Combination metathesis processes

Ring closing and cross metathesis allow the rapid synthesis of simple cyclic and acyclic systems. The metathesis activity that is now possible using well-defined catalysts allows for the rapid generation of complexity from simple starting materials by relay processes and combinations of metathesis steps. Many of these reactions have been recognized only recently, are now beginning to be used in complex synthetic transformations. A few of these types of reactions will be outlined here to demonstrate the power of these multistep, relay processes. In these processes, an initial metathesis step leads to a new carbene that results in further transformations of the substrate. 

Sufficient examples have been demonstrated for this reaction to move into the synthesis of complex molecules. For example, the Nicolaou group has recently demonstrated that such a process can be used for the rapid generation of complex poly-cylic ethers (Eq. 6.26(a)) [45]. 

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]. 

With the advent of the new catalysts systems that will undergo efficient reactions with electron-deficient olefins, the tandem process can be extended to the synthesis of a variety of polycyclic lactones (Eq. 6.27) [47]. 

As indicated in the following examples, very complex ring systems can be generated by using such processes, with the release of ethylene being used to drive the formation of highly congested structures (Eq. 6.28). 

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Our group has used a combined metathesis-PKR for the synthesis of tricyclic compounds in one step. The process starts from pure cobalt complexed dienynes 52. The cobalt cluster acts first as a protecting group to avoid undesired enyne metathesis processes. The methodology allows the formation of tricyclic [6.5.5] (53) and [7.5.5] (54) structures including, in some examples, oxygen or nitrogen. Tricycles 53 are obtained in a total stereoselective manner, while compounds 54 are formed as mixtures of two diastereomers (Scheme 17) [110]. 

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... 

Although intermolecular enyne metathesis is the simplest to envision, intramolecular enyne metathesis was the major focus of the initial work. Two representative intramolecular enyne meta theses are shown in Equations 21.44 and 21.45. The reaction in Equation 21.44 shows the value of this chemistry to form heterocycles. The reaction in Equation 21.45 shows how enyne metathesis can be used in combination with olefin metathesis to form bicyclic products. The initial enyne metathesis process in Equation 21.45 terminates in a ruthenium carbene complex. The carbene complex is then trapped by the remaining olefin in a [2+2] and retro-[2+2] cycloaddition sequence to generate the bicyclic organic product and a ruthenium carbene complex that re-enters the catalytic cycle by reaction witii the yne diene. 

The PLATSOL M treatment of a nickel rich concentrate and a pyrrhotite 3 cleaner concentrate was demonstrated. The PLATSOL autoclave process was combined with precious metal precipitation, copper concentrate enrichment, copper removal, iron/aluminum removal, mixed hydroxide precipitation of nickel and cobalt and finally magnesium removal. The copper concentrate enrichment process proved to be a novel addition to the NorthMet flowsheet. The copper in solution from the autoclave processing was recovered by metathesis on the copper concentrate in the enrichment process. The solvent extraction and electrowinning of copper process applied to precious metal free PLATSOL solutions is no longer required by using this metathesis process route. This development provides maximum operational flexibility for treatment of the NorthMet ore. 

These results are intriguing, and they suggest that a similar ethylene-based deactivation process could also have been responsible for the results observed by Cole-Hamilton and coworkers described above rather than catalyst decomposition, which had originally been postulated. More importantly, these combined results bring into question the role that ethylene plays in continuous-flow olefin metathesis processes. 

The reversible nature of the metathesis reaction can lead to ROM reaction of endocyclic olefins under the thermodynamically favored conditions. The self-metathesis process of the ring-opened carbene intermediate, which brings about a polymerization (ROMP), is generally used as the preparation of polymers (Scheme 24.28). On the other hand, the combined process of ROM with the other metathesis is very useful for the synthesis of a monomeric molecule. In contrast to normal RCM and CM reactions, in... 

One problem in the combination of metathesis transformations using alkenes is the fact that they are equilibrium reactions. In contrast, metathesis reactions of ene-ynes are irreversible as they give 1,3-butadienes, which are usually inert under the reaction conditions. Thus, the combination of a RCM and a ROM of ene-ynes of type 6/3-48 in the presence of an alkene (e. g., ethylene) led to 6/3-49 in good yield (Scheme 6/3.13) [242]. In these transformations the terminal triple bond reacts first. The process is not suitable for the formation of six-ring heterocycles. 

Trirhenium nonabromide has been made (1) by direct combination of the elements 1 (2) by the thermal decomposition of rhenium (V) bromide, obtained by treating elemental rhenium with bromine at 650° 2 or (3) by the thermal decomposition of silver hexabromorhenate(IV),3-6 obtained from the metathesis of silver nitrate with potassium hexabromorhenate(IV).5-8 Of these methods, (3) has proven to be the simplest and most efficient route to pure trirhenium nonabromide. The following procedure is superior to that previously given,6 in that simpler equipment is used and larger quantities can be processed, with a resultant saving in time. 

Imine metathesis has continued to be a popular exchange reaction for DCLs. Various groups have found novel systems in which the reaction can be applied, as well as interesting ways to halt the equilibration. For example, Wessjohann and coworkers have demonstrated that Ugi reactions can efficiently halt equilibration of an imine DCL, combining an irreversible diversification process with areversible library selection [24]. Xu and Giusep-pone have integrated reversible imine formation with a self-duplication process [25], and Ziach and Jurczak have examined the ability of ions to template the synthesis of complex azamacrocycles [26]. The mechanistically related reactions of hydrazone [27] and oxime [28] exchange have also been explored as suitable foundations for DCL experiments. 

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

Using the catalyst system described above in combination with a rhodium phosphine catalyst Lebel reported the de novo synthesis of alkenes from alcohols [100]. They developed a one-pot process, avoiding the isolation and purification of the potentially instable aldehyde intermediate. They combined the oxidation of alcohols developed by Sigman [89] with their rhodium-catalyzed methylenation of carbonyl derivatives. The cascade process is compatible with primary and secondary aliphatic as well as benzyUc alcohols in good yields. They even added another reaction catalyzed by a NHC complex, the metathesis reaction, which has not been addressed in this review as there are many good reviews, which exclusively and in great depth describe all aspects of the reaction. 

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