Synlett 2012; 23(18): 2687-2691
DOI: 10.1055/s-0032-1317382
letter
© Georg Thieme Verlag Stuttgart · New York

One-Pot Enantioselective Synthesis of Tryptophan Derivatives via Phase-Transfer Catalytic Alkylation of Glycine Using a Cinchona-Derived Catalyst

Robert Todd
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211-3029, USA   Fax: +1(920)2295530   Email: [email protected]
,
Matthew Huisman
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211-3029, USA   Fax: +1(920)2295530   Email: [email protected]
,
Nazim Uddin
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211-3029, USA   Fax: +1(920)2295530   Email: [email protected]
,
Sarah Oehm
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211-3029, USA   Fax: +1(920)2295530   Email: [email protected]
,
M. Mahmun Hossain*
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211-3029, USA   Fax: +1(920)2295530   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 12 July 2012

Accepted after revision: 18 September 2012

Publication Date:
18 October 2012 (online)


Abstract

Tryptophans are building blocks for many natural products. This paper describes the enantiospecific synthesis of ring-A substituted tryptophan derivatives from commercially available gramines using chiral phase-transfer conditions. This one-pot reaction avoids protecting/deprotecting the indolylic nitrogen of gramine by choosing a chemoselective quaternization reagent, 4-(trifluoro-methoxy)benzyl bromide, to produce an electrophilic salt intermediate, which is subsequently alkylated in good yield with high enantiomeric excess.

Supporting Information

 
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  • 8 Synthesis of tert-Butyl 2-(Diphenylmethyleneamino)-3-(1H-indol-3-yl)propanoate (Scheme 6; Compound 5a); Typical Procedure: To a solution of gramine (0.300 g, 1.7 mmol, 1 equiv) in CH2Cl2 (10 mL) was added 4-(trifluoromethoxy)benzyl bromide (0.430 g, 1.7 mmol, 1 equiv) and the mixture was stirred for 30 min. N-(Diphenylmethylene)glycine tert-butyl ester (0.502 g, 1.7 mmol, 1 equiv) and O-allyl-N-(9-anthracenylmethyl)cinchoninium bromide (0.209 g, 0.3 mmol, 0.2 equiv) were added to the solution. The reaction mixture was then cooled to –30 °C. While stirring, solid KOH (2.0 g, 36 mmol, 20 equiv) and deionized H2O (0.2 mL, 11.1 mmol, 6 equiv) were added to the reaction mixture, which was stirred for an additional 12 h at –30 °C. The reaction mixture was concentrated by rotary evaporation and the products were isolated by column chromatography (silica gel; EtOAc–pentane, 10%) providing 5a (0.580 g, 80% yield) as a yellow oil. The identity of 5a was confirmed by comparing its spectra to those of 1H NMR spectra from authentic samples.9 tert-Butyl 2-(Diphenylmethyleneamino)-3-(5-methoxy-1H-indol-3-yl)propanoate (Scheme 6 ; Compound 8): 1H NMR (300 MHz, CDCl3): δ = 8.19 (s, 1 H), 7.59 (d, J = 7.9 Hz, 2 H), 7.27–7.43 (m, 4 H), 7.15–7.20 (m, 3 H), 6.93 (s, 1 H), 6.78–6.83 (m, 2 H), 6.61 (d, J = 7.5 Hz, 2 H), 4.33 (dd, J = 8.7, 4.5 Hz, 1 H), 3.69 (s, 3 H), 3.44 (dd, J = 14.1, 4.5 Hz, 1 H), 3.30 (dd, J = 14.1, 8.7 Hz, 1 H), 1.47 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ = 171.4, 170.1, 153.6, 139.6, 136.1, 131.1, 130.0, 128.7, 128.3, 128.0, 127.9, 127.6, 124.0, 112.0, 111.8, 111.6, 100.5, 81.0, 66.6, 55.7, 45.2, 29.3, 28.0. HRMS: m/z [M + H]+ calcd. for C29H30N2O3: 455.2335; found: 455.2353. tert-Butyl 2-(Diphenylmethyleneamino)-3-(6-methoxy-1H-indol-3-yl)propanoate (Scheme 6; Compound 9): 1H NMR (300 MHz, CDCl3): δ = 8.39 (s, 1 H), 7.63–7.71 (d, J = 7.9 Hz, 2 H), 7.28–7.41 (m, 4 H), 7.18–7.25 (m, 3 H), 6.84 (d, J = 2.4 Hz, 2 H), 6.67–6.80 (m, 3 H), 4.36 (dd, J = 8.4, 4.8 Hz, 1 H), 3.82 (s 3 H), 3.46 (dd, J = 14.1, 4.8 Hz, 1 H), 3.27 (dd, J = 14.1, 8.4 Hz, 1 H), 1.48 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ = 171.5, 170.2, 156.1, 139.6, 136.7, 136.2, 130.1, 128.7, 128.1, 128.0, 127.9, 127.6, 122.0, 119.4, 111.7, 109.0, 94.4, 80.9, 66.8, 55.6, 45.2, 29.4, 28.0. HRMS: m/z [M + H]+ calcd. for C29H30N2O3: 455.2335; found: 455.2349. tert-Butyl 3-(5-Bromo-1H-indol-3-yl)-2-(diphenyl-methyleneamino)propanoate (Scheme 6; Compound 10): 1H NMR (300 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.80–7.90 (d, J = 7.9 Hz, 2 H), 7.60–7.70 (m, 3 H), 7.18–7.41 (m, 9 H), 7.00 (s, 1 H), 6.65 (d, J = 3.32 Hz, 2 H), 4.24 (dd, J = 8.4, 4.8 Hz, 1 H), 3.36 (dd, J = 14.1, 4.8 Hz, 1 H), 3.21 (dd, J = 14.1, 8.4 Hz, 1 H), 1.45 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ = 171.0, 170.2, 135.9, 134.5, 130.0, 129.9, 128.6, 128.3, 128.2, 128.0, 127.9, 127.4, 124.4, 124.3, 121.6, 112.4, 112.2, 112.0, 81.0, 66.4, 28.9, 28.0. HRMS: m/z [M + H]+ calcd. for C28H27BrN2O2: 503.1334; found: 503.1297.
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