Metathesis, tandem

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. 

Figure 3.42 shows some examples of such tandem-metathesis-olefination reactions. 

Apart from the tandem metathesis/carbonyl o[efination reaction mediated by the Tebbe reagent (Section 3.2.4.2), few examples of the use of stoichiometric amounts of Schrock-type carbene complexes have been reported. A stoichiometric variant of cross metathesis has been described by Takeda in 1998 [634]. Titanium carbene complexes, generated in situ from dithioacetals, Cp2TiCl2, magnesium, and triethylphosphite (see Experimental Procedures 3.2.2 and 3.2.6), were found to undergo stoichiometric cross-metathesis reactions with allylsilanes [634]. The scope of this reaction remains to be explored. 

Synthesis of a polyoxygenated bicyclic compound containing a medium-sized ring is achieved via tandem metathesis of the dienyne derived from D-ribose (Equation (11)). ... 

The two-directional tandem metathesis of 1 to 2 proceeded smoothly using 20 mol % of the second generation Grubbs catalyst (now commercially available only from Aldrich and from Materia) under an atmosphere of ethylene. The conversion of 2 to 3 took advantage of the differing reactivity of the two ketones. Addition of hydride to 2 from the less hindered face of the less hindered ketone delivered 4. 

Scheme 2.26 Tandem metathesis/hydrogen transfer/hydrogenation sequence.

In a similar way, acetylenes can serve as the relay elements in a tandem metathesis process, and such reactions result in polycyclic dienes. The starting materials are easy to prepare through standard techniques (Eq. 6.26(b)) [46]. 

Hsung et al. reported the tandem metathesis of dienynamides gave the bicyclic heterocycles. The reaction of 42a, which had two sterically differentiated olefinic tethers, gave the six-membered lactam 43 as the major product along with the seven-membered lactam 44, while the reaction of 42b having two monosubstituted olefin produced a 1 1 mixture of 43 and 44 (Scheme 14).95d... 

Scheme 76. A three-component tandem metathesis/Diels-Alder reaction promoted by second generation Grubbs catalyst to form functionabzed tricycles.

Fukuyama and coworkers [48] have also utilized an olefin additive in the optimization of a crucial ring-rearrangement metathesis sequence to form the key 5,6-ring system in the synthesis of (-)-isoschizogamine (Scheme 12.27). The tandem metathesis reaction of the norbornene 87 was difficult due to the substitution pattern of norbornene skeleton, which restricted the approach of the Ru catalyst. For example, the treatment of norbornene 87 with the second-generation Hoveyda - Grubbs catalyst 4 at reflux in benzene provided lactone 89 in only 24% isolated yield. To optimize this reaction, the use ofthe modified Hoveyda-Grubbs catalyst 88 [49] and the addition of 20 equiv of 1,6-heptadiene as an additive were quired. The desired lactone 89 was then obtained in 73% yield. 

The first total synthesis of (-l-)-cyanthiwigin U was accomplished in 12 steps and 17% overall yield by the group of Phillips in 2005 (Scheme 13.23) [28]. Key of the synthesis featured an efficient two-directional tandem metathesis which converted the... 

Scheme 13.23 Total synthesis of (-1-(-cyanthiwigin U (156) employing two-directional tandem metathesis.

SCHEME 7.32 Tandem metathesis reaction used in the total synthesis of alkaloid natural products. 

In 2001, the Grubbs group reported the use oftheirseeondgeneration ruthenium complex [(SIMes)RuCl2(=CHPh)(PCyj)] 57 in tandem metathesis/TH reactions leading to the formation of a series of unsaturated heteroeyclic alcohols in <56% overall yield. This strategy was notably used for the preparation of (R)-(-)-muscone, a natural product with a pleasant fragranee. 

Codesido EM, Castedo L, Granja JR. Access to [6.4.0]carbo-cyclic systems by tandem metathesis of dienynes. A step toward the synthesis of a PreD3-D3 transition state analogue. Org. Lett. 2001 3 1483 1486. 

A concise asymmetric total synthesis of (+)-cyanthiwigin U (307) was reported by Phillips and Pfeiffer relying on the clever use of tandem metathesis of bi-cyclo[2.2.2]octenes (Scheme 1.56) [76]. The two-directional tandem ROM-RCM of compound 308, using catalyst [Ru]-II under an atmosphere of ethylene, simultaneously generated the cyclopentenone and the cycloheptenone rings of... 

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