Macrocycles by Ring-closure Metathesis

Joelle Prunet, Anderson Rouge dos Santos, and Jean-Pierre Ferezou 

This chapter concerns the preparation of macrocyclic products by ring-closing metathesis (RCM) or related processes combining RCM with other types of metathesis, starting from suitably substituted diene, ene-yne, or diyne precursors. Macro-cyclic rings of 10 or more members have been taken in consideration. Such macrocycles can exist individually or as part of a polycyclic system of the bridged, fused, or ansa type. 

Modem Supramolecular Chemistry Strategies for Macrocycle Synthesis. Edited by Francis Diederich, Peter J. Stang, and Rik R. Tykwinski Copyright 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31826-1 

The advent of RCM [3] as an essential tool for the synthesis of macrocycles undoubtedly arose from two derisive factors  

First generation Grubbs type ruthenium catalysts 

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Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

Synthetic highlights Natural macrocycUc compounds have been subjected to both extensive and peripheral structural modifications in the search for new lead compounds. An example of the former is the antibiotic azithromycin, whereas 12-aza-epothilones must be approached by total synthesis. This total synthesis of epothilones involves ring closure metathesis using heteroleptic complexes as catalysts and has proved to be an efficient approach to non-natural, macrocyclic natural products . In one of the critical steps of this pathway to azathilones, creative site-selective diimide reduction of an allylic C=C bond was applied. 

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. 

Considering the facility with which dimerization products 81 and 84 are obtained, we reasoned that, in catalytic ring closure of 77, the derived dimer is perhaps initially formed as well. If the metathesis process is reversible [17b], such adducts may subsequently be converted to the desired macrocycle 76. To examine the validity of this paradigm, diene 77 was dimerized (— 85) by treatment with Ru catalyst lb. When 85 was treated with 22 mol% 2 (after pretreatment with ethylene to ensure formation of the active complex), 50-55% conversion to macrolactam 76 was detected within 7 h by 400 MHz H NMR analysis (Eq. 8). When 76 was subjected to the same reaction conditions, <2% of any of the acyclic products was detected. Although we do not as yet have a positive proof that 85 is formed in cyclization of 77, this observation suggests that if dimerization were to occur, the material can be readily converted to the desired macrolactam, which is kinetically immune to cleavage. 

Two routes for synthesizing macrolides via olefin metathesis (WCl6/Me4Sn catalyst) have been described by Villemin one route involves the preparation of co-hydroxyacid by metathesis followed by cyclization, the second involves macrocyclic ring closure by metathesis of co,co -diunsaturated ester. 

The polarity of chlorinated solvents can also play a role in affecting the product distribution of an olefin metathesis reaction. Clark and Ghadiri [8] observed that the macrocyclic peptide 10 self assembles by inter molecular H-bonding in nonpolar solvents. The cylindrical conformation that resulted did not allow for successful dimerization to occur between macrocycles. When the cyclization of the cyclic peptide 10 was conducted with Ru catalyst 12 in chloroform (Scheme 12.5), the chloroform was proposed to disrupt the H-bonding within molecules. The new conformation produced in solution with the CHClj proved conducive to ring closure. The cyclic dimer 11 was obtained in 65% isolated yield as a mixture of cisicis, transitrans, and cisitrans isomers. 

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