LETTER
Synthesis of Lysergic Acid Methyl Ester
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(4) (a) Kornfeld, E. C.; Fornefeld, E. J.; Kline, G. B.; Mann,
M. J.; Morrison, D. E.; Jones, R. G.; Woodward, R. B. J. Am.
Chem. Soc. 1956, 78, 3087. (b) Julia, M.; Goffic, F. L.;
Igolen, J.; Baillarge, M. Tetrahedron Lett. 1969, 20, 1569.
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Suppl. 1981, 37, 157. (d) Oppolzer, W.; Francotte, E.;
Battig, K. Helv. Chim. Acta 1981, 64, 478. (e) Rebek, J. Jr.;
Tai, D. F.; Shue, Y. K. J. Am. Chem. Soc. 1984, 106, 1813.
(f) Ninomiya, I.; Hashimoto, C.; Kiguchi, T.; Naito, T.
J. Chem. Soc., Perkin Trans. 1 1985, 941. (g) Kurihara, T.;
Terada, T.; Yoneda, R. Chem. Pharm. Bull. 1986, 34, 442.
(h) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
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amination and Heck reaction quite smoothly to furnish the
desired tetracyclic ergoline skeleton 18 in good yield.13
Having successfully constructed the tetracyclic ergoline
skeleton, we then executed the functional group manipu-
lations. After deprotection of the TBDPS group in 18,
stepwise oxidation of the resulting alcohol to carboxylic
acid followed by treatment with diazomethane gave meth-
yl ester 19. Indoline moiety was then converted into in-
dole by removal of the Boc group and the subsequent
oxidation with benzeneselenic anhydride in the presence
of indole.14 For smooth migration of the C8–C9 double
bond to C9–C10 position, deprotection of the methyl car-
bamate and protection of the two nitrogen atoms with Boc
groups were necessary at this stage. The double bond
migration4d,15 of the di-Boc compound 21 was effected by
treatment with DBU to afford 22 as a mixture of diastereo-
mers.4f Finally, stepwise deprotection of the both Boc
groups and reductive methylation of the dehydropiperi-
dine furnished lysergic acid methyl ester (23) as a mixture
of diastereomers, whose spectroscopic data were identical
to those reported in the literature.4k Since a mixture of 23
and 8-epi-23 has been converted into (+)-lysergic acid (1)
with epimerization of 8-epi-23,4k a formal total synthesis
of (+)-lysergic acid was achieved.
(j) Hendrickson, J. B.; Wang, J. Org. Lett. 2004, 6, 3.
(k) Moldvai, I.; Temesvári-Major, E.; Incze, M.;
Szentirmay, E.; Gács-Baitz, E.; Szántay, C. J. Org. Chem.
2004, 69, 5993.
(5) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron
1996, 52, 7525.
(6) For a palladium-mediated formation of the C-ring, see ref. 3e.
(7) (a) Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama,
T. J. Am. Chem. Soc. 2003, 125, 6630. (b) Okano, K.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2006, 128,
7136. (c) Okano, K.; Tokuyama, H.; Fukuyama, T. Chem.
Asian J. 2008, 3, 296.
(8) For an example of lipase PS mediated desymmetrization of
diol 9, see: Danieli, B.; Lesma, G.; Macecchini, S.;
Passarella, D.; Silvani, A. Tetrahedron: Asymmetry 1999,
10, 4057.
In conclusion, we have achieved an asymmetric synthesis
of (+)-lysergic acid methyl ester featuring highly diastereo-
seleticive allylation reaction and the efficient palladium-
mediated double-cyclization strategy.
(9) (a) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301.
(b) For a review, see: Kan, T.; Fukuyama, T. Chem.
Commun. 2004, 353.
(10) Mitsunobu, O. Synthesis 1981, 1.
(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):
[a]D24 –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): d = 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): d = 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.
Acknowledgment
This work was financially supported in part by Grant-in-Aid from
The Ministry of Education, Culture, Sports, Science, and Technolo-
gy, Japan.
References and Notes
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2000, 1.
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Synlett 2009, No. 5, 775–778 © Thieme Stuttgart · New York