Enantioselective synthesis of (-)-cis-clavicipitic acid

Article abstract of DOI:10.1021/jo071162h

(Chemical Equation Presented) An enantioselective synthetic method for (-)-cis-clavicipitic acid (1) was reported. 1 was obtained in 10 steps (99% ee and 20% overall yield) from 1H-indole-3-carboxylic acid methyl ester (9) via asymmetric phase-transfer ca

Full text of DOI:10.1021/jo071162h

activity of 1, we need to develop an efficient synthetic method.
So far there have been several enantioselective synthetic
methods, but the chemical yield or enantioselectivities were not
suitable for large-scale preparation and the stereocontrolled
synthesis of the C(10)-position was not reported.3,4 In this note,
we report a new efficient enantioselective synthesis of (-)-cis-
clavicipitic acid via asymmetric phase-transfer catalytic alky-
lation for C(5S) chirality and diastereoselective Pd(II)-catalyzed
intramolecular aminocyclization for C(10S) chirality.
Enantioselective Synthesis of (-)-cis-Clavicipitic
Acid
Jin-Mo Ku,† Byeong-Seon Jeong,‡ Sang-sup Jew,*,† and
Hyeung-geun Park*,†
Research Institute of Pharmaceutical Science and College of
Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea,
and College of Pharmacy, Yeungnam UniVersity,
Gyeongsan 712-749, Korea
SCHEME 1
hgpk@snu.ac.kr
ReceiVed June 1, 2007
An enantioselective synthetic method for (-)-cis-clavicipitic
acid (1) was reported. 1 was obtained in 10 steps (99% ee
and 20% overall yield) from 1H-indole-3-carboxylic acid
methyl ester (9) via asymmetric phase-transfer catalytic
alkylation and diastereoselective Pd(II)-catalyzed intramo-
lecular aminocyclization as key steps.
Recently, we developed the asymmetric phase-transfer alky-
lation of the N-(diphenylmethylene)glycine tert-butyl ester (4)
in the presence of cinchona alkaloid-derived quaternary am-
monium salts, and successfully applied them to the enantiose-
lective synthesis of natural and non-natural R-amino acids.5 As
shown in the retrosynthetic analysis (Scheme 1), the enantiose-
lective phase-transfer catalytic alkylation was employed as the
key step for the introduction of the 5S chirality in 1 and the
construction of the azepinoindole ring system was planned by
a Pd(0)-catalyzed Heck reaction,4a followed by diastereoselective
Clavicipitic acid (1), an ergot alkaloid isolated from SD58
and ClaViceps fusiformis, has a unique tricyclic azepinoindole
skeleton.1 There are two chiral centers (C(5) and C(10)) in 1
but a mixture of diastereomers bearing C(5S) was naturally
obtained. 1 is regarded as a derailed product at high pH
environmental condition in the clavine alkaloid biosynthetic
pathway.2
(3) (a) Kozikowski, A. P.; Greco, M. N. J. Org. Chem. 1984, 49, 2310.
(b) Kozikowski, A. P.; Greco, M. N. Tetrahedron Lett. 1982, 23, 2005. (c)
Kozikowski, A. P.; Okita, M. Tetrahedron Lett. 1985, 26, 4043. (d) Robbers,
J. E.; Otsuka, H.; Floss, H. G.; Arnold, E. V.; Clardy, J. J. Org. Chem.
1980, 45, 1117. (e) Boyles, D. A.; Nichols, D. E. J. Org. Chem. 1988, 53,
5128. (f) Harrington, P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am. Chem.
Soc. 1987, 109, 4335.
(4) (a) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995,
60, 1486. (b) Iwao, M.; Ishibashi, F. Tetrahedron 1997, 53, 51. (c)
Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Murakami, Y.
Tetrahedron Lett. 1999, 40, 7803. (d) Shinohara, H.; Kukuda, T.; Iwao, M.
Tetrahedron 1999, 55, 10989. (e) Yokoyama, Y.; Hikawa, H.; Mitsuhashi,
M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem. 2004, 1244.
(5) (a) Lee, J.-H.; Jeong, B.-S.; Ku, J.-M.; Jew, S.-s.; Park, H.-g. J. Org.
Chem. 2006, 71, 6690. (b) Kim, S.; Lee, J.; Lee, T.; Park, H.-g.; Kim, D.
Org. Lett. 2003, 5, 2703. (c) Jew, S.-s.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.;
Park, H.-g. Chem. Commun. 2001, 1244. (d) Park, H.-g.; Jeong, B.-S.; Yoo,
M.-S.; Lee, J.-H.; Park, M.-K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-s. Angew.
Chem., Int. Ed. 2002, 41, 3036. (e) Jew, S-s.; Jeong, B.-S.; Lee, J.-H.; Yoo,
M.-S.; Lee, Y.-J.; Park, B.-S.; Kim, M.-G.; Park, H.-g. J. Org. Chem. 2003,
68, 4514. (f) Park, H.-g.; Kim, M.-J.; Park, M.-K.; Jung, H.-J.; Lee, J.;
Choi, S.-h.; Lee, Y.-J.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Ku, J.-M.;
Jew, S.-s. J. Org. Chem. 2005, 70, 1904.
Because of the low amount of production of 1, a systematic
evaluation of its biological activities has not been extensively
performed. As a part of our program to study the biological
* Address correspondence to this author. Phone: 82-2-880-8264. Fax: 82-
2-872-9129.
† Seoul National University.
‡ Yeungnam University.
(1) (a) Robbers, J. E.; Floss, H. G. Tetrahedron Lett. 1969, 1857. (b)
King, G. S.; Mantle, P. G.; Szczyrbak, C. A.; Waight, E. S. J. Chem. Soc.
1977, 2099.
(2) (a) Saini, M. S.; Cheng, M.; Anderson, J. A. Phytochemistry 1976,
15, 1497. (b) Bajwa, R. S.; Kohler, R.-D.; Saini, M. S.; Cheng, M.;
Anderson, J. A. Phytochemistry 1975, 14, 735.
10.1021/jo071162h CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/18/2007
J. Org. Chem. 2007, 72, 8115-8118
8115

FIGURE 1. Chiral phase-transfer catalyst.
SCHEME 2
intramolecular aminocyclization induced by C(5S) chirality for
the introduction of the C(10S) chirality.4b
TABLE 1. The Enantioselective Phase-Transfer Catalytic
Alkylationa
First, the alkylating agent 13 for the asymmetric phase-transfer
catalytic alkylation was prepared in 4 steps from 1H-indole-3-
carboxylic acid methyl ester (9). The addition of thallium(III)
trifluoroacetate in a TFA solution of 9, followed by the treatment
of potassium iodide afforded 10 (74%). The N-Boc protection
of indole 10 with (Boc)2O in the presence of DMAP gave 11
(98%). The reduction of methyl ester of 11 with DIBAL-H,
followed by benzylic bromination with PBr3 provided the
alkylating agent 13 (62%).
The phase-transfer catalytic alkylation was performed from
4 with 4-iodo-N-Boc-3-bromomethylindole (13) under phase-
transfer catalytic reaction conditions of 50% aqueous KOH in
toluene-chloroform (volume ratio ) 7:3) at 0 °C (Scheme 2).
We employed three representative catalysts (PTCs, 6-8, Figure
1) which showed excellent catalytic efficiencies in the enantio-
selective catalytic alkylation 4.5d,6
no.
catalyst
time, h
yield,b %
ee,c % (config)d
1
2
3
6
7
8
12
12
12
97
85
69
99 (S)
99 (S)
65 (S)
a The reaction was carried out with 1.0 equiv of alkylating agent and
3.0 equiv of 50% KOH in the presence of catalyst (10 mol %) in toluene/
CHCl3 (7:3). b Isolated yields. c Enantiopurity was determined by HPLC
analysis of 14, using a chiral column (Chiralcel OD) with hexane/2-propanol
as an eluent; in this case it was established by analysis of the racemate, of
which the enantioisomers were fully resolved. d Absolute configuration was
determined by comparison of the optical rotation of (-)-cis-clavicipitic acid
(1) transformed from 14 with the reported value.4b
As shown in Table 1, very high enantioselectivities were
observed in the case of both 65d (99% ee) and 76a (99% ee), but
6 (97%) showed higher chemical yield compared to that of 7
(85%). The non-cinchona catalyst, 8,6b afforded relatively poor
results in both chemical yield and enantioselectivity. The
enantiopurities were determined by chiral HPLC analysis with
(6) (a) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, B.-s.; Kim,
M. G.; Jew, S.-s. Tetrahedron Lett. 2003, 44, 3497. (b) Ooi, T.; Kameda,
M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519. (c) Corey, E. J.; Xu,
F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
8116 J. Org. Chem., Vol. 72, No. 21, 2007

TABLE 2. The Synthesis of 15 with Use of the Heck Reactiona
No.
catalyst
additives
base
solvent
DMF
toluene
DMF
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
temp, °C
time, h
yield,b %
1
2
3
4
5
6
7
8
9
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
Pd(Ph3P)4
Pd(DIPHOS)2
[Pd(η3-C3H5)Cl]2
Pd(OAc)2
Ag2CO3 (1.0 equiv)
Ag2CO3 (1.0 equiv)
Ag2CO3 (1.0 equiv)
Ag2CO3 (1.0 equiv)
Et3N (10 equiv)
Et3N (10 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
100
110
100
90
90
90
90
90
90
3
3
6
3
3
2
3
3
2
21
N.R.
53
52
54
N.R
65
42
90
a The above reaction was allowed to stir with 45 equiv of 2-methylbut-3-en-2-ol and base in the presence of catalyst (0.1 equiv) in solvent until dark
material was precipitated. b Isolated yields.
use of Chiralcel OD. The absolute configuration of 14 was
determined as S by comparison of the optical rotation of the
final product, (-)-cis-Clavicipitic acid {1, [R]25D -238 (c 0.2,
EtOH)} transformed from 14 with the reported values {1, [R]25
D
-249 (EtOH)4b}.
We next investigated the Pd(0)-catalyzed Heck reaction of
14 to afford 15. At the beginning, we adapted the previous Heck
reaction condition for the synthesis of clavicipitic acid reported
by Yokoyama et al. in 1995.4a The Heck reaction of 14 with
FIGURE 2. Plausible transition state in the Pd(II)-catalyzed aminocy-
clization.
Pd(Ph3P)2Cl2 in the presence of Ag2CO3 under DMF solvent at
100 °C gave 15 in only 21% chemical yield (Table 2, entry 1).
The Heck reaction conditions needed to be optimized by the
variation of solvent, catalyst, and base. Toluene solvent showed
no reaction but quite increased chemical yield could be observed
by replacing Et3N with K2CO3 (entry 3, 53%). The aqueous
DMF solvent system, DMF-H2O (volume ratio ) 1:1), showed
comparable chemical yield but two times faster reaction rate
than the DMF only solvent system (entries 3 and 4). Interest-
ingly, the removal of Ag2CO3 did not show any significant
change in chemical yield (entries 4 and 5). We then moved our
attention to optimize Pd(0) catalyst. An additional four kinds
of Pd(0) catalysts were chosen and their catalytic efficiency was
evaluated (entries 6-9). Among the used catalysts, Pd(OAc)2
gave the highest chemical yield in the presence of K2CO3 under
the 50% aqueous DMF solvent system to give 15 (entry 9, 90%).
solvent at 90 °C for 24 h, which could afford cis-18 and trans-
18 at the ratio of 5 to 1, respectively.8
On the basis of the diastereoselectivity, the plausible transition
state in the aminocyclization is proposed in Figure 2. The Pd-
(II) catalyst forms a complex with the allylic alcohol group in
17 from the upside, followed by the approach of C(5S)-BocNH
from the downside to afford cis-18. In the case of trans-18, the
Pd(II) catalyst should form a complex with the allylic alcohol
group from the downside and C(5S)-BocNH approach from the
upside to the allylic alcohol group, but there might be severe
t
steric hindrance between C(5S)-CO2 Bu and the Pd(II)-allylic
alcohol complex, which might give the trans-isomer as a minor
product. The nonseparable diastereomeric mixture of 18 was
directly adapted to hydrolysis without further separation. Since
Shinohara et al. reported that a partial epimerization of the
C(10)-position occurred during the thermolytic deprotection
catalyzed by silica gel (SiO2),9 we need to find a milder reaction
condition at low temperature. After several trials with various
hydrolysis methods, we finally overcame the epimerization by
using ZnBr2.10 18 could be selectively converted to the (-)-
Next, the benzophenone imine moiety of 15 was selectively
hydrolyzed with 0.1 M citric acid to afford 16 (96%). The direct
azepinoindole ring construction from 16 was attempted by acidic
condition with PPTS in CH2Cl2, but only a diastereomeric
mixture (1:1.2) of the corresponding trans-(5S,10R)-N(1)-Boc-
clavicipitic acid tert-butyl ester and cis-(5S,10S)-N(1)-Boc-
clavicipitic acid tert-butyl ester was obtained, respectively (data
not shown). We speculate that the poor diastereoselectivity of
the C(10)-position induced by C(5S) chirality might be due to
the less steric hindered environment. So we finally employed
Pd(II)-catalyzed intramolecular aminocyclization.7 The N-Boc
protection of 16 was performed with (Boc)2O in the presence
of DMAP to give 17 (93%). The intramolecular aminocycliza-
(7) (a) Hirai, Y.; Terada, T.; Amemiya, Y.; Momose, T. Tetrahedron
Lett. 1992, 33, 7893. (b) Makabe, H.; Kong, L.-K.; Hirota, M. Org. Lett.
2003, 5, 27. (c) Yokoyma, H.; Otaya, K.; Kobayashi, H.; Hirai, Y. Org.
Lett. 2000, 2, 2427.
(8) Since cis-18 and trans-18 were not separable, their ratio was
confirmed by the ratio of cis-1 and trans-1 derived from the hydrolysis of
the diastereomeric mixture of 18.
(9) Otey, C.; Greentein, J. P. J. Am. Chem. Soc. 1955, 77, 3112.
(10) Kaul, R.; Brouillette, Y.; Sajjadi, Z.; Hansford, K. A.; Lubell, W.
D. J. Org. Chem. 2004, 69, 6131.
tion of 17 was performed with PdCl2(CH3CN) in CH3CN
2
J. Org. Chem, Vol. 72, No. 21, 2007 8117

suspension was diluted with diethyl ether (20 mL), washed with
water (2 × 5 mL), dried over Na2SO4, filtered, and concentrated
in vacuo. Purification of residue by column chromatography on
silica gel (hexanes:EtOAc ) 10:1) afforded the desired product 14
(42 mg, 97% yield) as a pale yellow oil. The enantioselectivity
was determined by chiral HPLC analysis (Chiralcel OD, hexanes:
2-propanol ) 500:2.5, flow rate ) 1.0 mL/min, 23 °C, λ ) 254
nm, retention times: R (minor) 19 min, S (major) 23.3 min, 98.8%
ee).
Representative Procedure for the Pd(II)-Catalyzed Intramo-
lecular Aminocyclization (18). To an acetonitrile solution of 17
(90 mg, 0.16 mmol) was added PdCl2(CH3CN)2 (4 mg, 0.016 mmol)
at room temperature. The reaction solution was allowed to stir at
room temperature until the starting material was consumed. After
cooling, the reaction mixture was quenched with water, diluted with
ethyl acetate, washed with water, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexanes:EtOAc ) 6:1) to afford
inseparable mixture of diastereomer, cis-18 and trans-18 (5:1) (66
mg, 76% yield).
cis-clavicipitic acid (90%) by the treatment of ZnBr2 in CH2-
Cl2 without any epimerization.11
In conclusion, (-)-cis-clavicipitic acid has been synthesized
in 10 steps (20% overall yield, 99% ee) with asymmetric phase-
transfer catalytic alkylation and diastereoselective Pd(2)-
catalyzed intramolecular aminocyclization as key steps from 1H-
Indole-3-carboxylic acid methyl ester (9). We believe the
efficient synthetic method would facilitate the studies on the
biological evaluation of (-)-cis-clavicipitic acid.
Experimental Section
Representative Procedure for the Enantioselective Phase-
Transfer Catalytic Alkylation of 4 (14). To a mixture of 13 (29
mg, 0.067 mmol) and chiral catalyst 6 (6.6 mg, 0.0067 mmol) in
solvent (dichloromethane:toluene ) 3:7) (0.67 mL) was added
N-(diphenylmethylene)glycine tert-butyl ester (4) (19.6 mg, 0.067
mmol). The reaction mixture was then cooled (0 °C), aq 50% KOH
(13.7 mg, 0.24 mmol) was added, and the reaction mixture was
stirred at 0 °C until starting material was consumed (8 h). The
Acknowledgment. This work was supported by a grant
(E00257) from the Korea Research Foundation (2006).
(11) No epimerization was confirmed by the hydrolysis of the cis-(5S,-
10S)-N(1)-Boc-clavicipitic acid tert-butyl ester and trans-(5S,10R)-N(1)-
Boc-clavicipitic acid tert-butyl ester derived from 16 by the acidic
cyclization with PPTS in CH2Cl2. The separable cis- and trans-isomer could
be hydrolyzed to afford cis-1 and trans-1 without any epimerization by
ZnBr2 in CH2Cl2, respectively. The related scheme and procedure are
provided in the Supporting Information.
Supporting Information Available: Spectroscopic character-
izations of 1and 10-17. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO071162H
8118 J. Org. Chem., Vol. 72, No. 21, 2007