Ellman resin

For quantitative analysis of solid supported thiol residues on free macroporous or PEG grafts, Ellman s reagent has been used [5,5 -dithio-hfr-(2-nitrobenzoic acid]. However only qualitative information can be gained using lightly crosslinked polystyrene resins [Badyal et al. Tetrahedron Lett 42 8531 2007]. 

A parallel solution-phase asymmetric synthesis of a-branched amines has been reported by Ellman and coworkers based on stereoselective addition of organomag-nesium reagents to enantiomerically pure tert-butanesulfinyl imines [156]. Micro-wave heating was utilized in two of the steps of this synthesis of asymmetric amines, both for the imine formation and for the resin capture (Scheme 7.128). 

Ellman used silyl chemistry for the direct linkage of aromatics onto the solid support by converting an aryl bromide to aryl lithium and reacting this with a silyl resin.90 It is the production of the silyl resin that is of interest in the context of this review, since an in situ Suzuki coupling was used to link the allyl silane to bromomethyl polystyrene resin (Scheme 40). 9-BBN is used to carry out the regioselective hydroboration, and this is linked to the resin with palladium catalysis in the usual way. After brief exposure of this... 

A second side reaction suffered by Ar(4)-unfunctionalized quinoxali-nones leading to racemization at the a-carbon was revealed in the closely related studies of Morales and co-workers, who assembled the [6,6] ring system from 4-fluoro-3-nitrobenzoic acid coupled as an ester to Wang resin (lb) (Scheme 12).9 This undesirable side reaction could also be prevented by functionalization of iV(4) prior to cleavage, which in this instance was accomplished by acylation with chloroformates and thiochloroformates. Derivatization at (V(l) was again effected using the Ellman alkylation protocol and provided optically pure samples of the quinoxalinones (72). 

Other derivatives were prepared by modifications of the original Ellman route. Thus, a second cyclopentene precursor 18 containing the C5 6 cis double bond was carried through to give the resin-bound intermediate 19 via a Stille coupling and an oxidation. Subsequent cuprate addition, reduction, and cleavage give 20 and 21 (the F and E series) with the C56 double bond intact. This type of approach was used to synthesize 11 more compounds in this series. 

In planning fhe solid-supported total synfhesis of 6-epi-dysidiohde and other related phosphatase inhibitors, Brohm and co-workers [226] developed a robust linker, which provided the terminal alkene by means of a traceless RCM release from the resin. Thus, suitable precursor (112) was prepared, after intensive investigations, on Ellman s dihydropyran resin [227]. Subsequent RCM with the Grubbs catalyst afforded the expected triene (113) in 82% isolated yield along with the solid-supported cyclopentene derivative (114) (Scheme 26). The tetrahydro-pyran link has a great impact on the yield of the RCM a direct benzylic resin attachment resulted in much lower yields. 

Ellman s group also developed a traceless linker sequence of a different type based on HF release of an aiyl silicon link to the resin (Fig. 1.17) (122). 

Ellman and coworkers have also reported the use of these resin-bound isocyanates for the scavenging of thiols in the parallel synthesis of a small library of cysteine protease inhibitors (Scheme 8.3) [7]. Simple filtration afforded the hydroxy sulfide products in moderate to good yields. Excess Dess-Martin periodinane, as well as the by-product in the final step, were scavenged using a resin-bound thiosulfate to yield target compounds. 

The most common anchors for traceless linkage of arenes are based on silyl linkers due to the well-known protodesilylation of the Si-aryl bond. The first traceless silyl linkers were described independently by Ellman et al. and Veber et al. in 1995 [104, 106], Starting from resin-bound arylstannane 113, Ellman has shown the advantages of this type of detachment in the synthesis of a diverse benzodiazepine library (Scheme 16.27). Improvements in the chemoselectivity of the cleav-... 

Another closely related application of this type of chemistry is an elegant method of intramolecular disulfide formation on the solid phase using a polymer-bound version of Ellman s reagent [35]. Although similar conceptual schemes had been previously applied to solid-phase heterodimer formation [36,37] from single Cys-containing fragments, in this account the solid-phase chemistry has been especially adapted to favor intramolecular reaction and minimize irreversibly resin-bound intermediates. 

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