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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Tetrahedron. Author manuscript; available in PMC 2016 June 3.
Published in final edited form as:
PMCID: PMC4429905
NIHMSID: NIHMS638763

Stereochemical evaluation of bis(phosphine) copper catalysts for the asymmetric alkylation of 3-bromooxindoles with α-arylated malonate esters

Abstract

An improved method for the asymetric alkylation of 3-bromooxindoles with α-arylated malonate esters is described. The asymmetric alkylation demonstrated was achieved up to 70% ee utilizing a copper(II) bis(phosphine) complex.

Keywords: 3,3-Disubstituted oxindole; Chiral bis(phosphine) ligands; Copper catalysis; Asymmetric catalysis

1. Introduction

3,3-Disubstituted oxindole moieties are present in a wide variety of natural products and pharmaceutical agents.1 Accordingly, methods for the asymmetric construction of 3,3-disubstituted oxindoles have attracted considerable attention from the synthetic community, and a number of catalytic stereoselective approaches to provide C3 quaternary stereocenters on oxindoles have been reported.2,3 In 2007, we discovered that 3,3-disubstituted oxidoles 3 were furnished efficiently by base-mediated alkylation of reactive electrophilic o-azaxylyxene 2, generated from 3-halooxindole 1, with nucleophilic malonate esters (Scheme 1a).4a Additionally, we developed a method for the stereoselective alkylation of 3-bromooxindoles by using a copper (R)-Ph-BOX ligand complex (Scheme 1b).4b

Scheme 1
Construction of 3,3-disubstituted oxindoles by alkylation of 3-halooxindoles.

Following our development of these methods, our attention turned to the syntheses of the polycyclic alkaloids communesin F and perophoramidine.5,6 We envisioned that the stereochemistry at the vicinal quaternary centers on communesin F and perophoramidine could be installed utilizing the conditions described in Scheme 1b. However, attempts to produce diesters 8 and 9 via copper(II) bisoxazoline catalyzed enantioselective alkylation of 3-bromooxindoles 4 and 5 with α-arylated malonate esters 6 and 7 were unsuccessful (Scheme 2). Perhaps this result was to be expected, since the nucleophiles (α-arylated malonate esters 6 and 7) were both sterically demanding and electronically deactivated by resonance stabilization through the o-nitrophenyl substituent. Therefore, we pursued the development of an alternative catalytic system.

Scheme 2
Attempts for alkylation of 3-bromooxindoles with α-arylated malonate esters.

In our previous studies, we tested a variety of metal catalysts (e.g. CuII, MgII, LaIII, and NiII) and discovered that the combination of CuII and a chiral bisoxazoline ligand effectively promoted the catalytic reaction.4 Chiral Cu(II) bis(phosphine) complexes have also found use in stereoselective synthesis.7 Since the catalytic system can be formed with a number of different chiral bis(phosphine) ligands, quite a few options would be available for developing a stereoselective reaction. Herein, we describe several screening studies designed and undertaken to optimize the reaction conditions for the alkylation of 3-bromooxindoles with α-arylated malonate esters using a copper(II) bis(phosphine) catalyst.

2. Results and discussion

2.1. Initial screening results

To develop a stereoselective alkylation method, we chose simple substrates for optimization studies; specifically, we used bromooxindole 5 without a substituent on the aromatic ring and o-nitrophenyl dimethylmalonate 12 as a coupling partner. Bromooxindole 5 was easily prepared from indole in four steps by a known sequence,5 which was then added to o-nitrophenyl dimethylmalonate 12 and cesium carbonate in THF solvent to afford a racemic product 13 in good yield. (Scheme 3).

Scheme 3
Synthesis of the racemic product.

Choosing (R)-BINAP as a chiral ligand, we began our research by screening various copper sources, bases, and solvents. For instance we attempted the following variations of copper ions: Copper(II) triflate, copper(II) chloride with silver hexafluoroantimonate, copper(II) isobutyrate, copper(II) tert-butoxide (generated in situ by adding lithium tert-butoxide to copper(II) isobutyrate and ligand mixture), copper(II) ethylhexanoate, and copper(II) trifluoroacetylacetonate. We explored both organic and inorganic bases, including diisopropylethylamine, pyridine, tetramethylethylenediamine (TMEDA), triethylamine, diisopropylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), sodium carbonate, potassium acetate, sodium ethylhexanoate and cesium carbonate. The various reactions combinations were attempted in the following solvents: dichloromethane, tetrahydrofuran, benzene, acetonitrile, and dioxane. Evaluating the 93 reactions that were explored,8 we found that copper(II) tert-butoxide and the ligand complex generated in THF, which was similar to Fandrick’s conditions for asymmetric propargylation,7 exhibited the best reactivity without generation of side products for the coupling of the arylated malonate 12 and bromooxindole 5 in CH2Cl2 (high conversion, 20% ee).

2.2. Ligand screening and optimization studies

Based on previous studies, we selected copper(II) isobutyrate, lithium tert-butoxide and THF solvent for generation of the catalytic species with chiral ligands, diisopropylamine as the base and CH2Cl2 as solvent. We have screened 69 chiral bis(phosphine) ligands8 under similar condition, finding WALPHOS and DiazaPHOS to give the best enantioselectivities (Figure 1).

Figure 1
Results with DiazaPHOS and WALPHOS

Having identified the most effective ligands, we next screened several copper sources under lower temperatures. Although none of these sources exhibited better results than the combination of copper(II) isobutyrate and lithium tert-butoxide for WALPHOS (N1 and N2), we were able to observe better stereoselectivity at low temperature (Table 1, entries 6 and 16). With DiazaPHOS (W1), copper(II) triflate showed better selectivity at 0 °C (Table 1, entries 22 and 23).

Table 1
Further investigations using WALPHOS and DiazaPHOS in the alkylation reaction.

With a suitable bis(phosphine) ligand in hand (N1), we tested multiple solvents and bases. However, amine bases weaker than Hünig’s base (Table 2, entries 1-12) could not initiate the reaction, whereas stronger base (entries 13-18) decreased the stereoselectivity. The copper bis(phosphine) complex demonstrated similar selectivity in dichloromethane (entry 19), THF (entry 20), and chloroform (entry 22), however it showed worse selectivity in acetonitrile (entry 21) and failed to proceed at all in toluene and 1,2-dimethoxyethane (DME).

Table 2
Investigation of reaction solvents and bases with WALPHOS in the alkylation reaction.

In addition to these studies, we examined the effect of the catalyst and ligand loading on the stereoselectivity of our alkylation reaction. Unsatisfactory results were produced with low catalyst or ligand loading (Table 3, entries 1,2 and 4), but 20 mol % of copper(II) isobutyrate and 40 mol % of the ligand gave the product in 56% ee (Table 3, entry 3). Stoichiometric amounts of the copper presursor and ligand produced only a slight increase in ee (Table 3, entry 5). Additionally, we investigated the impact of the equivalents of Hünig’s base on the selectivity of the reaction. Results showed the amount of Hünig’s base had little effect on the stereoselectivity of the product (Table 3, entries 6-13). Subsequent examination of concentration effects showed lowering the concentration of the reaction mixture from 0.05 M to 0.02 M resulted in increase stereoselectivity (Table 4).

Table 3
Examination of the amount of catalyst and ligand loading in the alkylation reaction.
Table 4
Examination of concentration in the malonate addition reaction.

Finally, we explored a set of WALPHOS ligands (N1N8) under our optimized conditions. Gratifyingly, we observed improved ee by using (Ph,Cy)-WALPHOS (Table 5, entry 5), leading to product formation in 70% ee with moderate conversion, whereas other ligands showed diminished selectivity. To date, this is the best result we have, which is a great improvement over the starting point.

Table 5
The effect of WALPHOS substituents under optimized condition in the alkylation reaction.

3. Conclusion

Asymmetric alkylation of 3-halooxindoles with malonate esters is an effective method to construct 3,3,-disubstituted oxindole moieties. Herein, we have reported that copper(II) chiral bis(phosphine) complex demonstrated reactivity with a highly stabilized and sterically hindered α-arylated malonate ester, which were unreactive substrates in previously developed conditions. This method could be applied to the installation of vicinal quaternary centers on the communesin F and perophoramidine scaffolds and could be useful in the synthesis of a variety of other natural products.

4. Selected experimentals

4.1. Synthesis of rac-13

To a flame-dried round-bottomed flask equipped with a stirbar, was added bromooxindole 5 (20 mg, 0.045 mmol), o-nitrophenyl dimethylmalonate 12 (37 mg, 0.135 mmol) and THF (0.5 mL). To the mixture was added cesium carbonate (47.4 mg, 0.045 mmol) at ambient temperature and the reaction mixture was then stirred for 3 hr. The reaction mixture was then treated with saturated NH4Cl aqueous solution, extracted with EtOAc, washed with brine and dried over MgSO4. After concentration in vacuo, the crude product was obtained. Chromatography (6:1 hexanes: ethyl acetate) on silica gel afforded the title compound 13 (23 mg, 80% yield) as colorless oil: 1H NMR (500 MHz, CDCl3) δ 8.0 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.74 (dd, J = 7.9, 1.7 Hz, 1H), 7.40 (dtd, J = 26.6, 7.4, 1.5 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.14 (td, J = 7.7, 1.3 Hz, 1H), 6.90 (td, J = 7.7, 1.2 Hz,1H), 6.75 (dd, J = 7.8, 1.1 Hz, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 3.35 (ddd, J = 9.5, 8.4, 6.9 Hz, 1H), 3.06 (td, J = 9.3, 4.5, 1H), 2.93 (ddd, J = 12.6, 8.8, 6.7 Hz, 1H), 2.54 (ddd, J = 12.8, 8.4, 4.4 Hz, 1H), 0.89 (s, 21H). 13C NMR (126 MHz, CDCl3) δ 177.86, 167.63, 167.27, 150.34, 140.67, 132.46, 131.12, 129.49, 129.23, 128.63, 128.61, 126.73, 125.39, 122.45, 109.98, 109.12, 59.52, 56.71, 52.81, 52.80, 38.34, 29.70, 17.85, 17,84, 11.80. IR (Neat Film, NaCl) 2923, 2852, 1722, 1617, 1532, 1463, 1353, 1259, 1097, 992, 799, 753 cm−1; HRMS (MM) m/z calc’d for C30H40N2O8Si [M+H]+: 585.2627, found 585.2636.

4.2. Ligand Screening procedure

Every step was performed in a nitrogen-filled glove box. Solutions of copper(II) isoburtyrate (8 mg, 0.034 mmol) in THF (3.5 mL), lithium tert-butoxide (2.72 mg, 0.034 mmol) in THF (3.5 mL), bromooxindole 5 (70 mg, 0.17 mmol) and malonate 12 (129 mg, 0.51 mmol) in CH2Cl2 (1.75 mL), i-Pr2NEt (0.1 ml, 0.57 mmol) in CH2Cl2 (2 mL) were prepared in 2 dram vials prior to reaction setup. To 1 dram vials equipped with stirbars, and ligand (1.1 μmol, 22 mol %) were distributed copper(II) isobutyrate in THF (0.1 mL, 0.97 μmol, 20 mol %). The heterogeneous solution was agitated at room temperature for 10-20 min until a clear homogeneous solution was generated. The reaction mixtures were charged with lithium tert-butoxide in THF (0.1 mL, 0.97 μmol, 20 mol %). Reaction mixtures were allowed to stir for 5 min and concentrated under reduced pressure. A mixture of bromooxindole 5 and malonate 12 in CH2Cl2 (0.05 mL, 4.85 μmol, 14.55 μmol) was dispensed to each vial and allowed to stir for 10 min. After setting the reaction temperature, i-Pr2NEt in CH2Cl2 (0.05 mL, 14.55 μmol, 3 equiv) was added to the reaction vials and allowed to stir for 48 h. Upon completion, sat. aq. ammonium chloride solution (0.1 mL) was added, and the mixture was filtered through silica gel. Each filtrate was diluted by 1 mL of solvent (ethyl acetate or isopropanol) and analyzed by chiral SFC. The mixture was separated by an AD-H column with 20% isopropanol as eluent. See supplementary material for more details.

Supplementary Material

Acknowledgments

The authors wish to thank NIH-NIGMS (R01GM080269-01), Amgen, the Gordon and Betty Moore Foundation, and Caltech for financial support. S.-J.H thanks Fulbright (Foreign Student Program, No. 15111120) and the Ilju Foundation of Education & Culture (Pre-doctoral Research Fellowship) for financial support. Catalyst center (Caltech) is acknowledged for assistance with reaction screenings. Drs. Florian Vogt, Sandy Ma, Xiaoquing Han, and Shyam Krishnan are acknowledged for preliminary research.

Footnotes

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Supplementary Material

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References and notes

1. (a) Tokunaga T, Hume WE, Umezome T, Okazaki K, Ueki Y, Kumagai K, Hourai S, Nagamine J, Seki H, Taiji M, Noguchi H, Nagata R. J. Med. Chem. 2001;44:4641–4649. [PubMed](b) Woodward C;L, Li Z, Kathcart AK, Terrell J, Gerena L, Lopez-Sanchez M, Kyle DE, Bhattacharjee AK, Nichols DA, Ellis W, Prigge ST, Geyer JA, Waters NC. J. Med. Chem. 2003;46:3877–3882. [PubMed](c) Galliford CV, Scheidt KA. Angew. Chem., Int. Ed. 2007;46:8748–8758. [PubMed](d) Marti C, Carreira EM. Eur. J. Org. Chem. 2003:2209–2219.(e) Lin H, Danishefsky SJ. Angew. Chem., Int. Ed. 2003;42:36–51. [PubMed](f) Trost BM, Brennan MK. Synthesis. 2009:3003–3025.(g) Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S, Gao W, Qin D, Stuckey J, Krajewski K, Roller PP, Wang S. J. Med. Chem. 2006;49:3432–3435. [PubMed]
2. Reviews: Zhou F, Liu Y-L, Zhou J. Adv. Synth. Catal. 2010;352:1381–1407. Klein JEMN, Taylor RJK. Eur. J. Org. Chem. 2011:6821–6841. Dalpozzo R, Bartoli G, Bencivenni G. Chem. Soc. Rev. 2012;41:7247–7290. [PubMed] Singh GS, Desta ZY. Chem. Rev. 2012;112:6104–6155. [PubMed]
3. Recent examples: Holmquist M, Blay G, Pedro JR. Chem. Commun. 2014;50:9309–9312. [PubMed] Hu F-L, Wei Y, Shi M. Chem. Commun. 2014;50:8912–8914. [PubMed] Chen D, Xu M-H. J. Org. Chem. 2014;79:7746–7751. [PubMed] Li C, Guo F, Xu K, Zhang S, Hu Y, Zha Z, Wang Z. Org. Lett. 2014;16:3192–3195. [PubMed] Zhu X-L, Xu J-H, Cheng D-J, Zhao L-J, Liu X-Y, Tan B. Org. Lett. 2014;16:2192–2195. [PubMed] Liu Z-M, Li N-K, Huang X-F, Wu B, Li N, Kwok C-Y, Wang Y, Wang X-W. Tetrahedron. 2014;70:2406–2415. Cao Z-Y, Wang Y-H, Zeng X-P, Zhou J. Tetrahedron Lett. 2014;55:2571–2584. Trost BM, Osipov M. Angew. Chem., Int. Ed. 2013;52:9176–9181. [PMC free article] [PubMed] Zhou F, Zeng X-P, Wang C, Zhao X-L, Zhou J. Chem. Commun. 2013;49:2022–2024. [PubMed] Katayev D, Jia Y-X, Sharma AK, Banerjee D, Besnard C, Sunoj RB, Kündig EP. Chem. Eur. J. 2013;19:11916–11927. [PubMed] Zhing F, Dou X, Han X, Yao W, Zhu Q, Meng Y, Lu Y. Angew. Chem., Int. Ed. 2013;52:943–947. [PubMed] Shen K, Liu X, Feng X. Chem. Sci. 2012;3:327–334. Uraguchi D, Koshimoto K, Ooi T. J. Am. Chem. Soc. 2012;134:6972–6975. [PubMed] Trost BM, Xie J, Sieber JD. J. Am. Chem. Soc. 2011;133:20611–20622. [PubMed] Ding M, Zhou F, Qian Z-Q, Zhou J. Org. Biomol. Chem. 2010;8:2912–2914. [PubMed] Trost BM, Zhang Y. Chem. Eur. J. 2010;16:296–303. [PubMed] Trost BM, Czabaniuk LC. J. Am. Chem. Soc. 2010;132:15534–15536. [PubMed] Tian X, Jiang K, Peng J, Du W, Chen Y-C. Org. Lett. 2008;10:3583–3586. [PubMed] Trost BM, Frederiken MU. Angew. Chem., Int. Ed. 2005;44:308–310. [PubMed]
4. (a) Krishnan S, Stoltz BM. Tetrahedron Lett. 2007;48:7571–7573.(b) Ma S, Han X, Krishnan S, Virgil SC, Stoltz BM. Angew. Chem., Int. Ed. 2009;48:8037–8041. [PubMed]
5. Han S-J, Vogt F, Krishnan S, May JA, Gatti M, Virgil SC, Stoltz BM. Org. Lett. 2014;16:3316–3319. [PMC free article] [PubMed]
6. Other efforts toward total syntheses of communesins and perophoramidine; May JA, Zeidan RK, Stoltz BM. Tetrahedron Lett. 2003;44:1203–1205. Crawley SL, Funk RL. Org. Lett. 2003;5:3169–3171. [PubMed] May JA, Stoltz BM. Tetrahedron. 2006;62:5262–5271. Yang J, Song H, Xiao X, Wang J, Qin Y. Org. Lett. 2006;8:2187–2190. [PubMed] Crawley SL, Funk RL. Org. Lett. 2006;8:3995–3998. [PubMed] Seo JH, Artman GD, III, Weinreb SM. J. Org. Chem. 2006;71:8891–8900. [PubMed] Yang J, Wu H, Shen L, Qin Y. J. Am. Chem. Soc. 2007;129:13794–13795. [PubMed] George JH, Adlington RM. Synlett. 2008:2093–2096. Siengalewicz P, Gaich T, Mulzer J. Angew. Chem., Int. Ed. 2008;47:8170–8176. [PubMed] Liu P, Seo JH, Weinreb SM. Angew. Chem., Int. Ed. 2010;49:2000–2003. [PMC free article] [PubMed] Zuo Z, Xie W, Ma D. J. Am. Chem. Soc. 2010;132:13226–13228. [PubMed] Zuo Z, Ma D. Angew. Chem., Int. Ed. 2011;50:12008–12011. [PubMed] Belmar J, Funk RL. J. Am. Chem. Soc. 2012;134:16941–16943. [PubMed] Artman GD, III, Weinreb SM. Org. Lett. 2003;5:1523–1526. [PubMed] Fuchs JR, Funk RL. J. Am. Chem. Soc. 2004;126:5068–5069. [PubMed] Sabahi A, Novikov A, Rainier JD. Angew. Chem., Int. Ed. 2006;45:4317–4320. [PubMed] Evans MA, Sacher JR, Weinreb SM. Tetrahedron. 2009;65:6712–6719. Wu H, Xue F, Xiao X, Qin Y. J. Am. Chem. Soc. 2010;132:14052–14054. [PubMed] Schammel AW, Chiou G, Garg NK. Org. Lett. 2012;14:4556–4559. [PubMed] Ishida T, Takemoto Y. Tetrahedron. 2013;69:4517–4523. Ishida T, Ikota H, Kurahashi K, Tsukano C, Takemoto Y. Angew. Chem., Int. Ed. 2013;52:10204–10207. [PubMed] Zhang H, Hong L, Kang H, Wang R. J. Am. Chem. Soc. 2013;135:14098–14101. [PubMed] Trost BM, Osipov M, Krüger S, Zhang Y. Chem. Sci. 2014 DOI:10.1039/C4SC01826E.
7. (a) Fandrick DR, Fandrick KR, Reeves JT, Tan Z, Tang W, Capacci AG, Rodriguez S, Song JJ, Lee H, Yee NK, Senanayake CH. J. Am. Chem. Soc. 2010;132:7600–7601. [PubMed](b) Fandrick KR, Fandrick DR, Reeves JT, Ma S, Li W, Lee H, Grinberg N, Lu B, Senanayake CH. J. Am. Chem. Soc. 2011;133:10332–10335. [PubMed](c) Fandrick KR, Ogikubo J, Fandrick DR, Patel ND, Saha J, Lee H, Ma S, Grinberg N, Busacca CA, Senanayake CH. Org. Lett. 2013;15:1214–1217. [PubMed]
8. See supplementary material for the list of chiral bis(phosphine) ligands and screening results.