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Synlett 2009(3): 466-468  
DOI: 10.1055/s-0028-1087548
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of l-3-Hydroxy-4-methoxy-5-methylphenylalanol

Nicolas Demoulin, Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax: +33(1)69077247; e-Mail: zhu@icsn.cnrs-gif.fr;
Further Information

Publication History

Received 17 October 2008
Publication Date:
21 January 2009 (online)

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Abstract

The l-3-hydroxy-4-methoxy-5-methylphenylalanol, a common subunit of ecteinascidin and safracin family alkaloids, was synthesized from l-tyrosine in eight steps with an overall yield of 50%.

Key words

amino acid - amino alcohol - Friedel-Crafts reaction - Suzuki-Miyaura reaction

    References and Notes

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13

Conversion of 6 into 8 by Suzuki-Miyaura Reaction
To a solution of the iodoester (6, 250 mg, 0.49 mmol), K2CO3 (138 mg, 1 mmol, 2 equiv), Pd(PPh3)4 (56 mg, 0.05 mmol, 0.1 equiv), and BHT (15 mg, 0.05 mmol, 0.1 equiv) in degassed dioxane (2.0 mL), TMB (204 µL, 184 mg, 1.5 equiv) was added dropwise under argon. After being heated at 100 ˚C under microwave conditions for 2 h (Microwave heating with a Discover microwave reactor from CEM. Irradiation power: 20 W; ramp time: 5 min, 100 ˚C), the mixture was filtered over Celite and purified by flash column chromatography (heptane-EtOAc, 9:1 to 7:3) to afford the desired product 8 (172 mg, 0.42 mmol, 85%) as a yellow oil; [α]D ²8.4 +43 (c 2.0, CHCl3). IR: 3340, 2950, 1715, 1697, 1681, 1518, 1435, 1354, 1257, 1213, 1177, 1058, 1003, 738, 697 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.20-7.37 (m, 5 H), 7.16 (d, J = 2.2 Hz, 1 H), 7.04 (d, J = 2.2 Hz, 1 H), 5.22 (br d, J = 7.9 Hz, 1 H), 5.10 (d, J = 12.2 Hz, 1 H), 5.05 (d, J = 12.2 Hz, 1 H), 4.60 (br m, 1 H), 3.67-3.73 (m, 6 H), 3.07 (dd, J = 14.0, 5.3 Hz, 1 H), 2.99 (dd, J = 14.0, 6.1 Hz, 1 H), 2.57 (s, 3 H), 2.24 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 200.6, 171.8, 157.0, 155.6, 135.8, 133.2, 132.4, 128.6, 128.3, 128.1, 67.0, 61.8, 54.8, 52.4, 37.4, 30.5, 16.1. MS (ESI+, MeOH): m/z = 422.1 [M + Na]+. HRMS (ESI+, MeOH): m/z [M + Na]+ calcd for C22H25NO6Na: 422.1580; found: 422.1570.

16

Conversion of 8 into 9 by Baeyer-Villiger Oxidation
To a solution of the accetophenone (8, 40.0 mg, 1.0 mmol) in CH2Cl2 (1 mL), MCPBA (70%; 50 mg, 2.0 mmol, 2.0 equiv) was added. After being stirred at r.t. for 5 d, the reaction mixture was diluted with aq Na2CO3 and extracted with CH2Cl2. The combined extracts were washed with aq Na2CO3, brine and dried (Na2SO4). Evaporation of the volatile under reduced pressure afforded the desired acetate 9 (35.7 mg, 86%) as a pale yellow oil; [α]D ²8.4 +37 (c 1.0, CHCl3). IR: 3332, 2950, 1715 (br), 1519, 1493, 1435, 1230, 1199, 1045, 1004, 738, 697 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.20-7.37 (m, 5 H), 6.78 (br s, 1 H), 6.66 (br s, 1 H), 5.49 (br d, J = 8.0 Hz, 1 H), 5.10 (d, J = 12.2 Hz, 1 H), 5.04 (d, J = 12.2 Hz, 1 H), 4.58 (br m, 1 H), 3.69 (s, 3 H), 3.62 and 3.67 (rotamers, 3 H), 3.01 (dd, J = 14.1, 5.8 Hz,
1 H), 2.94 (dd, J = 14.1, 6.6 Hz, 1 H), 2.20 (s, 3 H), 2.25 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 172.0, 169.0, 155.6, 149.0, 143.6, 136.4, 133.7, 131.7, 129.4, 128.5, 128.1, 128.0, 121.7, 67.0, 60.5, 54.9, 52.3, 37.4, 20.8, 16.0. MS (ESI+, MeOH): m/z = 438.1 [M + Na]+. HRMS (ESI+, MeOH): m/z [M + Na]+ calcd for C22H25NO7Na: 438.1529; found: 438.1488.

19

Conversion of 10 into 1 by Hydrogenolysis
To a solution of the amino alcohol 10 (3.8 g, 11.0 mmol) in anhyd MeOH (60 mL), Pd/C (400 mg) was added. The mixture was degassed and flushed several times with H2. The reaction was stirred at r.t. under H2 for 2 h. Filtration over Celite and concentration under vacuum gave the final product 1 (2.3 g, 100%) as a pale yellow oil; [α]D ²7.4 -15 (c 1.0, MeOH). IR: 3346, 2928, 1585, 1435, 1316, 1216, 1142, 1047, 1000, 860, 822 cm-¹. ¹H NMR (300 MHz, CD3OD):
δ = 6.56 (d, J = 2.0 Hz, 1 H), 6.49 (d, J = 2.0 Hz, 1 H), 3.69 (s, 3 H), 3.56 (dd, J = 11.1, 4.0 Hz, 1 H), 3.39 (dd, J = 11.1, 6.7 Hz, 1 H), 3.12 (br m, 1 H), 2.65 (dd, J = 13.6, 6.8 Hz, 1 H), 2.52 (dd, J = 13.6, 7.2 Hz, 1 H), 2.17 (s, 3 H). ¹³C NMR (75 MHz, CD3OD): δ = 149.8, 144.8, 133.3, 131.5, 122.1, 114.7, 63.2, 59.1, 54.2, 37.1, 14.7. MS (ESI+, MeOH):
m/z = 212.1 [M + H]+, 234.1 [M + Na]+. HRMS (ESI+, MeOH): m/z [M + Na]+ calcd for C22H25NO7Na: 234.1106; found: 234.1101.

21

On a fifty-gram scale, we used Stille coupling for the conversion of 6 into 8 due to the price difference between tetramethyltin (Aldrich: 50 mL, 145 ı) and trimethyl-boroxine (Aldrich: 5 g, 116 ı). The overall yield in this case is about 41%.