Total syntheses of (±)-folicanthine and (±)-chimonanthine via a double intramolecular carbamoylketene-alkene [2+2] cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2012.12.057

Total syntheses of the dimeric pyrrolidinoindoline alkaloids folicanthine and chimonanthine have been accomplished in racemic forms employing a double intramolecular carbamoylketene-alkene [2+2] cycloaddition as the key step.

Full text of DOI:10.1016/j.tetlet.2012.12.057

Tetrahedron Letters 54 (2013) 1012–1014
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Total syntheses of ( )-folicanthine and ( )-chimonanthine via a double
intramolecular carbamoylketene–alkene [2+2] cycloaddition
Takaaki Araki, Yuki Manabe, Kosuke Fujioka, Hiromasa Yokoe, Makoto Kanematsu, Masahiro Yoshida,
⇑
Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Total syntheses of the dimeric pyrrolidinoindoline alkaloids folicanthine and chimonanthine have been
accomplished in racemic forms employing a double intramolecular carbamoylketene–alkene [2+2] cyclo-
addition as the key step.
Received 3 November 2012
Revised 5 December 2012
Accepted 14 December 2012
Available online 22 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Alkaloid
Cycloaddition
Indole
Nitrone
Folicanthine (1)1 and chimonanthine (2)2 are representatives of
the dimeric pyrrolidinoindoline alkaloids3 that have been isolated
from the leaves of Calycanthus floridus L. and from the deciduous
shrub Chimonanthus fragrans, respectively. Because of their fasci-
nating structural array and biological profile,4 these alkaloids are
considered attractive targets for total synthesis. To date, a number
of syntheses of the racemic5 and optically active forms6 have been
reported. Interestingly, it was found that chimonanthine (2) could
be converted into the isomeric alkaloid calycanthine (3) and foli-
canthine (1) by acidic treatment and reductive N-methylation,
respectively6c,d (Fig. 1).
Previously, we developed an efficient intramolecular
carbamoylketene–alkene [2+2] cycloaddition reaction (4 ? 5) and
demonstrated that the methodology could be successfully applied
to the syntheses of the physovenine intermediate 6,7a esermethole
(7),7b and debromoflustramines B (8) and E (9).7c In an attempt to
probe the further applicability of the cycloaddition, we chose both
alkaloids 1 and 2 as the synthetic targets. Here we describe the
total syntheses of ( )-folicanthine (1) and ( )-chimonanthine (2),
employing a novel type of double intramolecular carbamoylketene–
alkene [2+2] cycloaddition as the key step (Scheme 1).
be assembled by a double intramolecular [2+2] cycloaddition of
the dienyl ketene 11, which could be derived from 2,3-diaryl-1,
3-butadiene 12. The symmetrical diene can be prepared by palla-
dium-catalyzed coupling of 2-nitrophenylboronic acid (13)8 with
the carbonate of butynediol 149 (Scheme 2).
Based on the procedure reported by Grigg,10a we examined the
preparation of the starting 2,20-(buta-1,3-diene-2,3-diyl)bis(nitro-
benzene) (12) shown in Table 1. Treatment of a mixture of 13
and 14 with a 10 mol % of Pd(PPh3)4 in THF at 70 °C provided the
requisite diene 12 in 52% yield (entry 1). The reaction at the higher
temperature of 100 °C in dioxane resulted in a slightly improved
yield of 58% (entry 2). When the reaction was conducted with
Pd2(dba)3ꢀCHCl3 (10 mol %) in the presence of a ligand (40 mol %)
in THF at 70 °C, the yields increased gradually depending upon
the ligand (entries 3–5). The best result was obtained with dppe,
which provided 12 in 68% yield (entry 5).
Our retrosynthetic analysis is shown in Scheme 2. We thought
that folicanthine (1) and chimonanthine (2) might be derived from
10 via a regio-selective ring expansion followed by appropriate
functional group transformations. The bis-cyclobutanone 10 could
⇑
Corresponding author. Tel.: +81 88 6337287; fax: +81 88 6339575.
E-mail address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
Figure 1. Dimeric pyrrolidinoindoline alkaloids.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.057

T. Araki et al. / Tetrahedron Letters 54 (2013) 1012–1014
1013
Scheme 3. Synthesis of ( )-folicanthine (1). Reagents and conditions: (a) Zn, AcOH,
rt, 1 h, 73%; (b) ClCO2Me, K2CO3, THF, H2O, rt, 10 min, 86%; (c) BrCH2CO2Me, NaH,
DMF, rt, 1.5 h, quant.; (d) LiOHꢀH2O, THF, H2O, rt, 1 h, quant.; (e) (COCl)2, benzene,
rt, 1 h then 85 °C, 30 min; (f) Et3N, benzene, 90 °C, 1 h, 89% (2 steps); (g)
MeNHOHꢀHCl, NaHCO3, MS 3A, EtOH, 50 °C, 4 h then p-TsCl, 4-DMAP, CHCl3,
70 °C, 3 h, 62% (2 steps); (h) LiAlH4, THF, reflux, 1.5 h, 36% for 1, 28% for meso-1.
Scheme 1. Syntheses of pyrrolidinoindoline alkaloids.
oxalyl chloride in benzene provided the acid chloride, to which tri-
ethylamine was added in one pot at 90 °C to give an inseparable
mixture of ( )-10 and the meso-1011 in 89% yield. The mixture
was then treated with N-methylhydroxylamine hydrochloride,
NaHCO3, and 3A molecular sieves in ethanol at 50 °C to afford
the corresponding nitrone,12 which, without purification, was
immediately reacted with p-TsCl and 4-dimethylaminopyridine
(4-DMAP) in refluxing chloroform to furnish the bis-lactam 1913
in 62% yield as an inseparable mixture. Thus, we were able to in-
stall the bis-hexahydropyrrolo[2,3-b]indole backbone by a double
carbamoylketene–alkene [2+2] cycloaddition. Reduction of 19 with
lithium aluminum hydride (LiAlH4) in refluxing THF for 1.5 h pro-
vided a mixture of ( )-folicanthine (1)14 and meso-folicanthine
(meso-1),15 which was separated by preparative TLC, in 36% and
28% yields, respectively. The spectroscopic properties of the syn-
thetic 1 and meso-1 were identical with those reported in the liter-
ature5f,16 (Scheme 3).
Scheme 2. Retrosynthetic analysis.
Table 1
Pd-catalyzed preparation of diarylated diene 12
For the synthesis of chimonanthine (2), 19 was hydrolyzed
under alkaline conditions to give a 1.7:1 mixture (from 1H NMR)
of ( )-2017 and the meso-2018 in 79% yield.19 When placed in
chloroform, the ( )-20 dissolved smoothly whereas the meso-20
remained an insoluble solid. Thus, we were able to separate the
mixture without using chromatography. The ( )-20 was exposed
to LiAlH4 in refluxing THF for 0.5 h to give ( )-chimonanthine
(2)20 in 73% yield, the spectral properties of which were identical
with those reported in the literature.6d It should be noted that
attempted reduction of the meso-20 with LiAlH4 did not give
meso-chimonanthine at all, but instead a mixture of unidentified
products (Scheme 4).
Entry Pd species
(10 mol %)
Ligand
(40 mol %)
Solvent
Temp
(°C)
Yield
(%)
1
2
Pd(PPh3)4
Pd(PPh3)4
—
—
THF
1,4-
Dioxane
THF
THF
70
100
52
58
3
4
5
Pd2(dba)3ꢀCHCl3
Pd2(dba)3ꢀCHCl3
Pd2(dba)3ꢀCHCl3
dppb
dppm
dppe
70
70
70
53
61
68
THF
With the symmetrical diene 12 in hand, we then turned our
attention to the key double [2+2] cycloaddition. Initially, diene
12 was converted into bis-carboxylic acid 18, which is a precursor
of ketene 11, by sequential reduction of the nitro group, carbo-
methoxylation, alkylation with methyl bromoacetate, and alkaline
hydrolysis in 63% yield for the four steps. Treatment of 18 with
In summary, the total syntheses of ( )-folicanthine (1) and ( )-
chimonanthine (2) have been accomplished employing a novel and
efficient double intramolecular carbamoylketene–alkene [2+2]
cycloaddition as the key step, thus opening a fascinating entry to
the dimeric pyrrolidino[2,3-b]indolines. The synthetic method
developed here is general and efficient and could also be applied

1014
T. Araki et al. / Tetrahedron Letters 54 (2013) 1012–1014
8. Collibee, S. E.; Yu, J. Tetrahedron Lett. 2005, 46, 4453–4455.
9. Kiji, J.; Okano, T.; Fujii, E.; Tsuji, J. Synthesis 1997, 869–870.
10. (a) Bohmer, J.; Grigg, R. Tetrahedron 1999, 55, 13463–13470; (b) Nishioka, N.;
Hayashi, S.; Koizumi, T. Angew. Chem., Int. Ed. 2012, 51, 3682–3685.
11. Compound 10 (1:1 mixture of ( )-10 and meso-10): IR (neat) 2955, 1794,
1714 cmꢁ1 1H NMR (CDCl3, 400 MHz) d 3.38 (2H, dd, J = 2.8, 12.0 Hz), 3.40 (2H,
;
dd, J = 2.8, 17.6 Hz), 3.77–3.92 (16H, m), 5.20–5.75 (4H, m), 6.73 (2H, d,
J = 7.6 Hz), 6.90–6.99 (2H, m), 6.97 (2H, t, J = 7.6 Hz), 7.13 (2H, d, J = 7.6 Hz),
7.15–7.26 (2H, m), 7.33 (2H, t, J = 7.6 Hz), 7.70–7.95 (4H, m); 13C NMR (CDCl3,
100 MHz) d 47.5 (C ꢂ 4), 53.1 (CH3 ꢂ 2), 53.3 (CH3 ꢂ 2), 57.3 (CH2 ꢂ 2), 57.5
(CH2 ꢂ 2), 78.2 (CH ꢂ 2), 78.9 (CH ꢂ 2), 116.2 (CH ꢂ 4), 123.8 (CH ꢂ 2), 124.2
(CH ꢂ 4), 124.6 (CH ꢂ 2), 129.7 (CH ꢂ 2), 130.1 (CH ꢂ 2), 130.9 (C ꢂ 4), 143.8
(C ꢂ 4), 152.3 (C ꢂ 4), 200.9 (C ꢂ 2), 201.1 (C ꢂ 2); HRMS (ESI-TOF) m/z calcd
for C24H21N2O6 [M+H]+: 433.1400, found 433.1394.
12. (a) Barton, D. H. R.; Day, M. J.; Hesse, R. H.; Pechet, M. M. J. Chem. Soc., Chem.
Commun. 1971, 945–946; (b) Jeffs, P. W.; Molina, G.; Cortesst, N. A.; Hauck, P.
R.; Wolfram, J. J. Org. Chem. 1982, 47, 3876–3881; (c) Hoffman, R. V.; Salvador, J.
M. Tetrahedron Lett. 1989, 30, 4207–4210.
Scheme 4. Synthesis of ( )-chimonanthine.
13. Compound 19 (1:1 mixture of ( )-19 and meso-19): IR (neat) 2956, 1704,
1485 cmꢁ1 1H NMR (CDCl3, 400 MHz) d 2.66–3.08 (20H, m), 3.62–3.95 (12H,
;
m), 5.15–5.95 (4H, m), 6.98–7.81 (16H, m); 13C NMR (CDCl3, 100 MHz) d 27.2
(CH3 ꢂ 2), 27.3 (CH3 ꢂ 2), 38.0 (CH2 ꢂ 4), 39.2 (C ꢂ 4), 53.3 (CH3 ꢂ 4), 79.9
(CH ꢂ 2), 80.5 (CH ꢂ 2), 117.3 (CH ꢂ 2), 117.6 (CH ꢂ 2), 124.1 (CH ꢂ 2), 124.3
(CH ꢂ 2), 124.8 (CH ꢂ 4), 130.0 (CH ꢂ 2), 130.2 (CH ꢂ 2), 131.8 (C ꢂ 4), 139.6
(C ꢂ 2), 140.5 (C ꢂ 2), 152.1 (C ꢂ 2), 154.2 (C ꢂ 2), 170.2 (C ꢂ 2), 170.5 (C ꢂ 2);
HRMS (ESI-TOF) m/z calcd for C26H27N4O6 [M+H]+: 491.1931, found 491.1908.
14. Compound ( )-1: Mp 166–167 °C (hexane/AcOEt); IR (KBr) 1602, 1490, 1347,
to the synthesis of other related dimeric alkaloids with more com-
plicated molecular structures.
Acknowledgments
We are grateful to Professor Hiromitsu Takayama, Chiba
University, for providing a sample of the natural folicanthine and
spectral data (1H and 13C NMR) of meso-folicanthine. This work
was supported financially by a Grant-in-Aid for the Program for
Promotion of Basic and Applied Research for Innovations in the
Bio-oriented Industry (BRAIN) and a Grant-in-Aid for Scientific
Research (B) (23390026) from the JSPS.
1157, 735 cmꢁ1 1H NMR (CDCl3, 400 MHz) d 1.92–1.98 (2H, m), 2.30–2.49 (4H,
;
m), 2.41 (6H, s), 2.58–2.67 (2H, m), 3.00 (6H, s), 4.40 (2H, br), 6.46 (2H, d,
J = 7.6 Hz), 6.47–6.51 (2H, m), 6.88–6.93 (2H, m), 6.97 (2H, t, J = 7.2 Hz); 13C
NMR (CDCl3, 100 MHz) d 35.2 (CH2 ꢂ 2), 35.4 (CH3 ꢂ 2), 37.7 (CH3 ꢂ 2), 52.5
(CH2 ꢂ 2), 62.5 (CH ꢂ 2), 91.8 (C ꢂ 2), 105.7 (CH ꢂ 2), 116.5 (CH ꢂ 2), 123.6
(CH ꢂ 2), 128.0 (CH ꢂ 2), 132.6 (C ꢂ 2), 152.8 (C ꢂ 2); HRMS (ESI-TOF) m/z
calcd for C24H30N4Na [M+Na]+: 397.2368, found 397.2361.
15. meso-1: Mp 161–162 °C (hexane/AcOEt); IR (KBr) 2926, 1601, 1494, 743 cmꢁ1
;
1H NMR (C5D5N, 400 MHz) d 1.68 (2H, dd, J = 4.6, 11.4 Hz), 2.09 (6H, s), 2.18–
2.46 (12H, m), 4.17 (2H, br), 6.17 (2H, d, J = 7.6 Hz), 6.20–6.40 (2H, m), 6.50–
7.05 (4H, m); 13C NMR (C5D5N, 100 MHz, 90 °C)
d
37.0 (CH2 ꢂ 2), 37.4
References and notes
(CH3 ꢂ 2), 37.7 (CH3 ꢂ 2), 53.5 (CH2 ꢂ 2), 64.6 (CH ꢂ 2), 91.9 (C ꢂ 2), 108.4
(CH ꢂ 2), 118.5 (CH ꢂ 2), 125.3 (CH ꢂ 2), 129.5 (CH ꢂ 2), 135.7 (C ꢂ 2), 155.2
(C ꢂ 2); HRMS (ESI-TOF) m/z calcd for C24H31N4 [M+H]+: 375.2549, found
375.2533.
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1031–1033; (i) Li, Y.-X.; Wang, H.-X.; Ali, S.; Xia, X.-F.; Liang, Y.-M. Chem.
Commun. 2012, 48, 2343–2345.
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Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc. 1999, 121, 7702–
7703; (b) Overman, L. E.; Larrow, J. F.; Stearns, B. A.; Vance, J. M. Angew. Chem.,
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Tetrahedron 2004, 60, 893–900.
17. Compound ( )-20: IR (neat) 3403, 1662, 1484 cmꢁ1 1H NMR (CDCl3, 400 MHz)
;
d 2.66 (6H, s), 2.78 (2H, d, J = 16.8 Hz), 3.11 (2H, d, J = 16.8 Hz), 4.70 (2H, s), 6.68
(2H, d, J = 7.6 Hz), 6.84 (2H, t, J = 7.6 Hz), 7.15 (2H, t, J = 7.6 Hz), 7.23 (2H, d,
J = 7.6 Hz), 2H of –NH– were not observed clearly; 13C NMR (CDCl3, 100 MHz) d
26.4 (CH3 ꢂ 2), 39.3 (CH2 ꢂ 2), 55.3 (C ꢂ 2), 80.4 (CH ꢂ 2), 111.1 (CH ꢂ 2),
120.6 (CH ꢂ 2), 125.1 (CH ꢂ 2), 129.8 (CH ꢂ 2), 130.8 (C ꢂ 2), 148.2 (C ꢂ 2),
171.4 (C ꢂ 2); HRMS (ESI-TOF) m/z calcd for C22H23N4O2 [M+H]+: 375.1821,
found 375.1830.
18. meso-20: Mp 360 °C (decomp.) (MeOH/CHCl3); IR (KBr) 3403, 1661,
1482 cmꢁ1
; d 2.87 (6H, s), 3.10 (2H, d,
1H NMR (C5D5N, 400 MHz)
J = 16.8 Hz), 3.37 (2H, d, J = 16.8 Hz), 5.52 (2H, d, J = 2.4 Hz), 6.68 (2H, d,
J = 8.0 Hz), 6.72 (2H, br), 6.81 (2H, br), 7.14 (4H, t, J = 8.0 Hz); 13C NMR (C5D5N,
100 MHz) d 26.6 (CH3 ꢂ 2), 41.5 (CH2 ꢂ 2), 56.3 (C ꢂ 2), 79.9 (CH ꢂ 2), 110.7
(CH ꢂ 2), 119.3 (CH ꢂ 2), 125.1 (CH ꢂ 2), 129.8 (CH ꢂ 2), 132.0 (C ꢂ 2), 150.6
(C ꢂ 2), 171.4 (C ꢂ 2); HRMS (ESI-TOF) m/z calcd for C22H23N4O2 [M+H]+:
375.1821, found 375.1829.
19. Treatment of a mixture (1.7:1) of 20 with LiAlH4 in refluxing THF for 3 h
provided ( )-2 and the recovered meso-20 in 29% and 6% yield, respectively.
20. Compound ( )-2: Mp 168–172 °C (benzene); IR (KBr) 3297, 2932, 1605,
1486 cmꢁ1 1H NMR (CDCl3, 500 MHz, 50 °C) d 2.03–2.08 (2H, m), 2.31 (6H,
;
s), 2.49–2.58 (6H, m), 4.44 (2H, br), 6.53 (2H, d, J = 7.5 Hz), 6.66 (2H, t,
J = 7.5 Hz), 6.98 (2H, t, J = 7.5 Hz), 7.18 (2H, d, J = 7.5 Hz), 2H of –NH– were not
observed clearly; 13C NMR (CDCl3, 125 MHz, 50 °C) d 35.5 (CH2 ꢂ 2), 37.0
(CH3 ꢂ 2), 52.7 (CH2 ꢂ 2), 63.3 (C ꢂ 2), 85.3 (CH ꢂ 2), 109.3 (CH ꢂ 2), 118.7
(CH ꢂ 2), 124.4 (CH ꢂ 2), 128.2 (CH ꢂ 2), 133.0 (C ꢂ 2), 150.7 (C ꢂ 2); HRMS
(ESI-TOF) m/z calcd for C22H26N4Na [M+Na]+: 369.2055, found 369.2054.