Golden opportunities in natural product synthesis: First total synthesis of (-)-isocyclocapitelline and (-)-isochrysotricine by gold-catalyzed allene cycloisomerization

Article abstract of DOI:10.1039/b703995f

The first enantioselective total syntheses of the β-carboline alkaloids (-)-isochrysotricine (1) and (-)-isocyclocapitelline (2) are reported which confirm the absolute configuration of these natural products. Key steps are the copper-mediated S_N

Full text of DOI:10.1039/b703995f

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Golden opportunities in natural product synthesis: first total synthesis of
(−)-isocyclocapitelline and (−)-isochrysotricine by gold-catalyzed allene
cycloisomerization†
Frank Volz and Norbert Krause*
Received 16th March 2007, Accepted 3rd April 2007
First published as an Advance Article on the web 16th April 2007
DOI: 10.1039/b703995f
The first enantioselective total syntheses of the b-carboline
alkaloids (−)-isochrysotricine (1) and (−)-isocyclocapitelline
(2) are reported which confirm the absolute configuration of
these natural products. Key steps are the copper-mediated
SN2ꢀ-substitution of propargyl oxiranes 13/14 and the gold-
catalyzed cycloisomerization of a-hydroxyallene 15, resulting
in a highly efficient center-to-axis-to-center chirality transfer.
in 1999 from the Rubiaceae plant Hedyotis capitellata which has
been widely used in traditional Chinese and Vietnamese herb
medicine.9 The constitution and relative configuration of these
b-carboline alkaloids were confirmed by NMR data and an X-
ray analysis; the absolute configuration has not been determined
so far. Studies of the biological activity of isochrysotricine and
isocyclocapitelline have been hampered by the minute amounts
of the alkaloids available from natural sources; for chrysotricine,
however, an interesting in vitro activity against the growth of HL-
60 leukemia cells has been found.10 Previous synthetic studies have
been limited to racemic chrysotricine/isochrysotricine11 and nor-
isocyclocapitelline.12
Since the absolute configuration of isochrysotricine and isocy-
clocapitelline is unknown, we decided to design a stereodivergent
route which should allow a rapid access to both enantiomers
of 1 and 2 (Scheme 2). Retrosynthetically, isochrysotricine
(1) can be traced back to isocyclocapitelline (N-methylation–
deprotonation), and the b-carboline moiety should be accessible
by Pictet–Spengler-cyclization–aromatization of the aldehyde 3
and tryptamine.11 As precursor of tetrahydrofuran 3, we envisaged
the 2,5-dihydrofuran 4 which should be accessible by chemo- and
stereoselective gold-catalyzed cycloisomerization of the allene 5.
Homogeneous gold catalysis is an emerging area of transition
metal catalysis with tremendous potential for the synthesis of
complex target molecules.1 Based on their ability to activate C–C
double or triple bonds as soft, carbophilic Lewis acids, gold salts
are ideally suited for the formation of C–C and C–heteroatom
bonds by nucleophilic attack at these activated substrates. Ad-
ditionally, reactive C–H bonds can be directly activated by gold
catalysts, opening a second efficient pathway for gold-catalyzed
bond formation. In spite of its utility, however, applications of
homogeneous gold catalysis in (stereoselective) natural product
synthesis are still scarce.2 In this paper, we report the first total
syntheses of the b-carboline alkaloids (−)-isochrysotricine and
(−)-isocyclocapitelline, taking advantage of the gold-catalyzed
cycloisomerization of a-hydroxyallenes.
Our group has been interested in the stereoselective synthesis
and transformation of functionalized allenes3 for some time.
Recently, we have reported the gold-catalyzed cycloisomerization
of a-hydroxyallenes to 2,5-dihydrofurans4 which combines a high
reactivity and excellent axis-to-center chirality transfer with a
tolerance to many functional groups. Moreover, the method
could be extended to the endo-cyclization of b-hydroxyallenes,5
a-/b-aminoallenes,5,6 and a-thioallenes7 to the corresponding 5-
or 6-membered O-, N-, or S-heterocycles (Scheme 1). These
transformations are perfect examples for atom economy.8
Scheme 1 Gold-catalyzed cycloisomerization of a- or b-heterosubstituted
allenes to 5- and 6-membered heterocycles.
Scheme 2 Retrosynthesis of (−)-isochrysotricine (1) and (−)-isocyclo-
capitelline (2); PG = protecting group.
Isochrysotricine (1) and isocyclocapitelline (2) were isolated (to-
gether with their diastereomers chrysotricine and cyclocapitelline)
Our approch started from the known ester 613 which was
converted into the enynoate 7 by a one-pot reduction–olefination
sequence14 (Scheme 3). Efficient transformation into the sec-
ondary alcohol 8 was achieved by standard reduction–oxidation–
Grignard addition. This enyne turned out to be an excellent sub-
strate for a kinetic resolution by Katsuki–Sharpless epoxidation;15
Organic Chemistry II, University of Dortmund, Otto-Hahn-Strasse 6,
D-44221, Dortmund, Germany. E-mail: norbert.krause@uni-dortmund.de;
Fax: + 49 2317553884; Tel: +49 2317553882
† Electronic supplementary information (ESI) available: NMR data of
compounds 1–3 and 7–16. See DOI: 10.1039/b703995f
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The key steps of the synthesis are the anti-selective copper-
mediated SN2ꢀ-substitution of propargyl oxirane 9, using a
methylmagnesium-cyanocuprate and triphenylphosphite as ligand
to copper,16 and the gold-catalyzed cycloisomerization of the
dihydroxyallene 10 thus formed. This center-to-axis-to-center
chirality transfer proceeds with excellent stereoselectivity (dr =
98 : 2 for 11) and good yield. As expected from previous results,4,5
only the hydroxy group in a-position participates in the cyclization.
With a catalyst loading of only 0.05 mol% AuCl3 in THF,17 the
cycloisomerization of 10 (over 1900 turnovers on a 2 g-scale!)
belongs to the most efficient transformations reported so far in
homogeneous gold catalysis.
In contrast to these unproblematic steps, the conversion of the
secondary alcohol 11 into the tertiary alcohol 12 turned out to be
tricky. The oxidation of 11 to the corresponding ketone could
be achieved with IBX (2-iodoxybenzoic acid) in DMSO (79%
yield) or with Dess–Martin periodinane18 in CH2Cl2 (91% yield).
Unfortunately, this ketone undergoes a very facile epimerization
(probably via the corresponding enol), so that the subsequent
Grignard addition afforded alcohol 12 as a 60 : 40 mixture of
diastereomers. The ease of this epimerization was surprising to us
because the corresponding ketone with a benzyloxymethyl instead
of the benzyloxyethyl side chain is configurationally stable under
the same conditions.19
Scheme 3 Copper-mediated and gold-catalyzed synthesis of 2,5-dihydro-
furan 11 and conversion into tertiary alcohol 12.
In order to circumvent this pitfall, we decided to change
the order of events (Scheme 4). Treatment of epoxyalcohol
9 with Dess–Martin periodinane18 (or with IBX; 88% yield)
gave the ketone 13 which turned out to be configurationally
stable. Subsequent Grignard addition and SN2ꢀ-substitution of the
tertiary alcohol 14 to allene 15 proceeded with excellent yield
and without any loss of stereochemical information (>98% ee).
Alternatively, the conversion of 13 into 15 can be carried out in a
tandem SN2ꢀ-substitution–1,2-addition by treating the substrate
first with the methylmagnesium cuprate and then with excess
with L-(+)-diethyl tartrate, both the epoxide ent-9 (42% yield,
not shown) and the unreacted starting material (R)-8 (43%
yield; configuration assigned according to the Katsuki–Sharpless
mnemonic device15) were obtained with >98% ee. The enyne (R)-8
was then converted into oxirane 9 by a matched Katsuki–Sharpless
epoxidation using D-(−)-diethyl tartrate. With both enantiomers
of the epoxyalcohol at hand, we decided to continue our synthesis
with the (R,R,R)-isomer 9 first.
Scheme 4 Synthesis of (−)-isocyclocapitelline (2) and (−)-isochrysotricine (1) via 2,5-dihydrofuran 12.
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Grignard reagent in a one-pot procedure. Also this sequence
afforded allenic diol 15 with 93% yield and excellent stereocontrol
(>98% ee). The subsequent axis-to-center chirality transfer by
gold-catalyzed cycloisomerization (0.05 mol% AuCl3 in THF)
proceeded as for allene 10 to give the key intermediate with
excellent yield (97%) and high stereochemical purity (96% de,
>98% ee).
Notes and references
1 (a) A. Arcadi and S. D. Giuseppe, Curr. Org. Chem., 2004, 8, 795; (b) A.
Hoffmann-Ro¨der and N. Krause, Org. Biomol. Chem., 2005, 3, 387;
(c) R. A. Widenhoefer and X. Han, Eur. J. Org. Chem., 2006, 4555; (d) N.
Krause and N. Morita, in Comprehensive Organometallic Chemistry III,
ed. R. H. Crabtree and D. M. P. Mingos, Elsevier, Oxford, 2006, vol. 9,
pp. 501–586; (e) A. S. K. Hashmi and G. J. Hutchings, Angew. Chem.,
2006, 118, 8064; A. S. K. Hashmi and G. J. Hutchings, Angew. Chem.,
Int. Ed., 2006, 45, 7896.
The next steps to the target molecules, hydrogenation–
debenzylation of 12 using palladium on charcoal as the catalyst,
as well as oxidation of 16 with Dess–Martin periodinane,18 gave
the aldehyde 3 with good yield. We then carried out a Pictet–
Spengler cyclization20 of 3 with tryptamine as has been reported
for the synthesis of chrysotricine;11 (−)-isocyclocapitelline (2) was
obtained with 53% yield over 2 steps and >98% de/ee after
aromatization of the crude tetrahydro-b-carboline with palladium
on charcoal in refluxing xylenes. Comparison of the optical
rotation of our product (aD20 = −92.4, CHCl3, c = 0.525) with that
of the natural product (aD20 = −75, CHCl3, c = 0.50) suggests that
the latter was not isolated as an enantiomerically pure compound.
More importantly, it confirms the absolute configuration of (−)-
isocyclocapitelline (2) to be (2S,5R). Finally, methylation of the
b-carboline with MeI in refluxing acetone and deprotonation
with aqueous NaOH11 afforded (2S,5R)-(−)-isochrysotricine (1)
with an optical rotation of a2D0 = −38.4 (MeOH, c = 1.020; no
literature value reported). The spectroscopic data of synthetic
1 and 2 are in excellent agreement with those described in the
literature.9
In summary we have developed the first enantioselective total
syntheses of the b-carboline alkaloids (−)-isochrysotricine (1)
and (−)-isocyclocapitelline (2) which also confirm the hitherto
unknown absolute configuration of these natural products. Due
to the regiodivergent nature of our approach, both enantiomers are
accessible via the same route, consisting of a crucial center-to-axis-
to-center chirality transfer by copper-mediated SN2ꢀ-substitution
of propargyl oxiranes 13/14 and gold-catalyzed cycloisomeriza-
tion of a-hydroxyallene 15. Our synthesis clearly demonstrates that
homogeneous gold catalysis is a perfect tool for the stereoselective
construction of complex natural products, and we are currently
pursuing the application of our methods to further interesting
target molecules.
2 (a) J. Zhu, A. R. Germain and J. A. Porco, Jr., Angew. Chem., 2004,
116, 1259; J. Zhu, A. R. Germain and J. A. Porco, Jr., Angew. Chem.,
Int. Ed., 2004, 43, 1239; (b) K. Sato, N. Asao and Y. Yamamoto, J. Org.
Chem., 2005, 70, 8977; (c) S. T. Staben, J. J. Kennedy-Smith, D. Huang,
B. K. Corkey, R. L. LaLonde and F. D. Toste, Angew. Chem., 2006,
118, 6137; S. T. Staben, J. J. Kennedy-Smith, D. Huang, B. K. Corkey,
R. L. LaLonde and F. D. Toste, Angew. Chem., Int. Ed., 2006, 45, 5991;
(d) Z. Liu, A. S. Wasmuth and S. G. Nelson, J. Am. Chem. Soc., 2006,
128, 10352; (e) Y. Li, F. Zhou and C. J. Forsyth, Angew. Chem., 2007,
119, 283; Y. Li, F. Zhou and C. J. Forsyth, Angew. Chem., Int. Ed., 2007,
46, 279.
3 (a) Modern Allene Chemistry, ed. N. Krause and A. S. K. Hashmi,
Wiley-VCH, Weinheim, 2004; (b) R. Zimmer, C. U. Dinesh, E.
Nandanan and F. A. Khan, Chem. Rev., 2000, 100, 3067; (c) J. A.
Marshall, Chem. Rev., 2000, 100, 3163; (d) S. Ma, Chem. Rev., 2005,
105, 2829.
4 (a) A. Hoffmann-Ro¨der and N. Krause, Org. Lett., 2000, 3, 2537; (b) N.
Krause, A. Hoffmann-Ro¨der and J. Canisius, Synthesis, 2002, 1759.
5 B. Gockel and N. Krause, Org. Lett., 2006, 8, 4485.
6 (a) N. Morita and N. Krause, Org. Lett., 2004, 6, 4121; (b) N. Morita
and N. Krause, Eur. J. Org. Chem., 2006, 4634.
7 N. Morita and N. Krause, Angew. Chem., 2006, 118, 1930; N. Morita
and N. Krause, Angew. Chem., Int. Ed., 2006, 45, 1897.
8 (a) B. M. Trost, Angew. Chem., 1995, 107, 285; B. M. Trost, Angew.
Chem., Int. Ed. Engl., 1995, 34, 259; (b) R. A. Sheldon, Pure Appl.
Chem., 2000, 72, 1233.
9 N. M. Phuong, T. V. Sung, A. Porzel, J. Schmidt, K. Merzweiler and
G. Adam, Phytochemistry, 1999, 52, 1725.
10 J. N. Peng, X. Z. Feng, Q. T. Zheng and X. T. Liang, Phytochemistry,
1997, 46, 1119.
11 (a) G. X. Wang, S. F. Chen and X. T. Liang, Chin. Chem. Lett., 1998, 9,
357; (b) S. Mahboobi, M. Koller and D. Schollmeyer, Monatsh. Chem.,
2000, 131, 383; (c) J.-X. Zhang, G.-X. Wang, P. Xie, S.-F. Chen and
X.-T. Liang, Tetrahedron Lett., 2000, 41, 2211; (d) G. X. Wang, J. X.
Zhang, S. F. Chen and X. T. Liang, Chin. Chem. Lett., 2001, 12, 199.
12 J. Hartung, S. Drees, B. Geiss and P. Schmidt, Synlett, 2003, 223.
13 D.-G. Qin, H.-Y. Zha and Z.-J. Yao, J. Org. Chem., 2002, 67, 1038.
14 U. Koop, G. Handke and N. Krause, Liebigs Ann., 1996, 1487.
15 (a) V. S. Martin, S. S. Woodward, T. Katsuki, Y. Yamada, M. Ikeda and
K. B. Sharpless, J. Am. Chem. Soc., 1981, 103, 6237; (b) A. Pfenninger,
Synthesis, 1986, 89; (c) K. B. Sharpless, Tetrahedron, 1994, 50, 4235.
16 Review: N. Krause and A. Hoffmann-Ro¨der, Tetrahedron, 2004, 60,
11671.
17 C. Deutsch, B. Gockel, A. Hoffmann-Ro¨der and N. Krause, Synlett,
Acknowledgements
submitted.
18 (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155; (b) R. K.
Boeckman, Jr., P. Shao and J. J. Mullins, Org. Synth., 2000, 77, 141.
19 F. Volz and N. Krause, to be published.
Continuous support of our work by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie, and the
European Community is gratefully acknowledged.
20 Review: E. D. Cox and J. M. Cook, Chem. Rev., 1995, 95, 1797.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1519–1521 | 1521
©