Synthesis of the erythrina alkaloid erysotramidine

Article abstract of DOI:10.1021/jo501583c

A concise synthesis of erysotramidine (an alkaloid belonging to the erythrina family) was achieved starting with an inexpensive phenol and amine derivative. The synthesis is based on oxidative phenol dearomatizations mediated by a hypervalent iodine reage

Full text of DOI:10.1021/jo501583c

Note
pubs.acs.org/joc
Synthesis of the Erythrina Alkaloid Erysotramidine
Chloe L’Homme, Marc-Andre Menard, and Sylvain Canesi*
́ ́ ́
Laboratoire de Met
́
hodologie et Synthes
ec, Canada
̀
e de Produits Naturels, Universite
́
du Queb
́
ec a
̀
Montrea
́
l, C.P. 8888, Succ. Centre-Ville,
Montreal, H3C 3P8 Queb
́
́
*
S Supporting Information
ABSTRACT: A concise synthesis of erysotramidine (an alkaloid belonging to the erythrina family) was achieved starting with an
inexpensive phenol and amine derivative. The synthesis is based on oxidative phenol dearomatizations mediated by a hypervalent
iodine reagent and includes a novel route to a key indolinone moiety.
1
rythrina alkaloids are natural tetracyclic compounds 1
of this note is to illustrate the effectiveness of hypervalent iodine
E
isolated from wide variety of tropical plants (Figure 1). The
reagents in total synthesis of natural products, Figure 2.
Figure 1. Erythrina alkaloid members.
structures contain an aza-spiran ring and exhibit hypotensive,
sedative, and anticonvulsive properties as well as curare-like
2
effects. The compounds may be divided into aromatic structures
3
2c
such as erysotramidine 2 and erysotrine 3 and nonaromatic
Figure 2. Retrosynthesis of erysotramidine.
4
structures such as β-erythroidine 4. The publication of several
elegant syntheses has generated widespread interest in these
compounds in the scientific community.
5
,6
The synthesis began with commercially available phenol 5 and
amine 6, which were joined through an amide linkage to produce
In this note, we describe a concise preparation of
erysotramidine, an alkaloid belonging to the aromatic erythrina
family, in eight steps.
10
7
in 84% yield using a reaction promoted by an aluminum salt.
Amide 7 was treated in methanol with (diacetoxyiodo)-benzene
(DIB) to induce the first oxidative dearomatization, resulting in
the functionalized prochiral dienone 8 in 62% yield. An
interesting aspect of this transformation is its ability to
reconfigure the inert unsaturations of the phenol moiety 7 into
the oxidized intermediate 8, in which the unsaturated bonds are
readily functionalized, Scheme 1.
7
Our approach employed a hypervalent iodine reagent to
promote dearomatization of phenol subunits into advanced
functionalized intermediates. Hypervalent iodine reagents are
often used in synthetic procedures because these environ-
mentally benign and inexpensive reagents reduce the need for
toxic heavy metals. Transformations involving hypervalent
iodine have already demonstrated their remarkable synthetic
utility, as described in the pioneering work of Kita and co-
Treatment of dienone 8 with TMS-OTf followed by BF ·Et O
3
2
led directly to indolinone 10. This transformation took place
8
through silyl activation of the enone functionality, enabling a 1,4
workers. Our synthesis involved two oxidative dearomatiza-
tions, a new tandem aza-Michael-rearomatization process to9
produce a key indolinone moiety, a Pictet−Spengler cyclization,
a stereoselective reduction, and an etherification. One objective
Received: July 15, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501583c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. First Oxidative Dearomatization Process
Selectride primarily produced the undesired diastereomer 14
(
9:1 by NMR). Interestingly, and for reasons that are unclear,
only Luche’s conditions resulted in a favorable ratio (2.4:1 by
14
NMR) of the desired diastereomer 15, Scheme 3.
Scheme 3. Formation of the Main Tetracyclic System
attack via a Michael process to afford the bicyclic intermediate 9,
which was subsequently transformed into the aromatic
compound 10 through further Lewis acid activation of the
methoxy group. The transformation of compound 7 into 10
represents a new two-step route to indolinone derivatives
through the equivalent of a C−H activation mediated by a
11
hypervalent iodine reagent, Scheme 2. The first step of this
Scheme 2. Second Oxidative Dearomatization Process
If compound 15 represented a potential precursor of
erysotramidine 2, then the stereoselectivity observed during
the reduction process was not good and required optimization.
Consequently, the transformation of compound 13 into the
desired target was improved by delaying the ketone reduction in
order to produce the desired alcohol stereocenter with greater
stereoselectivity at the end of the synthesis. Consequently, the
polyconjugated system appearing in the structure of 2 was first
obtained by treatment of compound 13 with KHMDS, leading to
the flattened structure 16 through an E1cB mechanism in 82%
yield. It should be noted that the conformation of the
polyconjugated scaffold 16 is more conducive to the desired
stereochemistry than its precursor 13, and treatment of 16 with a
hydride provided the desired alcohol with a diastereoselectivity
of 9:1 by NMR. The synthesis of erysotramidine 2 was concluded
sequence is related to the noteworthy stereoselective process
12
with a mild and quantitative methylation in the presence of Ag O
2
developed by Wipf and Kim to produce hydroindole cores. It
should be noted that the prochiral dienone 8 obtained during the
first activation could be used in an enantioselective synthesis of
the erythrina alkaloids if the first aza-Michael process was
and iodomethane in 86% yield overall from compound 16. The
NMR and mass spectrometry data obtained were identical with
6i
the data reported in the literature. It should be noted that
13
erysotrine 3, a relative alkaloid of the same family, may be
enantioselectively controlled. Unfortunately, in our hands, all
asymmetric 1,4-addition attempts failed. At this stage, a second
aromatic activation mediated by bis(trifluoroacetoxy)-
iodobenzene (PIFA) led to a separable mixture of the desired
dienone 11 and a similar byproduct 12 bearing one more
methoxy group in 68% yield, in a favorable ratio (3.5:1) of
compound 11. Formation of compound 12 could be explained
by a first methanol addition, during the oxidative activation, in
ortho position instead of the required para position followed by a
rearomatization process that would lead to an ortho-methoxy
analogue of compound 10 that would be then oxidized into
byproduct 12, Scheme 2.
obtained by further treatment of erysotramidine 2 with AlH in
3
15
8
0% yield, as previously reported in the literature, Scheme 4.
A natural product belonging to the erythrina family was
synthesized from inexpensive starting materials. The synthesis
demonstrated the power and utility of hypervalent iodine
chemistry in total synthesis and highlighted the development of a
novel method for producing indolinone cores.
Scheme 4. Syntheses of Erysotramidine and Erysotrine
The main tetracyclic core 13 was obtained under acidic
conditions in 71% yield. The transformation resembled a Pictet−
Spengler rearrangement, which is a popular method of producing
9
the aza-spiran moiety of the erythrina alkaloids. The ketone
functionality may be selectively reduced at this point using a
hydride reagent. We had supposed that the bowl-shape generated
by rings A and B would control the stereoselectivity, but
unfortunately hydride reduction using LiBH , Red-Al, or L-
4
B
dx.doi.org/10.1021/jo501583c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
8
1
1
1
1
1
4
.0 Hz, 4H), 6.70 (d, J = 10.0 Hz, 1H), 6.68 (s, 1H), 6.53 (d, J = 10.0 Hz,
H), 6.34 (dd, J = 10.0, 1.4 Hz, 1H), 5.78 (d, J = 1.4 Hz, 1H), 3.90 (m,
H), 3.82 (s, 3H), 3.80 (s, 3H), 3.52 (m, 1H), 3.35 (dd, J = 8.7, 5.1 Hz,
EXPERIMENTAL SECTION
■
Unless otherwise indicated, H and 13C NMR spectra were recorded at
1
3
00 and 75 MHz, respectively, in CDCl solutions. Chemical shifts are
3
H), 2.91 (s, 3H), 2.80 (t, 7.6 Hz, 2H), 2.72 (d, 16.2 Hz, 1H), 2.56 (d,
reported in ppm on the δ scale. Multiplicities are described as s (singlet),
d (doublet), dd, ddd, etc. (doublet of doublets, doublet of doublets of
doublets, etc.), t (triplet), q (quartet), quin (quintuplet), m (multiplet),
and further qualified as app (apparent), br (broad). Coupling constants,
J, are reported in Hz. HRMS were measured in the electrospray (ESI)
mode on a LC-MSD TOF mass analyzer.
N-(3,4-Dimethoxyphenethyl)-2-(4-hydroxyphenyl)-
acetamide (7). To a mixture of 2-(3,4-dimethoxyphenyl)ethanamine 6
6.16 mmol, 1.04 mL, 2.8 equiv) in anhydrous THF (17 mL, 0.1 M) at 0
C was added dropwise DIBAL-H in hexane (1.0 M, 6.65 mmol, 6.65
mL, 3.0 equiv). The solution was stirred for 10 min at 0 °C and then was
allowed to warm to room temperature. The mixture was stirred for 1.5 h,
a solution of methyl 2-(4-hydroxyphenyl)acetate 5 (2.2 mmol, 368.2
mg, 1.0 equiv) in THF (5 mL) was added, and the mixture was stirred
overnight. The reaction was quenched by addition of 1.0 M HCl, and the
organic layer was washed with brine and ethyl acetate and dried over
sodium sulfate. The crude was purified by flash silica gel chromatog-
raphy (65 → 90% ethyl acetate/hexane) to give 579.5 mg of product 7
84% yield) as a white solid. mp 156 °C; H NMR (300 MHz, DMSO-
d6) δ 9.25 (br, 1H), 7.97 (br, 1H), 7.04 (d, J = 7.8 Hz, 2H), 6.86 (d, J =
13
6.2 Hz, 1H); C NMR (75 MHz, CDCl ) δ 184.6, 173.1, 158.0, 148.8,
3
47.7, 136.9, 133.5, 129.5, 120.5, 111.6, 111.1, 103.9, 72.7, 55.7, 50.9,
2.1, 41.3, 32.6; HRMS (ESI) m/z: calcd for C H NO (M +
19
22
5
+
H) :344.1492; found: 344.1484.
-(3,4-Dimethoxyphenethyl)-3,3a-dihydro-3a,5-dimethoxy-
1
1
1
H-indole-2,6-dione (12). H NMR (300 MHz, CDCl ) δ 6.80 (d, J =
3
8
.0 Hz, 4H), 6.74 (dd, J = 8.2, 2.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.37
(t, J = 2.1 Hz, 1H), 5.52 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.78 (t, J = 8.0
(
°
1
3
Hz, 2H), 3.39 (s, 6H), 3.30 (d, J = 2.1 Hz, 2H), 2.82 (t, 8.0 Hz, 2H); C
NMR (75 MHz, CDCl ) δ 191.4, 172.7, 154.6, 149.0, 148.0, 129.6,
3
1
3
3
29.3, 128.5, 120.7, 111.8, 111.4, 97.2, 91.9, 55.9, 55.8, 50.2 (*2), 42.0,
+
2.4, 32.1,; HRMS (ESI) m/z: calcd for C H NNaO (M + Na) ,
20
23
6
96.1418; found, 396.1419.
4aS,13bR)-4a,11,12-Trimethoxy-4a,5,8,9-tetrahydro-1H-
indolo[7a,1-a]isoquinoline-2,6-dione (13). The compound 11
0.088 mmol, 30.0 mg, 1.0 equiv) and phosphoric acid 85% (11.1
(
(
mL) were stirred at reflux for 3 h. The mixture was poured into a 2 M
NaOH solution, extracted with DCM, washed with water, and dried with
Na SO . The residue was then purified by silica gel chromatography
1
(
2
4
with 100% ethyl acetate to give enone 13 (21.2 mg, 71%) as a brown oil.
8
2
(
1
.0 Hz, 1H), 6.80 (s, 1H), 6.70 (d, J = 8.0 Hz, 3H), 3.74 (s, 6H), 3.41 (s,
H, rotamer), 3.27 (t, J = 6.9 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H); C NMR
1
13
H NMR (300 MHz, CDCl ) δ 7.12 (d, J = 10.5 Hz, 1H), 6.59 (d, J =
3
1
1
0.5 Hz, 1H), 6.27 (d, J = 10.6 Hz, 1H), 4.31 (ddd, J = 13.0, 8.0, 2.2 Hz,
H), 3.82 (s, 3H), 3.68 (s, 3H), 3.12 (d, J = 16.2 Hz, 1H), 3.11 (m, 1H),
75 MHz, DMSO-d ) δ 170.4, 155.7, 148.4, 147.1, 131.8, 129.7, 126.4,
6
20.3, 114.8, 112.4, 111.7, 55.4, 55.2, 41.5, 40.3, 34.5; HRMS (ESI) m/z:
+
3.03 (s, 3H), 2.96 (d, J = 17.2 Hz, 1H), 2.91 (m, 1H), 2.81 (d, J = 17.2
Hz, 1H), 2.70 (d, J = 16.2 Hz, 1H), 2.69 (m, 1H); C NMR (75 MHz,
CDCl ) δ 195.1, 168.6, 148.2, 148.1, 147.3, 128.5, 126.8, 125.8, 111.7,
1
calcd for C H NO (M + H) , 316.1543; found, 316.1536.
18
22
4
13
N-(3,4-Dimethoxyphenethyl)-2-(1-methoxy-4-oxocyclo-
hexa-2,5-dien-1-yl)acetamide (8). To a solution of compound 7
0.944 mmol, 297.7 mg, 1.0 equiv) in methanol (7.4 mL) at 0 °C was
added a solution of DIB (1.322 mmol, 425.6 mg, 1.4 equiv) in methanol
2.0 mL). The reaction was stirred for 5 min and was filtered in silica gel
3
08.6, 78.8, 68.5, 55.6, 51.6, 51.4, 41.3, 35.1, 28.0; HRMS (ESI) m/z:
(
+
calcd for C H NO (M + H) :344.1492; found: 344.1487.
19 22
5
(
2S,4aS,13bR)-2-Hydroxy-4a,11,12-trimethoxy-4a,5,8,9-tet-
(
rahydro-1H-indolo[7a,1-a]isoquinolin-6(2H)-one (14). To a
solution of 13 (9 mg, 0.026 mmol, 1.0 equiv) in trifluoroethanol (0.26
mL) at 0 °C was added CeCl ·7H O (0.11 mmol, 20 mg, 4.1 equiv) and
then NaBH (0.110 mmol, 2.1 mg, 4.1 equiv). The solution was allowed
to room temperature, and the reaction was followed by TLC. The
reaction was quenched by a solution of NH Cl, and the organic layer was
washed with brine and DCM and dried over sodium sulfate. The residue
was then purified by silica gel chromatography (2% MeOH in DCM) to
with 20% MeOH in DCM. The crude was purified by flash silica gel
chromatography (80% ethyl acetate/hexane) to provide a yellow oil
1
(
201.2 mg, 62% yield). H NMR (300 MHz, CDCl ) δ 6.78 (d, J = 8.6
3 2
3
Hz, 1H), 6.72 (c, 2H), 6.67 (d, J = 10.2 Hz, 2H), 6.40 (t, J = 6.6 Hz, 1H),
.29 (d, J = 10.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.52 (q, J = 6.6 Hz,
H), 3.08 (s, 3H), 2.76 (t, J = 6.6 Hz, 1H), 2.45 (s, 2H); C NMR (75
4
6
2
13
4
MHz, CDCl ) δ 184.3, 167.7, 148.9, 148.3, 147.6, 131.4, 131.0, 120.5,
3
1
11.7, 111.1, 72.9, 55.7, 52.9, 49.8, 46.4, 40.3, 34.9; HRMS (ESI) m/z:
1
+
give the compound 14 (5.2 mg, 58%). H NMR (300 MHz, CDCl ) δ
calcd for C H NO (M + H) , 346.1649; found, 346.1650.
3
19
24
5
7
.07 (s, 1H), 6.58 (s, 1H), 6.06 (s, 2H), 4.28 (t, J = 6.0 Hz, 1H), 4.13
ddd, J = 13.1, 6.5, 3.3 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.26 (m, 1H),
.18 (s, 3H), 3.05 (m, 1H), 2.69 (d, J = 16.9 Hz, 1H), 2.68 (m, 1H), 2.49
(d, J = 16.9 Hz, 1H), 2.34 (dd, J = 14.3, 5.6 Hz, 1H), 2.19 (dd, J = 14.3,
5.6 Hz, 1H); 13C NMR (75 MHz, CDCl
) δ 172.2, 147.9, 146.7, 132.6,
130.0, 129.0, 126.5, 111.4, 77.8, 65.1, 64.2, 55.8, 55.6, 51.5, 43.0, 41.8,
1
-(3,4-Dimethoxyphenethyl)-6-hydroxyindolin-2-one (10).
(
3
Dienone 8 (0.037 mmol, 12.8 mg, 1.0 equiv) and anhydrous
triethylamine (0.11 mmol, 15.4 μL, 3.0 equiv) were dissolved in
anhydrous DCM (7.0 mL, 0.2 M). TMSOTf (0.092 mmol, 16.8 μL, 2.5
equiv) was added at 0 °C, and the reaction mixture was allowed to warm
to room temperature. The reaction was followed by TLC until the
starting material disappeared (10 min), and BF ·Et O was then added
0.11 mmol, 14.0 μL, 3.0 equiv) during 90 min. An aqueous solution of
ammonium chloride was added, and the organic layer was washed with
brine and dried over sodium sulfate. The product was purified by flash
3
+
35.9, 27.3; HRMS (ESI) m/z: calcd for C19H24NO (M + H) ,
346.1649; found, 346.1642.
3
2
5
(
(2R,4aS,13bR)-2-Hydroxy-4a,11,12-trimethoxy-4a,5,8,9-tet-
rahydro-1H-indolo[7a,1-a]isoquinolin-6(2H)-one (15). Pale yel-
low oil: 2.2 mg, 24%; H NMR (300 MHz, CDCl ) δ 6.83 (s, 1H), 6.64
1
column chromatography (60% ethyl acetate/hexane) to provide a
3
1
(s, 1H), 6.11 (dd, J = 10.4, 1.9 Hz, 1H), 6.02 (dt, J = 10.4, 1.9 Hz,
yellow oil 10 (7.6 mg, 68% yield). H NMR (300 MHz, CDCl ) δ 7.05
3
1
H),4.39 (br, 1H), 4.13 (m, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.40 (m,
(
8
(
(
d, J = 7.8 Hz, 1H), 6.78 (s, 1H), 6.76 (d, J = 14.6 Hz, 1H), 6.38 (dd, J =
.0, 2.1 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 3.86 (t, J = 8.0 Hz, 1H), 3.85
s, 3H), 3.83 (s, 3H), 3.43 (s, 3H), 2.89 (t, J = 8.0 Hz, 2H); C NMR
1H), 2.98 (s, 3H), 2.90 (m, 2H), 2.85 (d, J = 16.9 Hz, 1H), 2.72 (dd, J =
16.9, 1.2 Hz, 1H), 2.57 (ddd, J = 12.4, 5.1, 1.2 Hz, 1H), 1.73 (dd, J = 12.4,
10.2 Hz, 1H); C NMR (75 MHz, CDCl
130.7, 127.1, 125.6, 111.5, 109.9, 77.7, 66.4, 65.2, 55.9, 55.7, 51.1, 45.1,
41.7, 34.9, 27.4; HRMS (ESI) m/z: calcd for C19H24NO (M + H) ,
5
13
13
75 MHz, CDCl ) δ 175.8, 156.1, 148.9, 147.7, 145.6, 130.6, 125.0,
3
) δ 169.7, 148.1, 146.8, 132.1,
3
1
20.7, 116.0, 112.0, 111.3, 108.3, 97.1, 55.9, 55.8, 41.6, 35.1, 33.1;
+
+
HRMS (ESI) m/z: calcd for C H NO (M + H) , 314.1387; found,
18
20
4
3
14.1379.
-(3,4-Dimethoxyphenethyl)-3a-methoxy-3,3a-dihydro-1H-
indole-2,6-dione (11). To a solution of compound 10 (0.056 mmol,
7.6 mg, 1.0 equiv) in methanol (0.4 mL) at 60 °C was added a solution
of PIFA (0.078 mmol, 33.7 mg, 1.4 equiv) in methanol (0.4 mL). The
reaction was stirred for 5 min and was filtered on silica gel with 20%
MeOH in DCM. The crude was purified by flash silica gel
chromatography (40% ethyl acetate/hexane) to provide a brown oil
346.1649; found, 346.1653.
1
(S)-11,12-Dimethoxy-8,9-dihydro-1H-indolo[7a,1-a]-
isoquinoline-2,6-dione (16). To a solution of 15 (0.0273 mmol, 9.4
mg, 1.0 equiv) in anhydrous THF (0.4 mL) at −78 °C was added
KHMDS (0.5 M in toluene, 0.06 mmol, 0.12 mL, 2.2 equiv) dropwise.
The reaction was followed by TLC, and after completion, a solution of
1
NH
Cl was added. The organic layer was washed with brine and AcOEt
4
and dried with Na SO . The product was purified by silica gel
2
4
(
1
11.2 mg, 58% yield) of compound 11 and a dark yellow oil (2.0 mg,
chromatography (5% MeOH in DCM) to give the compound 16 (7.0
1
1
0% yield) of compound 12. H NMR (300 MHz, CDCl ) δ 6.76 (d, J =
mg, 82%) as a yellow oil. H NMR (300 MHz, CDCl ) δ 7.75 (d, J = 10.1
3
3
C
dx.doi.org/10.1021/jo501583c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 1H), 6.84 (s, 1H), 6.65 (s, 1H), 6.41 (d, J = 10.1 Hz, 1H), 6.38 (s,
A., Ed.; Academic Press: New York, 1981; Vol. 18, pp 1. (d) Chawala, A.
S.; Jackson, A. H. Nat. Prod. Rep. 1984, 1, 371.
1H), 4.21 (ddd, J = 11.6, 4.9, 1.7 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H), 3.39
(
m, 1H), 3.27 (d, J = 15.1 Hz, 1H), 3.02 (m, 1H), 2.82 (m, 1H), 2.79 (d,
(3) (a) Ito, K.; Furukawa, H.; Haruna, M. Yakugaku Zasshi 1973, 93,
1611. (b) Mantle, P. G.; Laws, I.; Widdowson, D. A. Phytochemistry
1984, 23, 1336.
(4) Aguilar, M. I.; Giral, F.; Espejo, O. Phytochemistry 1981, 20, 2061.
(5) (a) Joo, J. M.; David, R. A.; Yuan, Y.; Lee, C. Org. Lett. 2010, 12,
5704. (b) Tuan, L. A.; Kim, G. Bull. Korean Chem. Soc. 2010, 31, 1800.
13
J = 15.1 Hz, 1H); C NMR (75 MHz, CDCl ) δ 195.2, 169.7, 154.7,
1
5
3
48.7, 147.2, 138.4, 131.8, 128.0, 125.9, 125.5, 112.4, 107.8, 67.7, 55.9,
5.8, 52.4, 36.9, 27.6; HRMS (ESI) m/z: calcd for C H NO (M +
18
18
4
+
H) , 312.1230; found, 312.1235.
2R,13bS)-2-Hydroxy-11,12-dimethoxy-8,9-dihydro-1H-
indolo[7a,1-a]isoquinolin-6(2H)-one (17). To a solution of 16
0.0112 mmol, 3.5 mg, 1.0 equiv) in methanol (0.12 mL) at −78 °C was
added CeCl ·7H O (0.046 mmol, 17.1 mg, 4.1 equiv) and then NaBH
(
(c) Liang, J.; Chen, J.; Liu, J.; Li, L.; Zhang, H. Chem. Commun. 2010, 46,
(
3
666. (d) Onoda, T.; Takikawa, Y.; Fujimoto, T.; Yasui, Y.; Suzuki, K.;
3
2
4
Matsumoto, T. Synlett 2009, 1041. (e) Yoshida, Y.; Mohri, K.; Isobe, K.;
Itoh, T.; Yamamoto, K. J. Org. Chem. 2009, 74, 6010. (f) Stanislawski, P.
C.; Willis, A. C.; Banwell, M. G. Chem.Asian J. 2007, 2, 1127.
(
0.045 mmol, 1.7 mg, 4.0 equiv). After 5 min, the reaction was quenched
by aqueous NH Cl, and the organic layer was washed with brine and
4
DCM and dried over sodium sulfate. The residue may be purified by
silica gel chromatography (2% MeOH in chloroform) to afford
compound 17 (3.1 mg, 90%). However, this intermediate was air-
(g) Shimizu, K.; Takimoto, M.; Sato, Y.; Mori, M. J. Organomet. Chem.
2
006, 691, 5466. (h) Stanislawski, P. C.; Willis, A. C.; Banwell, M. G.
Org. Lett. 2006, 8, 2143. (i) Kim, G.; Kim, J. H.; Lee, K. Y. J. Org. Chem.
1
sensitive and was rapidly used for the further transformation. H NMR
2
006, 71, 2185. (j) Yasui, Y.; Suzuki, K.; Matsumoto, T. Synlett 2004,
(
300 MHz, CDCl ) δ 6.87 (dd, J = 10.1, 2.4 Hz, 1H), 6.79, (s, 1H), 6.71
3
6
19. (k) Fukumoto, H.; Esumi, T.; Ishihara, J.; Hatakeyama, S.
(
s, 1H), 6.30 (d, J = 10.2 Hz, 1H), 6.03 (s, 1H), 4.30 (br, 1H), 3.97 (m,
Tetrahedron Lett. 2003, 44, 8047. (l) Shimizu, K.; Takimoto, M.; Mori,
M. Org. Lett. 2003, 5, 2323. (m) Kalaitzakis, D.; Montagnon, T.;
Antonatou, E.; Vassilikogiannakis, G. Org. Lett. 2013, 15, 3714.
1
1
H), 3.85 (s, 3H), 3.75 (s, 3H), 3.60 (m, 1H), 3.07 (m, 1H), 2.96 (dd, J =
5.9, 1.9 Hz, 1H), 2.81 (dd, J = 11.2, 4.4 Hz, 1H), 1.70 (dd, J = 11.2, 10.4
13
Hz, 1H); C NMR (75 MHz, CDCl ) δ 170.9, 156.9, 148.5, 147.0,
1
2
3
(n) Isobe, K.; Mohri, K.; Takeda, N.; Suzuki, K.; Hosoi, S.; Tsuda, Y.
38.9, 128.4, 126.4, 123.7, 120.3, 112.1, 108.0, 66.5, 55.9, 45.0, 37.4,
+
Chem. Pharm. Bull. 1994, 42, 197. (o) Tsuda, Y.; Hosoi, S.; Katagiri, N.;
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Hosoi, S.; Sano, T.; Suzuki, H.; Toda, J. Heterocycles 1993, 36, 655.
7.0; HRMS (ESI) m/z: calcd for C H NO (M + H) , 314.1387;
18
20
4
found, 314.1392.
Erysotramidine (2). To a degassed solution of 17 (0.01 mmol, 3.1
(q) Isobe, K.; Mohri, K.; Suzuki, K.; Haruna, M.; Ito, K.; Hosoi, S.;
mg, 1.0 equiv) in anhydrous acetonitrile (0.2 mL) were added Ag O
2
Tsuda, Y. Chem. Pharm. Bull. 1991, 32, 1195. (r) Tsuda, Y.; Hosoi, S.;
Nakai, A.; Sakai, Y.; Abe, T.; Ishi, Y.; Kiuchi, F.; Sano, T. Chem. Pharm.
Bull. 1991, 39, 1365. (s) Sano, T.; Toda, J.; Kashiwaba, N.; Ohshima, T.;
Tsuda, Y. Chem. Pharm. Bull. 1987, 35, 479. (t) Ito, K.; Suzuki, F.;
Haruna, M. J. Chem. Soc., Chem. Commun. 1978, 733.
(6) (a) Ogawa, S.; Iida, N.; Tokunaga, E.; Shiro, M.; Shibata, N.
Chem.Eur. J. 2010, 16, 7090. (b) Juma, B.; Adeel, M.; Villinger, A.;
Reinke, H.; Spannenberg, A.; Fischer, C.; Langer, P. Adv. Synth. Catal.
(
0.05 mmol, 11.6 mg, 5.0 equiv) and MeI (0.05 mmol, 3 μL, 5.0 equiv).
The solution was stirred in a sealed tube overnight at reflux in the dark.
The reaction was quenched with water, and the organic layer was washed
with brine and AcOEt and dried with Na SO . The residue was purified
2
4
by flash column chromatography (5% MeOH in DCM) to provide
erysotramidine 2 (3.4 mg, 95%). H NMR (300 MHz, CDCl ) δ 6.89
1
3
(
1
(
dd, J = 10.1, 2.2 Hz, 1H), 6.80 (s, 1H), 6.72 (s, 1H), 6.33 (d, J = 10.1 Hz,
H), 6.04, (s, 1H), 4.00 (dt, J = 13.2, 7.5 Hz, 1H), 3.86 (s + m, 4H), 3.76
s, 3H), 3.62 (m, 1H), 3.34 (s, 3H), 3.04 (m, 2H), 2.81 (dd, J = 11.0, 5.0
2
009, 351, 1073. (c) Tietze, L. F.; Tolle, N.; Kratzert, D.; Stalke, D. Org.
13
Lett. 2009, 11, 5230. (d) Zhang, F.; Simpkins, N. S.; Blake, A. J. Org.
Biomol. Chem. 2009, 7, 1963. (e) Padwa, A.; Wang, Q. J. Org. Chem.
Hz, 1H), 1.71 (dd, J = 11.0, 10.1 Hz, 1H); C NMR (75 MHz, CDCl3)
δ 170.9, 157.0, 148.6, 147.0, 136.3, 128.7, 126.5, 124.1, 120.3, 112.2,
1
2
006, 71, 7391. (f) Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601. (g) Gao,
08.2, 74.9, 66.3, 56.4, 56.1, 55.9, 41.4, 37.3, 27.0; HRMS (ESI) m/z:
+
S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao, Y.; Fan, X.;
Zhang, S. Org. Lett. 2006, 8, 2373. (h) El Bialy, S. A. A.; Braun, H.;
Tietze, L. F. Angew. Chem., Int. Ed. 2004, 43, 5391. (i) Padwa, A.; Lee, H.
I.; Rashatasakhon, P.; Rose, M. J. Org. Chem. 2004, 69, 8209. (j) Lee, H.
I.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 5, 5067.
(k) Chikaoka, S.; Toyao, A.; Ogasawara, M.; Tamura, O.; Ishibashi, H. J.
Org. Chem. 2003, 68, 312. (l) Padwa, A.; Hennig, R.; Kappe, C. O.;
Reger, T. S. J. Org. Chem. 1998, 63, 1144. (m) Tsuda, Y.; Hosoi, S.;
Katagiri, N.; Kaneko, C.; Sano, T. Heterocycles 1992, 33, 497. (n) Rigby,
J. H.; Qabar, M. J. Am. Chem. Soc. 1991, 113, 8975. (o) Tsuda, Y.; Hosoi,
S.; Nakai, A.; Ohshima, T.; Sakai, Y.; Kiuchi, F. J. Chem. Soc., Chem.
Commun. 1984, 1216. (p) Sano, T.; Toda, J. Heterocycles 1982, 18, 229.
(q) Mondon, A.; Nestler, H. J. Chem. Ber. 1979, 112, 1329. (r) Haruna,
M.; Ito, K. J. Chem. Soc., Chem. Commun. 1976, 345. (s) Mondon, A.;
Nestler, H. J. Angew. Chem. 1964, 76, 651.
calcd for C H NO (M + H) , 328.1541; found, 328.1543.
19
22
4
ASSOCIATED CONTENT
Supporting Information
■
*
S
General experimental procedures and 1H and 13C NMR
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*
E-mail: canesi.sylvain@uqam.ca.
Notes
The authors declare no competing financial interest.
(
7) (a) Quideau, S.; Looney, M. A.; Pouyseg
́
u, L. Org. Lett. 1999, 1,
1
651. (b) Traore, M.; Ahmed-Ali, S.; Peuchmaur, M.; Wong, Y. S.
́
ACKNOWLEDGMENTS
■
Tetrahedron 2010, 66, 5863. (c) Andrez, J. A.; Giroux, M. A.; Lucien, J.;
Canesi, S. Org. Lett. 2010, 12, 4368. (d) Liang, H.; Ciufolini, M. A.
We are very grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Canada Foundation
for Innovation (CFI), and the provincial government of Quebec
Tetrahedron 2010, 66, 5884. (e) Pouyseg
Rojas, L. B.; Charris, J.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66,
908. (f) Guerard, K. C.; Sabot, C.; Beaulieu, M. A.; Giroux, M. A.;
́
u, L.; Sylla, T.; Garnier, T.;
5
́
(
FQRNT and CCVC) for their financial support of this research.
Canesi, S. Tetrahedron 2010, 66, 5893. (g) Jen, T.; Mendelsohn, B. A.;
Ciufolini, M. A. J. Org. Chem. 2011, 76, 728. (h) Beaulieu, M. A.; Sabot,
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