Efficient syntheses of crispine A and harmicine by Rh-catalyzed cyclohydrocarbonylation

Article abstract of DOI:10.1021/ol900702t

The first examples of Rh-catalyzed cyclohydrocarbonylation-bicyclization of N-allylic amides of arylacetic acids are reported. This novel carbonylative bicyclization process was successfully applied to the rapid syntheses of crispine A and its analogues (

Full text of DOI:10.1021/ol900702t

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2659-2662
Efficient Syntheses of Crispine A and
Harmicine by Rh-Catalyzed
Cyclohydrocarbonylation
Wen-Hua Chiou,*,† Gau-Hong Lin,† Che-Cheng Hsu,† Stephen J. Chaterpaul,‡ and
Iwao Ojima‡
Department of Chemistry, National Chung Hsing UniVersity, Taichung, Taiwan, R.O.C,
and Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York 11794-3400
wchiou@dragon.nchu.edu.tw
Received April 3, 2009
ABSTRACT
The first examples of Rh-catalyzed cyclohydrocarbonylation-bicyclization of N-allylic amides of arylacetic acids are reported. This novel
carbonylative bicyclization process was successfully applied to the rapid syntheses of crispine A and its analogues (tricyclic indolizidine
alkaloids) as well as harmicine (tetracyclic ꢀ-carboline alkaloid).
Transition-metal-catalyzed cyclization reactions provide pow-
erful tools for the syntheses of complex fused ring systems.1
In this regard, a suitable design of this process in a cascade
manner will furnish a greener and more economical process
by minimizing reaction steps and waste, since such a domino
process would dramatically reduce the consumption of
solvents, reagents, and energy, as compared to stepwise
reactions.2 We have shown that the cyclohydrocarbonylation
(CHC)3 of unsaturated dipeptide derivatives, bearing in-
tramolecular heteroatom nucleophiles such as hydroxyl,
carbamate, and thiol, proceeds efficiently to give the corre-
sponding 1-azabicyclo[x.y.0]alkane amino acids with ex-
tremely high diastereoselectivity.4,5 We envisioned that the
utility and scope of this carbonylative bicyclization process
would be further expanded if aromatic ring nucleophiles
could be used, which would instantly increase the complexity
of the products.6 Then, we have found that electron-rich
aromatic moieties indeed act as the intramolecular nucleo-
philes in the CHC process.
Figure 1 illustrates this novel CHC-bicyclization process.3
This domino process commences with an extremely linear-
selective hydroformylation of N-allylic amide of phenylacetic
acid 1 to yield aldehyde 2, which undergoes the first
cyclization to form hemiaminal 3 in the presence of an acid.
Dehydration of 3 generates an N-acyliminium ion 4, followed
by the second cyclization with an electron-rich aromatic
nucleophile to afford bicyclization product 5. This process
is applicable to N-allylamide of indole-3-acetic acid 1f,
yielding 5f.
† National Chung Hsing University.
‡ State University of New York at Stony Brook.
(1) (a) Ojima, I.; Commandeur, C.; Chiou, W.-H. In ComprehensiVe
Organometallic Chemistry-III; Hiyama, T., Ojima, I., Eds.; Elsevier: Oxford,
2006; Vol. 11, Chapter 11.15; pp 511-556. (b) Ojima, I.; Tzamarioudaki,
M; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635–662. (c) Lautens, M.;
Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49–92. (d) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D Angew. Chem., Int. Ed. 2005, 44, 4442–4489.
(2) (a) Tietze, L. F. Chem. ReV. 1996, 1, 115–136. (b) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967–1983.
(3) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem. 1995, 60,
7078–7079.
(4) Mizutani, N., N; Chiou, W.-H.; Ojima, I. Org. Lett. 2002, 4, 4575–
4578
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10.1021/ol900702t CCC: $40.75
Published on Web 05/20/2009
 2009 American Chemical Society

Rh-BIPHEPHOS complex and PTSA under CO and H2.
First, 1a was chosen as the substrate to investigate suitable
reaction conditions, which could be used as the standard
conditions for other substrates. Results are summarized in
Table 1.
Table 1. Optimization of the CHC-Bicyclization Reaction of
1aa
PTSA
(%)
CO
(atm)
H2
(atm)
T
(°C)
yieldb
(%)
entry
solvent
1
2
3
4
5
6
7
8
9
10
toluene
THF
10
10
10
50
10
50
100
10
10
10
2
2
2
2
2
2
2
6
2
2
2
2
2
2
2
2
2
6
2
2
60
60
60
60
60
60
60
60
40
60
dec
dec
dec
32
85
66
MeOH
MeCN
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
67
60
44
77c
a Reagents and Conditions: All reactions were run with 1.0 mmol of 1a
(0.05 M in 20 mL solvent), Rh(acac)(CO)2 (0.5 mol %), and BIPHEPHOS
(1 mol %) for 16 h. b Isolated yield. c Reaction was run at 0.01 M substrate
concentration.
Figure 1. New CHC-bicyclization process.
Reaction of 1a in toluene (entry 1), THF (entry 2), and
MeOH (entry 3) gave only a messy mixture, including
decomposition products. Use of acetonitrile as the solvent
led to the formation of bicyclization product 5a, but only in
32% isolated yield (entry 4). Employment of acetic acid as
the solvent was a breakthrough and the reaction gave 5a in
85% yield (entry 5) accompanied by a small amount of
branched aldehyde 2a′ (7%) (see Scheme 1). The use of a
smaller amount (<10 mol %) of PTSA often resulted in lower
conversion to 5a and substantial formation of uncyclized
linear aldehyde 2a. Thus, the presence of PTSA was found
to be essential for the cyclization to proceed even when acetic
acid was used as the solvent. However, the use of a larger
amount of PTSA (50 and 100 mol %) did not have any
beneficial effect and rather lowered the yield of 5a (entries
6 and 7). Increasing the pressure of CO (6 atm) and H2 (6
atm) did not show any favorable effect either (entry 8).
Lowering the reaction temperature to 40 °C resulted in the
appearance of 2a in addition to 5a after the standard 16 h
reaction time (entry 9). The reaction at a lower substrate
concentration (0.01 M) gave 5a in somewhat lower yield
(77%), but without 2a (entry 10). Thus, we concluded that
the use of 10 mol % of PTSA at 60 °C, 4 atm of CO/H2
(1/1), and 0.05 M substrate concentration would be the
optimal conditions so far, which would be used as the
standard conditions for the subsequent reactions with other
substrates.
We report here the first CHC-bicyclization process,
involving aromatic carbon nucleophiles, for the rapid con-
struction of naturally occurring alkaloids, crispine A and its
analogues, as well as harmicine. It has been shown that
indolizidine alkaloid crispine A, isolated from Carduus
crispus,7 is a potent antitumor agent against SKOV3, KB,
and HeLa human cancer cell lines,7 while ꢀ-carboline
alkaloid harmicine, isolated from Kopsia griffithii, possesses
strong antileishmania activity.8
N-Allylamides 1a-f were readily prepared from the
corresponding acid or acid chloride and allylamines (see the
Supporting Information). The CHC reactions of 1a-f were
carried out in the presence of catalytic amounts of
(6) Chiou, W.-H.; Lee, S.-Y.; Ojima, I. Can. J. Chem. 2005, 83, 681–
692.
(7) For isolation and cytotoxicity acitivity of crispine A, see: (a) Zhang,
Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795–6798. For
syntheses of crispine A, see: (b) Schell, F. M; Smith, A. M: Tetrahedron
Lett. 1983, 24, 1883–1884. (c) Kno¨lker, H.-J.; Agarwal, S. Tetrahedron
Lett. 2005, 46, 1173–1175. (d) Szawkalo, J.; Zawadzka, A.; Wojtasiewicz,
K.; Leniewski, A.; Drabowicz, J.; Czarnocki, Z. Tetrahedron: Asymmetry
2005, 16, 3619–3621. (e) Meyer, N.; Opatz, T. Eur. J. Org. Chem. 2006,
399, 7–4002. (f) King, F. D. Tetrahedron 2007, 63, 2053–2056. (g) Allin,
S. M.; Gaskell, S. N.; Towler, J. M. R.; Page, P. C. B.; Saha, B.; McKenzie,
M. J.; Martin, W. P. J. Org. Chem. 2007, 72, 8972–8975.
(8) For isolation and anti-leishmania activity of hamicine, see: (a) Kam,
T.-S.; Sim, K -M Phytochemistry 1998, 47, 145–147. For synthesis, see:
(b) Itoh, T.; Miyazaki, M.; Nagata, K.; Yokoya, M.; Nakamura, S.; Ohsawa,
A. Heterocycles 2002, 58, 115–118. (c) Allin, S. M.; Thomas, C. I.; Allard,
J. E.; Duncton, M.; Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett. 2003,
44, 2335–2337. (d) Kno¨lker, H.-J.; Agarwal, S. Synlett 2004, 1767–1768.
(e) Itoh, T.; Miyazaki, M.; Nagata, K.; Nakamura, S.; Ohsawa, Heterocycles
2004, 63, 655–661. (f) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404–13405. (g) Allin,
S. M.; Gaskell, S. N.; Elsegood, M. R. J.; Martin, W. P. Tetrahedron Lett.
2007, 48, 5669–5671. (h) Szawkalo, J.; Czarnocki, S. J.; Zawadzka, A.;
Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.; Czarnocki, Z.; Drabowicz,
J. Tetrahedron: Asymmetry 2007, 18, 406–413.
It should be noted that even though there were two possible
regioisomers in the second cyclization step, i.e., from 4 to 5
(see Figure 1), 5a was the only product formed, which was
supported by 2-D NMR analyses and comparison with
reported NMR data for 5a.7f
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Org. Lett., Vol. 11, No. 12, 2009

Scheme 1
.
CHC-Bicyclization of 1a-fa
Scheme 2
.
Bicyclization-Reduction Sequence to Crispine A, Its
Analogues, and Harmicinea
a Reagents and Conditions: (i) Rh(acac)(CO)2 (0.5 mol %), BIPHEPHOS
(1 mol %), and PTSA (10 mol %) in AcOH at 60 °C and 4 atm of CO/H2
(1/1) for 16 h; (ii) LiAlH4-Et3NHCl (5 equiv) in THF at 0 °C to rt overnight.
branched aldehyde 2c′ (8%) and alcohol 6c (18%), ac-
companied by a complex mixture of unidentified side
products. In contrast, the reaction of 1d, wherein the methoxy
group is para to the reacting C6-position, underwent CHC-
bicyclization to give 5d (33%), and a mixture of linear
alcohol 6d and branch aldehyde 2d′ (28%, 6d/2d′ ) 5:2).
The formation of alcohols 6c and 6d indicates that the
reduction of aldehydes 2c and 2d competes with the first
cyclization in these reactions because of the weak nucleo-
philicity of the monomethoxyphenyl moieities.
The formation of branched aldehydes 2a-d′ in spite of
the use of extremely linear selective Rh-BIPHEPHOS
catalyst3,10,11 may be ascribed to a partial amide-directed
chelation control12 that favors the formation of branched
aldehyde in the reactions of N-allylamides.
The reaction of N-hex-1-en-3-ylamide 1e was found to
require more forced conditions than the standard conditions
used for those of 1a-d to proceed. This is likely due to the
steric bulk at the allylic position imposed on the hydro-
formylation step catalyzed by a bulky Rh-BIPHEPHOS
complex. Thus, the reaction of 1e was carried out at 80 °C
and 20 atm of CO/H2 (1/1) for 16 h to give 5e in 83% yield
as a single diastereomer (Scheme 1). The 2-D NMR analysis
of 5e on the basis of HSQC and ROESY clearly indicated
2,5-trans stereochemistry of the pyrrolidine moiety (see the
Supporting Information).
a Reagents and conditions: (a) 1 (0.05 M), Rh(acac)(CO)2 (0.5 mol %),
BIPHEPHOS, (1 mol %), and PTSA (10 mol %) in AcOH at 60 °C and 4
atm of CO/H2 (1/1), 16 h. (b) Same as (a) except for the temperature and
pressure, i.e., at 80 °C and 20 atm of CO/H2 (1/1). (c) Same as (a) except
for the concentration; i.e., 0.01 M substrate concentration was used.
Reaction of N-allylamide 1b, bearing a 3,4,5-trimethoxy-
phenyl moiety, proceeded smoothly to give 5b in 83% yield,
accompanied by 2b′ (7%) (Scheme 1). The result is virtually
the same as that of 1a described above.
Next, we investigated the reactions of 1c and 1d, bearing
only one methoxy group in the phenyl moiety, i.e., 4-meth-
oxyphenyl and 3-methoxyphenyl, respectively (Scheme 1).
As anticipated,9 the reaction of 1c, wherein the methoxy
group is meta to the reacting C2 position, gave a mixture of
(10) Billig, E.; Abatjoglou, A. G.; Bryant, D. Union Carbide: U.S.
Pantents 4769498, 1988
.
(11) Cuny, G. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 2066–
2068
.
(12) (a) Ojima, I.; Zhang, Z. J. Org. Chem. 1988, 53, 4422–4425. (b)
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307–
1370. (c) Eilbracht, P.; Ba¨rfacker, L.; Buss, C.; Hollmann, C.; Kitsos-
Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt,
A. Chem. ReV. 1999, 99, 3329–3366.
(9) AM1 calculation results carried out by Spartan 06′ show the largest
coeffecients in HOMO of 4d is at the carbon para to the methoxy group,
while that in 4c is at the carbon ortho to the methoxy group, as anticipated.
Org. Lett., Vol. 11, No. 12, 2009
2661

In addition to N-allylic amides of methoxy-substituted
phenylacetic acids 1a-e, N-allylamide of indole-3-acetic acid
1f was employed as a substrate. The reaction of 1f under
the standard conditions afforded the corresponding bicy-
clization product 5f in 64% yield, which was improved to
75% when the reaction was run in more dilute conditions
(0.01M) (Scheme 1).
To convert tricyclic lactam 5a and tetracyclic lactam 5f
to crispine A and harmicine, respectively, the lactam moiety
needstobereduced.Itwaswell-knownthatalane-triethylamine
complex13,14 was an excellent reagent for this purpose, but
we modified the procedure to generate this reducing agent
in situ just by mixing equal amounts of LiAlH4 and Et3N·HCl
in THF (see the Supporting Information).
Reductions of 5a and 5f with LiAlH4 and Et3N·HCl in
THF gave crispine A (7a) and harmicine (7f) in 94% and
88% yields, respectively. In the same manner, crispine A
analogues 7b and 7e were obtained in 84% and 76% yields
from 5b and 5e, respectively. Results are summarized in
Scheme 2.
In summary, we reported the first examples of Rh-
catalyzed CHC-bicyclization of N-allylic amides of arylacetic
acids, wherein an electron-rich aromatic moiety acts as the
intramolecular nucleophile to undergo the second cyclization.
This novel carbonylative bicyclization process was success-
fully applied to the rapid syntheses of a tricyclic indolizidine
alkaloid, crispine A, and its analogues as well as a tetracyclic
ꢀ-carboline alkaloid, harmicine. Further studies on the
exploration and applications of cyclohydrocarbonylation
reactions are actively underway in these laboratories.
Acknowledgment. We thank the National Science Coun-
cil, Taiwan (NSC96-2113-M-005-003-MY2 to C.W.H.) and
the Instrument Center of National Chung Hsing University
as well as the National Science Foundation, USA (CHE-
0516797 and 0809315 to I.O.) for support of this research.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, as well as H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Yoon, N. M.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 2927–
2938
.
(14) Cha, J. S.; Brown, H. C. J. Org. Chem. 1993, 58, 3974–3979
.
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