Total synthesis of lysergic acid

Article abstract of DOI:10.1021/ol4019562

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.

Full text of DOI:10.1021/ol4019562

ORGANIC
LETTERS
XXXX
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
fukuyama@ps.nagoya-u.ac.jp
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
(2) (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.; Legoffic, F.; Igolen, J.; Baillarg, M.
Tetrahedron Lett. 1969, 1569. (c) Oppolzer, W.; Francotte, E.; Battig,
K. Helv. Chim. Acta 1981, 64, 478. (d) Ramage, R.; Armstrong, V. W.;
Coulton, S. Tetrahedron 1981, 37, 157. (e) Rebek, J.; Tai, D. F.; Shue, Y.-
K. J. Am. Chem. Soc. 1984, 106, 1813. (f) Ninomyia, 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. Tetrahedron Lett.
ꢀ
1988, 29, 3117. (i) Saa, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C.
Synlett 1994, 487. (j) Hendrickson, J. B.; Wang, J. Org. Lett. 2004, 6, 3.
† University of Tokyo.
ꢀ
(k) Moldvai, I.; Temesvari-Major, E.; Incze, M.; Szentirmay, E.; Gacs-
ꢀ
ꢀ
‡ Nagoya University.
ꢀ
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
The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 2000;
Vol. 54, pp 191À 257.
Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 5239. (m) Inuki, S.; Iwata, A.;
Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 2072. (n) Inuki, S.;
Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2011, 13, 2145. (o) Iwata, A.;
Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 5506. (p)
Liu, Q.; Jia, Y. Org. Lett. 2011, 13, 4810.
r
10.1021/ol4019562
XXXX American Chemical Society

through a ring-closing metathesis of diene 3,4 which would
be prepared by reductive amination of aldehyde 4 with
amine 5. This retrosynthesis addressed the issue of setting
the requisite stereochemistry in intermediate 2 by prepara-
tion of the simple units with the proper stereogenic centers
at the allylic positions.
allylation of 4-bromoindole (11) with chiral allyl alcohol
128 was carried out (Scheme 3). Protection of the indole
NH, followed by cleavage of the TBS ether, afforded an
alcohol, which was converted into carbamate 14. Treat-
ment of 14 with TFAA induced formation of a cyanate,9
which underwent a [3,3]-sigmatropic rearrangement to
afford an isocyanate.10 The isocyanate was converted into
allylamine 15 via the Troc-protected intermediate.
Scheme 1. Retrosynthesis
Scheme 3. Attempted Ring-Closing Metathesis
Our synthesis commenced with preparation of the syn-
thetic equivalent of aldehyde 4 by means of the Evans aldol
reaction (Scheme 2).5 Treatment of 6 with titanium tetra-
chloride and N,N-diisopropylethylamine generated a tita-
nium enolate,6 which, upon addition of aldehyde 7, gave
adduct 8 as the sole isomer. After protection of the
secondary hydroxy group with a TBS group, the carbonyl
group in 9 was partially reduced with DIBAL to afford
isolable hemiaminal 10 in 79% yield.
Scheme 2. Synthesis of 10
We next focused on the coupling of the amine and
aldehyde equivalents in preparation for the subsequent
ring-closing metathesis. Reductive alkylation of amine 15
with hemiaminal 10 followed by protection of the resulting
(5) (a) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetra-
hedron Lett. 1986, 27, 4957. (b) Bull, S. D.; Davies, S. G.; Jones, S.;
Polywka, M. E.; Prasad, R. S.; Sanganee, H. J. Synlett 1998, 1998, 519.
(c) Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 9,
1635.
(6) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J.
Org. Chem. 2001, 66, 894.
(7) (a) Kimura, M.;Futamata, M.;Mukai, R.;Tamaru, Y. J. Am. Chem.
Soc. 2005, 127, 4592. (b) Tamaru, Y. Eur. J. Org. Chem. 2005, 2647.
(8) Jamieson, A. G.; Sutherland, A. Org. Biomol. Chem. 2005, 3, 735.
(9) Toma, T.; Kita, Y.; Fukuyama, T. J. Am. Chem. Soc. 2010, 132,
10233.
(10) (a) Ichikawa, Y. Synlett 1991, 238. (b) Ichikawa, Y.; Tsuboi, K.;
Isobe, M. J. Chem. Soc., Perkin Trans. 1 1994, 2791. (c) Ichikawa, Y.; Osada,
M.; Ohtani, I.; Isobe, M. J. Chem. Soc., Perkin Trans. 1 1997, 1449. (d)
Ichikawa, Y.; Ito, T.; Nishiyama, T.; Isobe, M. Synlett 2003, 1034.
We next prepared the requisite amine unit. According to
the procedure developed by Tamaru and co-workers,7
(3) (a) Kurokawa, T.; Isomura, M.; Tokuyama, H.; Fukuyama, T.
Synlett 2009, 775. (b) Inoue, T.; Yokoshima, S.; Fukuyama, T. Hetero-
cycles 2009, 79, 373.
(4) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446. (b) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
B
Org. Lett., Vol. XX, No. XX, XXXX

adduct with a Boc group gave 16 in 65% yield over the two
steps. Subsequent ring-closing metathesis of 16, however,
proved to be challenging. Treatment of 16 with the second-
generation HoveydaÀGrubbs catalyst provided an inse-
parable mixture of the desired product 17 and byproduct
18 with a seven-membered ring.11 Completion of the
metathesis reaction required prolonged heating because
both olefins of 16 are situated in the sterically demanding
environment. The harsh reaction conditions resulted in
decomposition of the ruthenium catalyst, leading to the
formation of 18 via isomerization of the disubstituted
double bond. Although the methyl group was important
for the asymmetric preparation of the amine unit 15, it
caused an unavoidable problem for the metathesis reaction.
We therefore decided to prepare a substrate without the
methyl group. During the course of these investigations,12
we envisioned that the Evans aldol reaction of 6 could
effectively control the stereochemistry at the allylic position.
With this idea in mind, we carried out the Evans
aldol reaction of 6 with 4-bromo-3-formyl-1-tosylindole
Scheme 5. Synthesis of Lysergic Acid
Scheme 4. Synthesis of 23
retro-aldol reaction, treatment of 20 with hydrazine
cleanly afforded the corresponding hydrazide 21 in 94%
yield. Upon heating with tert-butyl nitrite under acidic
conditions, 21 was converted into an acyl azide,13 which
underwent a Curtius rearrangement under the same con-
ditions to give oxazolidinone 22 in 97% yield. Deoxygena-
tion was effected by treatment of 22 with triethylsilane and
titanium tetrachloride to give allylamine 23.
Reductive alkylation of amine 23 with hemiaminal 10,
followed by protection of the resulting amine with a Boc
group, gave 24 in 60% yield (Scheme 5). As expected, the
crucial ring-closing metathesis with the second-generation
Grubbs catalyst14 proceeded smoothly to afford 17 in a
nearly quantitative yield. The stereoselective construction
of the D ring was effectively accomplished, and the sub-
sequent intramolecular Heck reaction proceeded unevent-
fully to give 25 in good yield.
(19, Scheme 4).2n,5a,5c,6 The reaction proceeded smoothly
to afford adduct 20 as the sole isomer. While attempted
ammonolysis of the chiral auxiliary was accompanied by a
(11) The presence of 18 was detected by mass spectrum analysis of the
inseparable mixture of the products. In addition, two pairs of peaks
1
which could be assigned as the olefin were obsereved in the H NMR
spectrum.
(12) In our case, the asymmetric Overman rearrangement using (R)-
COP-Cl did not yield reproducible results. Anderson, C. E.; Overman,
L. E. J. Am. Chem. Soc. 2003, 125, 12412.
(13) Treatment of 21 with sodium nitrite in a mixture of CH2Cl2 and
aq HCl furnished carboxamide 29, which could also be converted into 22
via Hofmann rearrangement. Cf. Honzl, J.; Rudinger, J. Collect. Czech.
Chem. Commun. 1961, 26, 2333.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
Org. Lett., Vol. XX, No. XX, XXXX
C

Further functional group manipulations led to the com-
pletion of the total synthesis of lysergic acid (1). Thus, after
switching from the Ts group to a Boc group, the TBS
protecting groups were removed by treatment with TBAF.
The resulting 1,2-diol 26 was oxidatively cleaved with
(diacetoxyiodo)benzene to afford an aldehyde, which
was converted in two steps into methyl ester 27.15 Ester
27 was converted into lysergic acid according to the
literature procedure.2k,3a The double bond underwent
isomerization under the basic conditions to furnish a
β,γ-unsaturated ester. After cleavage of the Boc groups
with TFA, the resulting secondary amine was subjected to
reductive methylation with formalin to give 28. Finally,
hydrolysis of the methyl ester furnished lysergic acid (1).
In summary, we have achieved the total synthesis of
lysergic acid in 19 steps and 12% overall yield from the
known substrate 6. 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.
Acknowledgment. This work was financially supported
byJSPSKAKENHIGrant Numbers 20002004, 25221301,
the Research Foundation for Pharmaceutical Sciences, the
Mochida Memorial Foundation for Medical and Pharma-
ceutical Research, and the Uehara Memorial Foundation.
S.U. was a Research Fellow of JSPS.
Supporting Information Available. Experimental de-
1
tails and H and 13C NMR spectra for all new com-
pounds. This material is available free of charges via the
Internet at http://pubs.acs.org.
(15) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(b) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175. (c)
Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825. (d) Bal, B. S.;
Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX