Macrocycles, RCM

Another example of macrocyclic RCM with a diene-ene was disclosed in 2000 by Meyers and coworkers in the first total synthesis of griseoviridin (223) [ 107]. Griseoviridin is a highly complex member of the family of streptogramin antibiotics, featuring a 23-membered unsaturated bis-lactam core incorporat-... 

Thus far, chemists have been able to influence the stereoselectivity of macro-cyclic RCM through steric and electronic substrate features or by the choice of a catalyst with appropriate activity, but there still exists a lack of prediction over the stereochemistry of macrocyclic RCM. One of the most important extensions of the original metathesis reaction for the synthesis of stereochemi-cally defined (cyclo)alkenes is alkyne metathesis, followed by selective partial hydrogenation. 

In a related observation, Furstner and co-workers reported that while both the FMC and the MC2 lead to the same E Z alkene ratio in the case of 18-RCM, the use of the same conditions with 19 leads to product enriched selectively in either of the two isomers <02MI657> depending on catalyst selection (Scheme 9). Furstner notes that this "illustrates the subtle influence of remote substituents on the stereochemical outcome of RCM in the macrocyclic series." Studies concerning the effects of chelation of the reactivity of ruthenium carbene complexes were reported by Furstner and co-workers <02OM331>. Paquette and co-workers observed that the use of either the GMC or the MC2 led to different outcomes in the macrocyclization RCM of 1,2-amino-alcohol-templated ene-dienes <02HCA3033, 02MI615> hinting that catalyst selection is also an important consideration in those processes. 

The nature of the A -substituent is of critical importance for macrocyclic RCM of a trans-... 

One of the most important attributes of RCM is its suitability for forming macrocycles. RCM constitutes the key step of the synthesis of lasiodiplodin, epothilone-A, and the macrolactam segment of manzamine-A. Except in the last case, the RCM reaction is usually very efficient. 

Figure 3.5 Macrocyclic RCM (mRCM) of 17-membered rings with catalysts 10 and 19.

In other circumstances, the failure of an RCM reaction may lead to dimerization. As many natural products are dimers, this can be useful for their synthesis. This approach was used to prepare the cylindrocyclophanes 8.271 (Scheme 8.73). - The diene starting material 8.269 could not undergo simple RCM due to thepara-disubstituted aromatic ring. Instead, a cross-metathesis (see below) occurred, followed by a macrocyclic RCM to give 8.270. The natural product 8.271 could then be obtained by reduction of the two alkenes and deprotection. 

Abstract Alkene metathesis has become a synthetic method that has strongly modified approaches in the building of complex molecules. The review will concentrate on the recent applications of ring-closing metathesis (RCM) and crossmetathesis (CM) reactions for the design of useful molecules and architectures new functional macrocycles (RCM) and multifunctional linear alkenes (CM), but also cyclic ligands, rotaxanes, catenanes, and supramolecular systems. 

The importance of conformational effects on RCM-based macrocychzations was also highlighted by Bajwa and Jennings, who discoimected aigialomycin D at the Cl -C2 linkage (Scheme 7.22c) [83]. It was shown that the stereochemistry at C6 dramatically influences the outcome of the macrocyclization. RCM on triene 196 led to the exclusive formation of six-membered ring, whereas the reaction on the 6 -epimer of 196 was efficient in generating the 14-membered macrocycle [83]. 

The E/Z selectivity problem is restricted to cross metathesis and RCM leading to macrocycles (macro-RCM). Both aspects have recently been covered in reviews by Blechert et al. [8d] and by Prunet [44]. E/Z selectivity can be influenced by reaction temperature, solvent or substitution pattern of the substrate. Here, we will only discuss the influence of the precatalyst. 

Scheme 28 (Z)-selective RCM-based macrocyclization in the penultimate step in the total synthesis of halicholactone (151) [82]...

An example of the efficient formation of an electron-deficient double bond by RCM was disclosed by a Japanese group in a novel total synthesis of the macrosphelides A (209) and B (208) (Scheme 41) [100]. When the PMB-pro-tected compound 204 was examined as a metathesis substrate, the ring closure did not proceed at all in dichloromethane using catalysts A or C. When the reaction was carried out using equimolar amounts of catalyst C in refluxing 1,2-dichloroethane, the cyclized product 205 was obtained in 65% yield after 5 days. On the other hand, the free allylic alcohol 206 reacted smoothly at room temperature leading to the desired macrocycle 207 in improved yield. 

Also the novel antifungal antibiotic (-)-PF1163B (211), isolated from Strep-tomyces sp., which features a 13-membered macrocycle incorporating both a lactone and a lactam unit, was synthesized by an RCM route (Scheme 42) [101]. While only poor results were obtained by treatment of diene 210 (containing 8% of an unidentified epimer) with catalyst A, the use of NHC catalyst C led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimer-ization in a previous step. 

Scheme 42 Macrocyclization by RCM in the total synthesis of the antifungal antibiotic PF1163B (211) [101]...

The results obtained with the various metathesis substrates depicted in Scheme 44 demonstrate the lack of a stereopredictive model for the RCM-based formation of macrocycles, not only by the strong influence that may be exhibited by remote substituents, but also by the fact that the use of more reactive second-generation catalysts may be unfavorable for the stereochemical outcome of the reaction. Dienes 212a-f illustrate the influence of the substitution pattern. All reactions were performed with Grubbs first-generation catalyst A... 

Scheme 45 Macrocyclization by RCM in Fiirstner s total synthesis of the resin glycoside woodrosin I (218) [104]...

Scheme 47 Macrocyclization via diene-ene RCM in the first total synthesis of griseoviridin (223)[107]...

The first example of successful diene-diene RCM to construct a macrocyclic conjugated triene was disclosed by Wang and Porco in the first total synthesis of oximidine II (258) [121]. Oximidine II belongs to the family of salicylate en-... 

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