Enyne System Research Articles

Asymmetric Total Synthesis of Anti-HBV Drug Entecavir: Catalytic Strategies for the Stereospecific Construction of Densely Substituted Cyclopentene Cores.

We have successfully accomplished a catalytic asymmetric total synthesis of entecavir, a first-line antihepatitis B virus medication. The pivotal aspect of our strategy lies in the utilization of a Pd-catalyzed enyne borylative cyclization reaction, enabling the construction of a highly substituted cyclopentene scaffold with exceptional stereoselectivity. Additionally, we efficiently accessed the crucial 1,3-diol enyne system early in our synthetic route through a diarylprolinol organocatalyzed enantioselective cross-aldol reaction and Re-catalyzed allylic alcohol relocation. By strategically integrating these three catalytic protocols, we established a practical pathway for acquiring valuable densely heteroatom-substituted cyclopentene cores.

Nickel-Catalyzed trans-Carboamination across Internal Alkynes to Access Multifunctionalized Indoles.

A Ni-catalyzed reaction was developed for the synthesis of multifunctionalized indoles. The reaction proceeded through oxidative cyclization of the Ni(0)/P^N complex with an enyne system, 2-alkynyl anilinoacrylate, to provide a nickelacycle intermediate. The trans-carboamination around the internal alkyne was achieved by syn/anti-rotation of the Ni-carbenoid intermediate formed by C-N bond cleavage of the nickelacycle, and 3-alkenylated indoles were formed by C-N bond-forming reductive elimination. Notably, the synthesized indoles could be successfully transformed to functionalized carbazoles.

Cyclopropenylmethyl Cation: A Concealed Intermediate in Gold(I)-Catalyzed Reactions.

The last years have witnessed many gold‐catalyzed reactions of alkynes. One of the most prominent species in the reaction of two alkyne units is the vinyl‐substituted gold vinylidene intermediate. Here, we were able to show that the reaction of a haloacetylene and an alkyne proceeds via a hitherto overlooked intermediate, namely the cyclopropenylmethyl cation. The existence and relative stability of this concealed intermediate is verified by quantum chemical calculations and 13C‐labeling experiments. A comparison between the cyclopropenylmethyl cation and the well‐known vinylidene intermediate reveals that the latter is more stable only for smaller cycles. However, this stability reverses in larger cycles. In the case of the smallest representative of both species, the vinylidene cation is the transition state en route to the cyclopropenylmethyl cation. The discovery of this intermediate should help to get a deeper understanding for gold‐catalyzed carbon–carbon bond‐forming reactions of alkynes. Furthermore, since enynes can be formed from the cyclopropenylmethyl cation, the inclusion of this intermediate should enable the development of new synthetic methods for the construction of larger cyclic halogenated and non‐halogenated conjugated enyne systems.

1,3-Chlorine Shift to a Vinyl Cation: A Combined Experimental and Theoretical Investigation of the E-Selective Gold(I)-Catalyzed Dimerization of Chloroacetylenes.

Metal-catalyzed dimerization reactions of terminal acetylenes are well known in the literature. However, only a few examples of the dimerization of halogen-substituted acetylenes are described. The products of the latter metal-catalyzed dimerization are the branched head-to-tail enynes. The formation of the corresponding linear head-to-head enynes has not been reported yet. Herein, we demonstrate by means of quantum chemical methods and experiments that the head-to-head dimerization of chloroarylacetylenes can be achieved via mono gold catalysis. Under the optimized conditions, a clean and complete conversion of the starting materials is observed and the dimeric products are obtained up to 75% NMR yield. A mechanistic investigation of the dimerization reaction reveals that the branched head-to-tail vinyl cation is energetically more stable than the corresponding linear head-to-head cation. However, the latter can rearrange by an unusual 1,3-chlorine shift, resulting in the highly stereoselective formation of the trans product, which corresponds to the gold complex of the head-to-head E-enyne. The activation barrier for this rearrangement is extremely low (ca. 2 kcal/mol). As the mono gold-catalyzed dimerization can be conducted in a preparative scale, this simple synthesis of trans-1,2-dichloroenynes makes the gold(I)-catalyzed head-to-head dimerization of chloroarylacetylenes an attractive method en route to more complex conjugated enyne systems and their congeners.

Stereoselective synthesis of benzofuran and benzothiophene substituted dihydropyran derivatives via ring closing metathesis

Ring closing metathesis reactions have been applied to diene and enyne systems derived from homoallylic alcohol backbones are described. The key intermediates 2-benzofuranyl 1a and 2-benzothiophenyl 1b substituted homoallylic alcohols were synthesized from their corresponding carboxaldehyde derivatives. Racemic 2-heteroaryl-substituted homoallylic alcohols are successfully resolved to give the corresponding enantiopure acetates and alcohols with 80–99% ee through enzymatic resolution by various lipases. Enantiomerically enriched diene and enyne skeletons derived from homoallylic alcohols were subjected to the ring closing metathesis via first and second generation Grubbs’ catalysts and the corresponding chiral heteroaryl-substituted dihydropyran derivatives were obtained with good yields (41–96%).

Isoquinoline-substituted triazole and pyran derivatives: synthesis and computational studies

The one-pot synthesis of novel 1,4-disubstituted 1,2,3-triazoles from isoquinoline-substituted homopropargyl alcohol backbone is described (42%-88% yields). A ring closing metathesis reaction and an intramolecular Pauson-Khand reaction of enyne system derived from a homopropargyl alcohol backbone to afford the corresponding isoquinoline-substituted dihydropyran and cyclopentenone-pyran, respectively, are also described (54% and 78% yields). Information about the structural, electronic, and physico-chemical properties of the novel compounds, obtained by density functional theory application, is also reported.

ジインおよびエンイン系のドミノ環化反応による縮合ヘテロ多環式化合物合成の新手法

ジインおよびエンイン系のドミノ環化反応による縮合ヘテロ多環式化合物合成の新手法

Use of ionic liquids in the platinum- and gold-catalyzed cycloisomerization of enyne systems

The platinum- and gold-catalyzed cycloisomerization of enyne systems has been carried out in various ionic liquids (ILs). In some cases, better selectivities and shorter reaction times have been observed compared to conventional conditions.

Synthesis of Diverse Polycyclic Compounds via Catalytic Metathesis

A variety of olefin-metathesis protocols have been used to prepare spirocyclic compounds, cyclic sulfones, and constrained α-amino acid derivatives. Conceptually, a new approach to a novel cyclophane ring system has been realized via ring-closing meta-thesis (RCM). Also, tetracyclic compounds related to anthracycline antibiotics have been assembled using Claisen rearrangement and RCM as key steps. Further, a sequential use of the Diels-Alder -reaction and ring-opening cross-metathesis delivered highly functionalized spiroindane derivatives, and trisubstituted benzene derivatives have been assembled using Grubbs’ catalyst. Finally, the enyne and cross-enyne metathesis sequences have been used to prepare several constrained α-amino acid derivatives. 1 Introduction 2 Application of Ring-Closing Metathesis To Give Spiro-cyclic Compounds 3 Application of Ring-Closing Metathesis To Give Cyclophane Derivatives 4 Application of Ring-Closing Metathesis To Give Cyclic Sulfone Derivatives 5 Application of Ring-Closing Metathesis To Give Cyclic α-Amino Acid Derivatives and Modified Peptides 6 Application of Ring-Closing Metathesis to Benzannulation 7 Application of Enyne Metathesis to the Synthesis of Constrained α-Amino Acid and Naphthoxepin Derivatives 8 Application of Cross-Enyne Metathesis to the Synthesis of Highly Functionalized Phenylalanine Derivatives 9 Application of Ring-Opening Cross-Metathesis to Spiro-indanes 10 Synthesis of Trisubstituted Benzene Derivatives Using Grubbs’ Catalyst 11 Metathesis of a Novel Enyne System 12 Macroheterocycles via Cross-Enyne and Ring-Closing Metathesis Cascade Reactions 13 Conclusions

Asymmetric Total Syntheses of (+)-3-(Z)-Laureatin and (+)-3-(Z)-Isolaureatin by “Lone Pair−Lone Pair Interaction-Controlled” Isomerization

The first asymmetric total syntheses of the dihalogenated medium-sized dioxabicyclic marine natural products (+)-3-(Z)-isolaureatin (1) and (+)-3-(Z)-laureatin (2) have been accomplished. Notable features of the highly stereo-, regio-, and chemoselective syntheses of these alpha,alpha'-trans-oxocene natural products include an intramolecular amide enolate alkylation to construct the alpha,alpha'-cis-oxocene, novel "lone pair-lone pair interaction-controlled" epimerizations to the alpha,alpha'-trans-oxocenes, various strategies for stereoselective introduction of halogen atoms, and novel olefin cross-metatheses for construction of the (Z)-enyne systems.

Synthesis of a Series of Diiron Complexes Based on a Tetraethynylethene Skeleton and Related C6-Enediyne Spacers, (dppe)Cp*Fe−C⋮CC(R)C(R)C⋮C−FeCp*(dppe): Tunable Molecular Wires

A series of 3,4-disubstituted (hex-3-ene-1,5-diyne-1,6-diyl)diron complexes with FeCp*(dppe) (Fe) end caps, Fe−C⋮CC(R)C(R)C⋮C−Fe (R = H, C⋮C−SiMe3, C⋮C−H, C6H5, p-C6H4CF3), and the related (octa-3,5-diene-1,7-diyne-1,8-diyl)diron complex, Fe−C⋮C−C(H)C(H)C(H)C(H)C⋮C−Fe, has been prepared, and their performance as molecular wires has been evaluated. The enyne complexes have been synthesized via vinylidene intermediates, [FeCC(H)C(R)C(R)C(H)CFe]2+, derived from the corresponding terminal alkynes or the Me3Si-protected precursors (XC⋮CCC(R)C(R)C⋮C−X; X = H, SiMe3), and the products have been characterized spectroscopically and crystallographically. The performance of the obtained dinuclear enyne complexes as molecular wires has been evaluated on the basis of the comproportionation constants (KC) obtained by electrochemical measurements and the Vab values obtained from the spectral parameters of the intervalence charge transfer bands of the isolated monocationic radical species appearing in the near-IR region. As a result, the C6-enediyne complexes turn out to be excellent molecular wires, with KC values larger than 108 as well as Vab values larger than 0.35, belonging to class III compounds according to the Robin and Day classification and being comparable to the related polyynediyl complexes as well. It is notable that, in the enyne system, the performance can be readily tuned by introduction of appropriate substituents onto the olefinic part. Thus, diiron complexes containing an enyne spacer can be regarded as tunable molecular wires.

Reaction of Rosenthal's Zirconacyclocumulenes with Chlorophosphines

The zirconacyclocumulenes 1a (R = CH3) and 1b (R = Ph) were prepared by isomerization of bis(propynyl)ZrCp2 or bis(phenylethynyl)ZrCp2, respectively, catalyzed by B(C6F5)3 (6 mol %). The compounds 1 added PCl3, PhPCl2, or Ph2PCl with cleavage of only one zirconium−carbon single bond. Chloride was added to zirconium and the remaining −PCl2, −P(Ph)Cl, or −PPh2 moiety attached at the distal β-carbon atom of the strained ZrC4R2 metallacycle to yield the respective ring-opened Zr/P-substituted enyne systems (5−7). The complexes 7a and 7b (both with −PPh2) and 6b (with −P(Ph)Cl) were characterized by X-ray diffraction.

Tandem PtCl2 Catalyzed—Thermal [3,3] Rearrangements of Enyne Acetates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereoselective synthesis of sugar-modified enyne analogues of adenosine and uridine. Interaction with S-adenosyl-L-homocysteine hydrolase and antiviral and cytotoxic effects.

Sonogashira coupling of (E)-6'-iodohomovinyl nucleosides 1 with (trimethylsilyl)acetylene gave the conjugated 8'-(trimethylsilyl)enyne derivatives of the adenosine 2a and uridine 2b with expected E-stereochemistry. Desilylation of 2a,b with tetrabutylammonium fluoride followed by treatment with N-iodosuccinimide/AgNO(3) afforded 8'-iodoenynes 4a,b. Analogous coupling of (Z)-6'-iodohomovinyl nucleosides 7a,b produced (Z)-8'-(trimethylsilyl)enynes 8a,b, which were deprotected with aqueous trifluoroacetic acid to give the Z-enynes 9a,b. Stereoselective coupling of the adenosine 4'-acetylenic 11 and ethyl (Z)-3-bromoacrylate followed by deprotection gave the conjugated enyne system attached in the reverse orientation at C4' 13. Because of their diverse stereochemical attributes, deprotected enyne analogues 5a, 6a, 9a, and 13 derived from adenosine require a different vicinity for binding with S-adenosyl-l-homocysteine (AdoHcy) hydrolase and/or addition of enzyme-bound water across the conjugated enyne system. Enyne 5a and 8'-iodoenyne 6a produced time-dependent and concentration-dependent inhibition of AdoHcy hydrolase (K(i), 0.55 and 118.5 microM, respectively). No reduction in NAD(+) content of the enzyme and no iodide ion released were observed upon incubation of 6a with the enzyme, while incubation of 5a produced 30% reduction in the NAD(+) content of the enzyme. No specific antiviral activity was noted for 5a,b, 6a,b, 9a,b, and 13 against any of the viruses tested; the E-iodoenynes 6a and 6b inhibited HIV-1 virus (IC(50), 1.1 and 1.8 microM; selectivity index, 7 and 3, respectively). The E-enyne 5a showed activity against cytomegalovirus at a concentration (EC(50), 30 microM) that was 3- to 10-fold lower than the cytotoxic concentration.

Tandem PtCl 2 catalyzed–thermal [3,3] rearrangements of enyne acetates

1,6 Enyne systems flanked with an acetate group at the propargyl position undergo tandem PtCl 2-catalyzed–thermal [3,3] rearrangements leading to trienes. The scope of the transformation has been delineated by varying the nature of the alkynyl substituent R. For R=alkyl or phenyl, a direct 1,3-migration of the acetate group is proposed leading to an allenyl ester intermediate that undergoes a subsequent [3,3] rearrangement.

Substituent Effects on the Cyclization Mode of 7‐Sulfonyl‐3‐hepten‐1,5‐diynes and 11‐Sulfonylundeca‐3,7‐dien‐1,5,9‐triynes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Substituent effects on the cyclization mode of 7-sulfonyl-3-hepten-1,5-diynes and 11-sulfonylundeca-3,7-dien-1,5,9-triynes

In probing of cycloaromatization of 7-phenylsulfonyl-3-hepten-1,5-diyne systems to generate biradical intermediates under an alkaline condition suggested that the aryl moiety on C3–C4 also plays an important role to switch the Myers cyclization to Schmittel cyclization in the allen–enyne system, although the aryl group on the alkyne terminus does not work in the proceeding of the cycloaromatization. For example, treatment of 1-phenyl-7-phenylsulfonyl-3-hepten-1,5-diyne ( 8 ) with triethylamine in the presence of 1,4-cyclohexadiene in benzene offered biphenyl 13 in 51% yield. Under the same reaction conditions, cyclization of 1-(2-phenylethynyl)-2-(3-phenylsulfonyl-1-propynyl) benzene ( 28 ) gave naphthalene 34 in 42% yield along with indene 35 in 32% yield. Moreover, the substituent effect also occurred in the cyclization of 11-phenylsulfonylundeca-3,7-diene-1,5,9-triyne ( 38 ), which provided indene 39 in 50% yield as the major product.

Stereoselective Synthesis of Enynes by Nickel‐Catalyzed Cross‐Coupling of Divinylic Chalcogenides with Alkynes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereoselective synthesis of enynes by nickel-catalyzed cross-coupling of divinylic chalcogenides with alkynes.

(Z,Z)- and (E,E)-divinylic selenides and telurides undergo direct coupling with terminal alkynes in the presence of a nickel/CuI catalyst at room temperature to give (Z)- and (E)-enyne systems in good yields and with complete retention of configuration.

Synthesis of pentacarbonyltungsten(0) complexes of bulky 1,2-diphosphabut-1-en-3-ynes as a heavier enyne congener

Pentacarbonyltungsten(0) complexes of kinetically stabilized 1,2-diphosphabut-1-en-3-ynes were synthesized as a heavier conjugated enyne system featuring a phosphorusphosphorus double bond, and characterized by spectroscopic and crystallographic analyses.