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A Novel Catalyst System for Suzuki-Miyaura Coupling of Challenging DNA-Linked Aryl chlorides Yun Ding, Jennifer L. DeLorey, and Matthew A. Clark Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.6b00541 • Publication Date (Web): 05 Oct 2016 Downloaded from http://pubs.acs.org on October 9, 2016
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Bioconjugate Chemistry
A Novel Catalyst System for Suzuki-Miyaura Coupling of Challenging DNA-Linked Aryl Chlorides Yun Ding,* Jennifer L. DeLorey, † Matthew A. Clark§ GlaxoSmithKline, Platform Technology & Science, ELT-Boston, 830 Winter Street, Waltham, MA 02451, USA.
Supporting Information Placeholder ABSTRACT:
A novel Pd catalyst system, [(tBu)2P(OH)]2PdCl2 (POPd) with the ligand sodium 2'(dicyclohexylphosphino)-2,6-dimethoxy-[1,1'-biphenyl]-3sulfonate, is reported. It effectively catalyzes the SuzukiMiyaura coupling of challenging phenyl chlorides and pyrimidinyl chlorides that are covalently linked to a doublestranded DNA-template with various boronic acids/esters.
DNA-encoded library technology (ELT) has been proven to 1-2 be a powerful tool for hit identification in drug discovery. Potent inhibitors of various targets, including kinases, metal3-7 loproteases and hydrolases, have been reported. A primary factor for the success of this platform is the chemical diversity of accessible structures. In the last ten years, there have been an increasing number of reports describing synthetic transformations operating under aqueous conditions in the 8-11 presence of DNA. However, compared with traditional medicinal chemistry, the number of chemical transformations that can proceed on a DNA template is still quite limited. As one of the most widely employed reactions in medicinal chemistry, Suzuki-Miyaura coupling would be a desirable reaction to develop with on-DNA substrates. Since its initial report over thirty years ago, more active, general, and longlived catalysts have been developed for coupling more chal12-13 Delenging substrates, such as inactivated aryl chlorides. spite these advances, aryl-aryl bond formation employing nitrogen heterocycles as one or both of the coupling partners is still a challenge, especially under the aqueous condition. To our knowledge, very few examples of Suzuki-Miyaura coupling with challenging substrates such as heteroaryl halides and/or heteroaryl boronic acids/esters in aqueous media 14-15 have been published. In this paper, we disclose the development of a new catalyst system that can effectively catalyze the coupling of relatively unreactive aryl halides, such as pyrimidinyl and phenyl chlorides, that are covalently linked to a double stranded DNA, the “headpiece” (HP). In an early publication, we reported that Pd(PPh3)4 can effectively catalyze the coupling of DNA-linked phenyl halides (bromides or iodides) and pyridinyl bromides with various boronic acids/esters, including challenging heteroaryl bo16 ronic acids/esters. However, when we tried to couple pyrimidinyl chloride (HP-3) with various boronic acids/esters
using the same conditions, the results were not promising (Scheme 1). Phenyl boronic acid A gave about 80% yield, while 3,4-methylenedioxyphenyl boronic acid B yielded ~30% product and 4-trifluoromethyl phenyl boronic acid C yielded only ~25% coupling product. The sterically hindered boronate D and heterocyclic boronic esters E-H did not produce any coupling product. We attempted to improve yields by increasing the catalyst load, but observed no improvement. The failure of Pd(PPh3)4 with these challenging substrates forced us to investigate additional Pd catalysts and ligands.
Scheme 1. Suzuki-Miyaura coupling with Pd(PPh3)4
Air-stable phosphine oxides have been reported to coordinate with palladium to form air-stable palladium (II) complexes (POPd, POPd1, and POPd2), that serve as catalyst precursors for efficient C-C, C-N, and C-S bond formations 17 with aryl chlorides. These phosphinous acid/Pd catalyst systems have also been reported to be used for the aqueous18 phase Suzuki-Miyaura cross-coupling. We compared these catalysts with Pd(PPh3)4 in the coupling of HP-3 (Table 1). In the case of phenylboronic acid (Table 1, entry 1), POPd gave similar result as Pd(PPh3)4, while POPd1 and POPd2 gave relatively lower yield. In the case of electron-rich 3,4methylenedioxyphenyl boronic acid (Table 1, entry 2), both POPd and POPd2 gave equal or slightly better results than Pd(PPh3)4. Further exploration of POPd with 3,4methylenedioxyphenyl boronic acid showed that doubling
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the amount of the reagents (1 equivalent of Pd catalyst, 40 equivalents of boronic acid and 80 equivalents of base) and switching to other bases, such as Cs2CO3 and KOH, gave about 90% of coupling product. Under this optimized condition, we further tested the coupling with other boronic acids/esters using POPd (Table 2). The coupling with phenylboronic acid (Table 2, entry 1) afforded the biaryl in about 80% yield. Electron-poor phenyl boronic acid (Table 2, entry 3) afforded only about 50% coupling product. In the case of heterocyclic boronic esters (Table 2, entry 4-7), there was very low yield of coupling. We also tested POPd2 with representative boronates, and similarly low yields were observed. Use of different bases, Cs2CO3 and KOH, for both POPd and POPd2 gave almost identical results. Doubling the amount of catalyst did not help the reaction. Overall, POPd can catalyze the Suzuki-Miyaura coupling with electron-neutral or electron-rich phenyl boronic acid/ester, but not efficiently with electron-poor phenyl boronic acids and heterocyclic boronates. However, it yielded small amount of coupling product with some heterocyclic boronates that failed completely with Pd(PPh3)4.
Table 1. Comparison of Suzuki-Miyaura coupling with HP-3 using different Pd catalysts.a
b
Entry
Pd(PPh3)4
POPd
1
80%
2
30%
c
d
e
POPd1
POPd2
70%
40%
40%
30% f (90% )
15%
50%
a
Reaction conditions: 1 equiv of headpiece solution (1 mM in H2O), 20 equiv of Boronic acid (800 mM in DMA), 40 equiv of Na2CO3 (1.6 M in H2O), 0.5 equiv of Pd catalyst, 80 b c °C for 16 hours. Pd(PPh3)4 (3 mM in CH3CN, degassed). d POPd (5 mM in CH3CN). POPd1 (5 mM in CH3CN, undise f solved). POPd2 (5 mM in CH3CN). Adding double amount of reagents.
Table 2. Suzuki-Miyaura coupling with HP-3 using POPd.a Entry
Boronic acid/ester
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