Cascade CM/RCM

The opposite sequence is described with alkynyl silyloxy-tethered enynes. A cascade CM-RCM reaction proceeds in the presence of a second generation ruthenium carbene to give cyclic siloxanes. The initial CM is directed to occur on the alkyne by employing sterically hindered substituted alkenes tethered to the alkyne via a silyl ether group [24] (Scheme 11). 

The intermolecular enyne cross metathesis, and consecutive RCM, between a terminal alkyne and 1,5-hexadiene produces cyclohexadienes, by cascade CM-RCM reaction, and trienes, formed during the sole CM step. Studies of various parameters of the reaction conditions did not show any improvement of the ratio of desired cyclohexadiene product [25] (Scheme 12). The reaction with cyclopentene instead of hexadiene as the alkene leads to 2-substituted-l,3-cycloheptadienes [26]. After the first cyclopentene ROM, the enyne metathesis is favored rather than ROMP by an appropriate balance between cycloalkene ring strain and reactivity of the alkyne. 

The enantioselective synthesis of azabicyclic y-lactams starting from 2-azanorbornenones after treatment of a catalytic amount of RuCl2(PCy3)2 (= CHPh) in the presence of ethylene or allyl acetate proceeds also via ring rearrangement—alkene metathesis (ROM-CM-RCM) [41] (Scheme 19). If n = 0 or 3, no RCM occurs and a cyclic dialkenyl compound is formed by cascade ROM-CM reactions. 

Cross-metathesis of Alkyne with Cycloalkene (ROM-CM-RCM Sequence) A cascade metathesis with cycloalkene compounds is an interesting reaction because the different ring-size cyclic diene is formed from the starting cycloalkene via multiple processes in... 

Enynes without the cycloalkene moiety can also react with electron-deficient alkenes by a cascade ring-closing metathesis-cross metathesis (RCM-CM) process [23] (Scheme 10). The use of Hoveyda s catalyst is necessary, not to stop the reaction at the RCM step, but to perform the subsequent CM step. Indeed, the organic product arising from the RCM is first formed and then reacts with the alkene in the presence of the ruthenium complex to give the CM reaction. 

The cascade alkene metathesis processes described above result from the combination of ROM and RCM. The cascade alkene metathesis reaction involving ROM, RCM and CM reported in Scheme 18 leads to [n.3.0]bicycles in a stereo-controlled manner [40]. The reaction combines ring opening of... 

Phillips laboratory also extended the domino process in natural product synthesis by combining ROM, RCM, and CM. For this cascade reaction, regioselectivity... 

One of the most important cascade sequences by rhodium catalysis is the tandem RCM/cross-metathesis (CM) sequence, which includes two metathesis processes. The first process builds up the cyclic framework via an RCM process and then functionalizes the lateral chain of the intermediate vinyl intermediate 5, thanks to a subsequent CCM reaction with a conveniently chosen alkene. 

Hart and Phillips have used a CM for the preparation of a direct precursor of vinyl ketone 81, see Section 2.1 (Scheme 10.4) [6]. Their synthesis of cyhndramide A then involved an ROM/RCM cascade of norbornene derivative 81, followed by CM with alkene 82, which led to the fused 5,5-bicyclic compound 83 in 59% yield as a 2 1 mixture of separable B- and Z-diastereomers (Scheme 10.26). 

There are many combinations possible of metathesis reactions that can be used in domino metatheses, increasing process complexity with the number of transformations included. Natural product syntheses with ring-closing metathesis (RCM)-cross-metathesis (CM) sequences are described in this section. Ene-ene and ene-yne-ene cascade reactions in a two-metathesis step process will also be discussed. 

There is only one example in the literature where an enyne RCM coupled to an intermolecular CM in a sequence process has been applied in the synthesis of a natural product. The synthesis of (-i-)-8-epi-xanthatin, isolated from the leaves extracts from Xanthium canadense, was proposed by Martin et al. through an enyne RCM-CM cascade combining ring closing of 8 with a CM with 9 [13]. The special challenge for this transformation consists in the use of an electron-poor olefin for the final metathesis reaction. The use of [Ruj-III (20mol%), the catalyst of choice for this type of transformations [14], and an excess (10 equiv.) of the methyl vinyl ketone 9 resulted in the formation of the desired product in 83% yield (Scheme 11.3). 

The synthetic potential of RRM can be amphfied with the introduction of a third olefin, permitting the access to much more complex structures in one single transformation, by a further intermolecular CM or a second RCM. As discussed above, two mechanistic pathways can be envisaged. The metathesis cascade may involve an initial formation of a ruthenium-alkyhdene complex at the terminal olefin, or alternatively, the sequence may begin with [2+2]-cydoaddition of the ruthenium carbene onto endocychc double bond, followed by ROM-RCM or CM. Neither of these possibihties can be ruled out, and the occurrence of one or the other may be influenced according to ring strain, steric and electronic properties of the corresponding olefins, and also the reaction conditions employed (Scheme 11.22). 

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