ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Total Synthesis of Lysergic Acid
Satoshi Umezaki,† Satoshi Yokoshima,‡ and Tohru Fukuyama*,‡
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Graduate School of Pharmaceutical Sciences,
Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
Received July 10, 2013
ABSTRACT
A total synthesis of lysergic acid was accomplished. Key features of our synthesis include stereoselective construction of the stereogenic centers
at the allylic positions by using the Evans aldol reaction, and a sequential process with a ring-closing metathesis and an intramolecular Heck
reaction to construct the C and D rings.
Lysergic acid (1) is a compound obtained by alkaline
hydrolysis of ergot alkaloids. Ergot alkaloids are a class of
pharmacologicallyimportantnatural products thatexhibit
a wide spectrum of biological activities.1 These molecules
have long been the targets of numerous synthetic studies
because they have a unique tetracyclic ergoline skeleton
containing a tetrahydropyridineand a [cd]-fused indole. As
a result, a variety of total syntheses and synthetic studies
toward lysergic acid and the related ergot alkaloids have
been reported to date.2 Our own synthetic studies toward
lysergic acid feature an intramolecular Heck reaction to
construct the C ring.3 In addition, the stereochemistry of the
D ring unit must be controlled to carry out the crucial Heck
reaction. Herein we disclose an efficient construction of the
D-ring unit by means of an Evans aldol reaction and
subsequent completion of the total synthesis of lysergic acid.
Our retrosynthesis is shown in Scheme 1. Lysergic acid
would be derived from 2 via an intramolecular Heck
reaction. The tetrahydropyridine ring in 2 could be formed
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† University of Tokyo.
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(k) Moldvai, I.; Temesvari-Major, E.; Incze, M.; Szentirmay, E.; Gacs-
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‡ Nagoya University.
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Baitz, E.; Szantay, C. J. Org. Chem. 2004, 69, 5993. (l) Inuki, S.; Oishi, S.;
(1) (a) Ninomiya, I.; Kiguchi, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, 1990; Vol. 38, pp 1À156. (b) Somei, M.;
Yokoyama, Y.; Murakami, Y.; Ninomiya, I.; Kiguchi, T.; Naito, T. In
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r
10.1021/ol4019562
XXXX American Chemical Society