Direct olefination at the C-4 position of tryptophan via C-H activation: Application to biomimetic synthesis of clavicipitic acid

Article abstract of DOI:10.1021/ol4020877

The first Pd-catalyzed method for direct olefination at the C4 position of tryptophan derivatives has been developed via C-H activation to prepare 4-substituted tryptophans, which could be used for the synthesis of many hemiterpenoid indole alkaloids. This reaction proceeds under mild reaction conditions and with exceptional tolerance to a variety of functional groups. Furthermore, the efficiency of this method is demonstrated by the rapid and biomimetic synthesis of clavicipitic acid.

Full text of DOI:10.1021/ol4020877

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Olefination at the C‑4 Position
of Tryptophan via CꢀH Activation:
Application to Biomimetic Synthesis
of Clavicipitic Acid
Qiang Liu,†,§ Qingjiang Li,†,§ Yongfan Ma,† and Yanxing Jia*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China, and State Key
Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy
of Sciences, Shanghai 201203, China
yxjia@bjmu.edu.cn
Received July 24, 2013
ABSTRACT
The first Pd-catalyzed method for direct olefination at the C4 position of tryptophan derivatives has been developed via CꢀH activation to prepare
4-substituted tryptophans, which could be used for the synthesis of many hemiterpenoid indole alkaloids. This reaction proceeds under mild
reaction conditions and with exceptional tolerance to a variety of functional groups. Furthermore, the efficiency of this method is demonstrated by
the rapid and biomimetic synthesis of clavicipitic acid.
Tryptophan-derived hemiterpenoid indole alkaloids, re-
presented by the ergot alkaloids, have been considered
attractive synthetic targets because of their unique struc-
tures and potent biological activities.1 Indeed, several ergot
alkaloids and their synthetic analogues are useful thera-
peutics for human diseases.2 One of these compounds, the
lysergic acid diethylamide (LSD), is strongly and notori-
ously psychoactive. The commonly accepted biosynthesis
pathway for the ergot alkaloids is initiated by prenylation of
tryptophan with dimethylallyl pyrophosphate (1) (DMAPP)
to yield 4-dimethylallyltryptophane (2) (DMAT).3 Subsequent
transformations led to different classes of ergot alkaloids
(Scheme 1). The prenylation step is believed to be the rate-
limiting step catalyzed by an enzyme.4
Optically pure 4-substituted tryptophan derivatives
have been widely used as critical intermediates for the
synthesis of the ergot alkaloids and 3,4-fused indole
alkaloids.5ꢀ11 Classic approaches to the synthesis of these
skeletons mainly involve three general strategies (Scheme 2):
(1) palladium-catalyzed indole synthesis of o- haloanilines
5 and aldehydes or alkynes (path a);5bꢀe,9 (2) direct func-
tionalization at the reactive C3 position of an existing
(4) (a) Lee, S.-L.; Floss, H. G.; Heinstein, P. Arch. Biochem. Biophys.
1976, 177, 84–94. (b) Cress, W. A.; Chayet, L. T.; Rilling, H. C. J. Biol.
Chem. 1981, 256, 10917–10923. (c) Gebler, J. C.; Woodside, A. B.;
Poulter, C. D. J. Am. Chem. Soc. 1992, 114, 7354–7360. (d) Luk, L. Y. P.;
Tanner, M. E. J. Am. Chem. Soc. 2009, 131, 13932–13933.
(5) For selected applications of optically pure 4-substituted trypto-
phan derivatives in the total synthesis of nature products, see: (a) Inoue,
T.; Yokoshima, S.; Fukuyama, T. Heterocycles 2009, 79, 373–378. (b)
Liu, Q.; Jia, Y. Org. Lett. 2011, 13, 4810–4813. (c) Xu, Z.; Li, Q.; Zhang,
L.; Jia, Y. J. Org. Chem. 2009, 74, 6859–6862. (d) Xu, Z.; Hu, W.; Liu,
Q.; Zhang, L.; Jia, Y. J. Org. Chem. 2010, 75, 7626–7635. (e) Xu, Z.;
Zhang, F.; Zhang, L.; Jia, Y. Org. Biomol. Chem. 2011, 9, 2512–2517. (f)
Zhang, Y.; Liu, Q.; Wang, C.; Jia, Y. Org. Lett. 2013, 15, 3662–3665.
† Peking University.
‡ Chinese Academy of Sciences.
§ These authors contributed equally.
(1) (a) The Merck Index, 12th ed.; Merck and Co., Inc.: Whitehouse
Station, NY, 1996; p 231. (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 191ꢀ257.
(2) Mukherjee, J.; Menge, M. Adv. Biochem. Eng. Biotechnol. 2000,
68, 1–20.
(3) (a) Floss, H. G. Tetrahedron 1976, 32, 873–912. (b) Floss, H. G.;
Anderson, J. A. In The Biosynthesis of Mycotoxins; Steyn, P. S., Ed.;
Academic Press: New York, 1980; pp 17ꢀ67.
r
10.1021/ol4020877
XXXX American Chemical Society

Scheme 1. Ergot Alkaloid Biosynthesis Pathway
Scheme 2. Synthesis of Optically Pure C4-Substituted Trypto-
phan Derivatives
4-substituted indole nucleus 6 (path b);10 (3) nitration of
the C4 position of tryptophan derivatives 7 containing the
carbonyl group at the C3 position (path c).11 However, the
preparation of the special substrates such as aldehydes,
alkynes, 4-substituted indoles 6, and functionalized tryp-
tophans 7 normally require a multistep synthesis. Thus, the
development of a general synthetic method for the rapid
synthesisof these skeletonsinasingleoperation remainsan
important challengefor organicchemists. Infact, the direct
functionalization of the C4 position of the tryptophan
derivatives 9 by using the naturally abundant tryptophan
as starting material is an ideal route (Scheme 2). However,
the selective functionalization of the less reactive C4 posi-
tion of tryptophan is extremely difficult since most electro-
philes prefer attacking the C2 position. Therefore, although
thedirectintroductionofsucha substituent attheC4position
of tryptophan has been studied for a long time, no successful
method except the Witkop photocyclization was reported.12
Transition-metal-catalyzed direct CꢀH activation pre-
sents a powerful and economical way to construct CꢀC
bonds without prior functionalization, and some success-
ful applications of CꢀH activation for the total synthesis
of complex natural products are emerging.13 With our
ongoing study on the efficient synthesis of indole alkaloids,
and inspired by Yu’s work,14a we took the challenge to
functionalize directly the less reactive C4 position of
tryptophan 9. We faced two challenges to achieve this
transformation (Scheme 2): (1) Selection of a proper
directing group on the amino group to enhance reactivity
and direct metalation to the C4 position of tryptophan; (2)
protecting the nitrogen of indole with a bulky protective
group to improve the site selectivity at the C4 position.
Herein, we describe the development of a Pd(OAc)2-
catalyzed method for the regioselective and direct olefina-
tion of tryptophan via CꢀH activation to access the
4-substituted tryptophan derivatives and application of
this method to the biomimetic synthesis of clavicipitic acid.
We initiated our studies by examining different directing
groups and protecting groups under Yu’s conditions
(6) For the synthesis of 4-substituted tryptophan derivatives by
rearrangement, see: (a) Schwarzer, D. D.; Gritsch, P. J.; Gaich, T.
Angew. Chem., Int. Ed. 2012, 51, 11514–11516. (b) Bailey, P. D.;
Cochrane, P. J.; Irvine, F.; Morgan, K. M.; Pearson, D. P. J.; Veal,
K. T. Tetrahedron Lett. 1999, 40, 4593–4596. (c) Nyong, A. M.; Rainier,
J. D. J. Org. Chem. 2005, 70, 746–748.
(7) For the synthesis of 4-substituted tryptophan derivatives by enzy-
matic resolution, see: (a) Meseguer, B.; Alonso-Dı
Herget, T.; Waldmann, H. Angew. Chem., Int. Ed. 1999, 38, 2902–2906.
(b) Meseguer, B.; Alonso-Dıaz, D.; Griebenow, N.; Herget, T.; Waldmann,
´
az, D.; Griebenow, N.;
´
H. Chem.;Eur. J. 2000, 6, 3943–3957.
(8) Other examples for the synthesis of 3,4-disubstituted tryptophan
derivatives, see: (a) Shan, D.; Gao, Y.; Jia, Y. Angew. Chem., Int. Ed.
2013, 52, 4902–4905. (b) Fisher, E. L.; Wilkerson-Hill, S. M.; Sarpong,
R. J. Am. Chem. Soc. 2012, 134, 9946–9949. (c) Davies, H. M. L.;
Manning, J. R. J. Am. Chem. Soc. 2006, 128, 1060–1061. (d) Kalinin,
A. V.; Chauder, B. A.; Rakhit, S.; Snieckus, V. Org. Lett. 2003, 5, 3519–
3521. (e) Koizumi, Y.; Kobayashi, H.; Wakimoto, T.; Furuta, T.;
Fukuyama, T.; Kan, T. J. Am. Chem. Soc. 2008, 130, 16854–16855. (f)
Lim, H. J.; Gallucci, J. C.; RajanBabu, T. V. Org. Lett. 2010, 12, 2162–
2165. (g) Shan, D.; Jia, Y. Chin. J. Org. Chem. 2013, 33, 1144–1156.
(9) (a) Jia, Y.; Zhu, J. Synlett 2005, 2469–2472. (b) Jia, Y.; Zhu, J.
J. Org. Chem. 2006, 71, 7826–7834. (c) Ma, J.; Yin, W.; Zhou, H.; Cook,
J. M. Org. Lett. 2007, 9, 3491–3494. (d) Ma, J.; Yin, W.; Zhou, H.; Liao,
X.; Cook, J. M. J. Org. Chem. 2009, 74, 264–273.
(10) (a) Kieffer, M. E.; Repka, L. M.; Reisman, S. E. J. Am. Chem.
Soc. 2012, 134, 5131–5137. (b) Bronner, S. M.; Goetz, A. E.; Garg, N. K.
J. Am. Chem. Soc. 2011, 133, 3832–3835. (c) Bronner, S. M.; Goetz,
A. E.; Garg, N. K. Synlett. 2011, 2599–2604. (d) Arai, T.; Awata, A.;
Wasai, M.; Yokoyama, N.; Masu, H. J. Org. Chem. 2011, 76, 5450–5456.
(e) Goss, R. J. M.; Newill, P. L. A. Chem. Commun. 2006, 4924–4925. (f)
Sui, Y.; Liu, L.; Zhao, J.-L.; Wang, D.; Chen, Y.-J. Tetrahedron 2007,
63, 5173–5183. (g) Yokoyama, Y.; Osanai, K.; Mitsuhashi, M.;
Kondo, K.; Murakami, Y. Heterocycles 2001, 55, 653–659. (h) Sato, K.;
Kozikowski, A. P. Tetrahedron Lett. 1989, 30, 4073–4076. (i) Semmelhack,
M. F.; Rhee, H. Tetrahedron Lett. 1993, 34, 1395–1398. (j) Shinohara, H.;
Fukuda, T.; Iwao, M. Tetrahedron 1999, 55, 10989–11000.
(12) (a) Yonemitsu, O.; Cerutti, P.; Witkop, B. J. Am. Chem. Soc.
1966, 88, 3941–3945. (b) Kobayashi, T.; Spande, T. F.; Aoyagi, H.;
Witkop, B. J. Med. Chem. 1969, 12, 636–638. (c) Mascal, M.; Moody,
C. J.; Slawin, A. M. Z.; Williams, D. J. J. Chem. Soc., Perkin Trans. 1
1992, 823–830. (d) For a recent application of Witkop photocyclization,
see: Hu, W.; Qin, H.; Cui, Y.; Jia, Y. Chem.;Eur. J. 2013, 19, 3139–
3147and references therein.
(13) (a) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011,
40, 1885–1898. (b) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40,
1976–1991. (c) Chen, D. Y.-K.; Youn, S. W. Chem.;Eur. J. 2012, 18, 9452–
9474. (d) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int.
Ed. 2012, 51, 8960–9009. (e) Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc.
2011, 133, 5767–5769. (f) Wang, H.; Li, G.; Engle, K. M.; Yu, J.-Q.; Davies,
H. M. L. J. Am. Chem. Soc. 2013, 135, 6774–6777.
(11) (a) Nakatsuka, S.; Masuda, T.; Sakai, K.; Goto, T. Tetrahedron
Lett. 1986, 27, 5735–5738. (b) Kogan, T. P.; Somers, T. C.; Venuti, M. C.
Tetrahedron 1990, 46, 6623–6632.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditionsa
Scheme 3. Summary of the Substrate Scope
entry
oxidant
Ag2CO3
solvent
yield [%]b
1
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
DMF
28
2
Cu(OAc)2 H2O
9
3
3
AgOAc
PhI(OAc)2
BQ
42
4
0
5
4
6
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
0
7
CH3CN
21
8
HOAc
0
9
toluene
48
10c
11d
12e
toluene
91 (88)
40
toluene
toluene
78
a General reaction conditions: 11a (0.1 mmol, 0.1 M in solvent), 12a
(0.5 mmol), Pd(OAc)2 (0.01 mmol), oxidant (0.25 mmol), 100 °C for
8ꢀ16 h. b Yields determined by 400 MHz NMR using 1,3,5-trimethoxy-
benzene as the internal standard; isolated yield in parentheses. c Reac-
tion works under Ar. d 5 mol % Pd(OAc)2 was employed. e Reaction
works at 80 °C under Ar.
a Condition A: olefin (5.0 equiv), Pd(OAc)2 (10 mol %), AgOAc
(2.5 equiv), toluene, Ar, 100 °C, 16ꢀ72 h, 0.1 M. b Condition B: olefi1n
(5.0 equiv), Pd(OAc)2 (20 mol %), AgOAc (2.5 equiv), toluene, Ar, 100 °C,
(20 mol % Pd(OAc)2, 2.5 equiv of AgOAc, 4 equiv of
methyl acrylate, DMF/DCE = 1:10, 130 °C). BocNHꢀ,
CF3CONHꢀ, and TrocNHꢀ as directing groups to assist
CꢀH activation did not give satisfactory yields of the
desired products. However, the TfNHꢀ directing group
was found to give complete conversion with an acceptable
yield.14 The protection of the indole nitrogen with the bulky
TIPS group enhanced the site selectivity at the C4 position
more efficiently than the Piv and Boc protecting groups.15
Consequently, TIPS for the protection of the indole nitrogen
and TfNHꢀ as the directing group were used for the
regioselective olefination of tryptophan at the C4 position.
After determining the optimal combination of the direct-
ing group and protecting group, we turned our attention to
optimization of the reaction conditions. N-Triisopropylsilyl-
N-trifluoromethylsulfonamide tryptophan methyl ester 11a
and methyl acrylate 12a were employed as model substrates.
A wide variety of reaction conditions (oxidants, solvents)
were examined, and some of the representative results are
shown in Table 1. AgOAc was the best oxidant (entry 3),
c
72ꢀ140 h, 0.1 M. Yield based on recovered starting material in
parentheses.
transformation yield (entry 10). When the reaction was
conducted at a lower temperature (80 °C) or the catalyst
loading was reduced to 5 mol %, a significant decrease of the
yield was observed (entries 11ꢀ12).
With the optimized conditions in hand, we next investi-
gated the substrate scope of this reaction (Scheme 3). We
found that unsubstituted tryptophan substrates gave mod-
erate tohigh yields witha broadscope ofolefins (Scheme 3,
13aꢀ13i). Both aliphatic and aromatic olefins (Scheme 3,
13g) reacted smoothly. The presence of functional group1s
on the olefins including ester, ketone, amide, nitrile, benzene-
sulfonyl, and dimethoxy phosphoryl groups did not affect
the transformation (Scheme 3, 13aꢀ13i). The electron-
withdrawing groups on tryptophan slowed the reaction,
but products were still isolated in moderate yields based on
the recovered starting materials (Scheme 3, 13j and 13k).
Having established the methodology for the direct func-
tionalization at the C4 position of tryptophan derivatives,
we began to explore the feasibility of our original goal of
biomimetic synthesis of tryptophan-derived hemiterpene
indole alkaloids. Clavicipitic acid was selected as the target
(Scheme 4).5c,d,16 The synthesis commenced with 11a.
According to the biosynthesis of clavicipitic acid, a five
carbon unit should be used for cyclization to afford an
azepinoindole intermediate. Under our standard reaction
conditions, compound 11a and 2-methyl-3-buten-2-ol (14)
reacted smoothly, generating the allyl alcohol 15 in 17%
albeit Ag2CO3, Cu(OAc)2 H2O, and BQ (1,4-benzoquinone)
3
were also capable of promoting the reaction but with lower
yields (entries 1ꢀ2 and 4ꢀ5). The solvent also played an
important role. The use of toluene afforded a higher yield
(entry 9). Degassing would dramatically improve the
(14) (a) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008,
47, 6452–6455. (b) Vickers, C. J.; Mei, T.-S.; Yu, J.-Q. Org. Lett. 2010,
12, 2511–2513. (c) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc.
2009, 131, 10806–10807.
(15) (a) Beswick, P. J.; Greenwood, C. S.; Mowlem, T. J.; Nechvatal,
G.; Widdowson, D. A. Tetrahedron 1988, 44, 7325–7334. (b) Beck,
E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc.
2006, 128, 2528–2529.
Org. Lett., Vol. XX, No. XX, XXXX
C

product 16.16c,17 AgOAc was shown to be an effective
catalyst in this cyclization. To the best of our knowledge,
this was the first report that AgOAc catalyzed an intra-
molecular amination reaction of allylic alcohol. Treatment
of compound trans-16 with tert-BuOK in DMSO at room
temperature resulted in the simultaneous elimination of
trifluoromethanesulfonic acid and deprotection of triiso-
propylsilyl to afford enamine 17 in 80% yield.18 The reduc-
tion of an inert conjugated double bond in 17 presented a
considerable challenge.17a,19 After many conditions were
screened, enamine 17 was reduced with Mg in dry methanol
to give cis-ester 18 in 36% yield and trans-ester 19 in 44%
yield. Alkaline hydrolysis of cis-18 and trans-19 furnished
(þ)-cis-clavicipitic acid 20 and (ꢀ)-trans-clavicipitic acid 21,
respectively, according to the literature procedure.5c,d,16a
In summary, we have developed the first site-selective
Pd-catalyzed method for the direct olefination of trypto-
phan via CꢀH bond activation, which allows access to
3,4-disubstituted indole derivatives directly. A broad range
of terminal olefins and tryptophan derivatives can be
coupled in good yields. Based on this transformation, the
rapid biomimetic total synthesis of (þ)-cis- and (ꢀ)-trans-
clavicipitic acid was achieved. This methodology could
provide a facile means for accessing 3,4-disubstituted indole
alkaloids.
Scheme 4. Total Synthesis of Clavicipitic Acid
yield and 46% yield based on recovered starting material,
along with cyclized product 16 (trans/cis = 8:1) in 14%
yield and 38% yield based on recovered starting material.
It was noteworthy that a tandem olefination/aminocycliza-
tion sequence was found in this reaction, which was similar to
the biosynthetic process. Surprisingly, Pd-mediated cycliza-
tion conditions could not convert alcohol 15 to cyclized
Acknowledgment. This research was supported by the
National Natural Science Foundation of China (Nos.
21290180, 20972007), the National Basic Research Pro-
gramofChina(973 Program, No. 2010CB833200), and the
State Key Laboratory of Drug Research.
Supporting Information Available. Experimental pro-
cedures and analytical data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) For a recent total synthesis of optical active clavicipitic acids,
see: (a) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem.
1995, 60, 1486–1487. (b) Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.;
Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem. 2004, 1244–
1253. (c) Ku, J.-M.; Jeong, B.-S.; Jew, S.-s.; Park, H.-g. J. Org. Chem.
2007, 72, 8115–8118.
(17) (a) Harrington, P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am.
Chem. Soc. 1987, 109, 4335–4338. (b) Yokoyama, H.; Otaya, K.;
Kobayashi, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Org. Lett.
2000, 2, 2427–2429. (c) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett.
2003, 5, 27–29. (d) Hande, S. M.; Kawai, N.; Uenishi, J. J. Org. Chem.
2009, 74, 244–253.
(18) Shoji, T.; Yokoyama, R.; Ito, S.; Watanabe, M.; Toyota, K.;
Yasunami, M.; Morita, N. Tetrahedron Lett. 2007, 48, 1099–1103.
(19) Muratake, H.; Takahashi, T.; Natsume, M. Heterocycles 1983,
20, 1963–1968.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX