Diels-Alder reactions enyne metathesis

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. 

The enyne cross metathesis was first developed in 1997 [170,171]. Compared to CM it benefits from its inherent cross-selectivity and in theory it is atom economical, though in reality the aUcene cross-partner is usually added in excess. The inabihty to control product stereochemistry of ECM reactions is the main weakness of the method. ECM reactions are often directly combined with other transformations like cyclopropanation [172], Diels-Alder reactions [173], cychsations [174] or ring closing metathesis [175]. 

Enyne 112a having a boron moiety on the alkyne gives vinyl boron 113a [Eq. (6.83)], whose carbon-boron bond can be converted to a carbon-carbon bond. Enyne metathesis followed by Diels-Alder reaction of the resulting diene with DMAD gives tricyclic compound 114 [Eq. (6.84)]. ... 

As seen in the preceding sections, many multicomponent procedures are based on the production of conjugated dienes that are in situ involved in Diels-Alder reactions to obtain polycyclic compounds. In recent years, intramolecular enyne metathesis has become a very popular method by which to access cyclic conjugated dienes [172]. In line with this, Lee [173] has developed a new three-component re-... 

Ru-catalysed enyne metathesis offers a short approach to chiral derivatives of 3-vinyl-5,6-dihydro-2//-pyrans. Some epimerisation can occur at the pyranyl C atom at elevated temperatures (Scheme 3) <02T5627>. The bispropargyloxynorbomene derivative 6 undergoes a cascade of metathesis reactions in the presence of alkenes and Grubbs catalyst incorporating an enyne-RCM that leads to fused cyclic dienes. A dienophile can be added to the reaction mixture, resulting in Diels-Alder reactions and the formation of functionalised polycyclic products <02TL1561>. 

Cross-enyne metathesis has also been applied to solid-phase synthesis by immobilizing either the alkyne or the alkene (498,499). By combination with a Diels-Alder reaction, this process has been used to create a combinatorial library of various six-membered ring structures (500). Within this theme, intermolecular enyne metathesis is the integral synthetic method used to produce novel amino acid derivatives (501, 502). To this end, the aromatic ring of highly substituted phenylalanines was synthesized through enyne crossmetathesis and cycloaddition. 

The synthesis of 4/5/6, 4/6/6 and 4/7/6 tri- and tetracyclic P-lactams 48 has been carried out via one-pot enyne metathesis and Diels-Alder reactions <04S2665><04EJ04840>. The synthesis of unprecedented inner-outer-ring 2-[tert-butyldimethylsilyloxy] dienes with a carbacepham structure in optically pure form and their totally 7t-facial endo selective Diels-Alder reactions to structurally novel polycyclic P-lactams 49 has been reported <04TL7255>. 

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... 

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... 

The 1,3-dienes resulting from an enyne metathesis can often be coupled with Diels-Alder reactions in a domino transformation. Heating of benzyldimethylsi-lylacetylene with the styrenes 170 and N-phenylmaleimide in the presence of the... 

Enyne metathesis can also be combined with an intramolecular Diels-Alder reaction (IMDA) in a domino manner [35]. Reaction of the dienes 172 with the terminal alkynes 173 in the presence of the phosphine-free catalyst 4 at reflux temperature yielded the carbobicyclic products 174 preferentially via an exo-(E)-anti or endo-(2)-anti transition state for the [4- -2]-cycloaddition step, respectively (Scheme 2.60) [35a[. 

An outstanding example of a branching pathway exploited complementary cyclisation reactions to yield alternative molecular scaffolds (Scheme 1.5). A four-component Petasis condensation reaction was used to assemble flexible cyclisation precursors e.g. 14). Alternative cyclisation reactions were then used to yield products with distinct molecular scaffolds Pd-catalysed cyclisation (- 15a) enyne metathesis (- 15b) Ru-catalysed cycloheptatriene formation (- 15c) Au-catalysed cyclisation of the alcohol onto the alkyne (- 15d) base-induced cyclisation (- 15e) Pauson-Khand reaction 15f) and Miesenheimer [ 2,3]-sigmatropic rearrangement (not shown). Four of these cyclisation reactions could be used again to convert the enyne 15e into molecules with four further scaffolds (17a-d). In addition, Diels Alder reactions with 4-methyl-l,2,4-triazoline-3,5-dione converted the dienes 15b, 17a and 17d... 

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. 

ENYNE METATHESIS FOLLOWED BY THE DIELS-ALDER REACTION FOR THE SYNTHESIS OF BENZENE RINGS IN COMPLEX AROMATIC COMPOUNDS... 

The strategy of using the enyne metathesis reaction, followed by a Diels-Alder reaction, has been used extensively for the synthesis of aromatic componnds. The enyne metathesis reaction allows for the construction of a diene, which will undergo reactions with dienophiles to afford the desired aromatic compounds after aromatization of the intermediate Diels-Alder adduct. 

A number of research groups have utilized the strategy outlined above to synthesize benzene ring-containing compounds. For example, Kotha successfully employed it for the synthesis of phenylalanine derivatives [36]. Starting with aUcyne 87 and the aUcene allyl acetate, cross-enyne metathesis afforded diene 88. This readily underwent a Diels-Alder reaction with dimethyl acetylenedicarboxylate (DMAD) to afford cyclohexene 89. Aromatization of these compounds with DDQ subsequently furnished the phenylalanine 90 in good yield (Scheme 17.17). 

ENYNE METATHESIS EOLLOWED BY THE DIELS-ALDER REACTION... 

SCHEME 17.19 Synthesis of polysubstituled benzenes by way of an enyne metathesis followed by a Diels-Alder reaction. 

A similar strategy has been used by Kotha to synthesize naphthoquinones and anthraquinones containing amino acid functionahties [45]. In this case, the racemic amino acid alkyne hybrid 116 was treated with ethylene in an enyne metathesis fashion to yield the diene 117, which was then subjected to a Diels-Alder reaction with 2,3-dimethylbenzoquinone 118 (as shown in Scheme 17.23), to afford... 

FIGURE 17.6 Further examples of the angucyclinone skeleton formed by enyne metathesis followed by a Diels-Alder reaction (Adapted with permission from Ref. [10]. Copyright (2009) American Chemical Society). 

SCHEME 17.23 Enyne metathesis with ethylene to form dienes for Diels-Alder reactions. 

Botta and coworkers have used the enyne metathesis in the synthesis of the enantiopure antifungal agent (5 )-bifonazole 130 [47]. In this work, the diene for the Diels-Alder reaction had to be synthesized from an alkyne. Reaction of alkyne (R)-131 with ethyl vinyl ether, in the presence of catalyst 2-Ru, thus afforded the desired diene 132 (Scheme 17.25) in an excellent yield of 88%. Next, the diene 132 was reacted with methyl vinyl ketone in a Diels-Alder reaction to afford compound 133. Exposure of compound 133 to acid and then DDQ yielded the aromatic product 134, where a newly formed benzene ring had been assembled. Further manipulations, including the formation of the required imidazole ring, allowed for the enantioselective synthesis of (S)-bifonazole 130. 

Cross-Enyne Metathesis/Diels-Alder MCRs Ruthenium-based complexes are known to catalyze the metathesis between alkynes and alkenes to afford 1,3-dienes. Fnstero, del Pozo et al. further exploited this cross-enyne metathesis (CEYM) by trapping the 1,3-diene with a dieno-phile via an intermolecnlar Diels-Alder reaction [198]. Thns, the Ru-catalyzed MCR between alkynes 220-221 and 1,7-octadiene as an in situ sonrce of ethylene by RCM generates a 1,3-diene that can snbseqnently nndergo a Diels-Alder reaction with a wide variety of dienophiles 222... 

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. 

The allenylidene-ruthenium system also appeared as effieient catalyst precursors for enyne metathesis and they were applied to the preparation of fluorinated cyclic amino esters with a 1,3-diene structure allowing Diels-Alder reactions (Scheme 20) [43],... 

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