Synlett 2020; 31(06): 587-591
DOI: 10.1055/s-0039-1690851
cluster
© Georg Thieme Verlag Stuttgart · New York

Rational Design of New Dihydrobenzooxophosphole-Based Lewis Base Organocatalysts

Bo Qu
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
,
Lalith P. Samankumara
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
,
Anjan Saha
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
,
Mac G. Schumer
b   Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
,
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
,
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
,
Carl A. Busacca
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
,
Nathan K. Yee
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
,
b   Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
,
Jinghua J. Song
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
,
Chris H. Senanayake
a   Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
› Author Affiliations
M. C. K. thanks the NIH (GM087605) and Boehringer Ingelheim Pharmaceuticals for financial support.
Further Information

Publication History

Received: 22 January 2020

Accepted after revision: 20 February 2020

Publication Date:
12 March 2020 (online)


Published as part of the ISySyCat2019 Special Issue

Abstract

A series of new dihydrobenzooxophosphole-based Lewis base organocatalysts were designed and synthesized. They are shown to be effective in trichlorosilane-mediated stereoselective conjugate reductions of C=C bonds. DFT calculations reveal that the strong hydrogen bonds between the amide linker and the chloride on silicon in the transition state contribute to the high reactivity of the catalyst.

Supporting Information

 
  • References

  • 1 Current address: TCG Lifesciences Private Limited, 737 North 5th Street, Richmond, Virginia 23219, US.
    • 2a Denmark SE, Stavenger RA. Acc. Chem. Res. 2000; 33: 432
    • 2b Guizzetti S, Benaglia M. Eur. J. Org. Chem. 2010; 5529
    • 3a Shimoda Y, Kubo T, Sugiura M, Kotani S, Nakajima M. Angew. Chem. Int. Ed. 2013; 52: 3461
    • 3b Aoki S, Kotani S, Sugiura M, Nakajima M. Chem. Commun. 2012; 48: 5524
    • 4a Han ZS, Zhang L, Xu Y, Sieber JD, Marsini MA, Li Z, Reeves JT, Kandrick KR, Patel ND, Desrosiers J.-N, Qu B, Chen A, Rudzinski DM, Samankumara LP, Ma S, Grinberg N, Roschangar F, Yee NK, Wang G, Song JJ, Senanayake CH. Angew. Chem. Int. Ed. 2015; 54: 5474
    • 4b Sugiura M, Sato N, Kotani S, Nakajima M. Chem. Commun. 2008; 4309
  • 5 Li Z, Shi Y. Org. Lett. 2015; 17: 5752
  • 6 Ogasawara M, Kotani S, Nakajima H, Furusho H, Miyasaka M, Shimoda Y, Wu W.-Y, Sugiura M, Takahashi T, Nakajima M. Angew. Chem. Int. Ed. 2013; 52: 13798
  • 7 Kotani S, Hashimoto S, Nakajima M. Tetrahedron 2007; 63: 3122
    • 8a Chong E, Qu B, Zhang Y, Cannone ZP, Leung JC, Tcyrulnikov S, Nguyen KD, Haddad N, Biswas S, Hou X, Kaczanowska K, Chwalba M, Tracz A, Czarnocki S, Song JJ, Kozlowski MC, Senanayake CH. Chem. Sci. 2019; 10: 4339
    • 8b Tang W, Qu B, Capacci AG, Rodriguez S, Wei X, Haddad N, Narayanan B, Ma S, Grinberg N, Yee NK, Krishnamurthy D, Senanayake CH. Org. Lett. 2010; 12: 176
    • 9a Sui-Seng C, Freutel F, Lough AJ, Morris RH. Angew. Chem. Int. Ed. 2008; 47: 940
    • 9b Gao JX, Ikariya T, Noyori R. Organometallics 1996; 15: 1087
    • 10a Li Y.-Y, Yu S.-L, Shen W.-Y, Gao J.-X. Acc. Chem. Res. 2015; 48: 2587
    • 10b Trost BM. Tetrahedron 2015; 71: 5708
    • 10c Trost BM, Van Vranken DL. Angew. Chem. Int. Ed. 1992; 21: 228
  • 11 Qu B, Samankumara LP, Ma S, Fandrick KR, Desrosiers J.-N, Rodriguez S, Li Z, Haddad N, Han ZS, McKellop K, Pennino S, Grinberg N, Connella NC, Song JJ, Senanayake CH. Angew. Chem. Int. Ed. 2014; 53: 14428
  • 12 General procedure for catalyst preparation: To a solution of carboxylic acid phosphine oxide (5.0 g, 17.6 mmol, 2.2 equiv), diamine (8.0 mmol, 1 equiv) and triethylamine (32.0 mmol, 4 equiv) in acetonitrile at room temperature was added propylphosphonic anhydride (T3P) solution in DMF (16.0 mmol, 2 equiv) in portions over 3 h. The reaction was stopped after complete consumption of the carboxylic acid. The mixture was then treated with 50% aqueous NaOH (10 mL) and stirred at 35 °C for 3 h. The suspension was diluted with water and the resulting clear solution was extracted three times with EtOAc. The combined organic layer was washed with brine, dried with MgSO4 and concentrated, and the crude mixture was purified by chromatography on silica (100% EtOAc to 10% MeOH/EtOAc) to obtain a white solid after drying.(2R,2′R,3S,3′S)-N,N′-((1R,2R)-cyclohexane-1,2-diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3a): Yield: 3.67 g (71%). 1H NMR (500 MHz, CDCl3): δ = 7.46 (t, J = 8.23 Hz, 2 H), 6.80 (br d, J = 6.70 Hz, 2 H), 6.71 (dd, J = 8.3, 2.8 Hz, 2 H), 6.54 (dd, J = 8.2, 4.4 Hz, 2 H), 4.93 (s, 2 H), 3.88 (s, 6 H), 3.80 (br s, 2 H), 2.11 (br d, J = 7.3 Hz, 2 H), 1.65 (br s, 2 H), 1.37 (d, J = 17.0 Hz, 18 H), 1.25–1.23 (m, 4 H). 13C NMR (125 MHz, CDCl3): δ = 165.2 (d, J = 2.7 Hz), 164.5 (d, J = 14.2 Hz), 161.1 (d, J = 2.4 Hz), 136.9 (d, J = 0.87 Hz), 106.6 (d, J = 5.3 Hz), 104.1 (d, J = 5.7 Hz), 102.70 (d, J = 90.8 Hz), 75.4 (d, J = 48.4 Hz), 55.6, 53.7, 34.07 (d, J = 74.5 Hz), 32.4, 25.1 (d, J = 0.96 Hz), 24.5. 31P NMR (202 MHz, CDCl3): δ = 62.83. HRMS (ESI): m/z [M + H]+ calcd for C32H45O8N2P2: 647.26457; found: 647.26495.(2R,2′R,3S,3′S)-N,N′-((1S,2S)-cyclohexane-1,2-diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3b): Yield: 3.36 g (65%). 1H NMR (400 MHz, CDCl3): δ = 7.43 (t, J = 8.2 Hz, 2 H), 6.86 (br d, J = 6.0 Hz, 2 H), 6.62 (dd, J = 8.2, 3.0 Hz, 2 H), 6.50 (dd, J = 8.1, 4.4 Hz, 2 H), 5.22 (s, 2 H), 3.80 (s, 6 H), 3.73 (br s, 2 H), 2.12 (br d, J = 6.6 Hz, 2 H), 1.69 (br s, 2 H), 1.31–1.26 (overlapping d, J = 17.0 Hz, and m, 22 H). 13C NMR (100 MHz, CDCl3): δ = 165.7 (d, J = 2.0 Hz), 165.3 (d, J = 15.3 Hz), 161.3 (d, J = 2.1 Hz), 136.8, 106.4 (d, J = 5.4 Hz), 103.8 (d, J = 5.8 Hz), 101.6 (d, J = 91.6 Hz), 74.6 (d, J = 48.3 Hz), 55.6, 53.5, 34.3 (d, J = 74.0 Hz), 32.2, 24.6, 24.5. 31P NMR (162 MHz, CDCl3): δ = 62.36. HRMS (ESI): m/z [M + H]+ calcd for C32H45O8N2P2: 647.26457; found: 647.26433.(2R,2′R,3S,3′S)-N,N′-(1,2-phenylene)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3c): Yield: 3.07 g (60%); 1H NMR (400 MHz, CDCl3): δ = 8.65 (s, 2 H), 7.54 (m, 2 H), 7.44 (t, J = 8.2 Hz, 2 H), 7.16 (m, 2 H), 6.68 (dd, J = 8.3, 2.8 Hz, 2 H), 6.54 (dd, J = 8.2, 4.4 Hz, 2 H), 5.33 (s, 2 H), 3.86 (s, 6 H), 1.34 (d, J = 17.1 Hz, 18 H); 13C NMR (100 MHz, CDCl3): δ = 165.2 (d, J = 14.9 Hz), 164.5 (d, J = 2.6 Hz), 161.3 (d,J = 2.2 Hz), 137.0, 129.9, 126.7, 126.2, 106.5 (d, J = 5.4 Hz), 104.1 (d, J = 5.8 Hz), 102.0 (d, J = 91.6 Hz), 75.5 (d, J = 47.5 Hz), 55.7, 34.4 (d, J = 73.8 Hz), 24.7. 31P NMR (202 MHz, CDCl3): δ = 63.9. HRMS (ESI): m/z [M + H]+ calcd for C32H39O8N2P2: 641.21762; found: 641.21767.(2R,2′R,3S,3′S)-N,N′-((1R,2R)-1,2-dicyclohexylethane-1,2-diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3d): Yield: 3.03 g (50%); 1H NMR (400 MHz, CDCl3): δ = 7.45 (t, J = 8.2 Hz, 2 H), 6.72–6.68 (overlapping s and dd, J = 8.2, 3.0 Hz, 4 H), 6.54 (dd, J = 8.1, 4.3 Hz, 2 H), 4.92 (d, J = 0.48 Hz, 2 H), 4.06–4.00 (m, 6 H), 3.88 (s, 6 H), 1.74–1.67 (m, 9 H), 1.54–1.34 (overlapping d, J = 17.0 Hz, and m, 24 H), 1.22–1.02 (m, 10 H), 0.9–0.81 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 165.1 (d, J = 2.3 Hz), 164.4 (d, J = 13.9 Hz), 161.1 (d, J = 2.1 Hz), 136.7, 106.5 (d, J = 5.2 Hz), 104.1 (d, J = 5.7 Hz), 103.1 (d, J = 90.5 Hz), 75.6 (d, J = 48.9 Hz), 55.6, 54.7, 38.9, 34.1 (d, J = 74.4 Hz), 30.5, 27.3, 26.2, 26.16, 26.11, 25.2. 31P NMR (162 MHz, CDCl3): δ = 61.64. HRMS (ESI): m/z [M + H]+ calcd for C40H59O8N2P2: 757.37412; found: 757.37417.(2R,2′R,3S,3′S)-N,N′-((1R,2R)-1,2-diphenylethane-1,2-diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3e): Yield: 2.98 g (50%); 1H NMR (500 MHz, CDCl3): δ = 7.52 (br d, J = 2.8 Hz, 2 H), 7.43 (t, J = 8.2 Hz, 2 H), 7.11–7.06 (m, 10 H), 6.70 (dd, J = 8.3, 2.5 Hz, 2 H), 6.50 (dd, J = 8.1, 4.3 Hz, 2 H), 5.40–5.38 (m, 2 H), 5.00 (s, 2 H), 3.85 (s, 6 H), 1.35 (d, J = 16.9 Hz, 18 H). 13C NMR (100 MHz, CDCl3): δ = 165.5 (d, J = 2.4 Hz), 164.5 (d, J = 14.1 Hz), 161.1 (d, J = 2.3 Hz), 137.7, 136.8, 128.5, 127.74, 127.69, 106.5 (d, J = 5.3 Hz), 104.0 (d, J = 5.8 Hz), 102.7 (d, J = 91.1 Hz), 75.3 (d, J = 48.8 Hz), 59.1, 55.6, 34.1 (d, J = 74.5 Hz), 25.1 (d, J = 0.8 Hz). 31P NMR (202 MHz, CDCl3): δ = 62.13. HRMS (ESI): m/z [M + H]+ calcd for C40H47O8N2P2: 745.28022; found: 745.28012.General procedure for enone reduction: To a stirring solution of 1a (60 mg, 0.27 mmol) and catalyst 3a (0.027 mmol, 10 mol%) in acetonitrile (2 mL) at 0 °C was added HSiCl3 (1.35 mmol, 5 equiv) dropwise, and the mixture was stirred at 0 °C for 20 h. The reaction was then quenched with a solution of 5N aqueous NaOH (2 mL), and the mixture was warmed to room temperature then diluted with EtOAc and water. The phases were separated, and the aqueous phase was further extracted once with EtOAc. The combined organic layers were washed with water followed by brine, dried with Na2SO4 and concentrated. The product was purified on silica with a mixture of hexanes/EtOAc (10:1) to obtain a colorless oil after drying.(S)-1,3-Diphenylbutan-1-one (2a): Yield: 90%; 89.2:10.8 er; SFC (ES Industries CCA column 4.6 × 100 mm, 3 μm: 35 °C, A: CO2, B: isopropanol; gradient: 1% B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min, λ = 220 nm): tR = 2.50 (major), 2.80 (minor) min. NMR data match those reported in the literature.17 1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 7.9 Hz, 2 H), 7.57 (t, J = 7.3 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.35–7.21 (m, 4 H), 7.35–7.28 (m, 2 H), 7.23 (t, J = 6.8 Hz, 1 H), 3.54 (sextet, J = 6.9 Hz, 1 H), 3.33 (dd, J = 16.5, 5.7 Hz, 1 H), 3.22 (dd, J = 16.5, 8.3 Hz, 1 H), 1.37 (d, J= 6.9 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 199.1, 146.6, 137.2, 133.0, 128.6, 128.5, 128.1, 126.9, 126.3, 47.0, 35.6, 21.9.(S)-1-Phenyl-3-(4-(trifluoromethyl)phenyl)butan-1-one (2b): Yield: 92%; 89.4:10.6 er; SFC (ES Industries CCA column 4.6 × 100 mm, 3 μm: 35 °C, A: CO2, B: isopropanol; gradient: 1% B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min, λ = 220 nm): tR  = 1.69 (major), 1.91 (minor) min. NMR data match those reported in the literature.18 1H NMR (400 MHz, CDCl3): δ = 7.97–7.92 (m, 2 H), 7.60–7.56 (m, 3 H), 7.50–7.45 (m, 2 H), 7.41 (d, J = 8.3 Hz, 2 H), 3.69 (sextet, J = 6.9 Hz, 1 H), 3.35 (dd, J = 16.8, 6.4 Hz), 3.25 (dd, J = 16.9, 7.5 Hz, 1 H), 1.39 (d, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 198.4, 150.6, 137.0, 133.2, 128.6, 128.0, 127.3, 125.5 (q, J = 3.8 Hz), 46.5, 35.3, 21.9.(S)-3-(4-Chlorophenyl)-1-phenylbutan-1-one (2c): Yield: 94%; 90.2:9.8 er; SFC (ES Industries CCA column 4.6 × 100 mm, 3 μm: 35 °C, A: CO2, B: methanol; gradient: 1% B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min, λ = 220 nm): tR = 2.93 (major), 3.51 (minor) min. NMR data match those reported in the literature.18 1H NMR (400 MHz, CDCl3): δ = 7.95–7.92 (m, 2 H), 7.60–7.56 (m, 1 H), 7.50–7.45 (m, 2 H), 7.30–7.27 (m, 2 H), 7.25–7.21 (m, 2 H), 3.52 (sextet, J = 6.9 Hz, 1 H), 3.29 (dd, J = 16.7, 6.3 Hz), 3.2 (dd, J = 16.7, 7.7 Hz, 1 H), 1.35 (d, J= 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 198.7, 145.0, 137.1, 133.1, 131.9, 128.6, 128.3, 128.0, 46.8, 35.0, 22.0.(S)-3-(2-Methoxyphenyl)-1-phenylbutan-1-one (2d): Yield: 89%; 88.1:11.9 er; SFC (Lux Cel 1 column 4.6 × 100 mm, 3 μm: 35 °C, A: CO2, B: methanol; gradient: 1% B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min, λ = 220 nm): tR = 3.94 (major), 4.27 (minor) min. NMR data match those reported in the literature.19 1H NMR (500 MHz, CDCl3): δ = 7.90 (d, J = 7.8 Hz, 2 H), 7.45 (t, J = 7.3 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.15 (d, J = 7.3 Hz, 1 H), 7.11 (t, J = 7.7 Hz, 1 H), 6.85 (t, J = 7.4 Hz, 1 H), 6.77 (d, J = 8.1 Hz, 1 H), 3.78–3.73 (m, 1 H), 3.73 (s, 3 H), 3.27 (dd, J = 15.8, 4.8 Hz, 1 H), 2.97 (dd, J = 15.7, 9.2 Hz, 1 H), 1.23 (d, J = 7.0 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 199.7, 156.9, 137.3, 134.5, 132.8, 128.5, 128.2, 127.2, 126.9, 120.7, 110.6, 55.3, 46.0, 29.6, 19.7.
  • 13 (S)-isomer was assigned by comparison to the reported data in ref. 4b.
  • 14 Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Petersson G. A., Nakatsuji H., Li X., Caricato M., Marenich A. V., Bloino J., Janesko B. G., Gomperts R., Mennucci B., Hratchian H. P., Ortiz J. V. Izmaylov, A. F., Sonnenberg J. L., Williams-Young D., Ding F., Lipparini F., Egidi F., Goings J., Peng B., Petrone A., Henderson T., Ranasinghe D., Zakrzewski V. G., Gao J., Rega N., Zheng G., Liang W., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Vreven T., Throssell K., Montgomery J. A. Jr., Peralta J. E., Ogliaro F., Bearpark M. J., Heyd J. J., Brothers E. N., Kudin K. N., Staroverov V. N., Keith T. A., Kobayashi R., Normand J., Raghavachari K., Rendell A. P., Burant J. C., Iyengar S. S., Tomasi J., Cossi M., Millam J. M., Klene M., Adamo C., Cammi R., Ochterski J. W., Martin R. L., Morokuma K., Farkas O., Foresman J. B., Fox D. J.; Gaussian 16, Revision B.01; Gaussian, Inc., Wallingford CT, 2016
    • 15a Becke AD. J. Chem. Phys. 1993; 98: 5648
    • 15b Lee C, Yang W, Parr RG. Phys. Rev. B: Condens. Matter Mater. Phys. 1988; 37: 785
  • 16 Sugiura M, Ashikari Y, Takahashi Y, Yamaguchi K, Kotani S, Nakajima M. J. Org. Chem. 2019; 84: 11458
  • 17 Kanazawa Y, Tshchiya Y, Kobayashi K, Shiomi T, Itoh J.-I, Kikuchi M, Yamamoto Y, Nishiyama H. Chem. Eur. J. 2006; 12: 63
  • 18 Miaskiewicz S, Reed JH, Donets PA, Oliveira CC, Cramer N. Angew. Chem. Int. Ed. 2018; 57: 4039
  • 19 Yamamoto Y, Kurihara K, Takahashi Y, Miyaura N. Molecules 2013; 18: 14