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Synlett 2004(15): 2809-2811  
DOI: 10.1055/s-2004-835623
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Synthesis of Renieramide

Barry Lygo*, Luke D. Humphreys
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
e-Mail: B.Lygo@Nottingham.ac.uk;
Further Information

Publication History

Received 3 September 2004
Publication Date:
22 October 2004 (online)

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Abstract

A highly chemo- and enantioselective PTC alkylation has been developed that allows rapid access to orthogonally protected (S,S)-isodityrosine. Utility of this material in the construction of isodityrosine-containing cyclic peptides is demonstrated by synthesis of the natural product renieramide.

Key words

amino acids - asymmetric alkylation - phase-transfer ­catalysis - quaternary ammonium salts

10

The enantioselectivity of this alkylation was determined by chiral-phase HPLC comparison of the product 10 with racemic material generated using n-Bu4NBr as the PTC. Use of catalyst 8 led to similar regioselectivity and yield, but gave 10 with only 50% ee.

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Representative Alkylation-Hydrolysis Procedure (Preparation of 12): A solution of glycine imine 4a (161 mg, 0.54 mmol) in toluene (4 mL) was placed under a nitrogen atmosphere. Iodide 11 (312 mg, 0.45 mmol), catalyst 8 (36 mg 10 mol%) and 9 M aq KOH (400 µL) were added sequentially, and the resulting mixture stirred at r.t. for 18 h. The toluene layer was then separated and the aqueous layer extracted with EtOAc (3 × 2 mL). The combined organics were dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in Et2O (10 mL), filtered (to remove catalyst), and again concentrated under reduced pressure. The residue was then dissolved in THF (5 mL) and 15% aq citric acid (1.5 mL) added. The mixture was stirred at r.t. for 18 h, then extracted with CHCl3 (4 × 3 mL). The combined organics were washed with 10% aq Na2CO3 (2 × 4 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CHCl3-MeOH, 50:1) to yield the orthogonally protected isodityrosine 12 (269 mg, 85%) as a pale yellow oil. R f = 0.3 (CHCl3-MeOH, 25:1). [α]D +1 (c 0.9, CHCl3). IR (film): νmax = 3376, 2977, 2632, 1714, 1505 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.34-7.23 (10 H, m, ArH), 7.13 (2 H, d, J = 8.0 Hz, ArH), 6.84 (1 H, s, CHPh2), 6.81 (2 H, d, J = 8.0 Hz, ArH), 6.76 (1 H, d, J = 8.0 Hz, ArH), 6.68 (1 H, d, J = 8.0 Hz, ArH), 6.65 (1 H, s, ArH), 4.97 (1 H, br d, J = 8.0 Hz, NH), 4.68-4.60 (1 H, m, CHN), 3.78 (3 H, s, OCH3), 3.64-3.56 (1 H, m, CHN), 3.04 (1 H, dd, J = 6.0, 14.0 Hz, CHCH a Hb), 2.99-2.95 (2 H, m, CHCHa H b , CHCH a Hb), 2.82 (1 H, dd, J = 8.0, 14.0 Hz, CHCHa H b ), 1.44 [9 H, s, C(CH3)3], 1.40 [9 H, s, C(CH3)3]. 13C NMR (125 MHz, CDCl3): δ = 174.2 (C), 170.9 (C), 156.9 (C), 155.0 (C), 150.0 (C), 144.6 (C), 139.6 (C), 139.4 (C), 131.3 (C), 130.5 (CH), 128.6 (CH), 128.5 (CH), 128.2 (CH), 128.0 (CH), 127.5 (CH), 127.0 (CH), 125.7 (CH), 122.4 (CH), 116.9 (CH), 112.8 (CH), 81.3 (C), 80.0 (C), 78.0 (CH), 56.3 (CH), 56.0 (CH3), 54.5 (CH), 40.3 (CH2), 37.4 (CH2), 28.3 (CH3), 28.1 (CH3). MS (ES+): m/z (%) = 719 (28) [M + Na+], 697 (100) [M + H+], 641 (10) [M - t-Bu + H+], 296 (68). HRMS: m/z calcd for C41H49N2O8 [M + H]+: 697.3489. Found: 697.3528.

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Selected data for synthetic renieramide (2): Mp 185-195 °C (decomp). [α]D -32 (c 0.1, MeOH) (lit. [α]D -30 (c 0.1, MeOH).6 1H NMR (500 MHz, CD3OD): δ = 7.42 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 7.20 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 7.01 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 6.86 (1 H, dd, J = 2.5, 8.0 Hz, ArH), 6.81 (1 H, d, J = 8.0 Hz, ArH), 6.65 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 5.98 (1 H, d, J = 2.0 Hz, ArH), 4.52 (1 H, dd, J = 3.5, 11.5 Hz, CHN), 4.48 (1 H, dd, J = 3.5, 12.5 Hz, CHN), 3.97 (1 H, dd, J = 2.0, 6.0 Hz, CHN), 3.38 (1 H, dd, J = 3.5, 13.0 Hz, CHCH a Hb), 3.15 (1 H, dd, J = 2.0, 15.0 Hz, CHCH a Hb), 2.91 (1 H, dd, J = 6.0, 15.0 Hz, CHCHa H b ), 2.60 (1 H, app. t, J = 12.5 Hz, CHCHa H b ) 1.70-1.62 [2 H, m, CH 2 CH(CH3)2], 1.61-1.51 [1 H, m, CH2CH(CH3)2], 0.95 (3 H, d, J = 6.0 Hz, CH3), 0.93 (3 H, d, J = 6.0 Hz, CH3). 13C NMR (125 MHz, CD3OD): δ = 178.1 (C), 172.7 (C), 169.1 (C), 154.6 (C), 149.8 (C), 147.2 (C), 137.1 (C), 133.0 (CH), 131.7 (CH), 125.0 (2 × CH), 123.1 (CH), 122.7 (CH), 117.2 (CH), 116.9 (CH), 58.1 (CH), 53.7 (CH), 52.1 (CH), 43.6 (CH2), 40.9 (CH2), 37.4 (CH2), 26.0 (CH), 23.8 (CH3), 21.6 (CH3).

18

There is a typographical error in the 13C NMR (CD3OD) reported for natural renieramide,6 the CH2 carbon of the l-DOPA fragment occurs at δ = 37.7 ppm (not 43.6). We thank Prof. R. Riccio and Dr. A. Casapullo for kindly providing this information.