Download PDF
Synlett 2009(5): 775-778  
DOI: 10.1055/s-0028-1087948
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Lysergic Acid Methyl Ester via the Double Cyclization Strategy

Toshiki Kurokawaa, Minetaka Isomuraa, Hidetoshi Tokuyamaa,b, Tohru Fukuyama*a
a Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax: +81(3)58028694; e-Mail: fukuyama@mol.f.u-tokyo.ac.jp;
b Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Further Information

Publication History

Received 19 December 2008
Publication Date:
24 February 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

An asymmetric synthesis of (+)-lysergic acid methyl ­ester was accomplished through construction of the tetracyclic ­ergoline skeleton by double cyclization consisting of intramolecular aromatic amination and Heck reaction.

Key words

allylations - aminations - Heck reaction - tandem reaction - alkaloids

6

For a palladium-mediated formation of the C-ring, see ref. 3e.

11

Synthesis of Compound 13: To a solution of 12 (663.0 mg, 1.389 mmol) in toluene (15 mL) was added allyltri-methylsilane (0.33 mL, 2.08 mmol) at -78 ˚C. To this solution was added SnCl4 (0.19 mL, 1.67 mmol) for 5 min at -78 ˚C. After completion, the reaction was quenched by addition of sat. NaHCO3, and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to give the crude product, which was used in the next step without further purification. To a solution of crude product in MeOH (15 mL) and CH2Cl2 (15 mL) was added K2CO3 and stirred at r.t. After completion of the reaction, H2O was added to the reaction mixture, and the resulting solution was extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. Purification of the residue by flash chromatography (n-hexane-EtOAc, 1:1) afforded the title compound 13 (407.9 mg, 87% in 2 steps): [α]D ²4 -343 (c 0.95, CHCl3). IR (film): 3563, 3421, 2929, 1543, 1373, 1337, 1165, 1138, 1028, 925, 852, 781, 746, 678 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.08-8.12 (m, 1 H), 7.64-7.74 (m, 3 H), 5.82 (dd, J = 10.6, 3.2 Hz, 1 H), 5.77 (dd, J = 10.6, 4.8 Hz, 1H), 5.53-5.64 (m, 1 H), 4.92 (ddd, J = 17.2, 1.2, 1.2 Hz, 1 H), 4.86 (dd, J = 10.0, 0.8 Hz, 1 H), 4.37-4.44 (br m, 1 H), 4.09 (d, J = 14.4 Hz, 1 H), 3.53 (ddd, J = 17.6, 11.2, 6.0 Hz, 1 H), 3.30-3.37 (m, 2 H), 2.19-2.35 (m, 3 H), 2.04 (t, J = 1.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 146.9, 134.6, 133.5, 133.2, 131.7, 131.0, 129.1, 125.5, 124.3, 118.2, 61.9, 53.9, 40.2, 38.7, 37.6. HRMS-FAB: m/z calcd for C15H35NO3Si [M+]: 338.0936; found: 338.0919.

13

Synthesis of Compound 18: To a stirred solution of 17 (44.1 mg, 0.055 mmol) in EtCN (0.94 mL) was added successively Cs2CO3 (26.9 mg, 0.082 mg), Pd(OAc)2 (3.7 mg, 0.0017 mmol), and Ph3P (10.8 mg, 0.041 mmol). The reaction mixture was evacuated and quickly backfilled with argon for several times. Et3N (23 µL, 0.165 mmol) was added to this solution, then allowed to warm to 110 ˚C, and the mixture was stirred for an additional 1 h. The reaction mixture was cooled to r.t. and filtrated through a pad of Celite. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by PTLC (n-hexane-EtOAc, 4:1) to give 18 (24.6 mg, 70%) as a mixture of diastereomers.
The more polar diastereomer: [α]D ²4 -56 (c 0.59, CHCl3).
IR (film): 3047, 2931, 2857, 1704, 1616, 1456, 1390, 1354, 1238, 1170, 1113, 1082, 1006, 910, 737, 702, 615 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 6.4 Hz, 4 H), 7.24-7.44 (m, 7 H), 7.16 (br m, 1 H), 6.80 (br dd, J = 7.6, 4.0 Hz, 1 H), 5.45 (br d, J = 7.6 Hz, 1 H), 4.79 and 4.63 (br s each, 1 H), 4.42 and 4.32 (d each, J = 18.2 Hz, 1 H), 4.24 (br s, 1 H), 4.07 (s, 2 H), 3.76 (s, 3 H), 3.67 (br s, 1 H), 3.48 (br d, J = 18.2 Hz, 1 H), 3.32-3.43 (br m, 2 H), 1.90 (br m, 1 H), 1.50-1.68 (br m, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 156.1, 152.6, 135.6, 135.5, 132.3, 131.8, 129.7, 129.7, 128.6, 127.6, 127.6, 125.0, 121.0, 112.2, 81.6, 65.7, 55.1, 52.8, 49.7, 40.0, 36.5, 36.1, 28.4, 27.4, 26.8, 19.2. HRMS-FAB: m/z calcd for C38H46N2O5Si [M+]: 638.3176; found: 638.3162. The less polar diastereomer: [α]D ²4 -47 (c 0.25, CHCl3).
IR (film): 3052, 2930, 2857, 1700, 1623, 1449, 1390, 1351, 1310, 1237, 1163, 1137, 1113, 998, 910, 824, 789, 737, 702, 615 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.57-7.68 (m, 4 H), 7.30-7.44 (m, 7 H), 7.14 (dd, J = 7.2, 7.2 Hz, 1 H), 6.78 (d, J = 7.2 Hz, 1 H), 5.36 (s, 1 H), 4.77 (br s, 1 H), 4.10 (s, 2 H), 4.04-4.60 (br m, 2 H), 3.73 (s, 3 H), 3.68-3.77 (br m, 1 H), 3.65 (br s, 1 H), 3.41 (br s, 1 H), 3.21 (quintet-like, J = 9.2 Hz, 1 H), 1.94-2.11, 1.76-1.88, and 1.46-1.70 (br m each, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 156.0, 152.7, 135.6, 135.5, 134.4, 133.2, 132.2, 129.7, 128.7, 128.4, 127.6, 122.7, 120.4, 113.0, 80.5, 65.6, 56.3, 52.7, 47.8, 40.0, 38.7, 32.4, 31.9, 28.4, 26.8, 19.2. HRMS-FAB: m/z calcd for C38H46N2O5Si [M+]: 638.3176; found: 638.3146.