Studies of new indole alkaloid coupling methods for the synthesis of haplophytine

Article abstract of DOI:10.1021/ol061319c

The two novel bisindole alkaloid structures shown can be synthesized in a few steps from the canthiphytine derivative 9.

Full text of DOI:10.1021/ol061319c

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3117-3120
Studies of New Indole Alkaloid Coupling
Methods for the Synthesis of
Haplophytine
Pankaj D. Rege, Yuan Tian, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received May 30, 2006
ABSTRACT
The two novel bisindole alkaloid structures shown can be synthesized in a few steps from the canthiphytine derivative 9.
Haplophytine (1) is a potent insecticidal alkaloid isolated
from the Central American plant Haplophyton cimicidum
that consists of two alkaloidal subunits joined together in a
highly unusual way.1-4 Upon exposure to HBr, haplophytine
undergoes a unique 1,2-cationic shift to generate the rear-
ranged iminium bromide structure 2, which clearly contains
two indole moieties that are the most likely building blocks
for the biosynthetic pathway. The more complex of these
building blocks, aspidophytine (3), which is also naturally
occurring,4 has previously been synthesized in these labo-
ratories.5 The other coupling component may be a canthi-
phytine4 derivative derived from the tetracyclic indole
alkaloid 4. The chemical synthesis of haplophytine from
aspidophytine and a derivative of canthiphytine represents
a major challenge because of the obvious steric impediments
to such a coupling process and also the complete lack of
any precedent. In this paper we report on studies directed
toward this objective using a canthiphytine derivative and
an aspidophytine mimic.
(1) (a) Crosby, D. G. In Naturally Occurring Insecticides; Jacobson,
M., Crosby, D. G., Eds; Marcel Dekker: New York, 1991; p 213. (b)
Sukh Dev; Koul, O. In Insecticides of Natural Origin; Harwood
Academic Publishers: Amsterdam, The Netherlands, 1997; pp 250 and
251.
(2) (a) Rogers, E. F.; Snyder, H. R.; Fischer, R. F. J. Am. Chem. Soc.
1952, 74, 1987. (b) Snyder, H. R.; Fischer, R. F.; Walker, J. F.; Els, H. E.;
Nussberger, G. A. J. Am. Chem. Soc. 1954, 76, 2819, 4601. (c) Synder, H.
R.; Strohmayer, H. F.; Mooney, R. A. J. Am. Chem. Soc. 1958, 80,
3708.
(3) (a) Cava, M. P.; Talapatra, S. K.; Nomura, K.; Weisback, J. A.;
Douglas, B.; Shoop, E. C. Chem. Ind. (London) 1963, 1242. (b) Cava, M.
P.; Talapatra, S. K.; Yates, P.; Rosenberger, M.; Szabo, A. G.; Douglas,
B.; Raffauf, R. F.; Shoop, E. C.; Weisbach, J. A. Chem. Ind. (London)
1963, 1875. (c) Rae, I. D.; Rosenberger, M.; Szabo, A. G.; Willis, C. R.;
Yates, P.; Zacharias, D. E.; Jeffrey, G. A.; Douglas, B.; Kirkpatrick, J. L.;
Weisbach, J. A. J. Am. Chem. Soc. 1967, 89, 3061. (d) Zacharias, D. E.
Acta Crystallogr., Sect. B 1970, 26, 1455.
(4) Yates, P.; MacLachlan, F. N.; Rae, I. D.; Rosenberger, M.; Szabo,
A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M.
V.; Zeigler, W. J. Am. Chem. Soc. 1973, 95, 7842.
10.1021/ol061319c CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/15/2006

Scheme 1
As the canthiphytine coupling components we selected the
aminoanisole in CH2Cl2 at -20 °C to give 11 as an oil in
36% yield after rapid chromatography on basic alumina
(activity I). The structure of 11 was established by reaction
with methyl iodide to give a crystalline methiodide derivative
12 and subsequent X-ray crystallographic analysis. Unfor-
tunately, the occurrence of coupling R to the iminium
tetracyclic 7-methoxyindole derivatives 8b and 10. These
were synthesized from 7-methoxyindole via the keto amide
5 as shown in Scheme 1. Reduction of 5 to the tryptamine
6 was best accomplished by heating with BH3‚SMe2 in THF
at reflux for 6 h with subsequent purification by rapid flash
chromatography on silica gel. Pictet-Spengler condensation
of 6 with trifluoroethyl 3-formylpropionate (from the mono-
acid chloride by reduction with 1 atm of H2 and 10% Pd-C
catalyst in dry THF in the presence of 2,6-lutidine) afforded
the tricyclic ester 7. Treatment of 7 with sodium hydride in
THF at 0 °C yielded the N-protected canthiphytine derivative
8a, which was then transformed into the key intermediates
8b, 9, and 10 as shown in Scheme 1.
Scheme 2
The oxidation of amine 9 to imine 10 initially proved
difficult because of the propensity of the imine to undergo
further oxidation to a carbazole-type compound. How-
ever, this conversion was efficiently accomplished (after
examination of numerous alternative methods) in 2 steps
via the N-hydroxylamine derivative of 9 in 75% overall
yield. Treatment of amine 9 with 1 equiv of freshly pre-
pared dimethyldioxirane in acetone-CH2Cl2 provided
the corresponding N-hydroxylamine compound. De-
hydration of the latter with PPh3-DEAD (Mitsunobu
reagent) afforded the desired imine 10. The imine 10 could
be activated for coupling with π-electron-rich aromatic
substrates after N-acylation with 2 equiv of trichloroacetyl
chloride in CH2Cl2 at -20 °C.6,7 The results of coupling
experiments with two model substrates are summarized in
Scheme 2.
The N-trichloroacetyl iminium derivative of 10 underwent
coupling with the simple aspidophytine model 3-dimethyl-
(5) (a) He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc.
1999, 121, 6771. (b) For another synthesis see also: Sumi S.; Matsumoto
K.; Tokuyama H.; Fukuyama T. Org Lett. 2003, 5, 1891.
(6) One equivalent of Cl3CCOCl was suboptimal for the sub-
sequent coupling reactions, presumably because of attachment of
Cl3CCO to the lactam carbonyl oxygen as well as to the imine nitro-
gen.
(7) A variety of other imine activating reagents did not pro-
mote coupling: e.g., CH3I, CH3OSO2CF3, BF3, Ph3CBF4, (CF3SO2)2O, and
Me3SiOSO2CF3. p-Nitrophenylchloroformate and (CF3CO)2O did afford the
coupling product with 13 but only in lower yield.
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Org. Lett., Vol. 8, No. 14, 2006

Scheme 3
nitrogen, rather than γ (i.e., at C(3) of the indole moiety),
appears to preclude the use of this approach for the synthesis
of haplophytine. This point was reinforced by our results
with an even closer model of aspidophytine, N-methyl-6,7-
dimethoxy-2,3-dihydroindole (13), which was synthesized
from 3-methoxy-4-hydroxybenzaldehyde as shown in Scheme
3.
Figure 1. 1H NMR spectra of coupling products 11 and 15.9
Treatment of the N-trichloroacetyl iminium derivative of
10 with 13 in the presence of 2 equiv of the hindered base
i-Bu3N led to a facile union of the two components.8 A
nonaqueous workup followed by flash chromatography on
silica gel afforded a 1:1 mixture of 14 and 15 in a combined
yield of 84%. When the crude coupling product was passed
through a column of basic alumina (activity I) it was totally
converted to 15.
Compounds 11 and 14 are also unstable to strongly basic
aqueous conditions which lead to very complex mixtures.
Finally, treatment of 14 with acid causes dearylation (C-C
cleavage) to form 10.
Given the close correlation between the NMR spectra for
15 and 11 (see Figure 1) as well as their methio-
dide derivative (see the Supporting Information), 15 is
assigned the structure shown in Scheme 2. Unfortu-
nately, none of the desired coupling product 16 was de-
tected even on HPLC analysis of the crude reaction mix-
ture (see the Supporting Information for the HPLC trace).
The only other product, detected in trace amounts, is 17,
formed by deprotonation of the intermediate acyliminium
ion. This result clearly showed that this approach is not
applicable to the synthesis of haplophytine and led to the
study of other ways to accomplish the required C-C
coupling reaction.
The second approach investigated for the coupling of
the two components involved selective epoxidation of
the indole double bond in 8b (Scheme 4). Treatment of
8b with 2,2,2-trifluorodimethyldioxirane (TFMD) at -20 °C
for 2 h afforded the desired epoxide 18 (determined
by NMR). (Dimethyldioxirane gave no epoxide under
these conditions.) Exposure of the latter to catalytic
Bronsted acid such as TfOH10 and the 2,3-dihydroindole 13
led to 23% isolated yield of the coupling product 19.
The 13C NMR spectrum of 19 revealed the chemical
Coupling products 11 and 14 exhibit unusual behavior.
As evident from the above discussion, compounds of
this type show an unusually strong tendency to undergo
aerial oxidation in the presence of even a mild base. This
process is facilitated by easy enolization of the amidic
carbonyl. In fact enol ester 11a can be isolated from the
reaction of Cl3CCOCl and imine 10 with 3-dimethylami-
noanisole. Furthermore, treatment of iodide salt 14a with
Et3N in air leads to quantitative conversion of 14a to 15a.8
(9) The peak assignment is based on comparison with similar compounds
and their splitting pattern.
(10) It was found that protic acids seem to work best for this type of
reaction. Use of Lewis acid did not lead to high desired product formation.
The major product in these cases was the diol.
(8) See the Supporting Information for details.
Org. Lett., Vol. 8, No. 14, 2006
3119

instead of two peaks at ca. 95 and 67 ppm as one
would expect in the desired C(3) coupling product,11
thus indicating that the coupling had occurred at the C(2)
carbon.
Scheme 4
Our 13C NMR analysis was confirmed when the cou-
pling reaction was performed with the hydroxyindoline
20 to afford a crystalline coupling product (25%) that was
shown to be 21 by X-ray crystallographic analysis. Along
with the C-C coupling product, 5% of the C-O coupling
product 22 was obtained from this reaction along with diol
23.
The experimental results reported in this paper pro-
vide additional indications of the difficulty of achieving
by chemical means a biomimetic synthesis of haplo-
phytine by the direct coupling of two indole alkaloid
precursors. Nonetheless, we think that this challenge to
synthesis can be met and that the process of finding a solution
to this problem will be informed by the research described
herein.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and copies of H NMR, 13C
NMR, IR for the new compounds described herein; X-ray
crystal data for 12 and 21. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL061319C
(11) On the basis of comparison with closely related natural product
cimilophytine. See: Adesomoju, A. A.; Rawal, V. H.; Lakshmikantham,
M. V.; Cava, M. P. J. Org. Chem. 1983, 48, 3015.
shifts of the newly formed quaternary carbons (C(2) and C(3)
in the indole system) to be in the region of 80-82 ppm
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Org. Lett., Vol. 8, No. 14, 2006