seco-C/D Ring Analogues of Ergot Alkaloids. Synthesis via Intramolecular Heck and Ring-Closing Metathesis Reactions

Article abstract of DOI:10.1021/ol035398t

Equation presented. Intramolecular Heck and ring-closing metathesis reactions on key intermediates 10 and 15, respectively, provide efficient entries into seco-C/D ring analogues of Ergot alkaloids 12 and 16, compounds of potential synthetic and biologica

Full text of DOI:10.1021/ol035398t

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3519-3521
seco-C/D Ring Analogues of Ergot
Alkaloids. Synthesis via Intramolecular
Heck and Ring-Closing Metathesis
Reactions
,‡
Alexey V. Kalinin,† Brian A. Chauder,‡,§ Suman Rakhit, and Victor Snieckus*
Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario, Canada N2L 3G1; Department of Chemistry, Queen’s UniVersity,
Kingston, Ontario, Canada K7L 3N6; MCR Research, Inc., York UniVersity,
4700 Keele Street, Toronto, Ontario, Canada M3J 1P3
snieckus@chem.queensu.ca
Received July 25, 2003
ABSTRACT
Intramolecular Heck and ring-closing metathesis reactions on key intermediates 10 and 15, respectively, provide efficient entries into seco-C/D
ring analogues of Ergot alkaloids 12 and 16, compounds of potential synthetic and biological interest.
We report on the construction of compounds 12 and 16,
comprising seco-C/D ring Ergot alkaloid analogues using key
Heck1 and ring-closing metathesis (RCM)2 reactions. The
Ergots represent a significant class of indole alkaloids of
broad pharmacological activity.3 Historically, Ergot alkaloids
were among the first used drugs for the treatment of migraine
(ergotamine tartrate, 1920s, and dihydroergotamine mesylate,
1950s)4 and today, despite the advent of selective 5-HT
receptor inhibitors (sumatriptan5 and others6), methysergide
continues to be used as an antimigraine prescription drug
(Figure 1).7
† University of Waterloo.
‡ Queen’s University.
§ Present address: GlaxoSmithKline Research & Development, Five
Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709-3398.
MCR Research, Inc.
(1) For reviews on the intramolecular Heck reaction, see: (a) Link, J.
T. Org. React. 2002, 60, 157-534. (b) Braese, S.; de Meijere, A. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-i., de Meijere, A., Eds.; John Wiley and Sons: Hoboken; 2002; pp 1223-
1254. (c) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-
2964. (d) Whitcombe, N. J.; Hii, K. K. (Mimi); Gibson, S. E. Tetrahedron
2001, 57, 7449-7476. (e) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV.
2000, 100, 3009-3066. (f) Link, J. T.; Overman, L. In Metal Catalyzed
Cross Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; pp 99-154. (g) Amatore, C.; Jutland, A. Acc. Chem. Res.
2000, 33, 314. (h) Yet, L. Chem. ReV. 2000, 100, 2963-3007. For syntheses
of 16-, 21-, 22-, and 26-macrocycles by Heck reaction, see: Ziegler, F. E.;
Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 4035-4040.
Stocks, M. J.; Harrison, R. P.; Teague, S. J. Tetrahedron Lett. 1995, 36,
6555-6558. Hiroshige, M.; Hauske, J. R.; Zhou, P. J. Am. Chem. Soc.
1995, 117, 11590-11591. Harrowven, D. C.; Woodcock, T.; Howes, P. D.
Tetrahedron Lett. 2002, 43, 9327-9329.
(2) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1, 1-18 and ref-
erences therein. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18-29. Hoveyda, A. H.; Schrock, R. R. Chem., A Eur. J. 2001, 7, 945-
950.
(3) Somei, M.; Yokoyama, Y.; Murakami, Y.; Ninomiya, I.; Kiguchi,
T.; Naito, T. In The Alkaloids: Chemistry and Biology; Cordell, G. A.,
Ed.; Academic Press: San Diego, 2000; Vol. 54, pp 191-257. Kren, V.,
Cvak, L., Eds. In Medicinal and Aromatic Plants, Industrial Profiles.
Ergot: The Genus ClaViceps; Harwood Academic Publisher: Amsterdam,
1999. Ninomiya, I.; Kiguchi, T. In The Alkaloids: Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: San Diego, 1990; Vol.
38, pp 1-156.
(4) Silberstein, S. D.; McCrory, D. C. Headache 2003, 43, 144-166.
(5) Perry, C. M.; Markham, A. Drugs 1998, 55, 889-922. Goadsby, P.
J. CNS Drugs 1998, 10, 271-286. For an overview of the management of
migraine and the development of Sumatriptan, see: Oxford, A. W. Contemp.
Org. Synth. 1995, 2, 35-41.
10.1021/ol035398t CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/27/2003

of the formed tryptamine [PhCHO/NaBH(OAc)3],12 and
allylation provided the indole 2 (18% yield over five steps).
The main drawback of this route is the formation of N,N-
dibenzylated 4-bromotryptamine (up to 24% yield) during
the reductive amination step. Alternatively, cyanomethylation
of 1 and N-Boc protection13 gave 5, which was partially
reduced with DIBALH13,14 to the intermediate indolylacetal-
dehyde 6; the latter, without isolation, was subjected to
reductive amination12 with N-allyl-N-methylamine providing
7 in 23% overall yield.
The reaction of 2 with Pd(OAc)2 (25 mol %) and P(o-
Tol)3 (55 mol %) in refluxing MeCN (c 0.01 M) containing
2.5 equiv of NEt3 was complete within 12 h to afford
9-endo-3 and 8-exo-4 products in 24 and 21% yields,
respectively. In contrast, subjection of 7 to the same reaction
conditions led to 8-exo-8 in 30% yield as the only isolable
product. While it is premature to interpret the observed
regioselectivity of cyclization of 2 Vs 7 as a function of
difference in N-substituents, these results are consistent with
the observations of Roberts et al. on the cyclization of a
carbocyclic analogue.15 Despite this poor selectivity, we
proceeded to examine the 10-membered ring cyclization
based on the generalization that endo-cyclization predomi-
nates with increasing chain length.1e
Figure 1.
Consequently, the search for receptor-selective Ergot
analogues continues to be the subject of intense synthetic
activity.8
Our work provides new entries into indole 3,4-fused mac-
rocycles 12 and 16, representing the seco-C/D ring analogue
of the naturally occurring lysergol (Scheme 2), and offers
new structural types as further probes of 5-HT receptor
inhibitor activity.9
Model reactions (Scheme 1) were investigated as a prelude
to the Heck macrocyclization 10 f 11. Initiated from
Thus, the synthesis of the seco C/D-ring analogue (11)
was undertaken by rapid assembly of the Heck precursor 10
(48% yield) through reductive amination of 6 with homoal-
lylic amine 916 (Scheme 2). Unfortunately, direct adoption
Scheme 1a
Scheme 2a
a Reaction conditions: (a) POCl3, DMF, 0 to 40 °C (1 h) (78%);
then MeNO2, cat. NH4OAc, reflux, 3 h (80%); then LiAlH4, THF,
reflux, 4 h (88%); then PhCHO, NaBH(OAc)3, DCM-THF, rt
(46%); then AllylBr, MeCN, rt, 24 h (69-72%). (b) 25 mol %
Pd(OAc)2, 55 mol % P(o-Tol)3, NEt3, MeCN, reflux, 12 h (3, 24%;
4, 21%; 8, 30%). (c) DIBALH, 0 °C (15 min) to rt (2 h), DCM;
then AllylNHMe, NaBH(OAc)3, DCM, rt (overnight) (38%).
a Reaction conditions: (a) DIBALH, 0 °C (4 h) to rt (1 h), DCM,
then 9, NaBH(OAc)3, 0 °C to rt (overnight), DCM (48%). (b) 30
mol % Pd(OAc)2, 90 mol % P(o-Tol)3, DBU, Tol, 110 °C, 3-3.5
days, or 35 mol % Pd(OAc)2, 105 mol % P(o-Tol)3, DBU, Xylenes,
142 °C, 9 h. (c) TBAF, THF, rt, 1 h (32% from 10). (d) 3 N HCl,
MeOH, reflux, 8 h (41% from 10).
4-bromoindole (1),10 two routes toward the required
tryptamines 2 and 7 have been compared for efficiency. In
the first route, sequential Vilsmeier-Haack, Henry nitroaldol
condensation,11 reduction with LiAlH4, reductive amination
of the conditions used for the conversion of 2 and 7 led to
an intractable mixture of products. After extensive screening
of conditions, it was found that conducting the reaction in
refluxing toluene for prolonged times (up to 3 days) with
DBU as a base provided a ∼3:1 mixture of the trans-
macrocycle (E)-11 with a minor product assigned as a cis
(6) Glennon, R. A. J. Med. Chem. 2003, 46, 2795-2812. Humphrey,
P., Ferrari, M., Olesen, J., Eds. In Frontiers in Headache Research. The
Triptans: NoVel Drugs for Migraine; Oxford University Press: New York,
2001; Vol. 10.
(7) Eadie, M. J. CNS Drugs 2001, 15, 105-118. Le Jeunne, C. Pathologie
Biologie 2000, 48, 690-696. Hart, C. Modern Drug DiscoV. 1999, 2,
20-21, 23-24, 28, and 31.
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Org. Lett., Vol. 5, No. 19, 2003

isomer (confirmed from 1H NMR and LC-MS analysis).16,17
Replacement of the reaction solvent to xylenes allowed the
reaction time to be shortened to 9 h without affecting the
above ratio of products. Difficulty in separation of isomers
forced conversion of 11 into seco-C/D ring lysergol 12 and
its N-Boc derivative 13. Accordingly, treatment of the crude
Heck reaction mixture with HCl or TBAF afforded pure 12
and 13 in 32 and 41% yields from 10, respectively.
To test the RCM protocol2 for the construction of the seco-
C/D ring framework 16, the common starting 4-bromoindole
5 was subjected to sequential Stille coupling with allyltribu-
tyltin,18 LAH reduction, and acylation to furnish the 4-al-
lyltryptamine 14 in 42% overall yield (Scheme 3). Treatment
RudCHPh]2 in refluxing CH2Cl2 under syringe pump
addition of substrate and two loadings of catalyst19 afforded
smooth reaction to give 16 as a single (Z)-isomer (3J ) 10.4
Hz) in 69% yield.
In summary, the intramolecular Heck reaction has been
probed in context of 8- (4, 8) Vs 9-membered (3) ring
formation and applied to the construction of the macrocyclic
analogue 12 of lysergol. In addition, and more efficiently,
macrocycle 16, representing the first seco-C/D ring ergot
alkaloid core, has been prepared by RCM.20 Extension of
this rational methodology for the synthesis of other seco-
ergolines and related systems for bioactivity studies and the
transformation of prototypes 10 and 15 into the ergot
alkaloids may be anticipated.
Acknowledgment. We thank Dr. Malik Slassi for en-
thusiastic encouragement and bioscreening. We are grateful
to NSERC Canada and NPS Allelix for support under the
CRD program. B.A.C. is a recipient of a Queen’s Graduate
Fellowship (QGF), 1999-2000.
Scheme 3a
Supporting Information Available: Experimental details
and data of intermediate and final compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: (a) AllylSnBu3, 5 mol % Pd(PPh3)4, Tol,
110 °C, 14 h (69%). (b) LiAlH4, E2O-THF, rt, 12 h (61%). (c)
Ac2O, Py, rt, 20 h (97%). (d) Boc2O, NEt3, cat. DMAP, DCM, rt,
2 h (73%). (e) n-BuLi, AllylBr, THF, -78 °C (5 min) to rt (20 h)
(65%). (f) 30 mol % (PCy3)2(Cl)2RudCHPh, DCM (c 0.0021 M),
40 °C, 20 h (69%).
OL035398T
(10) Batcho, A. D.; Leimgruber, W. Organic Syntheses; Wiley: New
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with Boc2O followed by N-allylation afforded the RCM
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(16) For full experimental details, see Supporting Information.
(17) Trans and cis geometries of the double bond in 11 was assigned
from the characteristic signals 3J ) 16.3 and 12.2 Hz, respectively. For 12
3
and 13, J ) 16.3 and 16.2 Hz, respectively.
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Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652.
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see: Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202-7207.
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see: Deiters, A.; Martin, S. F. Org. Lett. 2002, 4, 3243-3245 and references
therein. Lee, K. L.; Goh, J. B.; Martin, S. F. Tetrahedron Lett. 2001, 42,
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(9) Cross-screening of compound 12 against a panel of serotonergic,
dopaminergic, and R-adrenergic receptors showed good potency (Ki ) 170
( 78) and moderate selectivity for the 5-HT7 receptor. Slassi, M.; Rakhit,
S.; Kalinin, A. V.; Chauder, B. A.; Snieckus, V. Unpublished results.
Org. Lett., Vol. 5, No. 19, 2003
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