New route to the ergoline skeleton via cyclization of 4-unsubstituted indoles

Article abstract of DOI:10.1021/ol400620a

A new route to the ergoline skeleton has been developed that does not require prior functionalization of the indole 4-position. The indole nucleus is introduced late in the synthesis to allow for eventual efficient introduction of substituents in this region. Key steps include Negishi coupling of a three-carbon chain to a bromonicotinate ester, Fischer indole synthesis to facilitate incorporation of substituents via phenylhydrazines, and Pd-catalyzed cyclization to form the ergoline C ring.

Full text of DOI:10.1021/ol400620a

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
New Route to the Ergoline Skeleton via
Cyclization of 4‑Unsubstituted Indoles
Scott D. Burley,† Vicky V. Lam,‡ Frederick J. Lakner,‡ B. Mikael Bergdahl,† and
Matthew A. Parker*,†
Department of Chemistry, San Diego State University, San Diego, California 92182,
United States, and ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego,
California 92121, United States
mparker@mail.sdsu.edu
Received March 8, 2013
ABSTRACT
A new route to the ergoline skeleton has been developed that does not require prior functionalization of the indole 4-position. The indole nucleus is
introduced late in the synthesis to allow for eventual efficient introduction of substituents in this region. Key steps include Negishi coupling of a
three-carbon chain to a bromonicotinate ester, Fischer indole synthesis to facilitate incorporation of substituents via phenylhydrazines, and
Pd-catalyzed cyclization to form the ergoline C ring.
Ergoline is a tetracyclic heterocycle (Figure 1) that forms
the skeleton of a series of natural and semisynthetic
compounds with a rich and well-studied pharmacology.1
Ergolines exhibit a diversity of bioactivities including
uterotonic, hypertensive, and antihypertensive activity;
induction of hyperthermia and emesis; hallucinogenesis;
neuroleptic activity; and control of the secretion of pitui-
tary hormones.2 Many have a potent influence on the
neuroendocrine system via their interactions with mono-
amine neurotransmitter receptors. Others exhibit in vivo
antitumor activity and tyrosine kinase inhibition.3
Figure 1. Rings AꢀD of the parent tetracycle ergoline.
Although routes to ergolines are well represented in the
literature,4 they generally require preparation of a 4-substituted
indole derivative at the outset.5 These strategies are poorly
† San Diego State University.
‡ ChemDiv, Inc.
(1) Schardl, C. L.; Panaccione, D. G.; Tudzynski, P. Alkaloids: Chem.
suited for generation of derivatives for pharmacological
exploration, particularly if diversity in the ergoline A ring
is desired. The recent appearance in this journal of a report
by Nichols6 refuting the earlier published route to lysergic
acid of Hendrickson7 further illustrates the need for sim-
pler, workable routes to these valuable compounds.
Biol. 2006, 63, 45–86.
(2) (a) Bovet, F. J. The Story of Ergot; Karger: Basel, 1970. (b) Berde,
B., Schild, H. O., Eds. Ergot Alkaloids and Related Compounds, Vol. 49,
Handbook of Experimental Pharmacology; Springer: Berlin, 1978. (c)
Stadler, P. A.; Giger, R. K. Natural Products and Drug Development;
Krogsgaard-Larsen, P., Christensen, C. H., Kofod, H. J., Eds.; Munksgaard:
Copenhagen, 1984; p 463. (d) Eich, E.; Pertz, H. Pharmazie 1994, 49, 867–
877.
(5) Typically, 4-haloindoles or indole-4-boronic acids are required;
e.g., the protected 4-iodotryptophan derivative required in ref 4.
(6) Bekkam, M.; Mo, H.; Nichols, D. E. Org. Lett. 2012, 14, 296–
298.
(3) (a) Eich, E.; Eichberg, D.; Muller, W. E. Biochem. Pharmacol.
1984, 33, 523–526. (b) Eich, E.; Becker, C.; Sieben, R.; Maidhof, A.;
Muller, W. E.; J.
(4) See, e.g., Liu’s recent total synthesis of lysergic acid and references
therein: Liu, Q.; Jia, Y. Org. Lett. 2011, 13, 4810–4813.
(7) Hendrickson, J. B.; Wang, J. Org. Lett. 2004, 6, 3–5.
r
10.1021/ol400620a
XXXX American Chemical Society

We therefore decided to pursue a route to the ergoline
skeleton in which the key cyclization step would take place
on a 4-unsubstituted indole (Scheme 1), greatly simplifying
the preparation of precursors and allowing the A ring to be
efficiently introduced late in the scheme. Interestingly,
a similar cyclization strategy employing a Pschorr ring clo-
sure was attempted over half a century ago by Plieninger
et al.,8 although it resulted in the undesired irreversible
oxidation of the newly formed C ring to a naphthalene
derivative. We circumvented this difficulty with our
choice of 1a and 1b as synthetic targets in which the indole
2,3-bond is reduced to the dihydro (indoline) derivative,
preventing the potential migration of this bond to the C
ring, a strategy first employed in Kornfeld’s tour de force
total synthesis of lysergic acid.9
substantially eliminated upon deprotonation, as indicated by
a marked difference in the Hammett substituent constant, σ,
for the different protonation states (σ = þ0.45 for p-CO2H
versus σ = þ0.0 for p-CO2ꢀ).10
Scheme 2. Synthesis of Indole 2 via Final Common Intermediate 3
Scheme 1. Retrosynthetic Analysis. Construction of the Indole
Ring at a Late Stage Facilitates Introduction of Diversity in
Ring A
DMC (2-chloro-1,3-dimethylimidazolinium chloride)11
was chosen as a suitable activating agent for esterification
of 5 (in ethanol, again as the DIPEA salt). The resulting
ethyl ester 6 was easily purified by flash chromatography.
A small amount of 6 was hydrolyzed with sodium hy-
droxide in methanol/water to give a clean sample of 5 as a
light yellow crystalline solid suitable for characterization.
Since we required a mild nucleophile that would not
attack the ester moiety of 6, we chose the Negishi
coupling12 for addition of the three-carbon acetal side
chain. We then required protection of the amino group
as a nonprotic functionality. Heating amine 6 with DMF
dimethyl acetal13 gave an excellent yield of formamidine 7,
Our first goal was to synthesize acetal 3 (Scheme 1), which
would serve as the final common intermediate before intro-
duction of diversity via the Fischer indole synthesis. We
began with readily available 5-aminonicotinic acid 4. The
€
carboxylate salt formed from 4 and Hunig’s base was
smoothly brominated with NBS in methanol/acetonitrile to
give reasonable yields of the crude 6-bromo derivative 5
(Scheme 2) as a finely divided dark brown precipitate upon
reacidification with HCl. Although this crude material was
practically insoluble in organic solvents other than DMF or
DMSO and therefore difficult to purify, it was sufficiently
pure to carry forward to the subsequent esterification step.
Attempts to brominate 4 as a neutral (protonated) species
resulted in complex mixtures, presumably because of the
deactivating effect of the p-carboxylic acid substituent to
electrophilic substitution at the desired 6-position. The elec-
tron-withdrawing nature of the carboxylic acid substituent is
(10) McDaniel, D. H.; Brown, H. C. J. Org. Chem. 1958, 23, 420–427.
(11) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984–6988.
(12) Negishi, E. Acc. Chem. Res. 1982, 15, 340–348.
(13) Initially, we attempted to protect 6 by condensing it with
benzaldehyde, but the resulting imine was sensitive to nucleophilic
attack by the organozinc reagent during the subsequent Negishi
coupling.
(14) Some examples of o-haloformamidines as substrates in
palladium-catalyzed coupling reactions: (a) Dohle, W.; Staubitz, A.;
Knochel, P. Chem. Eur. J. 2003, 9, 5323–5331. (b) Hikishima, S.;
Minakawa, N.; Kuramoto, K.; Fujisawa, Y.; Ogawa, M.; Matsuda, A.
Angew. Chem., Int. Ed. 2005, 44, 596–598. (c) Chuaqui, C.; Cossrow, J.;
Dowling, J.; Guan, B.; Hoemann, M.; Ishchenko, A.; Jones, J. H.;
Kabigting, L.; Kumaravel, G.; Peng, H.; Powell, N.; Raimundo, B.;
Tanaka, H.; Van Vloten, K.; Vessels, J.; Xin, Z. PCT Int. Appl. WO
2010078408, 08 Jul 2010.
(8) (a) Plieninger, H.; Schach von Wittenau, M.; Kiefer, B. Ber. 1958,
91, 1898–1905. (b) Plieninger, H.; Schach von Wittenau, M. Ber. 1958,
91, 1905–1909. (c) Plieninger, H.; Schach von Wittenau, M.; Kiefer, B.
Ber. 1958, 91, 2095–2103.
(9) 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, 3087–3114.
B
Org. Lett., Vol. XX, No. XX, XXXX

and the subsequent Negishi coupling proceeded in quanti-
tative yield to give acetal 8. Based on similar reactions we
have conducted on other substrates, it appears that the
formamidine moiety accelerates the coupling reaction by a
chelation effect.14 The required organozinc reagent, 2-[(1,3-
dioxolanyl)ethyl]zinc bromide, is commercially available.
The formamidine protecting group of 8 was most con-
veniently removed by catalytic hydrogenation15 in ethanol
to give amine 9 cleanly. Diazotization of 9 and displace-
ment with iodide proceeds in moderate yields due to the
necessity of using acids and/or electrophiles in the presence
of the sensitive acetal side chain. We initially attempted the
transformation under the anhydrous conditions of Hartley
et al.16 but obtained only a ∼35% yield of iodopyridine 3; a
better yield (56%) was eventually obtained by simply using
classical diazotization conditions (potassium nitrite/aque-
ous HCl).
Scheme 3. Reduction, Indoline Protection, and Cyclization
Iodopyridine 3 is the key final common intermediate,
allowing for the introduction of diversity by the choice of
substituted phenylhydrazines as reaction partners in the
Fischer indole synthesis, although in the present work we
utilize only the parent phenylhydrazine itself. The Fischer
synthesis is conducted in ethanol/H2O/H2SO4, and several
trials were required in order to find a combination of water
concentration and acidity that would allow for selective
hydrolysis of the acetal moiety in the presence of an ethyl
ester. In the end, ∼4 equiv of H2SO4 as a 12 M aqueous
solution added to the ethanolic reaction mixture appeared
to be optimal, and indole 2 was obtained in acceptable
yield.
Finding the proper strategy for cyclization of 2 or one of
its derivatives onto the unsubstituted indole 4-position to
create the ergoline C ring also required a bit of investigation.
The palladium-assisted cyclization conditions optimized by
Harayama17 during the synthesis of a benzo[c]phenanthridine
alkaloid (and later employed by Li et al.18 for cyclization of an
iodobenzene derivative to a dihydrophenanthridine) ap-
peared promising but were unsuccessful when applied to the
N-pivaloyl derivative of 2. (The pivaloyl protecting group had
previously been employed by Goto19 and then Moldvai20 as a
way to direct intramolecular acylation of indole-3-propio-
nic acid to the indole 4-position in preference to the
2-position, and we had hoped that it might also be
successful in directing the intramolecular Pd-catalyzed
cyclization in similar fashion.) Therefore, we decided to
eliminateall possibilityofreactivity atthe indole2-position
by first reducing the indole 2,3-bond and then acylating
with pivaloyl chloride using classical two-phase Schottenꢀ
Baumann conditions to give protected indoline 10a
(Scheme 3). Upon subjecting 10a to the cyclization condi-
tions in the presence of silver carbonate, we were thrilled to
observe a successful clean cyclization to give the target
tetracycle 1a.
In similar fashion, acylation with benzoyl chloride gave
10b, and cyclization under identical conditions gave 1b.
The yield of 1b was somewhat higher than that of 1a.
Electron-rich acyl substituents on the indoline N(1) posi-
tion may deactivate the system to cyclization as compared
to electron-poor substituents; this speculation is further
supported by our observation that N-Boc protection leads
to even lower cyclization yields.
Efforts are underway to reduce the D ring and reoxidize
the B ring of 1a and/or 1b to achieve the formal synthesis of
naturally occurring ergolines; we will report these devel-
opments in a future publication.
Acknowledgment. A portion of this work appears in the
M.S. thesis of S.B., San Diego State University, 2012. We
thank Dr. LeRoy Lafferty for NMR support and Chem-
Div, Inc., for a generous donation of equipment and
supplies. This work was funded in part by the San Diego
State University Research Foundation and by the National
Institutes of Health, Grant No. 7P41GM79583 (M.P.).
(15) Jaehne, G.; Stengelin, S.; Gossel, M.; Klabunde, T. PCT Int.
Appl. WO 2008017381, 14 Feb 2008.
(16) Hartley, C. S.; Elliott, E. L.; Moore, J. S. J. Am. Chem. Soc. 2007,
129, 4512–4513.
(17) Harayama, T.; Akiyama, T.; Kawano, K. Chem. Pharm. Bull.
1996, 44, 1634–1636.
(18) Li, W.-R.; Lin, Y.-S.; Hsu, N.-M. J. Comb. Chem. 2001, 3, 634–
643.
Supporting Information Available. Experimental pro-
cedures and spectral data (1H and 13C NMR) for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) Teranishi, K.; Hayashi, S.; Nakatsuka, S.; Goto, T. Tetrahedron
Lett. 1994, 35, 8173–8176.
ꢀ
(20) Moldvai, I.; Temesvari-Major, E.; Incze, M.; Szentirmay, E.;
ꢀ
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The authors declare no competing financial interest.
Gacs-Baitz, E.; Szantay, C. J. Org. Chem. 2004, 69, 5993–6000.
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