Synthesis of (±)-crispine A via a nitrosoalkene hetero-Diels-Alder addition to ethyl vinyl ether

Article abstract of DOI:10.1055/s-0030-1258333

The synthesis of (±)-crispine A in 9 steps and 24% overall- yield was achieved using a nitrosoalkene hetero-Diels-Alder- addition to ethyl vinyl ether as the key step. The synthesis starts from commercial 3,4- dimethoxyphenylacetic acid and uses simple me

Full text of DOI:10.1055/s-0030-1258333

142
PAPER
Synthesis of ( )-Crispine A via a Nitrosoalkene Hetero-Diels–Alder Addition
to Ethyl Vinyl Ether
Synthesis of
(
)
f
-Crispin
t
e
A
hymia G. Yioti, Ioulia K. Mati, Athanassios G. Arvanitidis, Zoe S. Massen, Elli S. Alexandraki, John K. Gallos*
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
Fax +30(2310)997679; E-mail: igallos@chem.auth.gr
Received 16 September 2010; revised 21 October 2010
Dedicated to Professor N. Argyropoulos on the occasion of his retirement
tion sequence we have developed for the stereoselective
Abstract: The synthesis of ( )-crispine A in 9 steps and 24%
overall yield was achieved using a nitrosoalkene hetero-Diels–
Alder addition to ethyl vinyl ether as the key step. The synthesis
starts from commercial 3,4-dimethoxyphenylacetic acid and uses
conversion of an oxazine ring into a pyrrolidine.7 Surpris-
ingly, however, when the reduction of the C=N bond with
sodium cyanoborohydride (NaBH3CN) in acetic acid was
simple methods, easily accessible materials and inexpensive re- attempted, 1-(3-ethoxypropyl)-6,7-dimethoxyisochroman
agents. An isochroman derivative was unexpectedly formed in an
attempted reduction of a dihydro-4H-1,2-oxazine intermediate.
(8) was isolated in 43% yield.
Key words: alkaloids, natural products, total synthesis, hetero-
Diels–Alder reaction, hydrogenation
MeO
MeO
MeO
MeO
CO2Me
3
N
O
N
4
2
6
1
OEt
5
(R)-(+)-Crispine A (1, Scheme 1) was isolated in 2002
from Carduus crispus L.,1 a popular invasive thistle oc-
curring in Asia and Europe which has been used in Chi-
nese folk medicine for the treatment of colds, stomach
ache and rheumatism. This alkaloid has also been proved
to inhibit the growth of some human cancer lines in vitro
(SKOV3, KB and HeLa human cancer lines) and shows
significant cytotoxic activity. As a result of this potent an-
titumor activity, various synthetic methods have been de-
veloped for the synthesis of crispine A, in both racemic2
and enantiomerically pure form,3 and a number of ana-
logues have been prepared.4
MeO
MeO
MeO
CO2H
CO2Me
Br
MeO
4
3
NOH
Scheme 1 Retrosynthetic analysis of ( )-crispine A
MeO
MeO
i
CO2Me
Br
CO2Me
MeO
MeO
Br
NOH
O
Our retrosynthetic plan towards ( )-crispine A involved a
hetero-Diels–Alder addition reaction5 of a nitrosoalkene,
in situ generated from oxime 3 by 1,4-elimination of hy-
drogen bromide,6 to ethyl vinyl ether to give adduct 2.
This compound has the requisite carbon skeleton and the
target molecule could be prepared from it by standard re-
duction–condensation manipulations.7 Compound 3 can
be prepared from commercial 3,4-dimethoxyphenylacetic
acid (4) by standard manipulations.8
5
2
7
3
6
8
ii
MeO
MeO
MeO
MeO
CO2Me
O
CO2Me
N
O
N
OEt
iii
Ketone 5 served as the immediate precursor for oxime 3
(Scheme 2). A solution of the oxime 3 in ethyl vinyl ether
was treated with sodium carbonate to give adduct 2, evi-
dently via the intermediate unstable nitrosoalkene 6, in
67% overall yield from 5.
MeO
MeO
MeO
MeO
OH
O
iv
O
N
OEt
OEt
What was remaining in order to construct the desired
compound was a set of appropriate reduction–condensa-
tion reactions. Thus, the ester group of adduct 2 was re-
duced with lithium borohydride in tetrahydrofuran to give
a 61% yield of alcohol 7. Then, we tried to apply the reac-
Scheme 2 Reagents and conditions: (i) NH2OH, MeOH, reflux, 24
h; (ii) ethyl vinyl ether, Na2CO3, r.t., 24 h, 67% from 5; (iii) LiBH4,
THF, r.t., 8 h, 61%; (iv) NaBH3CN, glacial AcOH, r.t., 2.5 h, 43%.
This is a quite interesting reaction and the mechanism de-
picted in Scheme 3 could account for the formation of 8.
Nitrogen protonation of the dihydro-4H-1,2-oxazine acti-
vates its C-3 center towards intramolecular 1,2-addition of
the primary alcoholic group. The intermediately formed
SYNTHESIS 2011, No. 1, pp 0142–0146
x
x
.
x
x
.2
0
1
0
Advanced online publication: 15.11.2010
DOI: 10.1055/s-0030-1258333; Art ID: T18610SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of ( )-Crispine A
143
spiro-N,O-acetal 10 undergoes further reductive oxazine hydride reduction gives the desired ( )-crispine A, ac-
ring opening upon protonation in an O-assisted reaction to cording to the literature.2c
give isochroman 13. The acetal group of this compound is
finally reduced in the same way to give isochroman 8. To
the best of our knowledge, this is the first example of such
a reaction of a dihydro-4H-1,2-oxazine system with an al-
cohol.9 The scope and limitations of this reaction are un-
der further examination.
MeO
MeO
O
i
CO2Me
N
O
N
11b
MeO
MeO
O
3
H
OEt
OEt
H
2
16
(major isomer)
OH
ii
MeO
MeO
MeO
MeO
– H+
MeO
MeO
O
MeO
MeO
O
iii
H
N+
O
N
N
O
NH
O
X
OEt
9
10
17 X = OMe
18 X = OH
19
OEt
+ H+
Scheme 4 Reagents and conditions: (i) NaBH3CN, glacial AcOH,
r.t., 2.5 h, 85% (dr 16:1); (ii) 17: Raney Ni, H2, H3BO3, MeOH, reflux,
5 d, 80%; 18: Raney Ni, H2, H3BO3, EtOAc, H2O, reflux, 4 d, 23%;
(iii) NaBH3CN, glacial AcOH, r.t., 12 h, 80% from 17 and 70% from
18.
MeO
MeO
MeO
MeO
O+
O
+ NH2
O
12
11
It is interesting to note that the NaBH3CN reduction of
compound 2 proceeds with very good diastereoselectivity
(dr 16:1). As indicated by the 1H NMR spectrum, the di-
hydro-4H-1,2-oxazine ring of compound 2 adopts a pseu-
do-chair conformation with an axial ethoxy group (for H-
6, d = 5.16, t, J = 2.5 Hz). Due to resonance, the aryl
group prefers, most probably, a coplanar arrangement
with the C=N double bond, which allows an anti hydride
addition relative to the ethoxy group. This was confirmed
by the 1H NMR signals of H-11b (d = 4.78, m)10 and H-3
(d = 5.04, d, J = 3.0 Hz) in 16, the latter being equatorial,
whereas for the minor epimer (epi-16) the same signals
appear at d = 4.71 (d, J = 11.4 Hz) and 4.84 (dd, J = 9.6
and 2.1 Hz), respectively, indicating thus that both pro-
tons are axial. This high diastereoselectivity, together
with the fact that the two diastereomers can be easily sep-
arated chromatographically, allows the possibility of the
asymmetric synthesis of crispine A using a chiral enol
ether.11
EtO
ONH2
OEt
+ H–
MeO
MeO
MeO
MeO
+ H+
O
O
13
14
+
EtO
– NH2OH
ONH3
EtO
ONH2
MeO
MeO
MeO
MeO
+ H–
O
O
+
8
15
OEt
OEt
Scheme 3 Plausible reaction mechanism for the reductive conver-
sion of dihydro-4H-1,2-oxazine 7 into isochroman 8
In conclusion, we report here a new approach to ( )-crisp-
ine A, an alkaloid isolated from Carduus crispus which
inhibits the growth of some human cancer lines in vitro
and shows significant cytotoxic activity. Our method
starts from easily accessible materials and uses simple
methods and inexpensive reagents to give the target crisp-
ine A in 24% overall yield from 3,4-dimethoxyphenylace-
tic acid. The fact that there is a highly diastereoselective
NaBH3CN reduction of the dihydro-4H-1,2-oxazine ring
allows the potential asymmetric synthesis of crispine A,
which is under consideration. In addition, an interesting
reduction of a dihydro-4H-1,2-oxazine by NaBH3CN in
acetic acid to an isochroman derivative was observed
when a free alcoholic hydroxy group was present in the
molecule.
Facing such problems in our initial plan, we decided to
manipulate firstly the oxazine ring. Thus, the C=N bond
of adduct 2 was reduced with NaBH3CN in acetic acid;
spontaneous cyclization afforded an 85% yield of com-
pound 16 (Scheme 4). Several attempted reductions of 16,
such as with lithium aluminum hydride or borane, failed
since they gave a very complex mixture of products, prob-
ably because this is a quite active amide. Finally, we
achieved the N–O bond cleavage with Raney nickel and
hydrogen in methanol or ethyl acetate–water, in the pres-
ence of boric acid, to give methyl ether 17 in good yield
or alcohol 18 in poor yield, respectively. Both of these
compounds were further reduced with NaBH3CN in acetic
acid to furnish lactam 19, which upon lithium aluminum
Synthesis 2011, No. 1, 142–146 © Thieme Stuttgart · New York

144
E. G. Yioti et al.
PAPER
1H and 13C NMR spectra were recorded in CDCl3 at 300 and 75
MHz, respectively, on a Bruker Avance III 300-MHz spectrometer.
Chemical shifts are given in parts per million and J in hertz using
solvent or tetramethylsilane as an internal reference. IR spectra
were recorded on a Perkin Elmer FTIR instrument. High-resolution
mass spectra (HRMS) were obtained on a VG ZAB-ZSE mass spec-
trometer under fast-atom bombardment (FAB) conditions with ni-
trobenzyl alcohol as the matrix or on an IonSpec FTMS instrument
(matrix-assisted laser desorption/ionization, MALDI) with 2,5-di-
hydroxybenzoic acid as the matrix. All commercially available,
reagent grade quality materials were used without further purifica-
tion. All solvents were purified by standard procedures before use.
Dry solvents were obtained by literature methods and stored over
molecular sieves. All reactions were conducted under a nitrogen at-
mosphere. All reactions were monitored on commercially available,
precoated Kieselgel 60 F254 TLC plates (layer thickness: 0.25
mm). Compounds were visualized by the use of a UV lamp or/and
p-anisaldehyde ethanolic solution and warming. Column chroma-
tography was performed in the usual way using Merck 60 (40–60
mm) silica gel.
and the aqueous layer was washed with CH2Cl2 (2 × 5 mL). The
combined organic extracts were dried (Na2SO4) and filtered, and the
solvent was removed under reduced pressure. The crude product
was purified by flash chromatography (EtOAc–hexane, 2:1 to 1:1)
to give 7 as a colorless oil; yield: 0.182 g (61%).
FTIR (film): 3387 (br), 2937, 1607, 1517 cm–1.
1H NMR (CDCl3): d = 1.26 (t, J = 7.2 Hz, 3 H), 1.70 (br s, 1 H), 2.10
(m, 2 H), 2.40 (dt, J = 18.3, 4.5 Hz, 1 H), 2.58 (dt, J = 18.3, 9.9 Hz,
1 H), 2.90 (m, 2 H), 3.66 (dq, J = 9.9, 7.2 Hz, 1 H), 3.85 (m, 2 H),
3.88 (s, 3 H), 3.90 (s, 3 H), 3.94 (dq, J = 9.9, 7.2 Hz, 1 H), 5.18 (t,
J = 2.5 Hz, 1 H), 6.72 (s, 1 H), 6.79 (s, 1 H).
13C NMR (CDCl3): d = 15.1, 21.0, 23.5, 35.5, 55.9, 56.1, 63.7, 63.9,
94.4, 110.5, 112.9, 129.0, 130.4, 147.5, 149.7, 159.3.
HRMS: m/z [M + H]+ calcd for C16H24NO5: 310.1649; found:
310.1650.
1-(3-Ethoxypropyl)-6,7-dimethoxyisochroman (8)
To a cold, stirred soln of alcohol 7 (0.068 g, 0.22 mmol) in glacial
AcOH (1.3 mL) was added NaBH3CN (0.044 g, 0.7 mmol) at 0 °C
and the mixture was stirred at r.t. for 2.5 h. Then, it was diluted with
CH2Cl2 (2 mL) and neutralized with sat. aq Na2CO3 soln. The aque-
ous layer was extracted with EtOAc (3 × 3 mL), the combined or-
ganic extracts were dried (Na2SO4) and the solvent was evaporated.
The crude product was purified by flash chromatography (EtOAc–
hexane, 2:1) to give 8 as a colorless oil; yield: 0.027 g (43%).
Methyl 2-{2-[2-Bromo-1-(hydroxyimino)ethyl]-4,5-dimethoxy-
phenyl}acetate (3)
To a well-stirred soln of ketone 58b (1.267 g, 3.83 mmol) in MeOH
(30 mL) was added NH2OH (0.8 g, 11.5 mmol) and the resultant
mixture was refluxed for 24 h. After the mixture was cooled to r.t.,
the MeOH was removed and the crude product was purified by flash
chromatography (EtOAc–hexane, 1:3) to give 3 as an amorphous
solid; yield: 0.929 g (70.5%).
FTIR (film): 2932, 2855, 1611, 1515 cm–1.
1H NMR (CDCl3): d = 1.20 (t, J = 6.9 Hz, 3 H), 1.75 (m, 3 H), 2.10
(m, 1 H), 2.60 (dt, J = 15.9, 3.6 Hz, 1 H), 2.90 (ddd, J = 15.9, 9.0,
5.1 Hz, 1 H), 3.47 (m, 4 H), 3.75 (m, 1 H), 3.85 (s, 3 H), 3.86 (s, 3
H), 4.11 (m, 1 H), 4.71 (d, J = 7.8 Hz, 1 H), 6.57 (s, 1 H), 6.59 (s, 1
H).
13C NMR (CDCl3): d = 15.3, 25.4, 28.6, 32.5, 55.8, 56.0, 63.1, 66.0,
70.5, 75.2, 107.5, 111.4, 126.0, 130.1, 147.4 (2 × C).
FTIR (film): 3423, 2953, 2848, 1735, 1607, 1521 cm–1.
1H NMR (CDCl3): d = 3.67 (s, 3 H), 3.86 (s, 2 H), 3.88 (s, 6 H), 4.40
(s, 2 H), 6.76 (s, 1 H), 6.91 (s, 1 H), 9.47 (br s, 1 H).
13C NMR (CDCl3): d = 38.3, 45.3, 51.9, 55.6, 55.7, 109.9, 113.1,
123.9, 124.8, 147.3, 147.9, 153.8, 172.1.
HRMS: m/z [M + H]+ calcd for C13H17BrNO5: 346.0285; found:
346.0278.
HRMS: m/z [M + H]+ calcd for C16H25O4: 281.1747; found:
281.1748.
Methyl 2-[2-(6-Ethoxy-5,6-dihydro-4H-1,2-oxazin-3-yl)-4,5-
dimethoxyphenyl]acetate (2)
(3R*,11bS*)-3-Ethoxy-9,10-dimethoxy-2,3,7,11b-tetrahy-
dro[1,2]oxazino[3,2-a]isoquinolin-6(1H)-one (16)
To a soln of oxime 3 (0.929 g, 2.68 mmol) in freshly distilled ethyl
vinyl ether (30 mL), Na2CO3 (1.420 g, 13.4 mmol) was added and
the reaction mixture was stirred at r.t. for 24 h. The mixture was fil-
tered through a Celite® pad and the excess ethyl vinyl ether was
evaporated. The crude product was purified by flash chromatogra-
phy (EtOAc–hexane, 1:3 to 1:2) to give 2 as a pale yellow oil; yield:
0.859 g (95%).
To a cold, stirred soln of adduct 2 (0.477 g, 1.4 mmol) in glacial
AcOH (8.4 mL) was added NaBH3CN (0.282, 4.5 mmol) at 0 °C.
The mixture was stirred at r.t. for 2.5 h, then diluted with CH2Cl2 (8
mL) and neutralized with sat. aq Na2CO3 soln. The aqueous layer
was extracted with EtOAc (3 × 10 mL), the combined organic ex-
tracts were dried (Na2SO4) and the solvent was evaporated. The
crude product was purified by flash chromatography (EtOAc–hex-
ane, 1:1) to give firstly the minor isomer (epi-16, 0.021 g), followed
by 16 (0.348 g), as colorless oils; combined yield: 85%.
FTIR (film): 2942, 1738, 1607, 1523 cm–1.
1H NMR (CDCl3): d = 1.25 (t, J = 7.2 Hz, 3 H), 2.06 (m, 2 H), 2.33
(ddd, J = 18.3, 5.1, 3.6 Hz, 1 H), 2.60 (ddd, J = 18.3, 10.8, 9.0 Hz,
1 H), 3.66 (dq, J = 9.6, 7.2 Hz, 1 H), 3.67 (s, 3 H), 3.73 (d, J = 16.2
Hz, 1 H), 3.79 (d, J = 16.2 Hz, 1 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 3.94
(dq, J = 9.6, 7.2 Hz, 1 H), 5.16 (t, J = 2.5 Hz, 1 H), 6.76 (s, 1 H),
6.79 (s, 1 H).
13C NMR (CDCl3): d = 15.0, 20.7, 23.3, 38.3, 52.0, 56.0, 56.1, 63.5,
94.4, 110.8, 113.8, 124.7, 129.6, 148.0, 149.1, 159.0, 172.3.
HRMS: m/z [M + H]+ calcd for C17H24NO6: 338.1598; found:
338.1582.
Major Isomer 16
FTIR (film): 2935, 1669, 1613, 1521 cm–1.
1H NMR (CDCl3): d = 1.15 (t, J = 7.1 Hz, 3 H), 1.95 (m, 3 H), 2.10
(m, 1 H), 3.63 (dq, J = 9.3, 7.1 Hz, 1 H), 3.65 (dd, J = 18.3, 2.2 Hz,
1 H), 3.74 (dd, J = 18.3, 2.2 Hz, 1 H), 3.84 (s, 6 H), 4.21 (dq, J = 9.3,
7.1 Hz, 1 H), 4.78 (m, 1 H), 5.04 (d, J = 3.0 Hz, 1 H), 6.52 (s, 1 H),
6.56 (s, 1 H).
13C NMR (CDCl3): d = 14.7, 27.9, 29.4, 35.5, 55.9, 56.0, 60.6, 65.3,
99.9, 107.6, 109.9, 121.3, 125.2, 148.3, 148.9, 162.3.
HRMS: m/z [M + H]+ calcd for C16H22NO5: 308.1492; found:
308.1487.
2-(2-(6-Ethoxy-5,6-dihydro-4H-1,2-oxazin-3-yl)-4,5-dimeth-
oxyphenyl)ethanol (7)
Compound 2 (0.323 g, 0.96 mmol) was dissolved in anhyd THF (3
mL) and LiBH4 (0.041 g, 1.91 mmol) was added at 0 °C. The mix-
ture was warmed to r.t. and then stirred for 8 h. The reaction was
quenched by the addition of H2O, the organic layer was separated
(3R*,11bR*)-3-Ethoxy-9,10-dimethoxy-2,3,7,11b-tetrahy-
dro[1,2]oxazino[3,2-a]isoquinolin-6(1H)-one (epi-16)
FTIR (film): 2933, 1668, 1613, 1521 cm–1.
Synthesis 2011, No. 1, 142–146 © Thieme Stuttgart · New York

PAPER
Synthesis of ( )-Crispine A
145
1H NMR (CDCl3): d = 1.30 (t, J = 7.1 Hz, 3 H), 1.68 (m, 1 H), 1.96
(m, 1 H), 2.08 (m, 1 H), 2.25 (m, 1 H), 3.64 (s, 2 H), 3.86 (s, 6 H),
3.90 (dq, J = 9.9, 7.1 Hz, 1 H), 4.21 (dq, J = 9.9, 7.1 Hz, 1 H), 4.71
(d, J = 11.4 Hz, 1 H), 4.84 (dd, J = 9.6, 2.1 Hz, 1 H), 6.55 (s, 1 H),
6.60 (s, 1 H).
13C NMR (CDCl3): d = 15.2, 30.7, 33.6, 35.8, 55.9, 56.0, 60.4, 66.3,
103.2, 108.1, 110.0, 121.0, 124.9, 148.3, 148.9, 163.7.
13C NMR (CDCl3): d = 28.9/29.7, 31.5/31.6, 37.7/38.6, 56.1, 56.2/
56.3, 58.1/60.1, 80.6/81.7, 107.8, 110.5/110.7, 123.9/124.6, 127.7/
128.5, 148.2, 148.8, 169.4/169.7.
HRMS: m/z [M + H]+ calcd for C14H18NO4: 264.1235; found:
264.1228.
8,9-Dimethoxy-2,3,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
5(1H)-one (19)
HRMS: m/z [M + H]+ calcd for C16H22NO5: 308.1492; found:
To a cold, stirred soln of the diastereomeric mixture of methyl ether
17 (0.070 g, 0.25 mmol) in glacial AcOH (1.5 mL) was added
NaBH3CN (0.021 g, 0.33 mmol) at 0 °C. The mixture was stirred at
r.t. for 12 h, then diluted with CH2Cl2 (2 mL) and neutralized with
sat. aq Na2CO3 soln. The aqueous layer was extracted with EtOAc
(3 × 5 mL), the combined organic extracts were dried (Na2SO4) and
the solvent was evaporated. The crude product was purified by flash
chromatography (EtOAc) to give 19 as a solid; yield: 0.049 g
(80%); mp 162–164 °C (Lit.2c 163–165 °C); 1H and 13C NMR data
identical to those reported in the literature.2c
308.1486.
3,8,9-Trimethoxy-2,3,6,10b-tetrahydropyrrolo[2,1-a]isoquino-
lin-5(1H)-one (17)
Compound 16 (0.150 g, 0.49 mmol) was dissolved in MeOH (5 mL)
and H3BO3 (0.603 g, 9.8 mmol) was added, together with a catalytic
amount of Raney Ni and MgSO4, under a H2 atmosphere. The mix-
ture was heated at 70 °C for 5 d in a sealed tube and then it was fil-
tered through a short Celite® pad and neutralized with sat. aq
Na2CO3 soln. The aqueous layer was extracted with EtOAc (3 × 10
mL). The combined organic extracts were dried (Na2SO4) and the
solvent was evaporated under reduced pressure. The crude material
was purified by flash chromatography (EtOAc–hexane, 1:1, to
EtOAc) to give an oily product, as a mixture of diastereomers (~2:1,
Under the same reaction conditions, compound 19 was obtained in
70% yield from alcohol 18.
1
References
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diastereomers were separated by careful chromatography of a small
amount of the mixture (silica gel, EtOAc–hexane, 3:1, to EtOAc).
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Major Isomer
1H NMR (CDCl3): d = 1.95 (m, 2 H), 2.10 (m, 1 H), 2.62 (m, 1 H),
3.48 (s, 3 H), 3.50 (d, J = 18.3 Hz, 1 H), 3.67 (dd, J = 18.3, 3.0 Hz,
1 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 4.82 (dt, J = 7.2, 3.0 Hz, 1 H), 5.65
(dd, J = 6.0, 2.4 Hz, 1 H), 6.65 (s, 1 H), 6.68 (s, 1 H).
13C NMR (CDCl3): d = 30.1, 30.2, 37.5, 55.9, 56.1, 56.4, 58.0, 87.0,
107.9, 110.3, 123.4, 127.1, 148.1, 148.6, 168.2.
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300.1197.
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P.-C.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366.
(4) (a) Kapat, A.; Kumar, P. S.; Baskaran, S. Beilstein J. Org.
Chem. 2007, 3, No. 49; DOI: 10.1186/1860-5397-3-49.
(b) Kumar, P. S.; Kapat, A.; Baskaran, S. Tetrahedron Lett.
2008, 49, 1241. (c) Saber, M.; Comesse, S.; Dalla, V.;
Daïch, A.; Sanselme, M.; Netchitaïlo, P. Synlett 2010, 2197.
(5) (a) Gilchrist, T. L. Chem. Soc. Rev. 1983, 12, 53.
(b) Gilchrist, T. L.; Wood, J. E. In Comprehensive
Heterocyclic Chemistry II, Vol. 6; Boulton, A. J., Ed.;
Pergamon Press: Oxford, 1996, 279–299. (c) Tietze, L. F.;
Kettschau, G. Top. Curr. Chem. 1997, 189, 1.
Minor Isomer
1H NMR (CDCl3): d = 1.95–2.5 (m, 4 H), 3.38 (s, 3 H), 3.51 (s, 2
H), 3.88 (s, 3 H), 3.89 (s, 3 H), 4.53 (dd, J = 10.2, 5.5 Hz, 1 H), 5.36
(d, J = 4.7 Hz, 1 H), 6.71 (s, 1 H), 6.72 (s, 1 H).
13C NMR (CDCl3): d = 27.1, 31.6, 39.6, 55.9, 56.2, 57.1, 59.6, 86.4,
107.3, 110.7, 125.9, 129.3, 147.9, 148.6, 170.0.
HRMS: m/z [M + Na]+ calcd for C15H19NO4Na: 300.1206; found:
300.1201.
3-Hydroxy-8,9-dimethoxy-2,3,6,10b-tetrahydropyrrolo[2,1-
a]isoquinolin-5(1H)-one (18)
Compound 16 (0.120 g, 0.39 mmol) was dissolved in EtOAc–H2O
(4:1, 5 mL) and H3BO3 (0.483 g, 7.8 mmol) was added, together
with a catalytic amount of Raney Ni and MgSO4, under a H2 atmo-
sphere. The mixture was heated at 60 °C for 4 d in a sealed tube and
then it was filtered through a short Celite® pad. More EtOAc was
added and the mixture was neutralized with sat. aq Na2CO3 soln.
The aqueous layer was extracted with EtOAc (3 × 20 mL), the com-
bined organic extracts were dried (Na2SO4) and the solvent was
evaporated under reduced pressure. The crude material was purified
by flash chromatography (EtOAc–hexane, 1:1, to EtOAc) to give
the product, as an inseparable mixture of diastereomers; yield:
0.024 g (23%).
(d) Tsoungas, P. G. Heterocycles 2002, 57, 1149.
(e) Reissig, H.-U.; Zimmer, R. In Science of Synthesis,
Houben–Weyl Methods of Molecular Transformations, Vol.
33; Molander, G. A., Ed.; Georg Thieme: Stuttgart, 2007,
371–379. (f) Lemos, A. Molecules 2009, 14, 4098.
(6) (a) Gilchrist, T. L.; Roberts, T. G. J. Chem. Soc., Perkin
Trans. 1 1983, 1283. (b) Gilchrist, T. L.; Lemos, A.
J. Chem. Soc., Perkin Trans. 1 1993, 1391.
1H NMR (CDCl3): d = 1.80–2.70 (m, 4 H), 3.45 (d, J = 18.0 Hz, 1
H), 3.61 (dt, J = 18.0, 3.3 Hz, 1 H), 3.86 and 3.87 (2 × s, 6 H), 4.62
and 4.85 (2 × m, 2 H), 5.76 (m, 1 H), 6.65, 6.68 and 6.70 (3 × s, 2
H).
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E. G. Yioti et al.
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