Synthesis of the Erythrina alkaloid 3-demethoxyerythratidinone. Novel acid-induced rearrangements of its precursors

Article abstract of DOI:10.1021/ol0527330

A new strategy for the synthesis of 3-demethoxyerythratidinone has been developed and is based on an extraordinarily facile intramolecular Diels-Alder reaction of a 2-imido-substituted furan. During the course of the synthesis, several novel acid-induced

Full text of DOI:10.1021/ol0527330

ORGANIC
LETTERS
2006
Vol. 8, No. 4
601-604
Synthesis of the Erythrina Alkaloid
3-Demethoxyerythratidinone. Novel
Acid-Induced Rearrangements of Its
Precursors
Qiu Wang and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received November 10, 2005
ABSTRACT
A new strategy for the synthesis of 3-demethoxyerythratidinone has been developed and is based on an extraordinarily facile intramolecular
Diels Alder reaction of a 2-imido-substituted furan. During the course of the synthesis, several novel acid-induced rearrangement reactions
−
were encountered.
Erythrina alkaloids, a large class of natural products found
in tropical and subtropical regions, represent attractive
synthetic targets due to their use in indigenous medicine.1
Members of the Erythrina family, as exemplified in Figure
1, display curare-like and hypnotic activity, and a variety of
pharmacological effects are associated with the erythrinane
skeleton, including sedative, hypotensive, neuromuscular
blocking, and CNS activity.2 Many different approaches have
been employed for the synthesis of this class of natural
products.3 Taking the final step of bond formation into
consideration, the methods for building up the erythrinan ring
system can be loosely classified into seven different reaction
types:
(1) C-ring formation with the C-5 quaternary center being
constructed by intramolecular cyclization;4 (2) C-ring forma-
tion by electrophilic substitution;5 (3) A-ring formation by
an intramolecular aldol reaction;6 (4) A-ring formation from
a benzoindolizidine fragment;7 (5) B-ring formation utilizing
a C-5 spiro-isoquinoline system;8 (6) B- and C-ring formation
by intramolecular annulation of dibenzazonine;9 and (7) an
assortment of miscellaneous methods.10 In this paper, we
(4) (a) Belleau, B. J. Am. Chem. Soc. 1953, 75, 5765. (b) Mondon, A.;
Hansen, K. F. Tetrahedron Lett. 1960, 5. (c) Ishibashi, H.; Sato, T.;
Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles 1988, 27, 2787. (d)
Tsuda, Y.; Hosoi, S.; Ishida, K.; Sangai, M. Chem. Pharm. Bull. 1994, 42,
204. (e) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron
Lett. 1998, 39, 8995. (f) Rigby, J. H.; Deur, C.; Heeg, M. J. Tetrahedron
Lett. 1999, 40, 6887. (g) Parsons, A. F.; Williams, D. A. J. Tetrahedron
2000, 56, 7217. (h) Toyao, A.; Chikaoka, S.; Takeda, Y.; Tamura, O.;
Muraoka, O.; Tanabe, G.; Ishibashi, H. Tetrahedron Lett. 2001, 42, 1729.
(i) Miranda, L. D.; Zard, S. Z. Org. Lett. 2002, 4, 1135. (j) Allin, S. M.;
James, S. L.; Elsegood, M. R. J.; Martin, W. P. J. Org. Chem. 2002, 67,
9464.
(5) (a) Toda, J.; Niimura, Y.; Takeda, K.; Sano, T.; Tsuda, Y. Chem.
Pharm. Bull. 1998, 46, 906. (b) Jousse, C.; Demae¨le, D. Eur. J. Org. Chem.
1999, 909.
(6) Wasserman, H. H.; Amici, R. M. J. Org. Chem. 1989, 54, 5843.
(7) (a) Sano, T.; Toda, J.; Kashiwaba, N.; Ohshima, T.; Tsuda, Y. Chem.
Pharm. Bull. 1987, 35, 479. (b) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko,
C.; Sano, T. Heterocycles 1992, 33, 497.
(1) (a) Tanaka, H.; Tanaka, T.; Etoh, H.; Goto, S.; Terada, Y.
Heterocycles 1999, 51, 2759. (b) Dyke, S. F.; Quessy, S. N. In The Alkaloids;
Rodrigo, R. G. A., Ed.; Academic Press: New York, 1981; Vol. 18, pp
1-98. (c) Chawla, A. S.; Kapoor, V. K. In The Alkaloids: Chemical and
Biological PerspectiVes: Pelletier, S. W., Ed.; Pergamon: New York, 1995;
Vol. 9, pp 86-153.
(2) Deulofeu, V. In Curare and Curarelike Agents; Bovet, D., Bovet-
Nitti, F., Marini-Bettolo, G. B., Eds.; Elsevier: Amsterdam, 1959; p 163.
(3) (a) Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995,
117, 7834. (b) Lete, E.; Egiarte, A.; Sotomayor, N.; Vicente, T.; Villa, M.-
J. Synlett 1993, 41. (c) Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E.
Tetrahedron Lett. 1996, 37, 7841. (d) Lee, Y. S.; Kang, D. W.; Lee, S. J.;
Park, H. J. Org. Chem. 1995, 60, 7149. (e) Lee, J. Y.; Lee, Y. S.; Chung,
B. Y.; Park, H. Tetrahedron 1997, 53, 2449. (f) Katritzky, A. R.; Mehta,
S.; He, H.-Y. J. Org. Chem. 2001, 66, 148. (g) Garcia, E.; Arrasate, S.;
Ardeo, A.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2001, 42, 1511. (h)
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10.1021/ol0527330 CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/28/2006

anticipated that the erythrinane skeleton of 1 would be
obtained by cyclization of a N-acyliminium ion15 derived
from a suitable aryl enamide precursor emanating from 5.
The synthesis of imidofuran 6 began by coupling the
known mixed anhydride of 3-carbomethoxy-3-butenoic acid
(7) with the lithiated carbamate 9, derived by treating furanyl-
2-carbamic acid tert-butyl ester (8)16 with n-BuLi at 10 °C.
However, the expected imidofuran 6 was not isolated since
the subsequent intramolecular [4 + 2]-cycloaddition occurred
so rapidly that it was not possible to detect 6, even at 0 °C.
Our ability to isolate the somewhat labile (acid, heat)
oxabicyclo adduct 10 (87%) is presumably a result of the
low reaction temperatures employed as well as the presence
of the carbonyl group, which diminishes the basicity of the
nitrogen atom thereby retarding the ring cleavage/rearrange-
ment reaction generally encountered with related furanyl
carbamates.17 We suspect that the facility of the cycloaddition
is due to both the placement of the carbonyl center within
the dienophile tether18 as well as the presence of the
carbomethoxy group which lowers the LUMO energy of the
π-bond, thereby facilitating the cycloaddition.
Figure 1. Some representative Erythrina alkaloids.
report on a distinctively different strategy for the construction
of the tetracyclic core of the erythrinane ring system.
Our approach toward the synthesis of a typical Erythrina
alkaloid such as 1 derives from a program underway in our
laboratory that is designed to exploit the facile Diels-Alder
reaction of imidofurans for the purposes of natural product
synthesis.11 3-Demethoxyerythratidinone (1) was first isolated
in 1973 by Barton and his collaborators from Erythrina
lithosperma.12 Even though several syntheses have been
reported,6,13 we felt that this compound could serve to
illustrate our methodology and provide a basis for a general
cycloaddition approach toward Erythrina alkaloids. Our
retrosynthetic analysis of 1 is shown in Scheme 1 and makes
Lautens and co-workers14a,19 have recently demonstrated
that the Rh(I)-catalyzed ring-opening reaction of unsym-
metrical oxabicyclic compounds is a highly regioselective
process, giving rise to products derived from the attack of
the nucleophile distal to the bridgehead substituent. By taking
advantage of this Rh(I)-catalyzed reaction, we were able to
convert 10 into the ring-opened boronate 5 (97%), which
was then converted to the corresponding diol by treatment
with pinacol/acetic acid. Oxidation of the allylic hydroxyl
group with MnO2 followed by protection of the secondary
OH group with TBSCl, removal of the Boc group, and a
subsequent N-alkylation with 4-(2-bromoethyl)-1,2-dimethox-
ybenzene afforded enamido lactam 11 in 61% yield for the
four-step sequence (Scheme 2).
Scheme 1
Several acids were examined in our attempt to promote
the planned acid-initiated Pictet-Spengler cyclization of
lactam 11. During the course of these studies, we encountered
several novel rearrangement reactions. For example, when
11 was treated with polyphosphoric acid (PPA) in refluxing
use of an IMDAF cycloaddition of imidofuran 6 followed
by a Rh(I)-catalyzed reaction of the resulting cycloadduct
with phenyl boronic acid14 to give hexahydroindoline 5. We
(14) (a) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org.
Lett. 2002, 4, 1311. (b) Wang, Q.; Padwa, A. Org. Lett. 2004, 6, 2189.
(15) (a) Ito, K.; Suzuki, F.; Haruna, M. J. Chem. Soc., Chem. Commun.
1978, 733. (b) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T.
Chem. Pharm. Bull. 1993, 41, 2087. (c) Hosoi, S.; Nagao, M.; Tsuda, Y.;
Isobe, K.; Sano, T.; Ohta, T. J. Chem. Soc., Perkin Trans. 1 2000, 1505.
(d) Padwa, A.; Kappe, C. O.; Reger, T. S. J. Org. Chem. 1996, 61, 4888.
(e) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J. Org. Chem. 1998,
63, 1144.
(16) Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J. Org. Chem.
1999, 64, 4617.
(17) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
63, 5304. (b) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
(c) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515.
(18) Dramatic effects on the rate of the Diels-Alder reaction were
previously noted to occur when an amido group was used to anchor the
diene and dienophile, see: (a) Oppolzer, W.; Fro¨stl, W. HelV. Chim. Acta
1975, 58, 590. (b) White, J. D.; Demnitz, F. W. J.; Oda, H.; Hassler, C.;
Snyder, J. P. Org. Lett. 2000, 2, 3313. (c) Padwa, A.; Ginn, J. D.; Bur, S.
K.; Eidell, C. K.; Lynch, S. M. J. Org. Chem. 2002, 67, 3412. (d) Tantillo,
D. J.; Houk, K. N.; Jung, M. E. J. Org. Chem. 2001, 66, 1938.
(19) (a) Lautens, M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000, 2,
5650. (b) Lautens, M.; Fagnou, K.; Taylor, M. Org. Lett. 2000, 2, 1677.
(c) Lautens, M.; Fagnou, K. Tetrahedron 2001, 57, 5067. (d) Lautens, M.;
Chiu, P.; Ma, S.; Rovis, T. J. Am. Chem. Soc. 1995, 117, 532.
(8) (a) Ahmed-Schofield, R.; Mariano, P. S. J. Org. Chem. 1987, 52,
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Lett. 2001, 42, 8003.
(9) (a) Gervay, J. E.; McCapra, F.; Money, T.; Sharma, G. M. J. Chem.
Soc., Chem. Commun. 1966, 142. (b) Tanaka, H.; Shibata, M.; Ito, K. Chem.
Pharm. Bull. 1984, 32, 1578. (c) Chou, C.-T.; Swenton, J. S. J. Am. Chem.
Soc. 1987, 109, 6898.
(10) (a) Mondon, A.; Ehrhardt, M. Tetrahedron Lett. 1966, 2557. (b)
Haruna, M.; Ito, K. J. Chem. Soc., Chem. Commun. 1976, 345. (c) Ishibashi,
H.; Sato, K.; Ikeda, M.; Maeda, H.; Akai, S.; Tamura, Y. J. Chem. Soc.,
Perkin Trans. 1 1985, 605. (d) Westling, M.; Smith, R.; Livinghouse, T. J.
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A.; Bur, S. K.; Zhang, H. J. Org. Chem. 2005, 70, 6833.
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M. F. T.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1973, 874.
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Y. Heterocycles 1989, 29, 1033.
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Org. Lett., Vol. 8, No. 4, 2006

In contrast to the rearrangement observed using PPA,
heating a sample of 11 in CH2Cl2 with trifluoromethane-
sulfonic acid (TfOH)20 followed by base workup afforded
phenol 15 in 76% yield. Careful monitoring of the rear-
rangement by 1H NMR spectroscopy revealed that the
reaction proceeded via the intermediacy of lactone 17,
which could be isolated in 80% yield by terminating the
thermolysis after 1 h. Further heating of 17 in the
presence of TfOH afforded phenol 15 in 95% yield. When
p-TsOH was employed as the acid promoter, a new inter-
mediate (i.e., 16) was now obtained in 95% yield. The
isolation of 16 under these milder acidic conditions
suggests that the initial step in the conversion of 11 f 15
involves formation of the γ-lactone ring. Exposure of
16 to TfOH in refluxing CH2Cl2 (1 h) resulted in the
preferential cyclization of the activated aromatic ring onto
the amido carbonyl group, producing 17 in 90% yield
(Scheme 4).
Scheme 2
Scheme 4
CH2Cl2, the rearranged benzo[4,5]azepino lactam 12 was
isolated in 80% yield and its structure was unequivocally
established by X-ray crystallography (see the Supporting
Information). This unusual reorganization can be rationalized
by the pathway proposed in Scheme 3. We assume that the
Scheme 3
Considering the difficulty we encountered with the tradi-
tional Pictet-Spengler reaction of enamido lactam 11, we
modified our approach toward 3-demethoxyerythratidinone
(1). Boronate 5 was converted to the corresponding diol using
pinacol/acetic acid, and this was followed by reaction with
acetone to give acetonide 18 in 90% yield. Removal of the
Boc group with Mg(ClO4)2 followed by N-alkylation using
4-(2-bromoethyldimethoxy)benzene gave lactam 19 (80%).
On treating 19 with trifluoroacetic acid (TFA) in CH2Cl2 at
25 °C, we were pleased to isolate the desired hexahydroin-
dolinone 21 (93%). As highlighted in Scheme 5, we believe
that the reaction of 19 proceeds by an acid-induced loss of
acetone to generate N-acyliminium ion 20, which then loses
the available allylic proton so as to dissipate the positive
charge. Ketonization of the resulting enol produces 21. The
first step involves generation of the tetracyclic erythrina
intermediate 13, which then undergoes a nitrogen-assisted
1,2-bond migration with simultaneous expulsion of water (or
TBSOH) to produce the ring-expanded N-acyliminium ion
14. Loss of a proton and subsequent enolization perfectly
accounts for the formation of the observed product 12.
(20) For an example of a TfOH-induced Pictet-Spengler cyclization,
see: Nakamura, S.; Tanaka, M.; Taniguchi, T.; Uchiyama, M.; Ohwada,
T. Org. Lett. 2003, 5, 2087.
Org. Lett., Vol. 8, No. 4, 2006
603

yield. Base hydrolysis of 22 gave carboxylic acid 23, which
was then subjected to Barton decarboxylation conditions21
using BrCCl3 as the solvent. A subsequent elimination of
HBr from the labile tertiary bromide afforded the known 5H-
indolo[7a,1a]isoquinolinedione 24.13a This compound was
converted to 3-demethoxyerythratidinone following the
reductive method of Tsuda and co-workers.13a
Scheme 5
In summary, a new strategy for the synthesis of the
erythrina alkaloid family has been developed, which is based
on an extraordinarily facile intramolecular Diels-Alder
reaction of a 2-imido-substituted furan. By using a Rh(I)-
catalyzed ring opening of the oxabicyclic adduct, it was
possible to synthesize the key hexahydroindolinone necessary
for a Pictet-Spengler cyclization. The application of this
approach to other natural product targets is currently under
investigation, the results of which will be disclosed in due
course.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM 059384)
and the National Science Foundation (CHE-0450779).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds together with an ORTEP drawing for compound
12. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0527330
Pictet-Spengler reaction of 21 was carried out uneventfully
with PPA to furnish the tetracyclic erythrinane 22 in 90%
(21) (a) Barton, D. H. R.; Togo, H.; Zard, S. Z. Tetrahedron 1985, 41,
5507. (b) Attardi, M. E.; Taddei, M. Tetrahedron Lett. 2001, 42, 3519.
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