Resin cleavage metathesis

A short and efficient synthetic approach to hydroxy-substituted ( )-stil-benoids, as exemplified by the natural compound resveratrol (371b) via solid-phase CM, was reported by a Korean group (Scheme 71) [154]. When two different stilbenes were allowed to couple by catalyst C, all three kinds of possible stilbenes were obtained as an inseparable mixture. Anchoring 4-vinylphenol to Merrifield resin, followed by exposing the supported styrenyl ether 368 and diacetoxy styrene 369 (10 equiv) to the catalyst, inhibited self-metathesis of the supported substrate. Sequential separation of the homodimer formed from 369 by washing and subsequent cleavage of the resin 370 with acid provided (E)-stilbene 371a with complete stereocontrol in 61% yield. 

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]. 

An example in which cleavage from the resin was achieved using a carbon electrophile demonstrated the ability of these polymer-bound metathesis products to act as substrates for carbon-carbon bond formation (Eq. 19). 

Two repeated exposures of resin 38 to the catalyst (9% mol) for 18 h in dichloromethane at room temperature afforded the expected allyl lactoside in an encouraging isolated yield of 81% from resin 35 (90% per step). Traces of dimerized compounds resulting from cross-metathesis were detected as the only side products. Extension of the oligosaccharide chain was subsequently performed first by deacetylation (excess NaOMe in 4/1 CH2Cl2/MeOH at r.t.) and glycosylation with known lactosyl donor 40 in conditions similar to those mentioned above. Cleavage was performed twice as described above, but with a reduced reaction time of 6 h in this case tetrasaccharide 42 was isolated in 51% yield from 35 (84% per step). No dimerized products were detected. 

The combination of ring opening and ring closing metathesis is used for the synthesis of polycyclic structures by Lee et al. [265]. The metathesis on solid-phase includes not only the chemical transformation of resin bound intermediates but as well as the cleavage of final products from the support [181]. 

For the cleavage of alkenes from a support by metathesis, several strategies can be envisaged. In most of the examples reported to date, ring-closing metathesis of resin-bound dienes has been used to release either a cycloalkene or an acyclic alkene into solution (Figure 3.38, Table 3.44). Further metathesis of the products in solution occurs only to a small extent when the initially released products are internal alkenes, because these normally react more slowly with the catalytically active carbene complex than terminal alkenes. If, however, terminal alkenes are to be prepared, selfmetathesis of the product (to yield ethene and a symmetrically disubstituted ethene) is likely to become a serious side reaction. This side reaction can be suppressed by conducting the metathesis reaction in the presence of ethene [782,783]. 

The allyl alcohol linker 1.48 (106), bound to an aldehyde PS resin, has been elaborated to the pentenoic acid derivative shown. This was cyclized with cleavage using ring-closing metathesis (RCM) (Ru catalyst in DCE at 80 °C for 16 h) to give pure Freidinger lactam in solution. 

In another variation on the same theme Seeberger and coworkers employed 2-0-acetyl-3,4,6-tri-0-benzyl-a-D-mannopyranosyl trichloroacetimidate 130 to construct the a-(l >2)-mannoheptaose 209 bound to the support by means of a m-4-octenyl linker.49 Cleavage from the resin was achieved with the first-generation Grubb s metathesis catalyst in the presence of ethylene, ultimately leading to the isolation of the heptasaccharide 210 in the form of a pentenyl glycoside ready for further transformations (Scheme 39). 

This chapter is divided into six subsections which cover the most prominent applications of the metathesis reaction in solid-phase organic chemistry RCM for cleavages from the resin synthesis of small rings to macrocycles on the resin via RCM the use of the metathesis reaction for dimerization of polymer-bound small molecules RCM to constrict peptide conformations (while this is formally an RCM, it is treated separately because of the unique considerations of peptide chemistry) CM between a polymer-bound alkene and an alkene in solution and ene-yne metathesis. As the field evolved relatively rapidly with major advances in the catalysts, each subsection is organized in chronological order for the sake of clarity. 

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