Double cross-metathesis

Double cross-metathesis describes the simultaneous reaction of a cycloalkene M with two symmetrical internal olefins represented as Q Q and Q Q. Fig. 15.7 shows the evolution of the telomer ratios Q MQ /Q MQ and Q MQ /Q MQ with the conversion for the case where M = cyclooctene, Q Q =cw-but-2-ene, = m-oct-4-ene, and the catalyst as indicated. The initial proportions of the three telomers are C 2 Cu C 6 = 2.5 0.25 1 0.090 0.007. 

The individual intercepts in Fig. 15.7 give = 6.5 0.9 for the relative reactivity of the two cis olefins at 0°C. The corresponding ratio for the trans olefins at 20°C is 3.08 0.16. Thus in each case oct-4-ene is substantially less reactive than but-2-ene, presumably for steric reasons. 

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First, Katz13 conducted an experiment similar to that of Herisson and Chauvin (equation 11.8), which he termed the double cross metathesis. If Mechanism 2 were operative, the product ratios [8]/[7] and [8]/[9] should be zero when concentrations were extrapolated back to the very beginning of the reaction (t0), because 8—the double cross product would have to form after the symmetrical products 7 and 9. 

A more stringent test is to react cyclooctene with a mixture of but-2-ene and oct-4-ene. If the metal carbene mechanism is correct, one may expect to find the C14 product of double cross-metathesis, i.e. MeCH=CH(CH2)6CH==CHPr, and an initial value of 4.0 for the product of the two ratios (C14/C12) and (C14/C16). The observed ratio is 4.05 0.05 for cis reactants and 4.11 0.09 for trans reactants (Katz 1977a). 

Scheme 15.3 Mechanism of double cross-metathesis between cyclooctene (M), cw-but-2-ene (Q Q ) and ds-cot-4-ene (Q Q ).

One of the classical experiments in the development of olefin metathesis was the double cross metathesis in which a mixture of cyclooctene, 2-butene, and 4-octene underwent metathesis. 

Fig. la—d Typical alkene metathesis reactions ring-closing (RCM) and ring-opening (ROM) metathesis (a), diene cross metathesis (CM, b), ROM-RCM (c), and ROM-double RCM (d) sequences (ring-rearrangement reactions, RRM)... 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

The reaction tolerated a variety of functionality, including ester and ether groups on the alkyl-substituted alkene at least two carbons away from the double bond, and raefa-nitro or para-methoxy substituents on the styrene. As expected, cross-metathesis occurred selectively at the less hindered monosubsti-tuted double bond of dienes also containing a disubstituted alkene (Eq. 8). 

The two alkenes were so similar electronically and sterically, with the ester group too far away to have any affect on the double bond, that there was very little cross-/self-metathesis selectivity. An approximately statistical mixture of ester 13 and diester 14 was isolated. The high yield of the cross-metathesis product 13 obtained is due to the excess of the volatile hex-l-ene used, rather than a good cross-/self-metathesis selectivity. Although not as predominant as in the reactions involving styrene, trans alkenes were still the major products. 

We have also studied the effect that moving the double bond closer to the amino acid moiety has upon the reactivity of unsaturated a-amino acids [43]. To this end, the cross-metathesis reactions of similarly protected homoallyl-, allyl-and vinylglycine with oct-l-ene were investigated under identical conditions (Eq. 25) (Table 3). 

The final stereochemistry of a metathesis reaction is controlled by the thermodynamics, as the reaction will continue as long as the catalyst is active and eventually equilibrium will be reached. For 1,2-substituted alkenes this means that there is a preference for the trans isomer the thermodynamic equilibrium at room temperature for cis and trans 2-butene leads to a ratio 1 3. For an RCM reaction in which small rings are made, clearly the result will be a cis product, but for cross metathesis, RCM for large rings, ROMP and ADMET both cis and trans double bonds can be made. The stereochemistry of the initially formed product is determined by the permanent ligands on the metal catalyst and the interactions between the substituents at the three carbon atoms in the metallacyclic intermediate. Cis reactants tend to produce more cis products and trans reactants tend to give relatively more trans products this is especially pronounced when one bulky substituent is present as in cis and trans 4-methyl-2-pentene [35], Since the transition states will resemble the metallacyclobutane intermediates we can use the interactions in the latter to explain these results. 

After successful completion of all rearrangement reactions, the incorporation of the different side chains of the tetraponerines was attempted by employing a cross metathesis reaction. However, the cross metathesis of 19 and 22 with allyltrimethylsilane in the presence of 10% [Ru-1] was unsuccessful due to the formation of a carbene with low reactivity. The use of Schrock s molybdenum catalyst26 [Mo] (Figure 7) also failed to show any conversion. The terminal double bonds of 19 and 22 were assumed to be too hindered for cross metathesis. An alternative route to incorporate the different alkyl chains of the tetraponerines was necessary (Scheme 8). 

Metathesis is a versatile reaction applicable to almost any olefinic substrate internal, terminal or cyclic alkenes, as well as dienes or polyenes. (Alkyne metathesis is a growing area, but will not be dealt with here.) The reaction is also known as olefin disproportionation or olefin transmutation, and involves the exchange of fragments between two double bonds. Cross metathesis (CM, Figure 1) is defined as the reaction of two discrete alkene molecules to form two new alkenes. Where the two starting alkene molecules are the same it is called self-metathesis. Ethenolysis is a specific type of cross metathesis where ethylene... 

Hoveyda and coworkers recently developed sequential catalytic cross metathesis/asymmetric conjugate addition utilizing (4b) to make acyclic aliphatic enones (equation 31)3 Blechert developed a synthetic route toward bicyclic N-heterocycles that hinged on cross metathesis and double reductive amination to access compounds like... 

Although the desired product is often produced in low yield, cross metathesis does not result in the loss of double bonds, and the olefin fragments remain intact hence, the byproducts can be recycled. Recycling is demonstrated in the application below, where cross metathesis is used to prepare an insect pheromone for the peach twig borer, an insect that attacks a variety of fruits (Eq. 6.15). The pheromone can be used to control the population of the insect through disruption of the insect s mating process [35]. 

Polymers with carbon-carbon double bonds in their backbone can undergo two types of metathesis, both leading to degradation. In an intramolecular reaction cyclic oligomers are formed, while many unsaturated polymers can be degraded by intermolecular cross-metathesis with low-molecular-weight olefins. Identification of the degradation products provides valuable information on the microstructure of the polymer [7] (cf Section 3.3.10.1). 

The total synthesis of Stemona alkaloid (-)-tuberostemonine was accomplished by P. Wipf. Late in the synthesis, the introduction of an ethyl sidechain was required. This could be achieved in a novel four-step sequence. First, the allyl sidechain was introduced by the Keck radical allylation. To this end, the secondary alkyl phenylselenide substrate was treated with allyltriphenyltin in the presence of catalytic amounts of AIBN. This was followed by the introduction of a methyl group onto the lactone moiety. The allyl group then was transformed into the desired ethyl group as follows the terminal double bond was isomerized to the internal double bond by the method of R. Roy. This was followed by ethylene cross metathesis and catalytic hydrogenation to provide the desired ethyl sidechain. 

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