Ring-closing metathesis macrocycles

Although five- and six-membered carbo- or heterocycles are most easily formed by ring-closing metathesis, macrocyclizations with simultaneous cleavage from the support have also been successfully performed [784], Illustrative examples are listed in Table 3.44. 

Interconversion of - and Z-macrocycles in metathesis reactions proceeds via a ring-opening metathesis/ring-closing metathesis sequence thus, more... 

With a-monosubstituted ylides the oxidation results in the formation of alkenes (by subsequent Wittig reaction on the intermediate aldehyde). A recent example of such synthesis is found in the preparation of all-(Z)-cyclododecate-traene by oxidation of the appropriate bis-ylide [33]. It must be pointed out that an approach of the same macrocycle based on ring closing metathesis was found ineffective. 

Diynes can be employed in intramolecular ring-closing metathesis. Several catalysts involving Mo and W have been investigated. These cyclizations can be combined with semihydrogenation to give macrocycles with Z-double bonds. 

In a more recent approach, the same group synthesized macrocycles using a Passerini reaction followed by a ring-closing metathesis [23], but the final cycliza-tion gave only low yields. 

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. 

Recent studies by Grubbs on the effect of stereochemistry on synthesis of macrocyclic peptides (disubstituted alkenes) by ring closing metathesis were not disclosed at the time of our planning. See (a) Ref. 6a. (b) Miller SJ, Blackwell H, Grubbs RH (1996) J Am Chem Soc 118 9606... 

Grasillas, A. Perez-Castells, J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products Reaction conditions and limitations. Angew. Chem. Int. Ed. 2006,45, 6086-6101. 

The recent enormous development in metathesis catalyst activity and stability has made ring-closing metathesis (RCM, Fig. 5) one of the most popular macrocyclization methods [38]. The enormous potential of this method lies in... 

The application of ring closing metathesis for the synthesis of Friedinger lactams was studied by Piscopio et al.4S (Fig. 15), as well as other groups,46 while the formation of macrocycles was accomplished by Blechert s group.47... 

P2N2 dianionic macrocycle, 1, 69 pyridinophane macrocycles, 1, 69 Macrolides, via ring-closing metathesis, 11, 239 Macromolecular materials overview, 12, 295-411 polymers (, see Polymers)... 

Ring-closing metathesis (RCM) of the 6,6 -diallyl ether afforded macrocyclic alkenes,314 which can be reduced (H2/Pd) to saturated compounds with simultaneous removal of all benzyl protecting groups (Scheme 35).68... 

Dienes are cyclized by intramolecular metathesis. In particular, cyclic alkenes 43 and ethylene are formed by the ring-closing metathesis of the a,co-diene 46. This is the reverse reaction of ethenolysis. Alkene metathesis is reversible, and usually an equilibrium mixture of alkenes is formed. However, the metathesis of a,co-dienes 46 generates ethylene as one product, which can be removed easily from reaction mixtures to afford cyclic compounds 43 nearly quantitatively. This is a most useful reaction, because from not only five to eight membered rings, but also macrocycles can be prepared by RCM under high-dilution conditions. However, it should be noted that RCM is an intramolecular reaction and competitive with acyclic diene metathesis polymerization (ADMET), which is intermolecular to form the polymer 47. In addition, the polymer 47 may be formed by ROMP of the cyclic compounds 43. 

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. 

---