A New Synthesis of Lysergic Acid

Article abstract of DOI:10.1021/ol0354369

(Equation presented) (±)-Lysergic acid (1) has been synthesized via an economical 8-step route from 4-bromoindole and isocinchomeronic acid without the need to protect the indole during the synthesis. Initial efforts to form the simpler 3-acylindole derivatives first and then cyclize these were unsuccessful in the cyclization step.

Full text of DOI:10.1021/ol0354369

ORGANIC
LETTERS
2
004
Vol. 6, No. 1
-5
A New Synthesis of Lysergic Acid
3
James B. Hendrickson* and Jian Wang
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
hendrickson@brandeis.edu
Received July 30, 2003
ABSTRACT
(±)-Lysergic acid (1) has been synthesized via an economical 8-step route from 4-bromoindole and isocinchomeronic acid without the need
to protect the indole during the synthesis. Initial efforts to form the simpler 3-acylindole derivatives first and then cyclize these were unsuccessful
in the cyclization step.
The ergot alkaloids pose an unusual opportunity for synthesis.
as indole starting materials reduced and acylated, only at
the end reconstituted to the indole form. To eliminate this
redundancy we decided that the indole should be carried
through intact.
The simplest convergent bondset for assembling the
lysergic skeleton should be the boldface bonds in ring C,
which just arise from indole and nicotinic acid starting
materials. No previous syntheses had utilized this approach
except the Julia route, which did not carry the indole moiety
through unchanged.
The central alkaloids are all amides of lysergic acid (1) and
1-3
all possess a broad range of pharmacological activity. Only
one of these, the diethylamide (LSD), however, is strongly
and notoriously psychoactive. As such it is listed as a class
I controlled substance. Since both the natural and synthetic
derivatives are easily convertible to lysergic acid and so to
its diethylamide, all of these are also controlled substances.
As a result this potential pharmacological treasure is es-
sentially unavailable for practical clinical testing.
We considered that a derivative of lysergic acid bearing
an unremoveable substituent, like an added C-alkyl group,
could not be converted to lysergic acid itself or its amide.
Such derivatives would probably retain the broad pharma-
cological activity of the ergot family but might easily avoid
the unique hallucinogenic property of LSD. This idea
encouraged us to seek a short, practical synthesis route to
lysergic acid suitable for incorporation of C-alkyl starting
materials to create these derivatives.
Of the two initial constructions necessary for the bondset
in Figure 1 we began with the simplest (bond b) via an
Lysergic acid has already been synthesized about eight
4
times. The shortest path has 11 steps and none are serious
candidates for practical manufacture. Every synthesis to date
contains redundant protection/deprotection sequences, often
Figure 1. Bondset of lysergic acid synthesis.
(
1) Hofmann, A. Ergot Alkaloids, Pharmacology; Spano, P. F., Trabucchi,
5
M., Eds.; Karger: Basel, Switzerland, 1978; Vol. 16, Supp. 1, p 1.
acylation of indole or 4-haloindoles 2 with the acid chloride
3
(2) Lemberger, L. Fed. Proc. 1978, 37, 2176.
from the commercially available 6-carboxynicotinic acid
(
3) Berde, D.; Schild, O. Handbook of Experimental Pharmacology;
Springer Verlag: Berlin, Germany, 1978; Vol. 49, p 1.
(isocinchomeronic acid), as outlined in Scheme 1. The acid
1
0.1021/ol0354369 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/10/2003

Scheme 1. Attempt via Bondset ba Approacha
Scheme 2. Synthesis of Lysergic Acid via Bondset ab
Approacha
a
2 2
Reagents: (i) EMgBr/ZnCl /Et O.
a
Reagents: (i) Pd(PPh
EtOH; (iii) MnO /CHCl
CH Cl ; (vi) MeI/CH Cl ; (vii) NaBH
4
3
)
4
/Na
; (iv) NaOH/MeOH; (v) NaBH
/MeOH; (viii) NaOH /EtOH.
2
CO
3
(aq)/EtOH; (ii) NaBH
4
/CaCl
2
/
was esterified, selectively hydrolyzed only at the 6-position6
with aqueous Cu(NO , and converted (SOCl ) to 3. The
2
3
4
/TFA/
3
)
2
2
2
2
2
2
Grignard reagents from 2 were acylated with 3 to form 4.
However, a number of attempts at palladium-catalyzed
cyclizations of 4 (X ) Br or I) or reduced pyridine
derivatives of 4 and their N-methyl salts were all unsuccess-
ful.
forming the normal, nonplanar p-chloro intermediate in
Figure 2, which can then collapse via the pericyclic rear-
We also considered that a thermal pericyclic cyclization
of the anion 5 of 4 might be accessible with subsequent loss
of HX to form 6, but several trials of this at elevated
temperatures, with or without added base, led only to
intractable tars.
The alternative path to close ring C, making bond a first,
was ultimately successful, as summarized in Scheme 2. For
this approach we needed a nicotinic acid derivative with a
halogen marking the 5-position.
The common introduction of halogen on pyridines, via
7
SOCl
2
on the N-oxide, provides only the ortho/para halides.
8
Figure 2. Proposed mechanism for formation of 7.
However, sulfonyl halides can give rise to meta substitution
and the reaction of the N-oxide of 6-carboxynicotinic acid
9
with thionyl chloride affords the m-chloro derivative 7 on
workup with methanol. We believe this results from first
rangement shown and subsequent loss of the p-chloride to
afford 7.
When the 4-haloindoles 2 were converted to the boronic
acid 8 (via KH + BuLi and B(OBu) ), the Suzuki coupling
3
was successful in forming 9a in 91% yield. While this work
(
4) (a) Kornfeld, E. A.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.;
Morrison, D. E.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1956,
8, 3087. (b) Julia, M.; LeGoffic, F.; Igolen, J.; Baillarge, M. Tetrahedron
7
Lett. 1969, 20, 1569. (c) Armstrong, V. W.; Coulton, S.; Ramage, R.
Tetrahedron Lett. 1976, 47, 4311. Ramage, R.; Armstrong, V. W.; Coulton,
S. Tetrahedron 1981, 9 (Suppl.), 157. (d) Oppolzer, W.; Francotte, E.;
Baettig, K. HelV. Chim. Acta 1981, 64 (2), 478. (e) Rebek, J., Jr.; Tai, D.
F. Tetrahedron Lett. 1983, 24 (9), 859. Rebek, J., Jr.; Tai, D. F.; Shue,Y.
K. J. Am. Chem. Soc. 1984, 106 (6), 1813. (f) Kurihara, T; Terada, T.;
Yoneda, R. Chem. Pharm. Bull. 1986, 34 (1), 442. Kurihara, T.; Terada,
T.; Harusawa, S.; Yoneda, R. Chem. Pharm. Bull. 1987, 35 (12), 4793. (g)
Kiguchi, T.; Hashimoto, C.; Naito, T.; Ninomyia, I. Heterocycles 1982, 19
was in progress, a closely related reaction appeared in a note
10
by Doll coupling 8 with 5-bromonicotinic ester, but the
subsequent addition of the missing carbon 4 for lysergic acid
failed.
We presumed that an appropriate base would easily initiate
the cyclization of the diester 9a to the tetracyclic ketone
corresponding to 10. However, treatment of the diester with
NaH, even in glycol at 197 °C, yielded only starting material.
A number of attempts to cyclize the corresponding, very
(
12), 2279. Ninomyia, I.; Hashimoto, C.; Kiguchi, T; Naito, T. J. Chem.
Soc., Perkin Trans. 1 1985, 941. (h) Cacchi, S.; Ciattini, P. G.; Morera, E.;
Ortar, G. Tetrahedron Lett. 1988, 29 (25), 3117.
(
(
(
5) Somei, M.; Kizu, K. Chem. Pharm. Bull. 1985, 33, 3696.
6) Ooi, G. K. S.; Magee, R. J. J. Inorg. Nucl. Chem. 1970, 32, 3315.
7) Joule, J. A.; Miller, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Science: Oxford, UK, 2000; p 100
8) Katritzky, A. R.; Lagowski, J. M. The Chemistry of the Pyridine
N-Oxides; Academic Press: New York, 1971; p 288.
(9) Quarroz, D. Swiss Patent CH 657,124, 1986; Chem. Abstr. 1987,
106, 32852.
(10) Doll, M. K.-H. J. Org. Chem. 1999, 64, 1372.
(
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Org. Lett., Vol. 6, No. 1, 2004

1
insoluble diacid with thionyl chloride or variants of PPA led
only to recovery of diacid or intractable mixtures with no
evidence of cyclization.
The H NMR spectra of the mixed esters were identical
with spectra kindly provided by Prof. Ichiya Ninomiya, and
1
13
the NMR spectra ( H and C) of the lysergic acid agreed
with that of a natural sample kindly provided by Dr. David
Nichols.
Following a similar but intermolecular version from
Potier11 we reduced the ester selectively12 with NaBH
and
to 9b and then oxidized it to the aldehyde 9c with
. The aldehyde cyclized at room temperature easily
4
CaCl
MnO
2
The last three operations (10 to 1) are carried out easily
in good yield without isolation and purification; this result
lends value to the initial conception in Figure 1 that the most
economical synthesis of lysergic acid is one that originates
in the two main starting materials, a simple indole and a
nicotinic acid derivative, both retaining their aromaticity to
the very end. This synthesis comprises eight steps from
isocinchomeronic acid and 4-bromoindole and proceeds in
an unoptimized overall yield of 10.6%. Chirality is only
introduced in the final reduction step, and enantioselective
measures for this reduction have not yet been examined, nor
has the parallel synthesis of C-alkyl derivatives.
2
and quantitatively with only 2 mol % of NaOH to yield 10.
Various efforts to cyclize the alcohol 9b or its tosylate to
11 all recovered only starting materials. The difference in
the ease of cyclization of 9c over its precursors surprised us
but we became convinced from models that there was severe
steric resistance to the stereoelectronic demands for cycliza-
tion except for the aldehyde case.
13
4
Typical reduction of the indole-alcohol 10 with NaBH /
TFA afforded 11, which proved to be unstable, decomposing
in a matter of hours. Accordingly, the remaining steps were
carried through without isolation. Freshly prepared 11 was
methylated directly with methyl iodide and the crude salt
1
4
2 reduced with excess NaBH in methanol to a mixture of
Acknowledgment. We thank Dr. Toby Sommer at
Brandeis University for his constant help and inspiring
discussion, Brandeis University for financial support of this
study, Prof. Ninomiya at Kobe Pharmaceutical University,
Japan for the comparison of NMR spectra and Dr. David
Nichols at Purdue University for a natural sample.
methyl lysergate and its cis-isomer isolysergate in a 6:1 ratio,
as a pale yellow solid.
These diastereomers are reported to be somewhat un-
14
stable and so were immediately hydrolyzed to lysergic acid
with NaOH, which also equilibrated them to the more stable
lysergic acid, which was then finally recrystallized to mp
241-242 °C (lit. 242-243 °C).
(
(
(
11) Potier, P.; Langlois, Y. Tetrahedron 1975, 31, 419.
12) Matsumoto, I.; Yoshizawa, J. Japanese Patent JP 48029783, 1973.
13) Gribble, G. W.; Nutaitis, C. F. Org. Prep. Proced. Int. 1985, 17,
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
3
17.
14) (a) Glenn, A. L. Quart. ReV. 1954, 8, 192. (b) Stoll, A.; Petrzilka,
T. HelV. Chim. Acta 1953, 36, 1125.
(
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