Concise synthesis of the (±)-Nb-desmethyl-meso- chimonanthine

Article abstract of DOI:10.1039/b610497e

The first total synthesis of the bis-pyrroloindoline alkaloid (±)-N_b-desmethyl-meso-chimonanthine, having a pseudo C ₂-symmetry, was realised in a seven-step convergent sequence without the use of protecting groups. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b610497e

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Concise synthesis of the (¡)-Nb-desmethyl-meso-chimonanthine{
Candice Menozzi, Peter I. Dalko* and Janine Cossy
Received (in Cambridge, UK) 21st July 2006, Accepted 14th September 2006
First published as an Advance Article on the web 3rd October 2006
DOI: 10.1039/b610497e
The first total synthesis of the bis-pyrroloindoline alkaloid (¡)-
Nb-desmethyl-meso-chimonanthine, having a pseudo C2-sym-
metry, was realised in a seven-step convergent sequence without
the use of protecting groups.
The synthesis of natural products having vicinal stereogenic
quaternary carbon centres, in particular benzylic centres, remains
one of the most challenging problems in organic chemistry.1,2 In
recent years increasing attention has been devoted to the synthesis
of calycanthaceous alkaloids,3 possessing such architectural motifs.
The simplest analogues, (2)- and (+)-chimonanthine4,5 (1), meso-
chimonanthine6 (2), and (2)- and (+)-calycanthine7 (4) have
dimeric structures (Fig. 1). More recently several new pyrrolidi-
noindoline alkaloids have been isolated, including Nb-desmethyl-
meso-chimonanthine (3) from Psychotria lyciiflora, as well as three
new alkaloids: quadrigemine I (6), oleoidine (7), and caledonine
(8), from P. oleoides,8 having a pseudo C2-symmetric backbone
(Fig. 1). As it has been suggested that the biosynthetic pathway
involves an oxidative dimerisation of tryptamine derivatives, this
biomimetic route has been exploited in several syntheses of this
type of alkaloid.3 More recently, the elegant work by Overman
et al., based on alkylation of isoindigo, has produced optically
active meso-chimonanthine, calycanthine,9 idiospermuline,10 quad-
rigemine C, psycholeine,11 hodgkinsine, hodgkinsine B,12 ditrypto-
phenaline and ent-WIN 64821.13 While bidirectional strategies are
the methods of choice for the preparation of symmetric
compounds, the desymmetrisation of the advanced intermediates,
and the access to non-symmetrical analogues, is difficult and
remains elusive.
We wish to report herein a highly convergent approach to
Nb-desmethyl-meso-chimonanthine (3), the structurally simplest
member of this class of alkaloid, which can provide access to
more complex desymmetrised pyrrolidinoindoline alkaloids. The
Fig. 1
described in Scheme 1, the primary cycloadduct should be
unstable, and should spontaneously rearrange to the cyclic imine,
which in turn will be trapped by the secondary amine to give the
desired pyrrolidinoindoline skeleton.
key step of the sequence is
a diastereoselective tandem
[4 + 2]-cycloaddition–cyclisation, inspired by the elegant synthesis
of (¡)-perophoramidine achieved by Fuchs and Funk.14 We
envisaged that this reaction could be applied in the preparation of
an advanced intermediate of Nb-desmethyl-meso-chimonanthine,
and could be performed in a highly diastereoselective manner.
According to our working hypothesis, the desymmetrised meso-
chimonanthine core could be obtained by a diastereoselective
tandem [4 + 2]-cycloaddition–cyclisation of a conveniently
functionalised bromooxindole and tryptamine derivative. As
The bromooxindole intermediate 9 was prepared in a five-step
sequence (Scheme 2). Friedel–Crafts acylation of indole with
oxalyl chloride followed by in situ esterification with methanol led
to the indolyl-3-methylglyoxylate, which was converted to the
corresponding alcohol by reduction with LiAlH4 (quantitative).
The azido function was introduced after standard iodination of the
obtained alcohol under Garreg’s conditions (PPh3, imidazole, I2),
followed by substitution with sodium azide. Finally, oxindole 9
was obtained by oxidation with NBS (2.0 equiv, t-BuOH–H2O). It
is noteworthy that when the reaction was performed under
standard conditions, at room temperature by addition of NBS in
one portion, the desired product was isolated in low yield due to
the competing dibromination of the indole. However, it was
observed that the slow addition of a solution of NBS in THF (2 h)
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue
Vauquelin, 75231, Paris Cedex 05, France. E-mail: peter.dalko@espci.fr;
Fax: +33 (0)140794660
{ Electronic supplementary information (ESI) available: Spectroscopic
data (IR, 1H and 13C NMR, MS) of (¡)-Nb-desmethyl-meso-chimo-
nanthine (3) and of compound 12. See DOI: 10.1039/b610497e
4638 | Chem. Commun., 2006, 4638–4640
This journal is ß The Royal Society of Chemistry 2006

View Article Online
Scheme 1 A plausible rationalisation for the stereoselective formation of pyrrolidinoindoline skeletons including tandem [4 + 2]-cycloaddition–cyclisation
steps.
Scheme 2 The synthesis of (¡)-Nb-desmethyl-meso-chimonanthine. (i) (COCl)2, Et2O then MeOH, rt, 12 h (88%); (ii) LiAlH4, THF, rt, 12 h (quant.); (iii)
I2, imidazole, PPh3, benzene, rt, 1 h (75%); (iv) NaN3, DMF, 50 uC, 1 h, (98%); (v) NBS, H2O, THF, t-BuOH, 30 min, (80%); (vi) Cs2CO3, CH2Cl2, rt, 12 h,
(35%); (vii) Cs2CO3, CH2Cl2, rt, 12 h (75%, dr = 95/5); (viii) Red-Al, toluene, 0 uC, rt, 100 uC, 8 h (57%).
to a t-BuOH–H2O–THF solution of indole, maintained at 0–5 uC,
resulted in suppression of the overoxidation and 9 was isolated in
80% yield.
diastereoselectivity (95/5). Finally, the desired product 3 was
obtained by reductive cyclisation of 12 using Red-Al in refluxing
toluene (8 h, 57%). As it was expected, under these reaction
conditions, the conversion of the N-methylcarbamate to the
N-methyl function was observed affording Nb-desmethyl-meso-
chimonanthine.
The coupling reaction of 9 with various tryptamine derivatives,
under the Funk conditions,14 (Cs2CO3, CH2Cl2, rt, 12 h) was
tested (Scheme 2). It was observed that the chemoselectivity of the
reaction is highly dependant on the nitrogen nucleophilicity of the
tryptamine side chain. When the aforementioned conditions were
applied to N-methyltryptamine 10a, by using Cs2CO3 as the base,
compound 11, which results from the formal substitution of the
bromide by the amine, was obtained in 35% yield. In turn, when
these conditions were applied to the N-carbamate derivative 10b,
the desired adduct 12 was isolated in 75% yield, with very high
In summary, the synthesis of (¡)-Nb-desmethyl-meso-chimo-
nanthine (3) was achieved in a seven-step sequence from indole in
22% overall yield. It is noteworthy that the described sequence
does not require the use of protecting groups. The 3a,3a9-bis-
quaternary carbon–carbon bond formation was completed via an
efficient tandem [4 + 2]-cycloaddition–cyclisation between a
conveniently functionalised bromooxindole 9 and the tryptamine
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 4638–4640 | 4639

View Article Online
66; (e) H. Ishikawa, H. Takayama and N. Aimi, Tetrahedron Lett.,
2002, 43, 5637.
derivative 10b. This highly convergent approach presents advan-
tages in terms of diastereoselectivity, step number, and flexibility
and should allow an easy entry to more complex desymmetrised
bis-pyrroloindolinoindoline alkaloids.
4 Isolation and characterisation of (2)-chimonanthine: (a) H. F.
Hodson, B. Robinson and G. F. Smith, Proc. Chem. Soc., London,
1961, 465; (b) R. K. Duke, R. D. Allan, G. A. R. Johnston,
K. N. Mewett, A. D. Mitrovic, C. C. Duke and T. W. Hambley, J. Nat.
Prod., 1995, 58, 1200.
5 Isolation and characterisation of (+)-chimonanthine: (a) T. Tokuyama
and J. W. Daly, Tetrahedron, 1983, 39, 41; (b) L. Verotta, T. Pilati,
M. Tato, E. Elisabetsky, T. A. Amador and D. S. Nunes, J. Nat. Prod.,
1998, 61, 392.
The authors wish to acknowledge Dr Franc¸oise Gue´ritte
(CNRS-ICSN, Gif-sur-Yvette) for kindly sending the 1H and
13C NMR spectra of the natural Nb-desmethyl-meso-chimo-
nanthine (3).
6 Y. Adjibade, R. Anton, B. Weniger, J. C. Quirion, B. Kuballa and
P. Calon, Phytochemistry, 1992, 31, 317.
Notes and references
7 (a) R. B. Woodward, N. C. Yang and T. J. Katz, Proc. Chem. Soc.,
London, 1960, 76; (b) see also ref. 3a.
1 For reviews of asymmetric synthesis of quaternary centres: (a) K. Fuji,
Chem. Rev., 1993, 93, 2037; (b) E. J. Corey and A. Guzman-Perez,
Angew. Chem., 1998, 110, 402, (Angew. Chem., Int. Ed., 1998, 37, 388);
(c) C. J. Douglas and L. E. Overman, ChemInform, 2004, 35, September
21; (d) E. A. Peterson and L. E. Overman, ChemInform, 2005, 36,
January 25; (e) Quaternary Stereocentres. Challenges and Solutions in
Organic Synthesis, ed. J. Christoffers and A. Baro, Wiley-VCH,
Weinheim, 2005; (f) B. M. Trost and C. Jiang, Synthesis, 2006, 369.
2 Examples for the stereoselective generation of vicinal stereogenic
quaternary centres: (a) R. M. Lemieux and A. I. Meyers, J. Am.
Chem. Soc., 1998, 120, 5453; (b) A. G. Griesbeck, S. Bondock and
J. Lex, Org. Biomol. Chem., 2004, 2, 1113.
8 V. Jannic, F. Gueritte, O. Lapre´vote, L. Serani, M.-T. Martin,
T. Sevenet and P. Potier, J. Nat. Prod., 1999, 62, 838.
9 (a) L. E. Overman, J. F. Larrow, B. A. Stearns and J. M. Vance, Angew.
Chem., Int. Ed., 2000, 39, 213; (b) L. E. Overman, D. V. Paone and
B. A. Stearns, J. Am. Chem. Soc., 1999, 121, 7702; (c) J. T. Link and
L. E. Overman, J. Am. Chem. Soc., 1996, 118, 8166.
10 L. E. Overman and E. A. Peterson, Tetrahedron, 2003, 59, 6905.
11 A. D. Lebsack, J. T. Link, L. E. Overman and B. A. Stearns, J. Am.
Chem. Soc., 2002, 124, 9008.
12 J. J. Kodanko and L. E. Overman, Angew. Chem., Int. Ed., 2003, 42,
2528.
13 L. E. Overman and D. V. Paone, J. Am. Chem. Soc., 2001, 123,
9465.
14 J. R. Fuchs and R. L. Funk, J. Am. Chem. Soc., 2004, 126, 5068.
3 (a) J. B. Hendrickson, R. Goschke and R. Rees, Tetrahedron, 1964,
20, 565; (b) E. S. Hall, F. McCapra and A. I. Scott, Tetrahedron,
1967, 23, 4131; (c) M. Lounasmaa and A. Nemes, Tetrahedron,
1982, 38, 223; (d) S. Hibino and T. Choshi, Nat. Prod. Rep., 2001, 18,
4640 | Chem. Commun., 2006, 4638–4640
This journal is ß The Royal Society of Chemistry 2006