Cascade reactions ring-closing

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). 

Illustrating the high potential of these reactions, cascade ring-closing metathesis of dienynes or trienynes have also provided access to fused 6,8,6-tricarbocyclic systems [14], and to a highly functionalized 5,7,6-tricyclic ring system related to the terpenoid guanacastepene A structure [15]. 

Recently, a catalytic system consisting of a second generation Grubbs catalyst or an in situ non-carbenic ruthenium complex have allowed a cascade catalytic reaction of cyclopropanation/ring closing metathesis of dienynes containing a malonate or bissulfone moiety. In this reaction, the interaction between the triple bond and one double bond gives a bicyclic product via cyclopropanation, and then the subsequent diene RCM produces the last cyclization step [16] (Scheme 6). 

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. 

A similar type of cascade reaction has been carried out with cyclic alkenes bearing only one olefinic side chain to obtain substituted heterocycles via ruthenium-catalyzed ring closing-ring opening metathesis (RCM-ROM) reactions. The preparation of enantiomerically pure cis- or trans-a,a -disubstituted piperidines has been achieved in the same yield for the two diastereoisomers [35] (Scheme 17). This reaction has also been used as a key step for the synthesis of natural products [36-39]. 

The full potential of ring-closing metathesis methodology in the synthesis of seven-membered heterocyclic systems is still to be realised, and there are many opportunities to investigate different substituents in the diene precursors. A combination of ring-closing metathesis with other reaction types in a cascade context is also likely to realise novel seven-membered ring based systems. 

More complex small molecules can also be made by metathesis cascades and tandem reaction sequences involving olehn metathesis components [41], The examples illustrated in Fig. 4.13 include inter- and intramolecular enyne metathesis between an olefin and an alkyne [42], ring-opening cross metathesis to form new substituted acyclic olefins [43], ring-opening ring-closing sequences... 

Based on enantioselective epoxidation and subsequent ring opening and closing, the so-called Achmatowicz reaction was developed. This is an organocatalytic one-pot cascade for the annulation of a,(J-unsaturated aldehydes, hydrogen peroxide, p-carbonyl compounds and NBS, which furnish optically active 3-pyrones. Other chiral heterocycles were also assembled by organocatalytic cascade reactions using diaiylprolinol silyl ethers as catalysts. ... 

In 2012, You and co-workers developed a cascade ring-closing metathesis/ isomerization/asymmetric Pictet-Spengler reaction, employing ruthenium complex (Hoveyda-Grubbs II catalyst) and chiral phosphoric acid as the... 

Ligand 29 (Table 15.1, entry 9) was also nsed in intramolecular Mizoroki-Heck reactions [72]. In combination with Pd(OAc)2, it catalysed a cascade ring-closing metathesis (RCM)/Mizoroki-Heck reaction. The RCM step was conducted at room temperature on (bromo or iodo) iV-alkenyl-A-allyl-2-halo-benzenesnlfonamides and the Mizoroki-Heck reaction was run at 110°C for 16 h in a perflnorons solvent system. The overall yield with fluorous conditions (0-67%) was significantly lower than a reference system with polymer-bound palladinm catalyst (58-80%). 

Grigg, R. and York, M. (2000) Bimetallic catalytic cascade ring-closing metathesis-intramolecular Heck reactions using a fluorous biphasic solvent system or a polymer-supported palladium catalyst. Tetrahedron Lett., 41, 7255-8. 

The 1,3-dipolar cycloadditions of azomethine ylides with aldehydes readily produced high yields of oxazolidines, which hydrolysed to anti a-amino-y -hydroxy esters." Non-stabilized azomethine ylides with isotonic anhydrides produced oxa-zolidine intermediates, which were converted into l,3-benzodiazepin-5-ones via ringopening-decarboxylation-ring-closing reaction cascades." ... 

Cascade Metathesis. When a ring-closing metathesis reaction results in a product that is also a precursor for a potential second ring-closing metathesis, the... 

Table 4. Examples of cascade ring closing metathesis reactions using Grubbs catalysts.

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