Enyne RCM

Clark and coworkers utilized enyne RCM for constructing the AB ring fragment of the manzamine alkaloids (Scheme 83) [177]. Exposing metathesis precursor 423 and ethylene gas to catalyst A provided bicycle 424 in near quantitative yield. Regioselective hydroboration of the vinyl group in 424, followed... 

Scheme 83 Synthesis of the manzamine AB ring segment 426 via enyne RCM [ 177]...

Scheme 84 Synthesis of cyclic enol ethers 428 by enyne RCM [179]...

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

Scheme 86 Regioselective enyne RCM for the synthesis of 1,3-disubstituted macrocyclic 1,3-dienes 433 and 434, main fragments in Shair s total synthesis of longithorone A [180]...

Guanacastepene A (444) is a novel tricyclic diterpene with fused five-, seven-, and six-membered rings. The possibility of constructing polycyclic compounds via tandem RCM of dienynes was used in Hanna s synthesis of a highly functionalized tricyclic system 443 related to 444. Under the conditions outlined in Scheme 87, trienyne 440 provided the desired tricycle 442 in a single step, as a result of sequential enyne RCM followed by RCM of intermediate 441. Compound 442 was then further functionalized to 443 [182]. 

For recent examples of small-ring enyne RCM following the endo mode, see (a) Kita-mura T, Sato Y, Mori M (2002) Adv Synth Catal 344 678 (b) Dolhem F, Lievre C, Demailly G (2003) Eur J Org Chem 2336... 

Kaliappan and coworkers [249] prepared dioxa-triquinanes 6/3-68 together with the spiro compound 6/3-67 by a domino enyne RCM of the ene-yne 6/3-66 (Scheme 6/3.19). 

S.2.3.4 lndenylidene-Ruthenium(arene) Catalyst in Diene and Enyne RCM... 

Indenylidene-Ruthenium Catalysts in Alkene Metathesis 265 Table 8.5 Diene and enyne RCM reactions with 2 mol% of complex XXb at room temperature. 

As the name suggests, enyne metathesis [94,95] is the metathetical reaction between an alkene and an alkyne to generate an often synthetically useful butadiene product.2 Two distinct reaction types can be classified enyne RCM and enyne CM. 

It should be noted that while enyne metathesis is considered incompatible with molybdenum catalyst 1, ruthenium catalysts other than the Grubbs type also promote the reaction. Semeril et al. [103] reported efficient enyne RCM with a catalyst conveniently generated in situ from [RuCl2(p-cymene)]2,1,3-bis(mesityl)imidazolium chloride and caesium carbonate. Interestingly the authors found that the in situ derived system gave better results than the isolated catalyst. One of the most impressive examples of the use of enyne RCM is the total synthesis of (-)-longithorone by Layton et al. [104]. Inspired by a pro-... 

Until recently, intermolecular enyne metathesis received scant attention. Competing CM homodimerisation of the alkene, alkyne metathesis and polymerisation were issues of concern which hampered the development of the enyne CM reaction. The first report of a selective ruthenium-catalysed enyne CM reaction came from our laboratories [106]. Reaction of various terminal alkynes 61 with terminal olefins 62 gave 1,3-substituted diene products 63 in good-to-excellent yields (Scheme 18). It is interesting that in these and all enyne CM reactions subsequently reported, terminal alkynes are more reactive than internal analogues, and 1,2-substituted diene products are never formed thus, in terms of reactivity and selectivity enyne CM is the antithesis of enyne RCM. The mechanism of enyne CM is not well understood. It would appear that initial attack is at the alkyne however, one report has demonstrated initial attack at the alkene (substrate-dependent) is also possible, see Ref. [107]. 

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>. 

Norbornene derivatives bearing two alkynes undergo cascade enyne metathesis reactions when treated with a first generation ruthenium carbene and ethylene, giving heterocyclic dienes [28]. The ROM of the norbornene moiety initiates the cascade enyne RCM reactions (Scheme 14). When ethylene is replaced by a monosubstituted alkene, a single enyne RCM takes place, after the initial ROM of norbornene. 

Treatment of an alkyne/alkene mixture with ruthenium carbene complexes results in the formation of diene derivatives without the evolution of byproducts this process is known as enyne cross-metathesis (Scheme 22). An intramolecular version of this reaction has also been demonstrated, sometimes referred to as enyne RCM. The yield of this reaction is frequently higher when ethylene is added to the reaction mixture. The preferred regiochemistry is opposite for enyne cross-metathesis and enyne RCM. The complex mechanistic pathways of Scheme 22 have been employed to account for the observed products of the enyne RCM reaction. Several experiments have shown that initial reaction is at the alkene and not the alkyne. The regiochemistry of enyne RCM can be attributed to the inability to form highly strained intermediate B from intermediate carbene complex A in the alkene-first mechanism. Enyne metathesis is a thermodynamically favorable process, and thus is not a subject to the equilibrium constraints facing alkene cross-metathesis and RCM. In a simple bond energy analysis, the 7r-bond of an alkyne is... 

Totally intramolecular enyne metathesis Diels-Alder sequences have been demonstrated (e.g., the conversion of 244 into 246). Enyne RCM of substrate 247 affords stereochemically pure 248 due to kinetic resolution during metathesis.A process equivalent to enyne metathesis that proceeds through a non-carbene mechanism has been demonstrated using platinum chloride as a catalyst. In addition to routine observations, some other interesting side-reactions have been noted (Scheme 29). Competitive cross-metathesis with ethylene and intramolecular enyne metathesis were observed in the treatment of substrate 249 with catalyst 16 and ethylene.Cyclopropane ring opening was observed in the attempted enyne metathesis of substrate 253, resulting in alkylidenecyclopentene 254. 

Scheme 27 Representative examples of enyne RCM prooeeding with alternate regioseleotivity.

Scheme 29 Side-reactions competing with enyne RCM.

The RCM reaction between a double bond and a simple triple bmid, the enyne RCM, produces a diene system with no loss of the terminal carbon atoms. This approach leads to a useful intermediate for the micrandUactones (Scheme 15) [50], The reactimi requires the catalyst Grubbs 11 possibly due to the presence of the propargylic acetate group. 

A one-pot enyne RCM-Diels-Alder sequence is reported, where initially the substituted enyne 198 undergoes RCM-CM upon reaction with a Grubbs catalyst and styrene (14T3700). After completion, the one-pot reaction produces polycyclic sulfamide 199 in 79% yield. 

Enyne RCM reactions have been successfully coupled with a CM event [16]. Thus, a domino enyne RCM/CM process with enyne 65 and methyl vinyl ketone was used as the final step in a concise total synthesis of the bioactive sesquiterpene lactone (+)-8-epi-xanthatin (66) (Scheme 2.25) [16a,b. Using the phosphine-free ruthenium catalyst 4, an efHcient transformation was achieved with the required electron-deficient co-olefin. 

Scheme 2.25 Domino enyne RCM/CM reaction to give (- -)-8-epi-xanthatin (66).

A relay enyne RCM/CM reaction of dienyne 69 and 2-methyl-3-buten-2-ol was the key step in a total synthesis of the epoxyquinoid natural product (-1-)-panepophenanthrin (Scheme 2.27) [16ej. TTiis domino transformation, which is initiated by attack of the mthenium carbene at the terminal alkene followed by an RCM with release of 2,5-dihydrofuran, worked best with the phosphine-free... 

Dendralenes can be rapidly synthesized by consecutive enyne RCM of allylsi-lyl propargyl ethers followed by rhenium oxide-catalyzed 1,4-elimination of the resultant siloxenes [21f]. Hence, an efficient preparation of [4]dendralene 122 was accomphshed via domino dienyne metathesis of the bis(silyl ether) 120 to give the bis-siloxene 121, which was subjected to catalytic amounts of rhenium oxide to induce a double 1,4-ehmination with the formation of 122 (Scheme 2.44). 

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