Enantioselective Synthesis of Difluoroalkylated Isoindolinones via Chiral Spirocyclic Phosphoric Acid Catalyzed Mannich-Type Reaction

Abstract

An enantioselective Mannich-type reaction of in situ generated cyclic ketimines with difluoroenoxysilanes catalyzed by chiral spirocyclic phosphoric acid has been developed. This methodology provides a facile route to difluoroalkyl-substituted chiral isoindolinones bearing a quaternary stereogenic center in high yields and up to 96% enantioselectivity.

Key words

enantioselective synthesis - Mannich-type reaction - chiral spirocyclic phosphoric acid - isoindolinone - difluoroenoxysilane

Publikationsverlauf

Eingereicht: 03. September 2020

Angenommen nach Revision: 29. September 2020

Accepted Manuscript online:
29. September 2020

Artikel online veröffentlicht:
02. November 2020

• References and Notes


For recent reviews, see:
• 1a Mikami K, Itoh Y, Yamanaka M. Chem. Rev. 2004; 104: 1
• 1b Ma J.-A, Cahard D. Chem. Rev. 2004; 104: 6119
• 1c O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
• 1d Zhang C.-P, Chen Q.-Y, Guo Y, Xiao J.-C, Gu Y.-C. Chem. Soc. Rev. 2012; 41: 4536
• 1e Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 1f Ma J.-A, Li S. Org. Chem. Front. 2014; 1: 712
• 1g Yang X, Wu T, Phipps RJ, Toste FD. Chem. Rev. 2015; 115: 826
• 1h Champagne PA, Desroches J, Hamel JD, Vandamme M, Paquin JF. Chem. Rev. 2015; 115: 9073
• 2a Erickson JA, McLoughlin JI. J. Org. Chem. 1995; 60: 1626
• 2b Jakeman DL, Ivory AJ, Williamson MP, Blackburn GM. J. Med. Chem. 1998; 41: 4439
• 2c Liu Y.-L, Yu J.-S, Zhou J. Asian J. Org. Chem. 2013; 2: 194
• 2d Ni C, Hu J. Chem. Soc. Rev. 2016; 45: 5441
• 3a Amii H, Kobayashi T, Hatamoto Y, Uneyama K. Chem. Commun. 1999; 1323
• 3b Schenck HA, Lenkowski PW, Choudhury-Mukherjee I, Ko S.-H, Stables JP, Patel MJ, Brown ML. Bioorg. Med. Chem. 2004; 12: 979
• 3c Decostanzi M, Campagne J.-M, Leclerc E. Org. Biomol. Chem. 2015; 13: 7351
• 3d Hu X.-S, Yu J.-S, Zhou J. Chem. Commun. 2019; 55: 13638
• 4a Hook DF, Gessier F, Noti C, Kast P, Seebach D. ChemBioChem 2004; 5: 691
• 4b Niida A, Tomita K, Mizumoto M, Tanigaki H, Terada T, Oishi S, Otaka A, Inui K, Fujii N. Org. Lett. 2006; 8: 613
• 4c Boyer N, Gloanec P, Nanteuil GD, Jubaulta P, Quiriona JC. Tetrahedron 2007; 63: 12352
• 4d Chu L, Zhang X, Qing F.-L. Org. Lett. 2009; 11: 2197
• 4e Poisson T, Belhomme MC, Pannecoucke X. J. Org. Chem. 2012; 77: 9277
• 4f Liu Y.-L, Zhou J. Chem. Commun. 2012; 48: 1919
• 4g Yu J.-S, Liu Y.-L, Tang J, Wang X, Zhou J. Angew. Chem. Int. Ed. 2014; 53: 9512
• 4h Yu J.-S, Zhou J. Org. Biomol. Chem. 2015; 13: 10968
• 4i Yu J.-S, Liao F.-M, Gao W.-M, Liao K, Zuo R.-L, Zhou J. Angew. Chem. Int. Ed. 2015; 54: 7381
• 4j Wu Y.-B, Lu G.-P, Zhou B.-J, Bu M.-J, Wan L, Cai C. Chem. Commun. 2016; 52: 5965
• 4k Huang X, Zhang Y, Zhang C, Zhang L, Xu Y, Kong L, Wang Z.-X, Peng B. Angew. Chem. Int. Ed. 2019; 58: 5956
• 4l Hu X.-S, Ding P.-G, Yu J.-S, Zhou J. Org. Chem. Front. 2019; 6: 2500
• 4m Gao X, Chen R, Xiao Y.-L, Wan X.-L, Zhang X. Chem. 2019; 5: 2987
• 5a Yuan Z, Wei Y, Shi M. Chin. J. Chem. 2010; 28: 1709
• 5b Yuan Z, Mei L, Wei Y, Shi M, Kattamuri PV, McDowell P, Li G. Org. Biomol. Chem. 2012; 10: 2509
• 6 Kashikura W, Mori K, Akiyama T. Org. Lett. 2011; 13: 1860
• 7 Yu J.-S, Zhou J. Org. Chem. Front. 2016; 3: 298
• 8 Li J.-S, Liu Y.-J, Zhang G.-W, Ma J.-A. Org. Lett. 2017; 19: 6364
• 9a Blasko G, Gula DJ, Shamma M. J. Nat. Prod. 1982; 45: 105
• 9b Ferland J.-M, Demerson CA, Humber LG. Can. J. Chem. 1985; 63: 361
• 9c Maier L, Diel PJ. Phosphorus, Sulfur Silicon Relat. Elem. 1991; 57: 57
• 9d De Clercq E. J. Med. Chem. 1995; 38: 2491
• 9e Anzini M, Cappelli A, Vomero S, Giorgi G, Langer T, Bruni G, Romeo MR, Basile AS. J. Med. Chem. 1996; 39: 4275
• 9f Taylor EC, Zhou P, Jennings LD, Mao Z, Hu B, Jun J.-G. Tetrahedron Lett. 1997; 38: 521
• 9g Gotor V, Limeres F, García R, Bayod M, Brieva R. Tetrahedron: Asymmetry 1997; 8: 995
• 9h Zhuang Z.-P, Kung MP, Mu M, Kung H.-F. J. Med. Chem. 1998; 41: 157
• 9i Belliotti TR, Brink WA, Kesten SR, Rubin JR, Wustrow DJ, Zoski KT, Whetzel SZ, Corbin AE, Pugsley TA, Heffner TG, Wise LD. Bioorg. Med. Chem. Lett. 1998; 8: 1499
• 10a Yu X, Wang Y, Wu G, Song H, Zhou Z, Tang C. Eur. J. Org. Chem. 2011; 3060
• 10b Nishimura T, Noishiki A, Tsui GC, Hayashi T. J. Am. Chem. Soc. 2012; 134: 5056
• 10c Chen M.-W, Chen Q.-A, Duan Y, Ye Z.-S, Zhou Y.-G. Chem. Commun. 2012; 48: 1698
• 10d Nishimura T, Noishiki A, Ebe Y, Hayashi T. Angew. Chem. Int. Ed. 2013; 52: 1777
• 10e Zhou J.-Q, Sheng W.-J, Jia J.-H, Ye Q, Gao J.-R, Jia Y.-X. Tetrahedron Lett. 2013; 54: 3082
• 10f Nagamoto M, Yamauchi D, Nishimura T. Chem. Commun. 2016; 52: 5876
• 10g Suć J, Dokli I, Gredičak M. Chem. Commun. 2016; 52: 2071
• 10h Suneja A, Unhale RA, Singh VK. Org. Lett. 2017; 19: 476
• 10i Unhale RA, Molleti N, Rana NK, Dhanasekaran S, Bhandary S, Singh VK. Tetrahedron Lett. 2017; 58: 145
• 10j Zhou B, Li K, Jiang C, Lu Y, Hayashi T. Adv. Synth. Catal. 2017; 359: 1969
• 10k Glavač D, Gredičak M. Synlett 2017; 28: 889
• 10l Glavač D, Zheng C, Dokli I, You S.-L, Gredičak M. J. Org. Chem. 2017; 82: 8752
• 10m Unhale RA, Sadhu MM, Ray SK, Biswas RG, Singh VK. Chem. Commun. 2018; 54: 3516
• 10n Zhang L, Wu B, Chen Z, Hu J, Zeng X, Zhong G. Chem. Commun. 2018; 54: 9230
• 10o Kang Z, Zhang D, Shou J, Hu W. Org. Lett. 2018; 20: 983
• 10p Feng F.-F, Li J.-S, Li S, Ma J.-A. Adv. Synth. Catal. 2019; 361: 4222
• 11a Munoz SB, Krishnamurti V, Barrio P, Mathew T, Prakash GK. S. Org. Lett. 2018; 20: 1042
• 11b Barrio P, Ibáñez I, Herrera L, Román R, Catalán S, Fustero S. Chem. Eur. J. 2015; 21: 11579

For recent examples by this group, see:
• 12a Xu F, Huang D, Han C, Shen W, Lin X, Wang Y. J. Org. Chem. 2010; 75: 8677
• 12b Xu F, Huang D, Lin X, Wang Y. Org. Biomol. Chem. 2012; 10: 4467
• 12c Huang D, Xu F, Lin X, Wang Y. Chem. Eur. J. 2012; 18: 3148
• 12d Li X, Zhao Y, Qu H, Mao Z, Lin X. Chem. Commun. 2013; 49: 1401
• 12e Huang D, Li X, Xu F, Li L, Lin X. ACS Catal. 2013; 3: 2244
• 12f Shen X, Wang Y, Wu T, Mao Z, Lin X. Chem. Eur. J. 2015; 21: 9039
• 12g Lou H, Wang Y, Jin E, Lin X. J. Org. Chem. 2016; 81: 2019
• 12h Xie E, Rahman A, Lin X. Org. Chem. Front. 2017; 4: 1407
• 12i Rahman A, Xie E, Lin X. Org. Biomol. Chem. 2018; 16: 1367
• 12j Wang L, Zhong J, Lin X. Angew. Chem. Int. Ed. 2019; 58: 15824
• 12k Luo J, Zhang T, Wang L, Liao G, Yao Q.-J, Wu Y.-J, Zhan B.-B, Lan Y, Lin X.-F, Shi B.-F. Angew. Chem. Int. Ed. 2019; 58: 6708
• 12l Zhan B.-B, Wang L, Luo J, Lin X.-F, Shi B.-F. Angew. Chem. Int. Ed. 2020; 59: 3568

For recent a review by this group, see:
• 12m Rahman A, Lin X. Org. Biomol. Chem. 2018; 16: 4753

For selected examples by other groups, see:
• 13a Čorić I, Müller S, List B. J. Am. Chem. Soc. 2010; 132: 17370
• 13b Müller S, Webber MJ, List B. J. Am. Chem. Soc. 2011; 133: 18534
• 13c Xu B, Zhu S.-F, Xie X.-L, Shen J.-J, Zhou Q.-L. Angew. Chem. Int. Ed. 2011; 50: 11483
• 13d Chen Z.-L, Wang B.-L, Wang Z.-B, Zhu G.-Y, Sun J.-W. Angew. Chem. Int. Ed. 2013; 52: 2027
• 13e Wu J, Wang Y.-M, Drljevic A, Rauniyar V, Phipps RJ, Toste FD. Natl. Acad. Sci. U.S.A. 2013; 110: 13729
• 13f Wang S.-G, You S.-L. Angew. Chem. Int. Ed. 2014; 53: 2194
• 13g Zhang Y, Zhao J, Jiang F, Sun S, Shi F. Angew. Chem. Int. Ed. 2014; 53: 13912
• 13h Gobé V, Guinchard X. Chem. Eur. J. 2015; 21: 8511
• 13i Rong Z, Zhang Y, Chua RH. B, Pan H, Zhao Y. J. Am. Chem. Soc. 2015; 137: 4944
• 13j Rubush DM, Morges MA, Rose BJ, Thamm DH, Rovis T. J. Am. Chem. Soc. 2012; 134: 13554
• 13k Li S, Zhang J.-W, Li X.-L, Cheng D.-J, Tan B. J. Am. Chem. Soc. 2016; 138: 16561
• 13l Lin J, Dong X, Li T, Jiang N, Tan B, Liu X. J. Am. Chem. Soc. 2016; 138: 9357
• 13m Zhu G, Bao G, Li Y, Sun W, Li J, Hong L, Wang R. Angew. Chem. Int. Ed. 2017; 56: 5332
• 13n Lin J.-S, Wang F.-L, Dong X.-Y, He W.-W, Yuan Y, Chen S, Liu X.-Y. Nat. Commun. 2017; 8: 14841
• 13o Wang F.-L, Dong X.-Y, Lin J.-S, Zeng Y, Jiao G.-Y, Gu Q.-S, Guo X.-Q, Ma C.-L, Liu X.-Y. Chem. 2017; 3: 979
• 13p Zhang L, Zhang J, Ma J, Cheng D.-J, Tan B. J. Am. Chem. Soc. 2017; 139: 1714
• 13q Qian D, Chen M, Bissember AC, Sun J. Angew. Chem. Int. Ed. 2018; 57: 3763
• 13r Zhang J.-W, Xu J.-H, Cheng D.-J, Shi C, Liu X.-Y, Tan B. Nat. Chem. 2018; 10: 58
• 13s Li J.-T, Kong M, Qiao B.-K, Lee R, Zhao X.-W, Jiang Z.-Y. Nat. Commun. 2018; 9: 2445
• 13t Zhang J, Yu P.-Y, Li S.-Y, Sun H, Xiang S.-H, Wang J, Houk KN, Tan B. Science 2018; 361: eaas8707
• 13u Lin J.-S, Li T.-T, Liu J.-R, Jiao G.-Y, Gu Q.-S, Cheng J.-T, Guo Y.-L, Hong X, Liu X.-Y. J. Am. Chem. Soc. 2019; 141: 1074
• 14a Akiyama T, Itoh J, Yokota K, Fuchibe K. Angew. Chem. Int. Ed. 2004; 43: 1566
• 14b Uraguchi D, Terada M. J. Am. Chem. Soc. 2004; 126: 5356

For recent reviews, see:
• 14c Akiyama T, Itoh J, Fuchibe K. Adv. Synth. Catal. 2006; 348: 999
• 14d Akiyama T. Chem. Rev. 2007; 107: 5744
• 14e Terada M. Chem. Commun. 2008; 4097
• 14f Adair G, Mukherjee S, List B. Aldrichimica Acta 2008; 41: 31
• 14g You S.-L, Cai Q, Zeng M. Chem. Soc. Rev. 2009; 38: 2190
• 14h Terada M. Synthesis 2010; 1929
• 14i Rueping M, Kuenkel A, Atodiresei I. Chem. Soc. Rev. 2011; 40: 4539
• 14j Parmar D, Sugiono E, Raja S, Rueping M. Chem. Rev. 2014; 114: 9047
• 15 General Procedure for the Reaction of 3-Hydroxyisoindolin-1-ones 1 with Difluoroenoxysilanes 2 To a mixture of 3-hydroxyisoindolin-1-ones 1 (0.05 mmol) and catalyst (S)-4e (0.005 mmol, 10 mol%) in toluene (0.5 mL) was added difluoroenoxysilanes 2 (0.1 mmol, 2 equiv). After stirring at 0 °C for 48 h, the residue was then purified by flash column chromatography with ethyl acetate/petroleum ether (1:4, v/v) on silica gel to give the desired product 3. 3-(1,1-Difluoro-2-oxo-2-phenylethyl)-3-phenylisoindolin-1-one (3a) White solid; mp 167–169 °C; 87% yield; 92% ee, determined by HPLC (Daicel Chiralcel OD-H column (250 × 4.6 mm), n-hexane/i-PrOH = 80:20, 0.8 mL/min, 254 nm; t _major = 8.176 min, t _minor = 7.063 min); [α]_D ²⁰ +143.2 (c 0.34, CH₂Cl₂). ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.03 (s, 1 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.87–7.78 (m, 4 H), 7.71–7.39 (m, 9 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 188.19 (dd, J = 30.8, 27.6 Hz), 168.95, 143.52 (d, J = 3.8 Hz), 135.59, 134.49, 132.64, 132.37, 131.53, 129.67, 128.74, 128.56, 127.01, 125.69, 123.17, 120.12, 117.46, 114.84, 68.39 (t, J = 25.8 Hz). ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –99.44 (d, J = 268.9 Hz, 1 F), –102.12 (d, J = 268.9 Hz, 1 F). IR (film): ν = 3432, 3054, 2970, 1701, 1266, 739, 704 cm^–1. HRMS (EI-TOF): m/z calcd for C₂₂H₁₅F₂NO₂: 363.1071; found: 363.1071.
• 16 Procedure for the 2 mmol Scale Reaction To a mixture of 3-hydroxyisoindolin-1-one 1a (450 mg, 2.0 mmol) and catalyst (S)-4e (0.2 mmol, 10 mol%) in toluene (40 mL) was added difluoroenoxysilane 2e (1.22 g, 4.0 mmol, 2 equiv). After stirring at 0 °C for 72 h, the solvent was removed under vacuo. The residue was then purified by flash column chromatography with ethyl acetate/petroleum ether (1:4, v/v) on silica gel to give the desired product 3q in 62% yield with 90% ee. Recovery of catalyst 4e was achieved after acidification of the relevant fractions as described previously (122 mg, 92%).
• 17 Procedure for the Synthetic Transformation of 3j To a solution of 3j (0.15 mmol, 95% ee) in THF (2.0 mL) was added NaOH (0.3 mmol, 2.0 equiv) at room temperature. The mixture was stirred until full consumption of 3j for 7 h, and then quenched by water, followed by extraction using DCM, and then dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with ethyl acetate/petrolem ether, 1:2) to afford 6 as white solid. 3-(Difluoromethyl)-3-(m-tolyl)isoindolin-1-one (6) White solid; mp 165–168 °C; 99% yield; 95% ee, determined by HPLC (Daicel Chiralcel AD-H column (250 × 4.6 mm), n-hexane/i-PrOH = 70:30, 0.8 mL/min, 254 nm; t _major = 10.131 min, t _minor = 6.871 min); [α]_D ²⁰ +156.2 (c 0.46, CH₂Cl₂). ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.69 (s, 1 H), 7.76 (dd, J = 16.8, 7.5 Hz, 2 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.57 (t, J = 7.3 Hz, 1 H), 7.48 (s, 2 H), 7.32 (t, J = 7.9 Hz, 1 H), 7.19 (d, J = 7.3 Hz, 1 H), 6.96 (t, J = 54.4 Hz, 1 H), 2.32 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.37, 144.38, 138.05, 136.41, 132.30, 131.63, 129.42, 129.01, 128.68, 126.58, 123.97, 123.28 (d, J = 8.7 Hz), 117.81, 115.36, 112.91, 67.54, 21.11. ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –125.16 (d, J = 273.4 Hz, 1 F), –127.96 (d, J = 273.4 Hz, 1 F). IR (film): ν = 3427, 3199, 3054, 2986, 1707, 1265, 1075, 741, 705 cm^–1. HRMS (EI-TOF): m/z calcd for C₁₆H₁₃F₂NO 273.0965; found: 273.0966. Procedure for the Synthetic Transformation of 3q A solution of benzyl bromide (0.24 mmol) in DMF (2.0 mL) was cooled to 0 °C. The mixture was charged with portion wise addition of NaH (0.24 mmol) at the same temperature. To the reaction mixture was then slowly added a cooled (0 °C) solution of 3q (0.2 mmol) in DMF (2.0 mL). Reaction mixture was allowed to stir for 3 h at room temperature. Upon completion of the reaction, the mixture was quenched with saturated aqueous NH₄Cl solution, and the solvent was removed in vacuo. The resulting aqueous solution was extracted with DCM, and then dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with ethyl acetate/petrolem ether, 1:50) to afford 7 as colorless oil. 2-Benzyl-3-[2-(4-bromophenyl)-1,1-difluoro-2-oxoethyl]-3-phenylisoindolin-1-one (7) Colorless oil; 88% yield; 94% ee, determined by HPLC (Daicel Chiralcel OD-H column (250 × 4.6 mm), n-hexane/i-PrOH = 99:1, 0.8 mL/min, 254 nm; t _major = 8.990 min, t _minor = 10.179 min); [α]_D ²⁰ +73.0 (c 0.33, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.07 (d, J = 7.7 Hz, 1 H), 7.97 (d, J = 7.8 Hz, 2 H), 7.92–7.82 (m, 2 H), 7.60–7.39 (m, 5 H), 7.38–7.26 (m, 8 H), 5.38 (d, J = 12.2 Hz, 1 H), 5.13 (d, J = 12.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.05, 151.94, 149.30, 137.34, 135.83, 134.27, 131.61, 130.93, 130.24, 129.88, 129.76, 129.61, 129.47, 129.40, 126.95, 122.55, 71.68. ¹⁹F NMR (376 MHz, CDCl₃): δ = –101.67, –102.34, –103.19, –103.85. IR (film): ν = 3054, 2985, 1695, 1624, 1575, 1351, 1265, 739, 704, 440 cm^–1. HRMS (EI-TOF): m/z calcd for C₂₉H₂₀BrF₂NO₂: 531.0645; found: 531.0641.
• 18a Ge S.-Z, Chaładaj W, Hartwig JF. J. Am. Chem. Soc. 2014; 136: 4149
• 18b Wu Y.-B, Lu G.-P, Zhou B.-J, Bu M.-J, Wan L, Cai C. Chem. Commun. 2016; 52: 5965
• 19 Banik SM, Medley JW, Jacobsen EN. Science 2016; 353: 51