Tandem enyne metathesis

The short total synthesis of (+)-differolide based on a tandem enyne metathesis / [4+2] cycloaddition was accomplished by T.R. Hoye et al." The enyne metathesis was carried out on ally propynoate using Grubbs s first-generation metathesis catalyst. The catalyst was added to the substrate slowly to maintain high substrate and low ruthenium carbene concentrations. The initially formed 2-vinylbutenolide readily dimerized via a Diels-Alder cycloaddition in which the vinyl group participated as the dienophile to afford the natural product. 

Rosillo M, Dominguez G et al (2004) Tandem enyne metathesis-Diels-Alder reaction for construction of natural product frameworks. J Org Chem 69 2084-2093... 

Enyne metathesis RCM can be performed in tandem with RCM using appropriately spaced diene-yne substrates. Many examples of this reaction featuring various degrees of complexity have been reported. Representative examples of tandem enyne metathesis-RCM are depicted in Scheme 30 and include (i) formation of the fused bicyclic compound 257 from dienyne 255 for securinine total synthesis/ (ii) synthesis of cyclic ethers (e.g., 261 and 262) from diene-alkynes (e.g, 258) and control of the product distribution through alkene substitution pattern,and (iii) double tandem RCM-enyne metatheses (conversion of 263 into 266) of appropriate polyene-polyyne systems. 

A simultaneous intermolecular/intramolecular enyne metathesis process using diynes (e.g., 267) and allylsilane 268 afforded conjugated triene derivatives (e.g., 270). Gyclopropanation was observed as a side-reaction in the tandem enyne metathesis RCM of diene-yne 271. ... 

Ring-closing enyne metathesis was also attempted by the group of Perez-Castells for the synthesis of vinylindoles (04JOC2084). However, they obtained a mixture of desired vinylindole, as well as dimerized product (not shown). Depending on the reaction times and dilution, the major product of the reaction could be altered. Mori and co workers performed a tandem enyne metathesis/Diels—Alder/oxidation approach for the synthesis of indoles (06T3872). However, both indoles along with indolines were obtained in low yields. 

Recently developed advances in Grubbs ruthenium alkylidene complex catalyzed reactions include tandem CM-aza-Michael reactions [10], tandem CM-hydroarylation reactions [11], tandem enyne metathesis-cyclopropanations... 

Li J, Park S, Miller RL, Lee D. Tandem enyne metathesis-metallotropic [l,3]-shift for a concise total s3mtheses of (-l-)-asperpentyn, (—)-harveynone, and (—)-tricholomenyn A. Org. Lett. 2009 11 571-574. 

Diver ST, Clark DA, Kulkami AA. Selective tandem enyne metathesis for the synthesis of functionalized cyclohepta-dienes. Tetrahedron 2008 64 6909 919. 

More research efforts have focused on the ring-closing enyne metathesis, which usually [176] provides conjugated vinyl cycloalkenes (cf Fig. 2a, exo mode) useful for further manipulation, but also allows tandem metathesis processes for the formation of polycyclic compounds. 

Enyne systems are also capable of impressive multiple RRM transformations. For the first such example see Ref. [119]. The reaction of a ruthenium alkyli-dene with an alkyne produces a new vinyl alkylidene, which can participate in further intramolecular or intermolecular metathesis reactions to form fused ring systems. This has led Grubbs to designate alkynes in such systems as relays . In a noteworthy example, Zuercher et al. [ 120] constructed the four fused rings of the steroid backbone 68 in one efficient step using tandem enyne re-... 

A catalytic tandem cyclopropanation-ring-closing metathesis of dienyne 80 led to derivative 81 in good yield (Scheme 30 <2004JA9524>). For internal alkynes, carbene-mediated ring-closing enyne metathesis was observed. Less favorable alkyne binding leads to preferential reactions of the metal carbene with the 1-alkene moiety. 

Enyne metathesis reactions in the context of natural product synthesis have been reviewed recently by Mori <2007ASC121>. Using the same ruthenium catalyst, a novel tandem diyne cycloisomerization-CM process has been devised to furnish 3,4-divinyl-2,5-dihydrofurans (Equation 57) <1999CC237>. 

Kuikarni, A. A., Diver, S. T. Cycioheptadiene Ring Synthesis by Tandem intermoiecuiar Enyne Metathesis. Org. Lett. 2003, 5, 3463-3466. 

Scheme 74. Tandem ring-closing enyne metathesis using first generation Grubbs catalyst to form...

More complex small molecules can also be made by metathesis cascades and tandem reaction sequences involving olehn metathesis components [41], The examples illustrated in Fig. 4.13 include inter- and intramolecular enyne metathesis between an olefin and an alkyne [42], ring-opening cross metathesis to form new substituted acyclic olefins [43], ring-opening ring-closing sequences... 

Perez-Castells and coworkers devised a tandem enyne methathesis Diels-Alder reaction strategy for the assembly of polycyclic indole structures [109]. The enyne metathesis reaction using Grubbs s catalyst (311) with the 2-alkynylaniline 310 in the absence of a dienophile proceeded to form the mono- and bis-indole derivatives 313 and 314 (Scheme 66). Testing the hypothesis that a Diels-Alder cycloaddition with an activated diene might be faster than the undesired cross-metathesis reaction which led to the formation of 314, a one-pot reaction with maleic anhydride (312) as the dienophile was conducted. Disappointingly, the above reaction resulted in a... 

A variety of 5,6-fused dihydropyran-2-ones can be obtained from an enyne tandem RCM. Initial formation of the cyclopentene ring from 26 in a Ru-catalysed enyne metathesis is followed by cyclisation involving the a,P-unsaturated ketone and formation of the pyranone ring (Scheme 28). The method enables 6,5,6- and 6,6,6- tricyclic systems to be synthesised <01CC2648>. 

Scheme 24 Cycloaddition through tandem enyne cross-metathesis-RCM.

Scheme 25 Ring expansion through tandem enyne oross-metathesis-RCM.

Additional aspects of enyne metathesis are depicted in Scheme 28. The conjugated diene products of enyne metathesis can undergo Diels-Alder reactions. Enyne metathesis—Diels-Alder can even be performed as a one-pot tandem reaction process, as exemplified by enyne metathesis of 240 in the presence of maleic anhydride. 

Scheme 30 Representative examples of enyne metathesis reactions occurring in tandem with other metathesis modes.

R] Although not focused on true tandem/cascade processes, for a review of the synthesis of polycyclics by a combination of enyne metathesis and the Diels-Alder reaction, see Kotha, S. Meshram, M. Tiwari, A. Chem. Soc. Rev. 2009,38,2065-2092. 

S. Fustero, P. Bello, J. Mird, A. Sim6n, C. del Pozo, Chem.-Eur. J. 2012, 18, 10991-10997. 1,7-Octadiene-assisted tandem multicomponent cross-enyne metathesis (CEYM)-Diels-Alder reactions a useful alternative to Mori s condition. 

Fig. 34) [83]. Initially they conducted a tandem enyne/alkene RCM reaction to generate the key tricyclic diene (131). However, they observed that the yield of this cascade reaction was low, presumably due to the further decomposition of the labile diene (131) under this condition. Therefore they decided to attempt a tandem catalysis sequence and selectively hydrogenate the less-substituted alkene moiety in situ after the metathesis. As a result, the desired tricyclic product (132) was produced in 52% yield over three transformations. 

It has been demonstrated that these ruthenium complexes are also effective precatalysts for hydrogenation reactions. In 2001, Louie et al. reported the first example of ruthenium-catalyzed tandem RCM/hydrogenation and RCEM/hydrogenation (Scheme 5.1) [1]. Tandem RCM/isomerization [2], RCM/Kharasch addition [3], RCM/dihydroxylation [4], enyne metathesis/Claisen rearrangement [5], enyne metathesis/cyclopropanation [6], ROMP/hydrogenation [7], and CM/aza-Michael addition [8] have also been developed successfully. 

Ring-closing enyne metathesis of 159 generated an intermediate ruthenium carbene which participated in a subsequent cross-metathesis reaction with methyl vinyl ketone to generate the seven-membered carbocycle and ( )-conjugated dienone subunit 162 in a single synthetic transformation. Specifically, treatment of enyne 159 with methyl vinyl ketone 160 in the presence of catalyst 162 (20mol%) provided (+)-8-epi-Xanthatin in 83% yield. It should be noted that the phosphine-free ruthenium catalyst 162 was employed in this step because it had been reported to be superior as a catalyst in tandem RCM-CM reactions reported previously. 

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