Seven-membered rings, ring-closing metathesis

RCM was also used in Yamamoto s total synthesis of the marine neurotoxin gambierol (81) [62], to close the central seven-membered E ring, thereby completing the octacyclic polyether core 80 (Scheme 15). Following previously developed methodology [63], metathesis precursor 79 was produced as the major epimer, by boron trifluoride etherate-mediated intramolecular allylation of a-chloroacetoxy ether 78. Subsequent treatment of 79 with catalyst C produced the octacyclic ether 80 in 88% yield. 

Related microwave-assisted ring-closing metathesis reactions, leading to seven-[154] and eight-membered aza-heterocyclic products [49], are depicted in Scheme 6.74. 

A further application of ring-closing metathesis in seven-membered heterocyclic ring formation is in the synthesis of the trans-fused oxpane systems. This process involved tandem RCM/allylstannane-aldehyde cyclizations and interaction of the process provides access to trans-fused polyoxepanes <00S883>. 

Evans and Kennedy later combined the regioselective rhodium-catalyzed allylic alkylation, using a-substituted malonates, with ring-closing metathesis for the construction of five-, six-, and seven-membered carbocycles (Scheme 10.2) [13]. The combination of these methodologies allowed for the rapid and flexible assembly of carbocycles possessing vicinal ternary-quaternary or quaternary-quaternary stereogenic centers. 

Several examples of ring-closing metathesis indicate the highly selective nature of this reaction.161,162,224-226 The application of various Mo and Ru carbene catalysts allow formation of five-, six-, and seven-membered mono- and bicyclic rings. Formation of substituted cyclopentenes, for example, was shown... 

An azepanone-based inhibitor, 179, of the cysteine protease inhibitor, cathepsin K, was prepared via an asymmetric synthesis from 171 and 172 (Xc = a 4(.V)-benzyloxazolidin-2-one moiety) with ring-closing metathesis of 173 then being used to complete the seven-membered ring in the intermediate 174 with a very high de (Scheme 23). Further functional group manipulations via 175-178 then resulted in 179 <2005TL2799>. 

The ring-closing metathesis reaction has also been applied to the formation of a seven-membered cyclic sulfonamide C1999TL4761 >. Thus, heating 27 at reflux in dichloromethane (DCM) with ruthenium catalysis (Grubbs I catalyst) gave 28 in high yield (Equation 5). 

The synthesis of polycyclic ethers with variable ring sizes can be conducted by two-directional double ring-closing metathesis. This methodology was used to prepare, in one-step, the tricyclic ether 73, which has a six-, seven-, and eight-membered ring (Scheme 9) <2000AGE372>. 

Kinetic resolntion of cyclic allylic ethers can be performed by asymmetric Zr-catalyzed carbomagnesation. Six-, seven-or eight-membered ethers can readily be resolved by the Zr-catalyzed protocol (with ee between 81 to 99%). As an example, the tandem Zr-catalyzed kinetic resolution followed by a Ru-catalyzed ring-opening/ring-closing metathesis affords chiral chromenes with high optical purity (ee > 99%). ... 

An alternative to ring-closing metathesis to access seven-membered rings has been described by Ohno et al. <03H(61)65>. Thus, reaction of the bromoallene 4 containing a nucleophilic moiety and Pd(PPh3)4 in the presence of methanol affords the azepine derivative 5 in good yield (76%). Oxepine derivatives can also be made in a similar way using an alcohol as the nucleophilic moiety in the allene. 

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. 

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