Highly efficient domino reaction for the synthesis of the erythrina and B-homoerythrina alkaloid skeleton

Article abstract of DOI:10.1055/s-2008-1032091

A Lewis acid catalyzed domino-amidation-spirocyclization reaction is described which provides the spirocyclic core of the erythrina and B-homoerythrina alkaloids, forming three bonds in one process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032091

LETTER
525
Highly Efficient Domino Reaction for the Synthesis of the Erythrina and
B-Homoerythrina Alkaloid Skeleton
S
ynthesis of the
u
E
rythrina an
t
dB-H
z
Alk
F
a
loidSkeleton. Tietze,* Nina Tölle, Claudia Noll
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(551)399476; E-mail: ltietze@gwdg.de
Received 28 October 2007
MeO
Abstract: A Lewis acid catalyzed domino–amidation–spirocy-
O
clization reaction is described which provides the spirocyclic core
of the erythrina and B-homoerythrina alkaloids, forming three
bonds in one process.
N
MeO
MeO
Key words: domino reactions, erythrina alkaloids, spiro com-
1
pounds, Lewis acids, indolizidine, lactams
Figure 1 Erysotramidine (1)
Ecological and economical aspects are increasingly im-
portant in modern synthetic chemistry. The domino con-
cept has proven to be very successful in this context.1 A
domino reaction is a transformation of two or more bond-
forming reactions – that in an ideal procedure proceeds
under identical reaction conditions – in which the latter
transformations take place at the functionalities obtained
in the former steps.1 Here we describe a domino process
which allows us to build up the erythrina and B-homo-
erythrina skeleton in one process starting from readily
available substrates. The erythrina alkaloids are a widely
spread class of natural products that can be found in trop-
ical and subtropical Febaceae plants of the erythrina ge-
nus.2 Numerous alkaloids of this family, such as
erysotramidine (1, Figure1), have been isolated which
show pronounced biological activity,3 e.g. curare-like
properties as well as hypotensive, sedative, anticonvul-
sive, and CNS-depressive properties.4 Some members of
this alkaloid family have already been synthesized.5
The characteristic tetracyclic aza-spiro structure 4a–d of
the erythrina and homoerythrina alkaloids was formed by
a Lewis acid catalyzed domino reaction of primary aryl-
ethylamines 2a,b and an oxocarboxylate 3 in the presence
of AlMe3; three bonds are formed succeedingly in this
process (Figure1, Table1). Similarly, also heteroanalo-
gous compounds 4e–h can be formed using heteroaryleth-
ylamines as 2c,d.
AlMe3, In(OTf)3
MeCN, 20–180 °C,
3–20 h
O
O
D
C
n
O
N
NH2
R
B
A
then
TfOH, r.t., 5 h
D
n
O
A
2a–d
3a: n = 1, R = Et
3b: n = 2, R = Me
4a–h
O
MeO
MeO
O
O
N
N
O
n
MeO
MeO
n
O
D =
O
4c: n = 1, 99%
4d: n = 2, 70%
4a: n = 1, 99%
4b: n = 2, 38%
2a
2c
2b
S
S
O
O
N
N
S
S
n
n
2d
4e: n = 1, 84%
4f: n = 2, 52%
4g: n = 1, 65%
4h: n = 2, 52%
Scheme 1 Lewis acid mediated domino reactions
SYNLETT 2008, No. 4, pp 0525–0528
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032091; Art ID: G34907ST
© Georg Thieme Verlag Stuttgart · New York

526
L. F. Tietze et al.
LETTER
O
O
MeO
NH2
MeO
MeO
NH
AlMe3, LA
OEt
EtO
+
AlMe2
+
MeO
O
O
2a
3a
5
3a
MeO
AlMe2
O
MeO
MeO
MeO
MeO
AlOEtMe2
AlOEtMe2
HN
O
O
MeO
HN
O
N
LA
O
LA
7
8
6
+
MeO
MeO
AlOEtMe2
MeO
O
MeO
O
N
O
N
TfOH
N
MeO
MeO
10
4a
9
OH
MeO
MeO
MeO
MeO
MeO
MeO
O
O
O
N
N
N
+
+
13
12
11
Scheme 2 Proposed mechanism of the domino reaction
As an example, the reaction of 2a and 2b with 3a using
two equivalents of AlMe3 and 4 mol% to 25 mol% of in-
dium triflate [In(OTf)3] at room temperature for 17 hours
followed by treatment of the reaction mixture with triflu-
oromethanesulfonic acid (TfOH) for 5 hours gave 4a and
4c, respectively, in 99% yield (Scheme1, Table1, entries
1 and 3). Similarly, transformation of 2b–d and 3b as well
as 2a–d and 3b led to 4b and 4d–4h in 38–84% yield em-
ploying the reaction conditions shown in Table1 (entries
2 and 4–8). The yields of the reaction leading to the homo-
erythrina skeleton are always somehow lower. Interest-
ingly, the reaction also works using the 2- and 3-
thienylethylamines 2c and 2d; however, again with lower
yields than in the case of 2a.
Table 1 Results of the Domino Reactions
Entry Amine Ester Temp Time In(OTf)3 Product
Yield
(%)
(°C)
(h)
17
3
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2c
2c
2d
2d
3a
3b
3a
3b
3a
3b
3a
3b
25
5
4a
4b
4c
4d
4e
4f
99
38
99
70
84
52
65
52
100
25
4
17
12
13
12
3
25
25
17
5
160
25
100
100
180
5
4g
4h
The mechanistic details of the domino process are not yet
fully understood. Online NMR investigations7 and isolat-
ed intermediates let us propose the following mode of ac-
tion (Scheme2). Treatment of the amine 2a with AlMe3
and 3a in the presence of catalytic amounts of In(OTf)3
gives the corresponding aluminum amide 5 which attacks
the ester 3a forming the aluminum aza-enolate 6. An at-
tack of the aluminum amide 5 onto the keto instead of the
ester functionality in 3a has not been observed, which cor-
responds well to the high oxophilicity of the aluminum
species. Subsequent intramolecular attack at the keto
functionality under Lewis acid catalysis leads to the for-
3
5
a Amine (2, 1.00 equiv), AlMe3 (2.00 equiv, 2 M, in toluene), keto es-
ter (3, 1.00 equiv), MeCN (0.5 mL/equiv), time, temp, then TfOH
(3.50 equiv), r.t., 5 h.6
mation of the enamines 8 and 9, indicated by the corre-
sponding lactam species 11–13 formed if the reaction is
quenched with base at this stage. Addition of TfOH to the
reaction mixture results in the formation of the iminium
ion 10, which undergoes a ring closure upon intramolecu-
Synlett 2008, No. 4, 525–528 © Thieme Stuttgart · New York

LETTER
Synthesis of the Erythrina and B-Homoerythrina Alkaloid Skeleton
527
(5) (a) Stanislawski, P. C.; Willis, A. C.; Banwell, M. G. Org.
Lett. 2006, 8, 2143. (b) Padwa, A.; Wang, Q. J. Org. Chem.
2006, 71, 7391. (c) Ganguly, A. K.; Wang, C. H.; Biswas,
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2373. (e) Fukumoto, H.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Angew. Chem. Int. Ed. 2006, 45, 2731.
(6) General Procedure
lar electrophilic attack at the aromatic ring to give the spi-
rocyclic product 4a.
The described process is much more convenient than the
reaction of the enol acetate of the keto esters 3a or 3b7
since it saves one step and gives better yields. We have in-
vestigated the use of other acids for the C-ring closure;
however, TfOH was the only reagent which allowed the
cyclization. It should be pointed out that the aryl ethyl
amines 2a and 2b with 3a gave similar results, though the
electron density of the aromatic moiety of the two sub-
strates, being important for the electrophilic aromatic sub-
stitution, is different. Thus, in the case of the
methylenedioxy-substituted compound the electron den-
sity should be lower due to a reduced overlap of the non-
bonding electron pairs at the oxygen atoms of the 1,3-
dioxy moiety and the π-system of the aromatic ring due to
an anomeric effect. However, acyl iminium ions as 10 are
highly reactive species that this difference of electron den-
sity does not affect the transformation in this case.
To a stirred solution of amine 2 (1.00 equiv) in MeCN (0.5
mL/mmol) was added dropwise at 0 °C AlMe3 (2.00 M in
toluene, 2.00 equiv), then In(OTf)3 (4–25 mol%) and the
ester 3 (1.00 equiv), and stirring was continued for 3–17 h at
r.t. or the mixture was heated to 100–180 °C under
microwave irradiation. The reaction mixture was cooled to
0 °C, TfOH (3.5 equiv) was added dropwise and stirring was
continued for 5 h at r.t. Subsequently, the mixture was
quenched by addition of sat. aq NaHCO3 at 0 °C with stirring
for 20 min. The mixture was extracted with EtOAc, the
combined organic layers were washed with brine, dried over
Na2SO4, and the solvent was removed under reduced
pressure. The crude product was subjected to column
chromatography to yield 38–99% of the spirocycle 4.
Compound 4a: 1H NMR (300 MHz, DMSO): δ = 1.35–1.60
(m, 5 H, 3-H2, 2-H2, 1-Ha), 1.75–1.82 (m, 2 H, 4-H2), 1.95–
1.99 (m, 1 H, 1-Hb), 2.12 (mc, 2 H, 7-H2), 2.54–2.60 (m, 1 H,
6-H), 2.63 (ddd, J = 3.0, 6.0, 16.5 Hz, 1 H, 11-Ha), 2.80 (ddd,
J = 7.4, 10.0, 16.5 Hz, 1 H, 11-Hb), 3.15 (ddd, J = 6.0, 10.0,
13.2 Hz, 1 H, 10-Ha), 3.71 (s, 3 H, OCH3), 3.76 (s, 3 H,
OCH3), 3.86 (ddd, J = 3.0, 7.4, 13.2 Hz, 1 H, 10-Hb), 6.67 (s,
1 H, 17-H), 6.91 (s, 1 H, 14-H). 13C NMR (300 MHz,
DMSO): δ = 20.06 (C-2), 20.57 (C-3), 26.14 (C-11), 27.17
(C-1), 34.26 (C-10), 35.01 (C-4), 36.29 (C-7), 36.67 (C-6),
55.42 (OCH3), 55.74 (OCH3), 61.75 (C-5), 108.7 (C-14),
112.5 (C-17), 125.5 (C-12), 134.7 (C-13), 147.0 (C-16),
147.5 (C-15), 173.6 (C-8).
The presented domino reaction with the formation of three
bonds is a highly efficient process, which allows the syn-
thesis of the erythrina and B-homoerythrina alkaloid skel-
etons in up to 99% yield.
Acknowledgment
This work has been supported by the DFG and the Fonds of the Ger-
man Chemical Industry.
References and Notes
Compound 4b: 1H NMR (300 MHz, DMSO): δ = 1.18–1.42
(m, 2 H, 11-Ha, 13*-Ha), 1.42–1.69 (m, 5 H, 2-H2, 12*-H2,
13*-Hb), 1.69–1.82 (m, 2 H, 1-H2), 2.05 (dd, J = 18.5, 6.2
Hz, 1 H, 14-Ha), 2.18–2.26 (m, 1 H, 11-Hb), 2.33–2.47 (m, 1
H, 14-Hb), 2.52 (d, J = 5.9 Hz, 1 H, 6-Ha), 2.63 (mc, 1 H, 14a-
H), 2.84–2.99 (m, 1 H, 6-Hb), 3.19 (td, J = 12.3, 5.9 Hz, 1 H,
5-Ha), 3.70 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 4.53 (dd,
J = 13.2, 7.5 Hz, 1 H, 5-Hb), 6.62 (s, 1 H, 7-H), 6.82 (s, 1 H,
10-H). 13C NMR (300 MHz, DMSO): δ = 21.42 (C-13*),
22.15 (C-12*), 25.07 (C-1), 25.60 (C-2), 26.06 (C-6), 28.14
(C-14), 34.48 (C-5), 34.77 (C-14a), 39.58 (C-11), 55.32
(OCH3), 55.89 (OCH3), 60.99 (C-10b), 107.2 (C-10), 112.9
(C-7), 126.5 (C-6a), 135.8 (C-10a), 146.9 (C-9), 147.4 (C-8),
171.0 (C-3).
(1) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino
Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
2006. (b) Tietze, L. F.; Haunert, F. In Stimulating Concepts
in Chemistry; Shibasaki, M.; Stoddart, J. F.; Vögtle, F., Eds.;
Wiley-VCH: Weinheim, 2000, 39. (c) Tietze, L. F.; Modi,
A. Med. Res. Rev. 2000, 20, 304. (d) Tietze, L. F. Chem.
Rev. 1996, 115. (e) Tietze, L. F.; Beifuss, U. Angew. Chem.,
Int Ed. Engl. 1993, 32, 131.
(2) Krukoff, B. A.; Barneby, R. C. Mem. New York Bot. Gard.
1970, 20, 1.
(3) (a) Chawla, A. S.; Kapor, V. K. In Handbook of Plant and
Fungal Toxicants; D’Mello, J. F., Ed.; CRC Press: New
York, 1997, 37. (b) Bhakuni, D. S. J. Indian Chem. Soc.
2002, 203. (c) Lehman, A. J. J. Pharmacol. 1937, 69.
(d) Williams, M.; Robinson, J. L. J. Neurosci. 1984, 2906.
(e) Decker, M. W.; Anderson, D. J.; Brioni, J. D.; Donnelly-
Roberts, D. L.; Kang, C. H.; O’Neil, A. B.; Piattoni-Kaplan,
M.; Swanson, S.; Sullivan, J. P. Eur. J. Pharmacol. 1995, 79.
(4) (a) Boekelheide, V. In The Alkaloids, Vol. 7; Manske, R. H.
F., Ed.; Academic Press: New York, 1960, 201. (b) Hill, R.
K. In The Alkaloids, Vol. 9; Manske, R. H. F., Ed.;
Academic Press: New York, 1967, 483. (c) Dyke, S. F.;
Quessy, S. N. In The Alkaloids, Vol. 18; Rodrigo, R. G. A.,
Ed.; Academic Press: New York, 1981, 1. (d) Jackson, A.
H. In Chemistry and Biology of Isoquinoline Alkaloids;
Phillipson, J. D.; Margaret, M. F.; Zenk, M. H., Eds.;
Springer: Berlin, 1985, 62. (e) Chawla, A. S.; Jackson, A. H.
Nat. Prod. Rep. 1984, 1, 371.
Compound 4c: 1H NMR (300 MHz, DMSO): δ = 1.28–1.48
(m, 3 H, 3-H2, 1-Ha), 1.49–1.58 (m, 2 H, 2-H2), 1.71–1.75
(m, 1 H, 4-Ha), 1.78–1.83 (m, 1 H, 4-Hb), 1.91–1.99, (m, 1
H, 1-Hb), 2.09–2.14 (m, 2 H, 7-H2), 2.49–2.54 (m, 1 H, 6-
H), 2.59–2.67 (m, 1 H, 11-Ha), 2.73–2.87 (m, 1 H, 11-Hb),
3.11–3.21 (m, 1 H, 10-Ha), 3.78–3.85 (m, 1 H, 10-Hb), 5.94
(s, 2 H, 18-H2), 6.65 (s, 1 H, 17-H), 6.97 (s, 1 H, 14-H). 13
C
NMR (300 MHz, DMSO): δ = 19.90 (C-2), 20.49 (C-3),
26.58 (C-11), 27.02 (C-1), 34.25 (C-10), 35.01 (C-4), 36.22
(C-7), 36.71 (C-6), 62.13 (C-5), 100.7 (C-18), 104.9 (C-14),
108.7 (C-17), 126.8 (C-12), 135.9 (C-13), 145.6 (C-
16), 145.7 (C-15), 173.6 (C-8).
Compound 4d: 1H NMR (300 MHz, DMSO): δ = 1.20–1.35
(m, 2 H, 11-Ha, 13*-Ha), 1.35–1.52 (m, 2 H, 1-H2), 1.50–1.80
(m, 5 H, 2-H2, 12*-H2, 13*-Hb), 2.04 (dd, J = 18.6, 6.6 Hz, 1
H, 14-Ha), 2.18–2.25 (m, 1 H, 11-Hb), 2.32–2.44 (m, 1 H, 14-
Hb), 2.55–2.70 (m, 2 H, 6-Ha, 14a-H), 2.80–2.92 (m, 1 H, 6-
Synlett 2008, No. 4, 525–528 © Thieme Stuttgart · New York

528
L. F. Tietze et al.
LETTER
Hb), 3.14 (td, J = 11.9, 5.8 Hz, 1 H, 5-Ha), 4.52 (dd, J = 13.7,
7.4 Hz, 1 H, 5-Hb), 5.96 (s, 2 H, OCH2O), 6.61 (s, 1 H, 7-H),
6.92 (s, 1-H, 10-H).13C NMR (300 MHz, DMSO): δ = 21.36
(C-13*), 22.07 (C-12*), 25.05 (C-1), 25.56 (C-2), 26.53 (C-
6), 28.10 (C-14), 34.22 (C-5), 34.83 (C-14a), 39.62 (C-11),
61.12 (C-10b), 100.5 (OCH2O), 103.3 (C-10), 109.1 (C-7),
127.6 (C-6a), 137.0 (C-10a), 145.4 (C-9), 145.5 (C-8), 170.8
(C-3).
(C-8), 34.88 (C-5), 38.20 (C-9), 39.34 (C-9a), 61.27 (C-13a),
122.8 (C-2), 127.3 (C-3), 134.3 (C-3a), 142.1 (C-13b), 170.2
(C-7).
Compound 4g: 1H NMR (300 MHz, DMSO-d6): δ = 1.46–
1.68 (m, 6 H, 5-H2, 6-H2, 7-Ha, 4-Ha), 1.85–2.99 (m, 2 H, 7-
Hb, 4-Hb), 2.14 (dd, J = 6.9, 14.0 Hz, 8-Ha), 2.21–2.29 (m, 1
H, 7a-H), 2.35 (ddd, J = 0.8, 8.9, 14.0 Hz, 1 H, 8-Hb), 2.70–
2.86 (m, 2 H, 12-H2), 3.01–3.11 (m, 1 H, 11-Ha), 4.09–4.16
(m, 1 H, 11-Hb), 7.18 (d, J = 5.3 Hz, 1 H, 3-H), 7.35 (d,
J = 5.3 Hz, 1 H, 2-H). 13C NMR (75 MHz, DMSO-d6):
δ = 19.95 (C-5), 20.23 (C-6), 23.88 (C-12), 24.97 (C-7),
33.45 (C-11), 34.12 (C-4), 35.08 (C-8), 37.68 (C-7a), 61.10
(C-3b), 123.4 (C-2), 124.3 (C-3), 132.3 (C-12a), 140.8 (C-
3a), 171.9 (C-9).
Compound 4e: 1H NMR (300 MHz, DMSO): δ = 1.48–1.64
(m, 6 H, 11-Ha, 10-H2, 9-H2, 8-Ha), 1.82–1.87 (m, 1 H, 11-
Hb), 1.94–1.99 (m, 1 H, 8-Hb), 2.10–2.19 (m, 2 H, 4-Ha, 8a-
H), 2.39–2.48 (m, 1 H, 4-Hb), 2.48–2.74 (m, 2 H, 12-H2),
2.96 (td, J = 12.3, 6.7 Hz, 1 H, 5-Ha), 4.00–4.11 (qd, 1 H,
J = 6.5, 1.3 Hz, 5-Hb), 6.85 (d, J = 5.4 Hz, 1 H, 3-H), 7.35 (d,
J = 5.4 Hz, 1 H, 2-H). 13C NMR (300 MHz, DMSO):
δ = 19.57 (C-10), 21.00 (C-9), 24.46 (C-11), 25.10 (C-12),
33.16 (C-5), 34.43 (C-8), 34.54 (C-4), 40.33 (C-8a), 61.03
(C-12a), 122.9 (C-2), 126.9 (C-3), 132.4 (C-12b), 139.2 (C-
3a), 171.0 (C-7).
Compound 4h: 1H NMR (300 MHz, DMSO-d6): δ = 1.21–
1.38 (m, 1 H, 4-Ha), 1.38–1.55 (m, 4 H, 4-Hb, 8-H2, 6-Ha),
1.55–1.68 (m, 2 H, 5-H2), 1.68–1.78 (m, 2 H, 7-H2), 2.09
(mc, 1 H, 9-Ha), 2.17–2.24 (m, 1 H, 6-Hb), 2.37–2.47 (m, 2
H, 7a-H, 9-Hb), 2.63 (dd, J = 5.3, 16.2 Hz, 1 H, 13-Ha), 2.90
(ddd, J = 6.9, 11.7, 16.2 Hz, 1 H, 13-Hb), 3.23 (ddd, J = 5.3,
11.7, 13.2 Hz, 1 H, 12-Ha), 4.58 (dd, J = 6.9, 13.2 Hz, 1 H,
12-Hb), 7.00 (d, J = 5.4 Hz, 1 H, 3-H), 7.27 (d, J = 5.4 Hz, 1
H, 2-H). 13C NMR (75 MHz, DMSO-d6): δ = 21.35 (C-4),
22.78 (C-8), 23.06 (C-13), 24.69 (C-7), 25.76 (C-5), 28.67
(C-9), 35.06 (C-12), 36.46 (C-7a), 38.31 (C-6), 61.42 (C-
3b), 122.7 (C-3), 123.2 (C-2), 134.1 (C-13a), 143.21 (C-3a),
171.3 (C-10).
Compound 4f: 1H NMR (300 MHz, DMSO-d6): δ = 1.35–
1.61 (m, 4 H, 12-Ha, 13-H2, 12-Hb), 1.61–1.80 (m, 4 H, 10-
H2, 9-Ha, 11-Ha), 1.84–1.94 (m, 2 H, 11-Hb), 2.03–2.09 (m,
1 H, 9a-H), 2.11–2.25 (m, 2 H, 8-Ha, 9-Hb), 2.37–2.49 (m, 1
H, 8-Hb), 2.53 (ddd, J = 1.0, 5.3, 16.5 Hz, 1 H, 4-Ha), 2.70
(ddd, J = 6.8, 11.7, 16.5 Hz, 1 H, 4-Hb), 3.16 (ddd, J = 5.3,
11.7, 13.3 Hz, 1 H, 5-Ha), 4.58 (ddd, J = 1.0, 6.8, 13.3 Hz, 1
H, 5-Hb), 6.80 (d, J = 5.0 Hz, 1 H, 3-H), 7.34 (d, J = 5.0 Hz,
1 H, 2-H). 13C NMR (75 MHz, DMSO-d6): δ = 21.69 (C-12),
22.77 (C-10), 23.10 (C-13), 24.30 (C-4), 26.82 (C-11), 29.68
(7) El Bialy, S. A. A.; Braun, H.; Tietze, L. F. Angew. Chem. Int.
Ed. 2004, 43, 5391.
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