Efficient total synthesis of (-)-cis-clavicipitic acid

Article abstract of DOI:10.1021/jo9012755

An efficient total synthesis of (-)-cis-clavicipitic acid has been achieved in seven linear steps (42% overall yield) from the known compound 6. The present synthesis features a palladium-catalyzed indole synthesis to provide the optically pure 4-chlorotr

Full text of DOI:10.1021/jo9012755

pubs.acs.org/joc
Efficient Total Synthesis of (-)-cis-Clavicipitic Acid
Zhengren Xu,† Qingjiang Li,† Lihe Zhang,† 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 Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, China
FIGURE 1. Structures of (-)-clavicipitic acid.
Due to its unique structure, clavicipitic acid has received
considerable attention from synthetic chemists over the past
three decades, and a number of novel synthetic strategies
have been developed.4-6 In all of its enantioselective synth-
eses, the chief obstacles have been the synthesis of optically
pure 4-substituted tryptophan derivatives and the stereose-
lective construction of the C6 center. In this context, the key
optically pure 4-substituted tryptophan derivatives have
been formed from a preexisting 4-substituted indole, fol-
lowed by introduction of the chiral amino acid moiety via
yxjia@bjmu.edu.cn
Received June 16, 2009
An efficient total synthesis of (-)-cis-clavicipitic acid has
been achieved in seven linear steps (42% overall yield)
from the known compound 6. The present synthesis
features a palladium-catalyzed indole synthesis to pro-
vide the optically pure 4-chlorotryptophan derivative and
a Heck reaction using aryl chloride as partner. It has
also been discovered that the key azepinoindole nucleus
could be stereoselectively constructed via a Mg(ClO4)2-
mediated intramolecular aminocyclization.
asymmetric reduction,5a enzymatic resolution,5b,c Schollkopf’s
€
amino acid synthesis,5d or asymmetric phase-transfer cata-
lytic alkylation.5e In 2007, Park and co-workers reported the
first stereocontrolled synthesis of the C6 center using palla-
dium-catalyzed intramolecular aminocyclization.5e Herein,
we report a highly efficient enantioselective synthesis of
(-)-cis-clavicipitic acid by utilizing a palladium-catalyzed
indole synthesis for the rapid construction of the key opti-
cally pure 4-chlorotryptophan derivative, a palladium-
catalyzed Heck reaction using aryl chloride as partner,
and a one-pot Mg(ClO4)2-mediated tandem deprotection/
aminocyclization reaction for stereoselective construction of
the key azepinoindole nucleus.
Clavicipitic acid, a derailment product of ergot alkaloid
biosynthesis, has been isolated as a mixture of cis-1a and
trans-1b diastereomers (Figure 1) from cultures of the
Claviceps strain SD58 or Claviceps fusiformis. The propor-
tions of 1a and 1b depend on the specific microorganism
from which it was isolated.1,2 The unique tricyclic azepinoin-
dole structure was proposed by King and Waight on the
basis of extensive NMR studies and confirmed by Floss
and Clardy via single-crystal X-ray analysis of the trans-
diastereomer.3
Our retrosynthetic analysis is outlined in Scheme 1. It was
envisioned that clavicipitic acid 1 should be formed by
diastereoselective intramolecular aminocyclization of 2,
which could be obtained from a Pd-catalyzed Heck reaction
of aryl chloride 3 by using bulky, electron-rich phosphine
ligands.7 The optically pure 3 could be directly formed by the
palladium-catalyzed reaction of 4 and 5.8
Our total synthesis of clavicipitic acid commenced with
1-chloro-2-iodo-3-nitrobenzene 6 (Scheme 2), which was pre-
pared from commercially available 1-chloro-3-nitrobenzene
following literature procedures.9 Reduction of the nitro group
(1) (a) Robbers, J. E.; Floss, H. G. Tetrahedron Lett. 1969, 10, 1857–1858.
(b) King, G. S.; Mantle, P. G.; Szczyrbak, C. A.; Waight, E. S. Tetrahedron
Lett. 1973, 14, 215–218. (c) King, G. S.; Waight, E. S.; Mantle, P. G.;
Szczyrbak, C. A. J. Chem. Soc., Perkin Trans. 1 1977, 2099–2103.
(2) Floss, H. G. Tetrahedron 1976, 32, 873–912.
of 6 with SnCl2 2H2O in EtOH gave 3-chloro-2-iodoaniline 4
3
(3) Robbers, J. E.; Otsuka, H.; Floss, H. G.; Arnold, E. V.; Clardy, J.
J. Org. Chem. 1980, 45, 1117–1121.
(4) For total syntheses of racemic clavicipitic acids, see: (a) Kozikowski,
A. P.; Greco, M. N. Heterocycles 1982, 19, 2269–2273. (b) Kozikowski, A. P.;
Greco, M. N. J. Org. Chem. 1984, 49, 2310–2314. (c) Kozikowski, A. P.;
Okita, M. Tetrahedron Lett. 1985, 26, 4043–4046. (d) Muratake, H.;
Takahashi, T.; Natsume, M. Heterocycles 1983, 20, 1963–1968. (e) Nakatsuka,
S.; Masuda, T.; Yamada, K.; Goto, T. Heterocycles 1984, 21, 407. (f )
Matsumoto, M.; Kobayashi, H.; Watanabe, N. Heterocycles 1987, 26, 1197–
1202. (g) Somei, M.; Hamamoto, S.; Nakagawa, K.; Yamada, F.; Ohta, T.
Heterocycles 1994, 37, 719–724. (h) Iwao, M.; Ishibashi, F. Tetrahedron 1997,
53, 51–58.
(6) For synthetic efforts to clavicipitic acids, see: (a) Harrington, P. J.;
Hegedus, L. S.; McDaniel, K. F. J. Am. Chem. Soc. 1987, 109, 4335–4338. (b)
Boyles, D. A.; Nichols, D. E. J. Org. Chem. 1988, 53, 5128–5130. (c)
Semmelhack, M. F.; Knochel, P.; Singleton, T. Tetrahedron Lett. 1993, 34,
5051–5054.
(7) For reviews of palladium-catalyzed cross-coupling reactions of aryl
chlorides, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176–4211. (b) Fu, G. C. J. Org. Chem. 2004, 69, 3245–3249. (c) Martin, R.;
Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–1473.
(5) For total syntheses of optically 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.;
Murakami, Y. Tetrahedron Lett. 1999, 40, 7803–7806. (c) Yokoyama, Y.;
Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J.
Org. Chem. 2004, 1244–1253. (d) Shinohara, H.; Fukuda, T.; Iwao, M.
Tetrahedron 1999, 55, 10989–11000. (e) Ku, J.-M.; Jeong, B.-S.; Jew, S.-s.;
Park, H.-g. J. Org. Chem. 2007, 72, 8115–8118.
(8) (a) Jia, Y.; Zhu, J. Synlett 2005, 2469–2472. (b) Jia, Y.; Zhu, J. J. Org.
€
Zhang, L.; Jia, Y. Synthesis 2008, 3981–3987. (d) Jia, Y.; Bois-Choussy, M.;
Zhu, J. Org. Lett. 2007, 9, 2401–2404. (e) Jia, Y.; Bois-Choussy, M.; Zhu, J.
Angew. Chem., Int. Ed. 2008, 47, 4167–4172.
(9) (a) Sohn, J.; Kiburz, B.; Li, Z.; Deng, L.; Safi, A.; Pirrung, M. C.;
Rudolph, J. J. Med. Chem. 2003, 46, 2580–2588. (b) Seko, S.; Kawamura, N.
J. Org. Chem. 1996, 61, 442–443.
Chem. 2006, 71, 7826–7834. (c) Xu, Z.; Hu, W.; Zhang, F.; Li, Q.; Lu, Z.;
DOI: 10.1021/jo9012755
r
Published on Web 07/29/2009
J. Org. Chem. 2009, 74, 6859–6862 6859
2009 American Chemical Society

Xu et al.
JOCNote
SCHEME 1. Retrosynthesis of Clavicipitic Acid
TABLE 1. Palladium-Catalyzed Vinylation of 3
entry
ligand
base
solvent
yield
1
2
3
4
(t-Bu3P)HBF4
XPhos
JohnPhos
Cyclohexyl
JohnPhos
PCy3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
23
18
23
20
5
6
K2CO3
t-
dioxane
dioxane
48
45
PCy3
SCHEME 2. Total Synthesis of (-)-Clavicipitic Acid
BuOK
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
7
8
9
10
11
a
PCy3
PCy3
PCy3
PCy3
PCy3
dioxane
dioxane
DMSO
DMA
25
26
20
18
23
CH3CN
General reaction conditions: concentration 0.06 M in solvent, 0.10
equiv of Pd(OAc)2, 0.20 equiv of ligand, 1.0 equiv of 3, 50 equiv of
2-methyl-3-buten-2-ol, 1.2 equiv of base, 120 °C. b Isolated yield.
To our delight, the yield could be increased to 80% by
using 2 equiv of 4, 45% of which was recovered and could
be reused.
The stage was now set for the investigation of the key Heck
reaction of 3 with 2-methyl-3-buten-2-ol. Heck reactions of
similar substrates, either 4-iodotryptophan derivative5e or
4-bromotryptophan derivatives,5a-c,6a have been achieved.
However, aryl chlorides are generally unreactive under
the conditions employed to couple bromides or iodides.
Although remarkable progress has been achieved in the
palladium-catalyzed Heck reaction of aryl chlorides in the
presence of the electron-rich and bulky phosphine ligands,7
only a limited number of these catalytic processes have been
applied to the coupling of highly deactivated (electron-rich)
aryl chlorides with deactivated (electron-rich) alkenes.13
A
wide variety of reaction conditions (ligands, bases, and
solvents) were examined, and some of the representative
results are shown in Table 1. Of the ligands examined
(entries 1-5), Cy3P was the most efficient. Among the bases
tested, K2CO3 was the best one, although t-BuOK was also
capable of promoting the reaction (entry 6). Dioxane could
promote the reaction greatly in comparison with other
solvents used (entries 8-11). In all cases, the major side
product frequently observed is the dechlorinated starting
material, resulting from a reductive process. It was note-
worthy that 50 equiv of alkenol and relatively dilute reaction
concentration (0.06 M) were also critical.
Subsequent selective cleavage of mono-Boc from di-Boc in
2 was proven to be challenging due to the electron-rich indole
ring. In addition, the desired product 2 was only achieved in
48% yield in the aforementioned Heck reaction. We envi-
sioned that the coordination of the lone pair electrons on the
indole nitrogen to palladium at some point of the catalytic
cycle would influence the efficiency of this reaction. Taking
in 98% yield.10 Palladium-catalyzed reaction of 4 with (S)-2-
N,N-di-tert-butoxycarbonyl-5-oxopentane 511 according to
the recently developed conditions afforded the protected
4-chlorotryptophan derivative 3 in 50% isolated yield.12
(10) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839–842.
ꢀ
(11) (a) Kokotos, G.; Padron, J. M.; Martı
V. S. J. Org. Chem. 1998, 63, 3741–3744. (b) Padron, J. M.; Kokotos, G.;
Martın, T.; Markidis, T.; Gibbons, W. A.; Martın, V. S. Tetrahedron:
Asymmetry 1998, 9, 3381–3394.
n, T.; Gibbons, W. A.; Martın,
´ ´
ꢀ
´
´
(12) The syntheses of 4-chlorotryptophan derivatives have been reported;
see: (a) Sakagami, Y.; Manabe, K.; Aitani, T.; Thiruvikraman, S. V.;
Marumo, S. Tetrahedron Lett. 1993, 34, 1057–1060. (b) Nishikawa, T.; Kajii,
S.; Wada, K.; Ishikawa, M.; Isobe, M. Synthesis 2002, 1658–1662.
(13) Yi, C.; Hua, R. Tetrahedron Lett. 2006, 47, 2573–2576.
6860 J. Org. Chem. Vol. 74, No. 17, 2009

Xu et al.
JOCNote
into consideration the two problematic reactions, an elec-
tron-withdrawing group was next planned to be introduced
at the indole nitrogen to reduce these effects.
compound 6. The 42% overall yield represents the highest
one. It was also discovered that the intramolecular amino-
cyclization could be mediated by Mg(ClO4)2, leading to the
azepinoindole nucleus. Key elements include a palladium-
catalyzed method for the synthesis of the optically pure
4-chlorotryptophan derivative, a Heck reaction using aryl
chloride as partner, and a one-pot Mg(ClO4)2-mediated
tandem deprotection/aminocyclization reaction. To the best
of our knowledge, this is the first example that aryl chloride
was used as the Heck reaction partner in natural product
total synthesis.
Treatment of 3 with Boc2O in the presence of DMAP gave
7 in 98% yield. As anticipated, a Heck reaction of 7 under the
aforementioned optimized conditions provided 8 in 75%
yield. Selective cleavage of mono-Boc in 8 was easily success-
ful using Mg(ClO4)2 in CH3CN at room temperature.14
Unexpectedly, during the deprotection using Mg(ClO4)2,
a small amount of the cyclization product 9 was isolated.
This result indicated that a cascade one-pot version of
Mg(ClO4)2-promoted deprotection/cyclization could be
achieved, thus streamlining the synthesis.15 After several
attempts, the one-pot process could be performed with a
catalytic amount of Mg(ClO4)2 in CH3CN at reflux for 2 h,
affording the cis-9a and trans-9b in 98% overall yield in a
ratio of 5:1, respectively. The diastereomeric product of cis-
9a and trans-9b, both of which appear as a pair of distinct
rotamers, could be separated by careful flash column chro-
matography, and their relative conformations were deduced
by the NOESY spectrum. The yield is higher and the
diastereoselectivity is similar to those reported using PdCl2-
(CH3CN)2 in a similar substrate.5e
Although, we cannot rationalize the exact mechanism of
Mg(ClO4)2-mediated cyclization, it is reasonable to postu-
late that the magnesium cation, acting as a mild Lewis acid,
first coordinates to the alcohol oxygen and activates the
allylic alcohol, thus facilitating the intramolecular SN20
substitution reaction. To the best of our knowledge, this is
the first example that Mg(ClO4)2 is used in such a carbon-
nitrogen bond-formation process.16 Its diastereoselectivity
may be due to the steric interactions between the allylic
methyl groups and the methyl ester group in the transition
state, similar to that of Park’s explanations.5e
The final deprotection of the two Boc groups in 9 proved
to be especially challenging. Under normal conditions, either
a partial epimerization at the C(6)-position occurred or a
complex mixture was obtained. After extensive trials, the
problem was finally overcome by first deprotection of N(5)-
Boc in 9a with TMSOTf in the presence of 2,6-lutidine (95%
yield),17 followed by deprotection of the Boc group at the
indole nitrogen and saponification of methyl ester with
K2CO3 in MeOH/H2O (3:1) to provide the target molecule
1a in 95% yield and without any epimerization.18,19 Mean-
while, 9b could be converted to 1b following the same
synthetic scheme as described for 9a. Spectroscopic data
for the synthetic materials were identical in all respects to
those reported for the natural products.
Experimental Section
Compound 8. A mixture of 7 (300 mg, 0.54 mmol), 2-methyl-3-
buten-2-ol (2.33 g, 27.12 mmol), and K2CO3 (89 mg, 0.65 mmol)
in dry dioxane (9.0 mL, 0.06 M) was degassed for 20 min.
Pd(OAc)2 (12.1 mg, 0.054 mmol) and PCy3 (30.2 mg, 0.108
mmol) were added to the reaction, and the resulting reaction
mixture was heated at 120 °C under argon atmosphere for 12 h.
After cooling, the solvent was evaporated under reduced pres-
sure and purified by FCC (PE-EtOAc, 3:1) to give 8 (243 mg,
75%) as white foam: [R]23 -21.4 (c 1.00, CHCl3); IR (KBr)
D
3433, 2979, 1738, 1424, 1370, 1283, 1255, 1141, 1094, 966, 853,
757 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 7.5 Hz,
1H), 7.15-7.28 (m, 4H), 6.19 (d, J = 15.3 Hz, 1H), 5.13 (dd, J =
2.7, 10.8 Hz, 1H), 3.83 (dd, J = 2.7, 15.0 Hz, 1H), 3.75 (s, 3H),
3.30 (dd, J = 10.8, 15.0 Hz, 1H), 2.42 (br s, 1H), 1.62 (s, 9H),
1.41 (s, 3H), 1.36 (s, 3H), 1.25 (s, 18H); 13C NMR (75 MHz,
CDCl3) δ 171.5, 151.6, 149.4, 141.7, 136.3, 131.9, 127.2, 125.3,
124.5, 123.8, 121.4, 116.7, 114.3, 83.5, 82.9, 70.8, 58.6, 52.4, 29.6,
29.5, 28.0, 27.6, 27.4; HRMS (ESI) m/z calcd for C32H46N2O9-
Na (M þ Na)þ 625.3096, found 625.3088.
Compounds 9a (cis) and 9b (trans). A stirred solution of 8 (500
mg, 0.83 mmol) and Mg(ClO4)2 (111 mg, 0.50 mmol) in CH3CN
(12.0 mL) was heated to reflux for 2 h. The reaction was allowed
to cool and evaporated to dryness. Careful purification by FCC
(PE-EtOAc, 10:1) afforded the cis-form 9a (328.5 mg, 82%)
and trans-form 9b (65.4 mg, 16%). cis-Form 9a: white foam,
[R]23D -157.3 (c 1.00, CHCl3); IR (KBr) 3435, 2977, 2931, 1740,
1698, 1425, 1383, 1369, 1349, 1287, 1251, 1161, 1106, 971, 916,
1
867, 784, 754 cm-1; H NMR (300 MHz, CDCl3) showed the
presence of two conformers in a ratio of 1/2.2, δ 8.06-8.11 (m,
1H, both), 7.45 (br s, 1H, both), 7.22-7.27 (m, 1H, both), 7.02
(d, J = 7.5 Hz, 1H, major), 6.96 (d, J = 7.5 Hz, 1H, minor), 6.41
(d, J = 6.9 Hz, 1H, major), 6.15 (d, J = 6.0 Hz, 1H, minor), 5.25
(br s, 1H, minor), 5.17 (d, J = 6.3 Hz, 1H, major), 4.36 (dd, J =
3.6, 11.4 Hz, 1H, both), 3.75 (s, 3H, major), 3.74 (s, 3H, minor),
3.40-3.63 (m, 2H, both), 1.88 (s, 3H, both), 1.77 (s, 3H, minor),
1.75 (s, 3H, major), 1.66 (s, 9H, both), 1.40 (s, 9H, major), 1.37
(s, 9H, minor); 13C NMR (75 MHz, CDCl3) major conformer
shown δ 171.6, 153.5, 149.5, 139.8, 137.5, 136.5, 126.7, 124.3,
124.0, 123.3, 121.4, 116.5, 113.4, 83.4, 80.7, 57.0, 55.6, 51.8, 28.1,
28.0, 27.2, 25.5, 18.6; HRMS (ESI) m/z calcd for C27H37N2O6
(M þ H)þ 485.2646, found 485.2650. trans-Form 9b: white foam;
[R]23D 105.0 (c 0.85, CHCl3); IR (KBr) 3436, 2974, 2928, 1736,
1695, 1439, 1389, 1317, 1303, 1284, 1167, 1106, 1049, 967, 952,
In conclusion, an efficient total synthesis of (-)-cis-clavi-
cipitic acid was achieved in seven linear steps from the known
ꢀ
(14) Hernandez, J. N.; Ramı
rez, M. A.; Martın, V. S. J. Org. Chem. 2003,
´ ´
68, 743–746.
864, 760 cm-1 1H NMR (300 MHz, CDCl3) showed the
;
(15) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136. (b) Denmark, S. E.;
Thorarensen, A. Chem. Rev. 1996, 96, 137–165. (c) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186.
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(19) No diastereomers of the final products were detected in the NMR
spectrum in cis-10a or trans-10b cases under such basic conditions.
presence of two conformers in a ratio of 1/1, δ 7.92-7.98 (m,
1H ꢀ 2), 7.43 (s, 1H), 7.41 (s, 1H), 7.16-7.24 (m, 1H ꢀ 2), 7.08
(d, J = 7.2 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.42 (d, J = 8.1 Hz,
1H), 6.03 (d, J = 8.1 Hz, 1H), 5.39 (d, J = 8.1 Hz, 1H), 5.36 (d,
J = 8.1 Hz, 1H), 5.16 (dd, J = 6.9, 12.3 Hz, 1H), 4.74 (dd, J =
5.1, 12.9 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.50-3.60 (m, 1H ꢀ
2), 3.35 (dd, J = 6.6, 15.6 Hz, 1H), 3.25 (dd, J = 4.8, 15.6 Hz,
1H), 1.86 (s, 3H ꢀ 2), 1.71 (s, 3H ꢀ 2), 1.65 (s, 9H ꢀ 2), 1.34 (s,
9H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) both conformers
J. Org. Chem. Vol. 74, No. 17, 2009 6861

Xu et al.
JOCNote
shown δ 173.2, 172.9, 155.6, 154.9, 149.74, 149.68, 139.7, 139.2,
137.7, 137.2, 136.1, 135.9, 128.5, 128.4, 124.7, 124.6, 124.2,
123.3, 122.5, 122.0, 121.0, 120.4, 117.1, 116.7, 114.14, 114.07,
83.6, 83.5, 80.5, 80.4, 60.2, 57.5, 55.8, 52.1, 51.9, 28.1, 27.1, 26.8,
25.6, 25.5, 18.8, 18.5; HRMS (ESI) m/z calcd for C27H37N2O6
(M þ H)þ 485.2646, found 485.2640.
20842004, 20802005), and The Scientific Research Founda-
tion for Returned Overseas Chinese Scholars (State Educa-
tion Ministry) are greatly appreciated.
Supporting Information Available: Experimental proce-
dures and physical data for compounds 1a,b, 2-4, 7, and 10a,b
and copies of spectra for compounds 1a,b, 2-4, 7, 8, 9a,b, and
10a,b. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support from Peking Uni-
versity, National Science Foundation of China (NO.
6862 J. Org. Chem. Vol. 74, No. 17, 2009