Grubbs ring-closing metathesis

Scheme 51. DoM-Grubbs ring-closing metathesis connections.

Scheme 52. Benzoazocinone ring system via DoM-Grubbs ring-closing metathesis (RCM) connections.

Until now, the most efficient approach to synthesize Freidinger lactams 147 started from a resin-bound cinnamylamine 144. A Fukuyama-Mitsunobu reaction to 145 followed by sulfonamide cleavage and a consecutive appropriate acylation built up the diene 146, which underwent ring-closing metathesis involving Grubb s catalyst 123 to generate the desired lactams 147 (Scheme 27, Table 5) [35d]. 

Allenes 111 undergo cycloisomerisation in presence of 20 mol% of catalyst 110 (Scheme 5.29) [32]. Interestingly, when the Grubbs first generation catalyst 109 is used in this reaction the ring-closing metathesis is observed [33]. 

The application of olefin metathesis to the synthesis of piperidines continues to be widely employed. The use of ring closing metathesis (RCM) in the synthesis of fluorovinyl-containing a,P-unsaturated lactams 148 and cyclic amino acid derivatives 149 is shown below. A key improvement in these reactions is the addition of the Grubbs 2nd generation catalyst (G2) in small portions during the reaction to compensate for catalyst decomposition that occurs at elevated reaction temperatures <06EJOl 166>. 

Other -substituted and reduced 2-azepinone derivatives 22 can also be accessed in high yields (Table 3) by ring closing metathesis on the precursors 21 using Grubbs II catalyst 18. A variety of IV-heteroaryl substitutent groups were tolerated in this reaction <06TL3295>. 

The synthesis of the /V-protected 7-methylazepine derivative 34 was achieved in 89% yield by a ring-closing metathesis reaction on 33 mediated by Grubbs I ruthenium catalyst. This azepine was an important precursor for the preparation, via epoxidation of the double bond, of a number of 7-methylazepanone derivatives for evaluation as cathepsin K inhibitors <06JMC1597>. 

The oxepine-fused beta-carboline 73 was synthesized in good yield (71%) from the diene precursor 72 using ring-closing metathesis and Grubbs I catalyst <06TL6895>. 

Ring-closing metathesis on the dienes 116 and 117 with Grubbs ruthenium catalyst II 18 afforded the 7-membered ring sulfones 118 and 119 respectively. The diene precursor 116 was accessed from reaction of the sulfonyl chloride 115 with 3-buten-l-ol 114 <06T9017>. 

Scheme 8.2. Batch-wise recycling of Grubbs catalyst for ring closing metathesis...

Representatives of the bridged sulfone system 70 have been subjected to ruthenium catalysed ring-closing metathesis reactions (Grubbs catalyst) and shown to afford, in low yields, a few selected cyclic dimers and trimers, of all the possibilities available. The diastereoselectivities observed were rationalised in terms of kinetic control involved with internal ruthenium/sulfonyl oxygen coordination . 

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... 

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