Solid-Phase Synthesis and Combinatorial Technologies

L20

96-member library of catalytic systems

5 ligands (9.71-9.75) used:

O O O O

N N N N

9.82

9.81

O O

N

N N N N

9.83

OH HO

H

H

H

9.84

7 metals used:

AgSbF6, Sc(OTf)3, [Rh(nbd)]BPh2,

(CuOTf).C6H6, La(OTf)3,

Yb(OTf)3, AuCl(SMe2)

4 solvents used:

THF, MeCN, CHCl3, toluene

Figure 9.33 Catalyzed hydrosilylation: structure of the solution-phase catalytic system discrete library L20.

a reaction, and two compounds, 9.88 and 9.89, containing an electron-donor ferrocenyl group and an electron-acceptor pyridinium group linked respectively by a C=C (9.88) or C=N (9.89) bond were selected as substrates. Their synthesis from intermediates 9.86 and 9.87 is reported in Fig. 9.34. These compounds had strong absorption maxima in the UV–visible area and were respectively deep purple and dark blue, while their hydrosilylation produced compounds 9.90 and 9.91, respectively, which lost the original color and became light yellow (Fig. 9.35).

A 12-member catalytic system library L21 (Fig. 9.35) was tested using the two substrates, and the color change in each reaction vessel containing a different catalytic

464 APPLICATIONS OF SYNTHETIC LIBRARIES

TABLE 9.4 Diastereomeric Ratios and Yields of 9.79 and 9.80 Using the Solution-Phase Catalytic System Discrete Library L20: Selected Entries

aDiastereomeric ratio 9.79/9.80 (yield after DDQ oxidation). bRepeated as discretes on a larger scale.

system–substrate mixture was monitored. Care was taken to minimize any interference due to catalysts or solvents in the color change, and blank control vessels were added. Images were recorded with a digital camera on the occasion of two distinct events: when the first sign of bleaching appeared (t1), corresponding to around 40% of hydrosilylation, and when the original color disappeared completely (t2), corresponding roughly to 95% of hydrosilylation. The latter measurement was more susceptible to color interferences, but both measurements were reliable enough (see the original paper for more details).

The screening results are reported in Table 9.5. The performance of the catalytic systems with the two substrates was similar, a significant change in the reaction times being observed in only one case (entry 2). Many results, such as the good performance of Wilkinson’s catalyst (entry 4), were expected, but a palladium-based catalyst (entry 10) with no previous history as a hydrosilylation catalyst provided the best results and validated the usefulness of dye-labeled substrates for the rapid screening of catalytic systems. Correlation of bleaching with hydrosilylation was confirmed for a specific case (entry 4), isolating the expected hydrosilylation product and characterizing it by

466 APPLICATIONS OF SYNTHETIC LIBRARIES

step a: single catalyst or L21, Ph2SiH2, dry THF, rt.

L21

12-member library of catalytic systems

12 catalysts used:

[Ir(cod)(PPh3)2]BF4, [Rh(cod)(PPh3)2]PF6, [Rh(nbd)(PPh3)2]PF6, RhCl(PPh3)3, [Rh(octanoate)2]2, RuCl2(PPh3)3, NiCl2(PPh3)2, [Ni(tss)]2, Cp2ZrClH, [Pd(Ar2PC6H4CH2)OAc]2, [(nbd)Rh(triphos)]SbF6, PtCl2(NH3)2

Figure 9.35 Hydrosilylation of 9.88 and 9.89 with the solution-phase-system discrete library

L21.

aza crown ligands (148), using similar structures also for the cleavage of phospho diand triesters and even DNA plasmids (149); Moye-Sherman et al. (150) selected optimal enantioselective metal complexes for the cyclopropanation of dehydrophenyl alanine derivatives; Bromidge (151) reported the identification of metal complexes that catalyzed an asymmetric aza Diels–Alder reaction producing a substituted pyridone; Huffman and Reider (152) optimized the stereoselectivity of the diastereoselective reductive amination leading to the angiotensin converting enzyme (ACE) inhibitor enalapril using high-throughput parallel screening of catalytic systems; Reetz et al. (153) reported a novel HTS method for enantioselective catalytic system libraries applied to several lipase-catalyzed reactions; Lavastre and Morken (154) presented a high throughput, visual assay to rapidly screen catalytic systems for allylic alkylation using various metal and ligands.

9.4.4 An Example: High-Throughput Screening of a Ligand Library for Heck C–C Coupling

Shaughnessy et al. (155) reported the rapid, sequential screening of three phosphine ligand libraries L22–L24 in a Heck coupling reaction involving a fluorescent substrate 9.92 and the supported aryl bromide 9.93, whose structure and synthesis are reported in Fig. 9.36.

These results were slightly better than those obtained employing t-butyl acrylate to produce 9.97 (GC determination after cleavage). When 9.93 was treated with fluorescent substrate 9.92 without catalyst, the washed resin beads showed no fluorescence, proving the overall reliability of the fluorescent screening and the absence of interferences.

Two 20-member libraries of monoand diphosphine ligands (L22 and L23, Fig. 9.38) were then screened in two parallel arrays, containing 9.92, 9.93, Pd(dba)2 and NaOAc, heated at 100°C for 4 h. The ligand structures of L22 included hindered o-substituted arylphosphines, arylphosphines with different electronic properties or with weak coordination properties, and alkylphosphines. L23 included diphosphines with various steric and electronic properties as well as with different backbones (Fig. 9.38). The level of bead fluorescence was measured roughly as being absent (F1), moderate (F2), or strong (F3), and the data for the best 12 ligands are reported in Table 9.6 (all the reactions were repeated twice, giving the same results). The same 40 reactions were also performed in solution, replacing 9.93 with a soluble aryl bromide, and their outcome was determined by GC. The results reported in Table 9.6 highlighted a general accordance between the homogeneous and heterogeneous reaction systems, with strongly fluorescent beads corresponding to >80% conversion in solution and nonfluorescent beads corresponding generally to poor ligands in solution (only one example produced >60% conversion in solution and did not produce any SP fluorescence; see Table 9.6). Most of the 11 ligands, 8 from L22 and 3 from L23, that showed moderate or strong fluorescence were sterically hindered structures (Table 9.6 and Fig. 9.39).

The best performers from L22 and L23 were tested using three more demanding reaction protocols, either decreasing the reaction temperature to 75°C, or to 50°C, or using a less reactive supported aryl chloride (replacing Br with Cl in 9.93). An additional 5 ligands (Fig. 9.39) were added to the 11 library-generated active ligands, producing the 16-member ligand library L24, whose screening results are reported in Table 9.7. Only 2 ligands produced strongly fluorescent beads in all the reaction conditions. Confirmation of these results in solution was successful, in that a best performer was selected (L2412). This ferrocene ligand (Fig. 9.39) was as effective as a known, optimized dimeric palladacycle ligand (156) when tested on activated substrates but was significantly better on unactivated substrates (155).

Fluorescent detection was successfully validated in this specific example. Its higher throughput, when compared to more classical LC/GC detection methods (2–3 h versus 16 h), makes it appealing to screen larger ligand libraries using fluorescent substrates. The known phenomenon of fluorescence quenching on resin beads (157) was not relevant in this example, but a rigorous assessment should always be made, as it was here, to determine the reliability of the fluorescent screen to predict real catalytic efficiency for any given reaction.

Many other reports of ligand libraries for specific catalytic applications have been reported. Among them, Gilbertson and co-workers reported a chiral phosphine library, tested in the rhodium-catalyzed asymmetric hydrogenation of an enamide (158, 159), and a similar library for the palladium-catalyzed allylation of malonates (160, 161); Hoveyda and co-workers (162, 163) reported a chiral Schiff base library, screened in the titanium-catalyzed opening of epoxides with (TMSCN) (trimethyl silyl cyanide);

TABLE 9.6 Ligands from Solution-Phase Discrete Monoand Diphosphine Libraries L22 and L23 for the Catalyzed Heck Reaction of Labeled Substrate 9.92 with Supported 9.93: Screening Results

aReaction on solid phase (9.93); F1 = no fluorescence, F2 = weak fluorescence, F3 = strong fluorescence. bReaction in solution (soluble aryl bromide).

Sigman and Jacobsen (164) reported a Schiff base library, screened for the asymmetric Strecker reaction; Porte et al. (165) presented the screening of a chiral phosphine oxazoline library in the palladium-catalyzed allylation of malonates; Gennari et al. (166) reported a chiral disulfonamide library, screened in the titanium-catalyzed addition of Et2Zn to aldehydes; Buck et al. (167) reported a library of novel carboxylate ligands, screened for the rhodium-catalyzed asymmetric carbenoid Si–H insertion; Ding et al. (168) reported a library of diol ligands–chiral nitrogen activators for the zinc-catalyzed addition of Et2Zn to aldehydes; Hinderling and Chen (169) reported the MSscreeningofaliganddiiminelibrarymadeforthePdII-catalyzed olefinpolymerization; Havranek et al. (170) reported the TLC/GC screening of 1,2-phenylene diamine amide peptidomimetics for the Mn-catalyzed oxidation of alkanes to carbonyl compounds and alkenes to carbonyl compounds and epoxides; Altava et al. (171) presented a library of supported, chiral β-aminoalcohols as chiral auxiliaries reacted with LiAlH4 to give reducing agents for the enantioselective reduction of acetophenone.

9.4.5 An Example: Screening of a Substrate Library of Ketones for Their Asymmetric Reduction

Gao and Kagan (172) reported the screening of several mixtures of ketones L25–L29, composed of compounds 9.98–9.111 (Fig. 9.40), as substrates for asymmetric catalytic reduction using Corey’s oxazaborolidine 9.112 (173), establishing its general applicability to the generic reaction shown in Fig. 9.40, top.

The substrates were discernible using chiral HPLC as a detection method for measuring the presence of residual ketones and formed alcohol stereoisomers. In several