Novel entry to the Ergot alkaloids via ring closing metathesis

Article abstract of DOI:10.1016/S0040-4039(01)00002-8

A novel entry the Ergot alkaloids has been developed. It features a Heck reaction followed by hydride capture to generate the key tricyclic intermediate 12 and a ring closing metathesis reaction to give the tetracyclic ergoline ring system 3.

Full text of DOI:10.1016/S0040-4039(01)00002-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1635–1638
Novel entry to the Ergot alkaloids via ring closing metathesis
Katherine L. Lee, Jane Betty Goh and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
Received 22 December 2000; accepted 29 December 2000
Abstract—A novel entry the Ergot alkaloids has been developed. It features a Heck reaction followed by hydride capture to
generate the key tricyclic intermediate 12 and a ring closing metathesis reaction to give the tetracyclic ergoline ring system 3.
© 2001 Elsevier Science Ltd. All rights reserved.
The development of new and general strategies for the
synthesis of biologically important natural and unnatu-
ral substances constitutes an area of considerable inter-
est in organic chemistry. In this context, we were
attracted some years ago to the potential of using ring
closing metathesis (RCM) reactions as key construc-
tions for alkaloid synthesis.1,2 We have recently
reported the application of such reactions to the synthe-
ses of manzamine A and FR900482.3,4 As part of an
ongoing program in developing the utility of RCM
reactions, we were intrigued by the possibility of
exploiting such a construction in formulating a novel
synthetic approach to the tetracyclic Ergot alkaloids
lysergic acid (1) and lysergine (2) via cyclization of a
precursor diene such as 4 (R=CO2Me, Me) (Scheme
1).5 We now report the successful completion of some
preliminary studies that establish the underlying viabil-
ity of a novel entry to the Ergot alkaloids as manifested
in the synthesis of the C(8) unsubstituted ergoline
derivative 3.
88% yield. If 10% Pd/C was used as the catalyst,
complete hydrogenolysis of the aryl bromide occurred.
Although the present route provides 9 as a racemate, it
should be possible to modify the synthetic plan to
prepare 9 or closely related analogs in an enantiomeri-
cally pure form.8
Developing the tactics for converting 9 into the key
tricyclic intermediate 12 required considerable experi-
mentation. The first plan was to induce radical cycliza-
tion of the bromo acetylene 10 into 12 via a 6-exo-dig
closure. Toward this end, reduction of the ester 9 with
DIBAL-H furnished an intermediate aldehyde that was
transformed directly into the acetylene 10 using 1-
diazo-(2-oxopropyl)phosphonate (73% overall yield
from 9).9 However, several preliminary attempts to
effect radical cyclization of 10 (Bu3SnH, cat. AIBN,
toluene, D) afforded only the corresponding debromi-
nated product. Placement of a trimethylsilyl group on
terminal acetylenes has been reported to facilitate radi-
cal cyclizations and to enhance the exo/endo selectiv-
ity,10 but when 11 was treated with (Bu3SnH in the
presence of AIBN, only traces of cyclized product were
detected in the reaction mixture.
The basic strategy that emerged for preparing 3 was
designed to be adaptable so it could be modified in a
straightforward fashion for the asymmetric syntheses of
the natural Ergot alkaloids, including lysergic acid (1)
and lysergine (2). The known dehydrotryptophan 7 was
readily prepared by palladium-mediated coupling of the
N-tosyl derivative of 4-bromoindole 6 with a protected
dehydroalanine in 56% overall yield from 5 (Scheme
2).6,7 N-Methylation of 7 followed by hydrogenation of
the dehydroamino acid moiety of 8 with Wilkinson’s
catalyst under 100 psi hydrogen proceeded efficiently,
albeit slowly, to give the bromotryptophan 9 in about
Keywords: ring closing metathesis; Heck reaction; organometallic;
amino acid.
* Corresponding author. E-mail: sfmartin@mail.utexas.edu
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00002-8

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K. L. Lee et al. / Tetrahedron Letters 42 (2001) 1635–1638
Scheme 2.
hydride capture.12 Use of other palladium catalysts,
bases, and additives led to the formation of 14 as a
significant and inseparable by-product.
These results did not bode well for preparing 12 by a
radical cyclization, so other options were considered,
and an intramolecular Heck cyclization emerged as an
attractive alternative. The requisite alkene 13 was read-
ily prepared from 9 by sequential DIBAL-H reduction
followed by Wittig olefination. However, subjecting 13
to typical Heck conditions [Pd(OAc)2, (o-tol)3P,
Bu4NCl, Et3N, MeCN, D) afforded the undesired
seven-membered ring product 14 in 65% yield. Subse-
quent examination of models suggested that the 7-endo
mode of cyclization allowed more facile attainment of
an eclipsed relationship between the aryl car-
bonꢀpalladium bond, which was formed by oxidative
addition, and the reacting carbonꢀcarbon double bond,
an arrangement Overman found to favor Heck cycliza-
tion.11 It then occurred to us that one way to disfavor
the 7-endo cyclization pathway would be to replace the
terminal olefin in 13 with an alkyne moiety, which
could not adopt an eclipsed relationship with the aryl
carbonꢀpalladium bond. The accessible twisted orienta-
tion between the alkyne and the carbonꢀpalladium
bond might then kinetically favor formation of a six-
membered ring. After considerable experimentation, we
discovered that 10 could be selectively converted into
12 in reasonable yield by a Heck reaction followed by
With quantities of 12 in hand, the stage was set to
examine the key ring closing metathesis. In this context
it is noteworthy that there are few examples of RCM
reactions involving exocyclic olefins and phenyl substi-
tuted alkenes, so success was clearly not assured.13,14
Removal of the Boc protecting group from 12 followed
by N-alkylation of the amine 15 thus obtained with
4-bromo-1-butene gave 16 in 71% overall yield (Scheme
3).15
When 16 was heated with the Grubbs catalyst 18, only
small quantities of 17 were formed; however, the RCM
of 16 to give 17 using the more reactive Schrock
catalyst 19 proceeded in 86% yield. Removal of the
tosyl protecting group then delivered the desired ergo-
line 3 in nearly quantitative yield.
These results further demonstrate the utility of RCM
reactions to elaborate the ring systems found in com-
plex alkaloid natural products. Further applications of
such processes are under active investigation, and the
results of these studies will be reported in due course.

K. L. Lee et al. / Tetrahedron Letters 42 (2001) 1635–1638
1637
Scheme 3.
7. (a) Yokoyama, Y.; Takashima, M.; Higaki, C.; Shidor,
K.; Moriguchi, S.; Ando, C.; Murakami, Y. Heterocycles
1993, 36, 1739–1742; (b) Yokoyama, Y.; Matsumoto, T.;
Murakami, Y. J. Org. Chem. 1995, 60, 1486–1487; (c)
Yokoyama, Y.; Kondo, K.; Misuhashi, M.; Murakami,
Y. Tetrahedron Lett. 1996, 37, 9309–9312.
8. See also: Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.;
Uyama, A.; Murakami, Y. Tetrahedron Lett. 1999, 40,
7803–7806.
Acknowledgements
We thank the National Institutes of Health, the Robert
A. Welch Foundation, Pfizer Inc. and Merck Research
Laboratories for their generous support of our
research.
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K. L. Lee et al. / Tetrahedron Letters 42 (2001) 1635–1638
112.3, 64.3, 53.8, 38.4, 31.9, 29.7, 23.4, 21.5; 17. 1H NMR
(CDCl3): l 7.74–7.71 (comp, 3H), 7.28–7.17 (comp, 5H),
6.46–6.44 (m, 1H), 3.51 (dd, J=15.1, 5.3 Hz, 1H), 3.09–
3.02 (m, 1H), 2.97–2.95 (m, 1H), 2.61–2.51 (comp, 3H),
2.52 (s, 3H), 2.31 (s, 3H), 2.22–2.17 (m, 1H). 13C NMR
(CDCl3): l 144.7, 135.6, 133.5, 133.0, 129.8, 129.7, 128.3,
126.7, 125.8, 122.4, 119.8, 117.9, 116.2, 112.1, 62.1, 52.3,
43.7, 26.7, 25.7, 21.5.
.
.