Synthetic studies toward (+)-lysergic acid: Construction of the tetracyclic ergoline skeleton

Article abstract of DOI:10.3987/COM-08-S(D)42

We have successfully constructed the tetracyclic skeleton of lysergic acid, which features an acylation at the C3 position of the indole as well as an intramolecular Heck reaction. The optically active D ring unit could be derived from L-pyroglutamic acid

Full text of DOI:10.3987/COM-08-S(D)42

HETEROCYCLES, Vol. 79, 2009
373
HETEROCYCLES, Vol. 79, 2009, pp. 373 - 378. © The Japan Institute of Heterocyclic Chemistry
Received, 29th September, 2008, Accepted, 16th January, 2009, Published online, 16th January, 2009.
DOI: 10.3987/COM-08-S(D)42
SYNTHETIC STUDIES TOWARD (+)-LYSERGIC ACID:
CONSTRUCTION OF THE TETRACYCLIC ERGOLINE SKELETON
Tohru Inoue, Satoshi Yokoshima, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Abstract – We have successfully constructed the tetracyclic skeleton of lysergic
acid, which features an acylation at the C3 position of the indole as well as an
intramolecular Heck reaction. The optically active D ring unit could be derived
from L-pyroglutamic acid via a disrotatory electrocyclic reaction of a
dibromocyclopropane.
INTRODUCTION
Ergot alkaloids are biosynthesized by coupling of a variety of amine moieties with a common carboxylic
acid, lysergic acid (1).1 Lysergic acid has attracted a lot of attention because of its unique tetracyclic
structure as well as the interesting biological activities of ergot alkaloids. While numerous synthetic
studies and total syntheses of racemic lysergic acid have been reported to date,2 the first total synthesis of
(+)-lysergic acid was reported in 2004 by Szántay and coworkers, which involves resolution of a racemic
tetracyclic intermediate using (–)-dibenzoyl-L-tartaric acid.3 We have recently achieved the total synthesis
of (+)-lysergic acid methyl ester, featuring an enzymatic desymmetrization of a 1,3-diol, an addition of
2,6-dibromophenyllithium to a nitroalkene, and most notably a palladium-mediated double cyclization.4
While we were successful in the asymmetric synthesis of (+)-lysergic acid methyl ester, we were not
particularly satisfied with the long synthetic route consisting of more than 30 steps. Herein, we report our
HO2C
Me
H
N
N
H
(+)-lysergic acid (1)
Figure 1. Structure of (+)-lysergic acid.

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HETEROCYCLES, Vol. 79, 2009
more recent studies toward the total synthesis of (+)-lysergic acid.
RESULTS AND DISCUSSION
As shown in the retrosynthesis outlined in Scheme 1, the C ring of 1 could be constructed by means of an
intramolecular Heck reaction. For smooth β-H elimination, the D ring should be prepared as a
trans-2,5-disubstituted 1,2,5,6-tetrahydropyridine. Disconnection of 3 at the 3-position of the indole could
lead to indole unit 4 and D-ring unit 5. We envisaged that the tetrahydropyridine moiety of D-ring unit 5
could be derived from L-pyroglutamic acid (7) using an electrocyclic reaction of dibromocyclopropane 6.5
H
MeO2C
MeO2C
H
R
H
HO2C
Me
H
N
N
H
NR
D
H
LnPd
Br
C
N
R
N
H
N
R
1
2
3
Br
Br
H
O
M
MeO2C
NR
H
Br
NR
NH
D
5
+
N
R
CO2H
H
H
X
X
7
6
4
Scheme 1
Our synthesis commenced with the acylation of the known lactam 8, which was derived from L-glutamic
acid (Scheme 2).6 Thus, successive treatment of 8 with LHMDS and CbzCl gave 9 in good yield.
Reduction of 9 with DIBAL and subsequent dehydration of the resulting hemiaminal under slightly acidic
conditions afforded enamide 10. Dibromocyclopropanation of the enamide proceeded smoothly under
1) DIBAL
THF, –78 °C
LHMDS
THF, –78 °C;
Cbz
N
Cbz
N
H
N
O
O
OPiv
OPiv
OPiv
CbzCl
91%
2) CSA, pyridine
toluene, reflux
80% (2 steps)
8
9
10
CHBr3
aq NaOH
BnNEt3Cl
Cbz
Br
Br
NCbz
NCbz
xylene
reflux
N
OPiv
Br
Br
87%
CH2Cl2, rt
84%
H
OPiv
OPiv
11
13
12
Scheme 2

HETEROCYCLES, Vol. 79, 2009
375
biphasic conditions in the presence of a phase-transfer catalyst to furnish dibromocyclopropane 11, which,
upon heating in refluxing xylene, underwent a disrotatory electrocyclic reaction to give directly the
optically active dihydropyridine 13 as a result of the spontaneous deprotonation of the cation 12.
Dihydropyridine 13 was transformed into D-ring unit 18 by way of a seven-step sequence (Scheme 3).
Thus, reduction of 13 with triethylsilane under acidic conditions occurred regioselectively to give 14,
which was then subjected to carbonylation with a palladium catalyst to afford ester 15. Removal of the
Cbz group in the presence of a double bond was achieved using Ritter’s method,7 and subsequent
nosylation of the resulting secondary amine furnished 16. Acidic cleavage of the pivalate ester followed
by Jones oxidation gave carboxylic acid 17,8 which was converted into acid chloride 18 according to
Ghosez’s procedure.9
Pd(PPh3)4
CO (100 psi)
Et3N
Et3SiH
Tf2NH
1) PdCl2, Et3SiH
Et3N, CH2Cl2
Br
Br
MeO2C
NCbz
NCbz
NCbz
AcOH, rt
DMF-MeOH
90 °C
33% (2 steps)
2) NsCl, NaHCO3
CH2Cl2-H2O
72% (2 steps)
OPiv
OPiv
OPiv
13
14
15
NMe2
Cl
Me
1) HCl, MeOH
reflux
MeO2C
MeO2C
MeO2C
NNs
NNs
NNs
Me
OH
Cl
CH2Cl2
rt
2) CrO3, H2SO4
acetone, 0 °C
79% (2 steps)
H
O
H
O
18
OPiv
16
17
Scheme 3
The crucial coupling between the D ring and the indole units was effected by acylation of the magnesium
salt of 4-bromoindole (Scheme 4).10 Thus, deprotonation of 4-bromoindole with ethylmagnesium bromide
and subsequent addition of acid chloride 18 provided coupling product 20 in moderate yield. We next
focused on reduction of the carbonyl functionality. Since a direct reduction of the ketone in 20 could not
be achieved due to the electron-donating nature of the indole nitrogen, an Alloc group was introduced at
the indole nitrogen to activate the carbonyl group. As expected, reduction of the N-Alloc compound
proceeded smoothly to furnish a diastereomeric mixture of secondary alcohol 21. Removal of the Ns
group and subsequent reductive methylation afforded 22.11 After cleavage of the Alloc group,
deoxygenation of the alcohol was achieved with triethylsilane under acidic conditions to give 24.12
After protection of the indole NH with a Boc group, isomerization of the double bond was performed
(Scheme 5). Thus, successive treatment of α,β-unsaturated ester 25 with lithium
2,2,6,6-tetramethylpiperidide (LTMP) and quenching with a bulky phenol, 2,6-di(t-Bu)phenol, furnished
β,γ-unsaturated ester 26 with a 3:1 diastereoselectivity. The diastereomers were separated and each

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HETEROCYCLES, Vol. 79, 2009
isomer was subjected to a Heck reaction. While the attempted Heck reaction of the minor isomer resulted
in the formation of an intractable mixture, the major isomer gave 27, suggesting that the isomerization
afforded the desired trans isomer as the major isomer. Finally, the Boc group was cleaved with
trifluoroacetic acid to give 28,13 which, according to the Oppolzer’s procedure,2e can be transformed into
lysergic acid.
Br
MeO2C
MeO2C
1) AllocCl
Et3N, DMAP
CH2Cl2, 0 °C
NNs
H
NNs
H
N
MeO2C
NNs
19
MgBr
Br
Br
O
OH
Cl
benzene
Et2O, 0 °C
2) NaBH4
H
O
THF-MeOH
–20 °C
58% (2 steps)
N
H
N
Alloc
18
48% (2 steps)
20
21
1) PhSH
MeO2C
MeO2C
MeO2C
Cs2CO3
DMF
0 °C to rt
NMe
H
NMe
H
NMe
H
Pd(PPh3)4
pyrrolidine
Et3SiH
TFA
Br
Br
Br
OH
OH
2) NaBH3CN
aq HCHO
AcOH
THF, rt
CH2Cl2
reflux
N
Alloc
N
H
N
H
MeOH, rt
36% from 21
22
23
24
Scheme 4.
MeO2C
MeO2C
NMe
H
NMe
H
Boc2O
Et3N, DMAP
LTMP, THF
–78 to 0 °C;
Br
Br
2,6-di(t-Bu)phenol
54%
MeCN, 0 °C
92%
N
H
N
Boc
24
25
3:1
H
MeO2C
MeO2C
MeO2C
Pd2(dba)3
P(o-tolyl)3
NaOAc
NMe
NMe
H
NMe
H
H
H
TFA
Br
H
MeCN, reflux
36%
CH2Cl2, rt
82%
N
Boc
N
H
N
Boc
26
27
28
Scheme 5
In summary, we have successfully constructed the tetracyclic ergoline skeleton, which features an
acylation at the C3 position of the indole as well as an intramolecular Heck reaction. The optically active

HETEROCYCLES, Vol. 79, 2009
377
D ring unit was synthesized by a disrotatory electrocyclic reaction of a dibromocyclopropane, which, to
the best of our knowledge, is the first example of an optically active dihydropyridine prepared from
L-pyroglutamic acid.
ACKNOWLEDGEMENTS
This work was financially supported in part by Grant-in-Aids (15109001, 16073205, and 20002004) from
the Ministry of Education, Culture, Sports, Science and Technology of Japan.
REFERENCES AND NOTES
1. For reviews of ergot alkaloids, see: (a) A. Stoll and A. Hofmann, ‘The Alkaloids,’ Vol. 8, ed. by R. H.
F. Manske, Academic Press, Inc., NewYork, 1965, pp. 725-783; (b) P. A. Stadler and P. Stütz, ‘The
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Alkaloids,’ Vol. 63, ed. by G. A. Cordell, Academic Press, Inc., New York, 2006, pp. 45-86.
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Woodward, J. Am. Chem. Soc., 1956, 78, 3087; (b) M. Julia, F. L. Goffic, J. Igolen, and M. Baillarge,
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37, 157; (e) W. Oppolzer, E. Francotte, and K. Battig, Helv. Chim. Acta, 1981, 64, 478; (f) J. Rebek,
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Yoneda, Chem. Pharm. Bull., 1986, 34, 442; (i) S. Cacchi, P. G. Ciattini, E. Morera, and G. Ortar,
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HETEROCYCLES, Vol. 79, 2009
6. B. Felix, de M. Pedro, F. Marta, F. Josep, G. Timothy, and M. Sergio, Tetrahedron: Asymmetry,
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24
8. 17: [α]D +7.46 (c 0.44, CHCl3); IR (film) 1718, 1544, 1439, 1370, 1281, 1168, 1120, 1095, 1062,
1
762 cm—1; H NMR (CDCl3, 400 MHz) δ 8.09-8.12 (m, 1H), 7.58-7.75 (m, 3H), 7.00 (br s, 1H),
4.99 (t, J = 3.2 Hz, 1H), 4.31 (d, J = 15.6 Hz, 1H), 4.11 (d, J = 15.6 Hz, 1H), 3.75 (s, 3H), 2.86 (br s,
13
2H); C NMR (CDCl3, 100 MHz) δ 175.6, 164.7, 147.6, 134.6, 133.9, 131.9, 131.8, 131.0, 126.6,
124.6, 52.2, 52.0, 41.5, 27.9; HRMS (FAB) Calcd for C14H14N2O8S (M+): 370.0471, Found:
370.0475.
9. (a) L. Ghosez, B. Haveaux, and H. G. Viehe, Angew. Chem., Int. Ed. Engl., 1969, 8, 454; (b) B.
Haveaux, A. Dekoker, M. Rens, A. R. Sidani, J. Toye, and L. Ghosez, Org. Synth. Coll. Vol. VI,
1982, 282.
10. J. Bergman and L. Venemalm, Tetrahedron Lett., 1987, 28, 3741.
11. While removing the Ns group, partial cleavage of the Alloc group concomitantly occurred to afford a
mixture of 32 and 33. 33 could be converted into 23 via a reductive amination (NaBH3CN, AcOH,
aq HCHO, MeOH, rt).
MeO2C
MeO2C
MeO2C
NNs
H
NH
H
NH
H
PhSH
Cs2CO3
Br
Br
Br
OH
OH
OH
+
DMF
0 °C to rt
N
Alloc
N
Alloc
N
H
21
32
33
24
12. 24: [α]D –15.7 (c 0.38, CHCl3); IR (film) 2949, 2925, 1700, 1653, 1437, 1397, 1336, 1305, 1267,
1
1192, 1158, 1141, 1098, 1067, 1042, 1025, 911, 800, 768 cm–1; H NMR (CDCl3, 400 MHz) δ 8.30
(br, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.05 (br, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.98 (br, 1H),
3.75 (s, 3H), 3.56 (dd, J= 14.1, 4.1 Hz, 1H), 3.52 (dd, J = 17.2, 3.4 Hz, 1H), 3.35 (dd, J = 17.2, 3.4
13
Hz, 1H), 3.16-3.19 (m, 1H), 2.75 (dd, J = 14.1, 10.3 Hz, 1H), 2.60 (s, 3H), 2.20 (s, 2H); C NMR
(CDCl3, 100 MHz) δ 166.4, 137.6, 137.6, 128.0, 125.4, 124.6, 124.1, 122.8, 114.2, 113.7, 110.6,
57.6, 51.6, 51.2, 41.0, 28.7, 25.6; HRMS (FAB) Calcd for C17H19BrN2O2 (M+): 362.0630, Found:
362.0632.
13. 28:1H NMR (CDCl3, 400 MHz) δ 7.90 (br, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H),
7.08 (s, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.88 (s, 1H), 4.10 (s, 1H), 3.70 (s, 3H), 3.52 (d, J = 18.4 Hz,
1H), 3.49-3.40 (m, 3H), 3.38 (d, J = 18.4 Hz, 1H), 3.02 (dd, J = 14.7, 4.6 Hz, 1H), 2.77 (dd, J = 14.7,
11.9 Hz, 1H), 2.63 (s, 3H); HRMS (FAB) Calcd for C17H18N2O2 (M+): 281.1290, Found: 281.1284.