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

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%.

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

References and Notes

Total synthesis:

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Formal total synthesis:

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Other synthetic approaches:

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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.

14 For a recent example from our group showing the distinct difference of thermal and microwave-assisted Suzuki-Miyaura reaction, see: Lépine R. Zhu J. Org. Lett.  2005,  7:  2981 

15 Chen C. Zhu Y.-F. Wilcoxen K. J. Org. Chem.  2000,  65:  2574 

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.

17 Bovicelli P. Antonioletti R. Barontini M. Borioni G. Bernini R. Mincione E. Tetrahedron Lett.  2005,  46:  1255 

18 Guzmán JA. Mendoza V. García E. Garibay CF. Olivares LZ. Maldonado LA. Synth. Commun.  1995,  25:  2121 

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.

We found that addition of BHT led to more reproducible results on this coupling reaction; BHT may suppress the oxidation of palladium species by adventurous oxygen and extend consequently the catalytic cycle. See:

20a McKean DR. Parrinello G. Renaldo AF. Stille JK. J. Org. Chem.  1987,  52:  422 

20b Cooper CB. MacFarland JW. Blair KT. Fontaine EH. Jones CS. Muzzi ML. Bioorg. Med. Chem. Lett.  1994,  4:  835 

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%.