Enantioenriched Naphthoquinone Mannich Bases by Organocatalyzed Nucleophilic Additions to in situ Formed Imines

Abstract

Organocatalytic nucleophilic addition of 2-hydroxylnaphthaquinone to imines is reported. This new route can be used to produce enantioenriched Mannich bases with excellent yields and moderate enantioselectivities.

organocatalysis - enantioselective Mannich reaction - 1,4-addition - α-amidosulfone - naphthoquinone

References and Notes

Some late reviews on organocatalysis:

1a Gaunt MJ. Johansson CCC. McNally A. Vo NT. Drug Discovery Today  2007,  12:  8 

1b Bertelsen S. Jørgensen KA. Chem. Soc. Rev.  2009,  38:  2178 

1c Rios R. Cordova A. Curr. Opin. Drug Discovery Dev.  2009,  12:  824 

1d Liu XH. Lin LL. Feng XM. Chem. Commun.  2009,  6145 

1e Xu LW. Luo J. Lu YX. Chem. Commun.  2009,  1807 

1f Zhang ZG. Schreiner PR. Chem. Soc. Rev.  2009,  38:  1187 

1g Connon SJ. Synlett  2009,  354 

2a Mase N. Tanaka F. Barbas CF. Angew. Chem. Int. Ed.  2004,  43:  2420 

2b Northrup AB. MacMillan DWC. Science  2004,  305:  1752 

2c Wang J. Li H. Zu LS. Wang W. Adv. Synth. Catal.  2006,  348:  425 

2d Enders D. Seki A. Synlett  2002,  26 

2e List B. J. Am. Chem. Soc.  2000,  122:  9336 

2f Brochu MP. Brown SP. MacMillan DWC. J. Am. Chem. Soc.  2004,  126:  4108 

2g Bertelsen S. Halland SN. Stephan B. Marigo M. Braunton A. Jørgensen KA. Chem. Commun.  2005,  4821 

2h Westermann B. Neuhaus C. Angew. Chem. Int. Ed.  2005,  44:  4077 

2i Clapham B. Cho CW. Janda KD. J. Org. Chem.  2001,  66:  868 

3a Ye J. Dixon DJ. Hynes PS. Chem. Commun.  2005,  4481 

3b Chen Y. Tian SK. Deng L. J. Am. Chem. Soc.  2000,  122:  9542 

4a Uraguchi D. Terada M. J. Am. Chem. Soc.  2004,  126:  5356 

4b Storer RI. Carrera DE. Ni Y. MacMillan DWC. J. Am. Chem. Soc.  2006,  128:  84 

4c Rueping M. Sugiono E. Azap C. Theissmann T. Bolte M. Org. Lett.  2005,  7:  3781 

4d Akiyama T. Morita H. Itoh J. Fuchibe K. Org. Lett.  2005,  7:  2583 

4e Wang J. Li H. Yu X.-H. Zu L.-S. Wang W. Org. Lett.  2005,  7:  4293 

5a Yoon TP. Jacobsen EN. Angew. Chem. Int. Ed.  2005,  44:  466 

5b Okino T. Nakamura S. Furukawa T. Takemoto Y. Org. Lett.  2004,  6:  625 

5c Berkessel A. Cleemann F. Mukherjee S. Müller TN. Lex J. Angew. Chem. Int. Ed.  2005,  44:  807 

5d Hoashi Y. Okino T. Takemoto Y. Angew. Chem. Int. Ed.  2005,  44:  4032 

5e Okino T. Hoashi Y. Furukawa T. Xu X. Takemoto Y. J. Am. Chem. Soc.  2005,  127:  119 

5f Berkessel A. Mukherjee S. Mueller TN. Cleemann F. Roland K. Brandenburg M. Neudoerfl JM. Lex J. Org. Biomol. Chem.  2006,  4:  4319 

6 Okino T. Hoashi Y. Takemoto Y. J. Am. Chem. Soc.  2003,  125:  12672 

7 Zhou WM. Liu H. Du DM. Org. Lett.  2008,  10:  2817 

8 Kamei H. Koide T. Kojima T. Hashimoto Y. Hasegawa M. Cancer Biother. Radiopharm.  1998,  13:  185 

9a Kayashima T. Mori M. Yoshida H. Mizushina K. Matsubara K. Cancer Lett.  2009,  278:  34 

9b Zhao LM. Xiw TP. He YQ. Xu DF. Li SS. Eur. J. Med. Chem.  2009,  1410 

10a Bolognesi ML. Lizzi F. Perozzo R. Brun R. Cavalli A. Bioorg. Med. Chem. Lett.  2008,  18:  2272 

10b Baramee A. Coppin A. Mortuaire M. Pelinski L. Tomavo S. Brocard J. Bioorg. Med. Chem.  2006,  14:  1294 

11 Austin JF. Kim SG. Sinz CJ. Xiao WJ. MacMillan DWC. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5482 

12

Under the same set of conditions, an attempt to carry out the reaction with benzaldehyde-derived α-amidosulfone (Cbz protected) and 1 resulted in 90% yield, however, enantioselectivity of the product was only 22%.

13

General Procedure for Addition of Hydroxynaphthoquinone to in situ Formed Imines In a 4 mL process vial α-amidosulfone (0.1 mmol),
2-hydroxy-1,4-naphthoquinone (1, 0.11 mmol), and catalyst (10 mol%) were dissolved in solvent (0.5 mL). The reaction was allowed to stir at r.t. (except where mentioned otherwise) for 24 h. Completion of the reaction was monitored by TLC after which the reaction mixture was directly subjected to column chromatography (CH₂Cl₂-MeOH = 99.5:0.5). The products were dissolved in freshly distilled THF (4-5 mL), and Et₃N (1.1 equiv) was added. After stirring the reaction mixture at r.t. for 5 min, it was cooled to 0 ˚C and acetyl chloride (1.2 equiv) was added slowly. The reaction mixture was stirred at the same temperature for another 30 min after which the product was filtered and concentrated under reduced pressure. Purification of the product was done by column chromatog-raphy (n-hexane-EtOAc = 90:10). The ee values for all the products were determined by HPLC on a chiral stationary phase [Daicel Chiralpak AD-H, n-hexane-i-PrOH (80:20), flow rate = 1.0 mL/min, λ = 254 nm].
3-(1-{[(Benzyloxy)carbonyl]amino}hexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl Acetate (5a) Yellow oil; yield 40.8 mg (91%); [α]_D ^²0 25.5 (c 0.38, CH₂Cl₂); ee 65%. ^¹H NMR (300 MHz, CDCl₃-d): δ = 0.86 (t, J = 6.60 Hz, 3 H), 1.20-1.46 (m, 5 H), 1.60-1.79 (m, 2 H), 1.80-1.97 (m, 1 H), 2.44 (s, 3 H), 4.96-5.20 (m, 3 H), 5.79 (d, J = 9.54 Hz, 1 H), 7.22-7.40 (m, 5 H), 7.66-7.79 (m, 2 H), 8.00-8.14 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃-d): δ = 13.9, 20.4, 22.4, 25.8, 31.3, 34.5, 47.8, 66.9, 126.7, 128.1, 128.5, 130.7, 132.0, 134.1, 134.3, 136.3, 136.5, 150.7, 155.8, 167.8, 177.9, 185.1. ESI-MS: m/z (%) = 472.5 (100) [M + Na]⁺. t _R(major) = 8.7 min; t _R(minor) = 14.9 min.
3-(1-{[(Benzyloxy)carbonyl]amino}ethyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl Acetate (5b) Yellow oil; yield 36.2 mg (92%); [α]_D ^²0 10.8 (c 0.95, CH₂Cl₂); ee 42%. ^¹H NMR (300 MHz, CDCl₃-d): δ = 1.49 (d, J = 6.95 Hz, 3 H), 2.45 (s, 3 H), 4.86-5.36 (m, 3 H), 5.90 (d, J = 9.51 Hz, 1 H), 7.28-7.42 (m, 5 H), 7.67-7.83 (m, 2 H), 8.08 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃-d): δ = 20.4, 20.6, 43.6, 66.9, 126.7, 128.1, 128.5, 130.6, 132.0, 134.1, 134.4, 136.2, 137.1, 150.1, 155.5, 167.9, 178.1, 184.9. ESI-MS: m/z (%) = 416.4 (100) [M + Na]⁺. t _R(major) = 10.9 min; t _R(minor) = 12.9 min.
3-{1-[( tert -Butoxycarbonyl)amino]hexyl}-1,4-dioxo-1,4-dihydronaphthalen-2-yl Acetate (12) Yellow oil; yield 27.8 mg (67%); [α]_D ^²0 7.2 (c 0.41, CH₂Cl₂); ee 33%. ^¹H NMR (300 MHz, CDCl₃-d): δ = 0.84 (t, J = 6.80 Hz, 3 H), 1.36 (m, 6 H), 1.40 (s, 9 H), 1.36-1.40 (m, 2 H), 2.42 (s, 3 H), 5.05 (m, 1 H), 5.49 (d, J = 9.57 Hz, 1 H), 7.78 (m, 2 H), 8.08 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃-d): δ = 13.9, 20.4, 22.4, 25.8, 28.3, 30.5, 31.3, 34.8, 47.2, 79.6, 126.7, 130.7, 132.0, 134.0, 134.3, 137.0, 150.6, 155.2, 167.8, 178.1. ESI-MS: m/z (%) = 438.4 (100) [M + Na]⁺. t _R(major) = 4.7 min; t _R(minor) = 6.0 min.
3-(1-{[(4-Methylphenyl)sulfonyl]amino}hexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl Acetate (13) Yellow oil; yield 41.7 mg (89%); [α]_D ^²0 -13.7 (c 0.34, CH₂Cl₂); ee -31%. ^¹H NMR (300 MHz, CDCl₃-d): δ = 0.82-0.92 (m, 3 H), 1.17-1.51 (m, 3 H), 1.55-1.68 (m, 4 H), 1.88 (dt, J = 9.17, 4.59 Hz, 1 H), 1.93 (s, 3 H), 2.43 (s, 3 H), 4.54 (d, J = 7.34 Hz, 1 H), 5.73 (br s, 1 H), 6.86 (d, J = 7.70 Hz, 2 H), 7.55 (d, J = 8.07 Hz, 2 H), 7.67-7.77 (m, 2 H), 7.83-7.91 (m, 1 H), 7.93-8.01 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃-d): δ = 13.9, 20.4, 20.9, 22.3, 25.5, 31.0, 34.8, 50.7, 126.4, 126.6, 127.5, 129.4, 130.3, 131.7, 134.2, 137.1, 143.3, 150.9, 167.5, 176.9. ESI-MS: m/z (%) = 492.3 (100) [M + Na]⁺. t _R(major) = 11.9 min; t _R(minor) = 16.3 min.