1,3-diene (+)-14 having fluorine-containing side chain at 2-position in good yield. Upon Diels-Alder reaction, followed by aromatization, this diene affords the new benzylic fluorides (+)-16 and (+)-17 in high ee values. This new strategy has been successfully extended to the corresponding gem-difluoro diene 21 and benzylic fluorides 23 and 24.

Stereoselective Synthesis of (−)‐Amphidinolide E

The total synthesis of (-)-amphidinolide E was accomplished by following a synthetic scheme that incorporates the labile C2 stereocenter at a very late stage. The oxolane unit was prepared by beta-alkoxyacrylate radical cyclization. The enyne metathesis reaction was employed for the synthesis of the side chain. The Kocienski-Julia reaction was used for the union of the two major fragments, and the Kita macrolactonization protocol was used for macrolide synthesis.

Synthesis of a Conformationally Constrained Phenylalanine Derivative by a Strategic Combination of Ring-Closing Enyne Metathesis and Diels-Alder Reaction

An efficient route towards the synthesis of a conformationally constrained phenylalanine derivative is demonstrated using the strategic combination of ring-closing enyne metathesis and Diels-Alder reaction as key steps.