A highly efficient synthesis of the erythrina and B-homoerythrina skeleton by an AlMe3-mediated domino reaction

Article abstract of DOI:10.1002/anie.200460283

Domino effect: The skeleton of erythrina and B-homoerythrina alkaloids can be constructed in an efficient manner from readily available substrates (see Scheme) by a three-step domino reaction. These natural products constitute an interesting class of comp

Full text of DOI:10.1002/anie.200460283

Angewandte
Chemie
Erythrina Alkaloids
domino reaction for the construction of three bonds in
sequential steps that allows efficient access to the skeleton of
the erythrina and B-homoerythrina alkaloids.
The erythrina alkaloids[2] such as erysodine (1) are a
widespread, structurally interestingclass of natural products
with extensive biological activity.[3]
A Highly Efficient Synthesis of the Erythrina and
B-Homoerythrina Skeleton by an AlMe3-
Mediated Domino Reaction**
Many compounds of this family exhibit
curare-like activity as well as hypoten-
Serry A. A. El Bialy, Holger Braun, and Lutz F. Tietze*
sive, sedative, and CNS depressant prop-
Dedicated to Professor Armin de Meijere
on the occasion of his 65th birthday
erties.[4]
The retrosynthesis of the skeleton of
the erythrina and B-homoerythrina
The development of efficient and environmentally acceptable
synthetic methods is an important task of modern chemistry.
In this context the domino concept has proved to be very
successful.[1] In domino reactions bonds and new function-
alities are constructed, which, in turn, react further in
subsequent steps under identical conditions to form new
bonds and functionalities. The larger the number of bonds
formed and the higher the complexity of the product is the
greater is the quality of a domino reaction. A plethora of two-
step domino reactions have been reported, but three-step
transformations are the exception. Here we describe a novel
alkaloids 2a and 2b within the context
of the domino concept leads to the
amine 5a and the cyclohexene derivatives 6a and 6b via the
N-acyliminium ions 3a and 3b and the metalated amides 4a
and 4b (Scheme 1). The intermediate N-acyliminium ions 3
could be formed by an intramolecular addition of an
aluminum complex of the primary carboxamide[5] to the
enol acetate moiety in 4 with subsequent elimination of acetic
acid. The aluminum complex might be accessible in situ by
reaction of the primary amine 5 with the ester function of the
enol acetate 6.
Scheme 1. Retrosynthesis and synthesis of the erythrina and B-homoerythrina skeleton 2 as well as the enamines 8 and 9.
[*] Dr. S. A. A. El Bialy, Dipl.-Chem. H. Braun, Prof. Dr. L. F. Tietze
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
The enol acetates 6a and 6b were readily obtained in 86
and 93% yield, respectively, by reaction of the known
ketones[6] 7a and 7b with isoprenyl acetate in the presence
of a catalytic amount of p-toluenesulfonic acid. For the
synthesis of 2a and 2c, the amines 5a and 5b, respectively,
were each treated with trimethylaluminum in benzene, stirred
for one hour at 208C, and after the addition of 6a heated
under reflux for five hours.[7] After workup 2a[8] and 2c were
isolated in 79 and 82% yield, respectively. In an analogous
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax: (+49)551-399-476
E-mail: ltietze@gwdg.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 416) and the Fonds der Chemischen Industrie. S.A.A.E.B.
thanks the Alexander von Humboldt-Stiftung for a research
stipendium.
Angew. Chem. Int. Ed. 2004, 43, 5391 –5393
DOI: 10.1002/anie.200460283
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5391

Communications
manner the homoerythrina alkaloids 2b[9] and 2d were
[1] a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 134 – 170;
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obtained in 89% and 85% yield, respectively, by the reaction
of 5a and 5b with 6b in the presence of trimethylaluminum.
In the reaction of the keto esters 7a and 7b with the amines
5a and 5b and trimethylaluminum, no cyclization to the
erythrina and homoerythrina skeleton occurred, but instead
as in the transformation of 5b and 7b, the enamines 8 and 9
were obtained in 32 and 58% yield, respectively.
On-line NMR investigations during the reaction of a
mixture of 5b, 6c, and AlMe3 show that at 208C the Lewis
acid/Lewis base complex 10 is formed from 5b with AlMe3
(Scheme 2); the ester function of 6c is not attacked. In
Scheme 2. Addition complexes 10 and 11 of the amine 5a with tri-
methylaluminum and the carboxamide 12.
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[6] G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz, R. J.
Terrell, J. Am. Chem. Soc. 1963, 85, 207 – 222.
[7] General method for the AlMe3-mediated domino reaction: One
equivalent of a 0.14m solution of amine 5 in benzene was treated
with two equivalents of a 1.36m AlMe3 solution in benzene at 08C
and stirred for 1 h at room temperature. After the addition of one
equivalent of a 0.14m solution of the enol acetate 6 in benzene,
the mixture was heated at 808C for 5 h in a pre-heated oil bath. At
08C 2n HCl (5 mLmmolÀ1) was then added and the mixture was
stirred for 30 min at this temperature. After phase separation, the
aqueous phase was extracted four times with ethyl acetate
(10 mLmmolÀ1), the combined extracts were dried over Na2SO4,
and the solvent was removed in vacuum. The crude product was
contrast, in the reaction of 6c with AlMe3 without the
addition of the amine 5b a transformation of the ester
function of 6c is observed even at 208C. Heatingthe mixture
of 5b, 6c, and AlMe3 to 708C leads to the formation of 11
together with the evolution of methane (Scheme 2), 11 then
reacts rapidly with the ester group of 6c. Amongthe products
isolated on workingup the reaction mixture after one hour is
the carboxamide 12 (Scheme 2), which, however, on reaction
with AlMe3 does not lead to the desired product. Thus, we
conclude that in the domino reaction the free carboxamide 12
is not generated but rather a metalated species (e.g. 4), which,
however, is not formed by the reaction of 12 with AlMe3.
The formation of the iminium ion 3 from 4 also appears to
be a very fast reaction. Thus, in the 1H NMR spectrum of the
reaction mixture a singlet at d = 1.13 ppm, which can be
assigned to a R2AlOAc group, is found after just a few
minutes in place of the signal at d = 1.76 ppm for the CH3
moiety of the enol acetate group of 6c. The rate-determining
step of the domino process is probably the electrophilic
substitution of the arene by the iminium ion 3.
The domino reaction presented here in which three
sequential bonds are formed in one reaction process allows
the efficient construction of the erythrina and B-homoery-
thrina alkaloid skeleton in good yields. The required sub-
strates are readily accessible and may be varied in many ways.
This method should therefore be of interest in drugresearch.
Received: April 9, 2004
Keywords: alkaloids · amides · domino reactions ·
.
iminium ions · Lewis acids
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Angewandte
Chemie
purified by column chromatography on silica (petroleum ether/
ethyl acetate = 1:1).
[8] 2a: 1H NMR (200 MHz, CDCl3, TMS): d = 6.83 (s, 1H; 13-H),
6.54 (s, 1H; 10-H), 4.11 (ddd, J = 13.2, 7.0, 3.2 Hz, 1H; 8-Heq), 3.83
(s, 3H; OMe at C-12), 3.77 (s, 3H; OMe at C-11), 3.18 (ddd, 1H;
J = 13.2, 9.8, 5.2 Hz, 8-Hax), 2.93 (ddd, 1H; J = 16.4, 9.8, 7.0 Hz, 9-
Heq), 2.63 (ddd, 1H; J = 16.4, 5.2, 3.2 Hz, 9-Hax), 2.60–2.52 (m,
1H; 4a-H), 2.36 (s, 1H; 5-Ha), 2.33 (d, 1H; J = 1.2 Hz, 5-Hb), 2.16–
1.92 (m, 1H; 1-Ha), 1.93–1.80 (m, 2H; 4-H2), 1.80–1.71 (m, 1H; 1-
Hb), 1.74–1.60 (m, 2H; 2-H), 1.60–1.48 ppm (m, 2H; 3-H); 13C
NMR (75 MHz, CDCl3, TMS): d = 174.9 (C-6), 147.6 (C-12),
147.1 (C-11), 134.7 (C-13a), 125.6 (C-9a), 111.7 (C-10), 108.0 (C-
13), 62.09 (C-13b), 55.99 (OMe at C-11), 55.67 (OMe at C-12),
37.51 (C4a), 36.46 (C-8), 35.74 (C-5), 34.67 (C-4), 27.02 (C-1, C-9),
20.63 (C-2), 20.20 ppm (C-3).
1
[9] 2b: H NMR (200 MHz, CDCl3, TMS): d = 6.70 (s, 1H; 14-H),
6.58 (s, 1H; 11-H), 4.79 (mc, 1H; 9-Ha) 3.96 (s, 3H; OMe at C-12),
3.87 (s, 3H; OMe at C-13), 3.35–3.08 (m, 2H; 9-Hb 10-Ha), 2.78–
2.42 (m, 3H; 4a-H, 6-H, 10-Hb), 2.38–2.20 (m, 2H; 5-H), 1.98–1.72
(m, 3H; 1-H, 2-Ha), 1.71–1.42 ppm (m, 6H; 6-H, 4-H, 2-Hb, 3-H);
13C NMR (75 MHz, CDCl3, TMS): d = 172.16 (C-7), 147.4 (C-12),
146.9 (C-13), 135.4 (C-14a), 126.84 (C-10a), 112.2 (C-14), 105.9
(C-11), 61.27 (C-14b), 55.96 (OMe at C-12), 55.43 (OMe at C-13),
40.47 (C-6), 35.75 (C-4a), 34.91 (C-9), 28.38 (C-5), 26.62 (C-10),
25.77 (C-4), 25.56 (C-1), 22.19 (C-2), 21.35 ppm (C-3).
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