Asymmetric synthesis of (R)-( + )- and (S)-( - )-2,3-methylenedioxy-8- oxoberbine (gusanlung D)

Article abstract of DOI:10.1016/j.tetasy.2004.02.017

The reaction of 6,7-methylenedioxy-3,4-dihydroisoquinoline with laterally lithiated o-toluamides in which the amine part derived from (1S,2S) -thiomicamine or (1R,2S)-2-amino-1-phenylpropanol, affording (R)-(+)- and (S)-(-)-2,3-methylenedioxy-8-oxoberbine

Full text of DOI:10.1016/j.tetasy.2004.02.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1113–1120
Asymmetric synthesis of (R)-(+)- and (S)-())-2,3-methylenedioxy-
8-oxoberbine (gusanlung D)
Maria Chrzanowska,* Agnieszka Dreas and Maria D. Rozwadowska
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznaꢀn, Poland
Received 8 January 2004; revised 13 February 2004; accepted 23 February 2004
Abstract—The reaction of 6,7-methylenedioxy-3,4-dihydroisoquinoline with laterally lithiated o-toluamides in which the amine part
derived from (1S,2S)-thiomicamine or (1R,2S)-2-amino-1-phenylpropanol, affording (R)-(þ)- and (S)-(À)-2,3-methylenedioxy-8-
oxoberbine in 77% and 64% yield, respectively, and with enantiomeric excess >99% is described. Physical and spectral data of the
synthetic product differ from those reported for the natural alkaloid, gusanlung D.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1.Introduction
The metallation methodology has been developed
for the synthesis of racemic heterocyclic com-
pounds, including protoberberines, and proceeded
with high regiochemical control.6;7 This feature
coupled with the simultaneous cyclization of the
addition product, offers a direct approach to the
protoberberine skeleton and its related structures. It
has been successfully applied to the asymmetric
synthesis of unnatural 2,3-dimethoxy-8-oxoberbine 2
and ent-2,8;9 as well as the naturally occurring (À)-
xylopinine 3.10
(À)-Gusanlung D isolated from Acangelisia gusanlung
H. S. Lo, by Zhang et al.1 in 1995 is the first optically
active natural protoberberine alkaloid unoxygenated at
ring D. Its structure as (S)-(À)-2,3-methylenedioxy-8-
oxoberbine 1 was elucidated on the basis of spectral
data analysis. Recently the synthesis of racemic amide
1
Herein we report the first asymmetric synthesis of
compound 1.
has been reported from three laboratories.2–4
As a continuation of our study on stereoselective syn-
theses of isoquinoline alkaloids based on the addition of
carbon nucleophiles to imines,5 we extended this
approach to the synthesis of the protoberberine system.
The key step of the synthesis, in which a new stereogenic
centre at C-13a was created, involved the addition of
laterally metallated chiral o-toluamides to cyclic imines.
In our concept of the asymmetric synthesis of gusanlung
D, an addition reaction of the carbon nucleophile,
derived from optically active o-toluamide 4, to 6,7-
methylenedioxy-3,4-dihydroisoquinoline 5 was planned.
The retrosynthetic analysis of this synthesis is shown in
Scheme 1. The chiral auxiliary was placed at the carbon
nucleophile, derived from commercially available,
4
5
3
2
6
O
O
H3CO
H3CO
H3CO
B
A
13a
8
N
C
O
N
N
O
H3CO
H
1
H
H
13
9
D
10
12
OCH3
OCH3
11
(-)-1
(-)-2
(-)-3
* Corresponding author. Fax: +48-61-8658008; e-mail: marylch@amu.edu.pl
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.017

1114
M. Chrzanowska et al. / Tetrahedron: Asymmetry 15 (2004) 1113–1120
O
O
N
OH
OH
O
O
KOH
O
O
N
H
Cl
(0.5 M)
5
N
O
*
+
+
CH2Cl2
7
OH
O
8
91%
SCH3
R*
HO
N
R1
NH2
SCH3
1
6
4
(CH3)2C(OCH3)2
Acetone
H2SO4
Scheme 1.
O
O
O
o-toluoyl chloride and enantiomerically pure (1S,2S)-
2-amino-1-[4-(methylthio)phenyl]-1,3-propanediol and
(1R,2S)-2-amino-1-phenylpropanol.
N
H
4a
49%
SCH3
2.Results and discussion
Scheme 2.
At first (1S,2S)-(þ)-thiomicamine 6, an industrial waste
product, which has been used successfully by our
research group as a source or promoter of stereochem-
istry in many types of organic syntheses, especially in
enantioselective syntheses of isoquinoline alkaloids,11–15
was chosen. In the reaction of thiomicamine 6 with o-
toluoyl chloride 7, amide 8 was obtained in 91% yield.
The two hydroxyl groups in compound 8 were protected
as a 1,3-O-isopropylidene derivative prepared in the
reaction of diol 8 with 2,2-dimethoxypropane in dry
acetone, catalyzed with concentrated sulfuric acid, giv-
ing compound 4a in 49% yield, after column chroma-
tography purification (Scheme 2).
deep brown coloured anion, which upon addition of 6,7-
methylenedioxy-3,4-dihydroisoquinoline 516 and sub-
sequent work-up provided amine 9 as a diastereomeric
mixture 55:45 (by HPLC) in 57% yield. The crude
product 9, when heated in refluxing toluene under an
argon atmosphere, was cyclized to 2,3-methylenedioxy-
8-oxoberbine 1 in 49% yield with 34% ee (by HPLC)
(Scheme 3). This compound was used as our reference
sample of ÔracemicÕ amide 1 for further HPLC com-
parison and enantiomeric excess determination.
The two diastereoisomers of compound 9 could be sep-
arated by column chromatography on silica gel. When
diastereomerically pure 9, characterized by a shorter
Treatment of 4a with n-butyllithium (2.2 equiv) in dry
THF, at À72 ꢁC for 30 min resulted in the formation of a
O
O
NH
PhCH3
n-BuLi
O
O
O
5 + 4a
(S)-(-)-1
N
H
∆
THF
49%, 34%ee
9
SCH3
57%, dr 55:45
1. Column chromatography
2. PhCH3, ∆
O
O
O
N
O
N
O
O
H
H
(R)-(+)-1
61%, >99% ee
(S)-(-)-1
77%, 97% ee
Scheme 3.

M. Chrzanowska et al. / Tetrahedron: Asymmetry 15 (2004) 1113–1120
1115
retention time on HPLC, was cyclized in the same con-
ditions as above, the laevorotatory enantiomer of amide
1, showing a longer retention time, was formed (97% ee)
in 77% yield. The cyclizaton of the diastereomer 9, with
longer retention time by HPLC, led to dextrorotatory
2,3-methylenedioxy-8-oxoberbine 1 in 61% yield. After
recrystallization from methanol, a sample of (R)-(þ)-1
with >99% ee was obtained, showing mp 194–196 ꢁC and
The secondary amine 12 was cyclized to 8-oxoberbine 1
by addition of n-butyllitium to the THF solution of 12
at À72 ꢁC, and then allowed to reach ambient temper-
ature. Pure 8-oxoberbine 1, with the same absolute
configuration at C-13a, was isolated with 98% ee
(Scheme 5). Therefore the total yield of compound 1 was
64%.
½aŠ ¼ þ415:3 (c 0.77, CHCl3).
After recrystallization from methanol, a sample of 2,3-
methylenedioxy-8-oxoberbine 1 with >99% ee was
obtained, showing mp 195–197 ꢁC (lit.1 mp 250–251 ꢁC)
and ½aŠ ¼ À432.6 (c 0.80, CHCl3) {lit.1 ½aŠ ¼ À345 (c
D
Since this initial study showed that the diastereoselec-
tivity of the addition reaction of amide 4a to imine 5 was
rather low and that intermediate amine 9 had to be
cyclized in the next step of the synthesis, we turned our
attention to amides with other chiral auxiliaries. Thus,
(1R,2S)-2-amino-1-phenylpropanol 10 was chosen and
reacted with o-toluoyl chloride 7 to give the amide 11 in
99% yield. The functional NH and OH groups were
protected as oxazolidine derivative 4b prepared in 96%
yield via reaction of 11 with 2,2-dimethoxypropane
catalyzed by p-toluenesulfonic acid, in refluxing benzene
under an argon atmosphere (Scheme 4).
D
D
0.018, CHCl3)}.
3.Conclusion
(R)-(þ)- and (S)-(À)-2,3-Methylenedioxy-8-oxoberbines
1 prepared in the above described asymmetric synthesis
were fully characterized by UV, IR, 1H NMR, 13C
NMR, 2D NMR and MS spectra (Table 1). The enan-
tiomeric excess was established by HPLC analysis using
a Chiracel OD-H column. The absolute configuration of
(þ)- and (À)-1 was postulated on the basis of the sign of
their specific rotation, which corresponded to that
reported for the other berbines, for example, 2,3-dime-
thoxy-8-oxoberbine 2.8;17;18 The synthesized laevorota-
tory (S)-enantiomer 1 was characterized on HPLC as
that of a longer retention time, while the dextrorotatory
(R)-enantiomer 1 as that of a shorter retention time,
relative to that of the sample of 1 with 34% ee.
O
O
KOH
Cl
Ph
OH
(0.5 M)
N
H
+
CH2Cl2
7
11
99%
Ph
OH
H2N
(CH3)2C(OCH3)2
Benzene
p-CH3C6H4SO3H
10
As shown in Table 1, the physical properties {mp, ½aŠD}
and spectral data of our synthetic product 1 differ from
those reported for natural gusanlung D, but are in line
with those reported for racemic compound 1.2;4
O
Ph
N
O
From our experience in the synthesis of 8-oxober-
bines,18;19 we have noticed that the main product could
often be accompanied by dehydrolactam, for example,
13.4;20 In our synthesis, the presence of the concomitant
compound 13 was difficult to notice by HPLC since its
retention time was similar to that of (S)-(À)-enantiomer-
1, which is illustrated in Figure 1.
4b
96%
Scheme 4.
The carbanion generated from compound 4b with the
aid of 1.1 M equiv of n-butyllithium, in reaction condi-
tions similar as for amide 4a, followed by addition of
6,7-methylenedioxy-3,4-dihydroisoquinoline 5 and sub-
sequent work-up, afforded 8-oxoberbine (À)-1, isolated
in 33% yield with 81% ee. Additionally, the secondary
amine 12 was isolated in 31% yield as a diastereomeric
mixture (Scheme 5).
However, these two compounds could be easily distin-
guished by UV spectra, as that of the dehydrolactam 13
showed a strong absorption at 330 nm.21 In the UV
spectrum of our pure 2,3-methylenedioxy-8-oxoberbine
1, there was no absorption in this region.
O
O
N
O
NH
n-BuLi
O
O
O
5 + 4a
+
H
H
N
Ph
THF
O
12
31%
(S)-(-)-1
33%, 81% ee
n-BuLi, THF, -72oC
Scheme 5.

1116
M. Chrzanowska et al. / Tetrahedron: Asymmetry 15 (2004) 1113–1120
Table 1. The physical and IR, 1H NMR and 13C NMR, and MS data for synthetic compound (S)-(À)-1 and natural gusanlung D
Synthetic 1
195–197 ꢁC (MeOH)
À432.6 (c 0.80, CHCl3)
209, 229, 289 nm
1637 cmÀ1
Gusanlung D
Mp
250–251 ꢁC
½aŠ
À345 (c 0.018, CHCl3)
222, 273, 294, 320 nm
1650 cmÀ1
D
UV kmax
IR m (KBr)
NMR
dH (300 MHz)
dC (75 MHz)
dH (300 MHz)
dC (75 MHz)
1
6.71 (s)
105.8
146.5a
146.7a
108.6
128.8
29.6
7.35 (s)
107.3
135.0
147.0
107.5
126.5
29.7
2
3
4
6.67 (s)
6.80 (s)
4a
5
2.70–2.80 (m)
2.82–3.02 (m)
2.82–3.02 (m)
4.93–4.99 (m)
2.70–3.40 (m)
6
38.7
2.70–3.40 (m)
4.80 (m)
42.0
8
164.5
137.2
128.6
127.3
131.8
126.8
129.0
38.1
162.0
117.3
128.7b
127.9b
127.1b
126.8b
124.6
33.5
8a
9
8.13 (d, 7.4)
7.34–7.40 (m)
7.41–7.49 (m)
7.24 (d, 7.4)
8.07 (d, 8.0)
7.29–7.41 (m)
7.29–7.41 (m)
7.29–7.41 (m)
10
11
12
12a
13
2.82–3.02 (m)
3.18 (dd, 15.6, 3.7)
4.83 (dd, 13.3, 3.7)
2.70–3.40 (m)
3.95 (m)
13a
13b
55.2
128.5
101.1
49.4
126.5
100.9
OCH2O
5.96 (s)
6.20, 6.06 (2s)z
MS m=z
HRMS
293, 276, 204, 174, 119, 118, 90
Calcd 293.1052, found 293.1034
293, 248, 235, 204, 178
Calcd 293.1047, found 293.1017
a
;bInterchangeable assignments.
O
O
Bruker FT-IR IFS 113 V in KBr pellets. NMR spectra:
Varian Gemini 300 in CDCl3 (unless stated otherwise),
with TMS as the internal standard. Mass spectra (EI):
instrument AM D402. Optical rotations: Perkin Elmer
polarimeter 242B at 20 ꢁC. Elemental analyses: Vario
EL III. Merck Kieselgel 60 (70–230 mesh) was used for
column chromatography and Merck DC-Alufolien
Kieselgel 60254 for TLC. Analytical HPLC: Waters
HPLC system with Mallinkrodt-Baker Chiracel OD-H
column.
N
O
13
In our opinion, there is the possibility that the isolated
natural gusanlung D could be contaminated with a
considerable amount of dehydrolactam 13, due to the
presence of the absorption band at 320 nm in the UV
spectra (Table 1). However, a comparison of physical
and NMR data published for gusanlung D with those
published for compound 134;20 and with our data for
synthetic 1 did not lead to any constructive explanation
of the differences in physical and spectral data for
gusanlung D and (À)-1. As a result, the problem
concerning the structure of the natural originated (À)-
gusanlung D remains to be clarified.
THF and diethyl ether were freshly distilled from
LiAlH4, benzene and toluene––from sodium wire and
acetone––from KMnO4. Unless stated otherwise, all
reagents were purchased from commercial sources and
used without additional purification. 6,7-Methylene-
dioxy-3,4-dihydroisoquinoline 5 was prepared as previ-
ously described.16
4.2. (1S,2S)-2-o-Toluamide-1-[4-(methylthio)phenyl]-1,3-
propanediol 8
To (1S,2S)-(þ)-thiomicamine 6 (2.13 g, 10 mmol) sus-
pended in dichloromethane22 (135 mL) aqueous 0.5 M
KOH (65 mL, 10 mmol) was added, then o-toluoyl
chloride 7 (1.54 g, 10 mmol) introduced dropwise with
stirring at 0 ꢁC. After 30 min the cooling bath was
removed and stirring continued at room temperature for
2 h. The resulting white precipitate of amide 8 was fil-
4.Experimental
4.1. General
Melting points: determined on a Koffler block and are
uncorrected. UV spectra: Jasco V-550. IR spectra:

M. Chrzanowska et al. / Tetrahedron: Asymmetry 15 (2004) 1113–1120
1117
1.30
1.20
1.10
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
(a)
0.00
200.00
300.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
Minutes
0.36
0.34
0.32
0.30
0.28
0.26
0.24
0.22
0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
(b)
0.02
0.00
200.00
300.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
Minutes
Figure 1. (a) 3D HPLC chromatogram of (S)-(À)-2,3-methylenedioxy-8-oxoberbine 1 contaminated with dehydrolactam 13. (b) 3D HPLC chro-
matogram of pure (S)-(À)-1.
tered off (2.115 g). The phases from the filtrate were
separated and the organic one was washed with water
(3 · 10 mL) and brine (10 mL) and dried. After removal
of organic solvent under reduced pressure an additional
amount of amide 8 (1.04 g) was obtained. Recrystalli-
zation from diethyl ether/diisopropyl ether gave crys-
4.22–4.29 (m, 1H, CHNH), 5.05 (d, J ¼ 3:6 Hz, 1H,
CH(OH)), 6.52 (d, J ¼ 8:2 Hz, 1H, NH(CO)), 7.12–7.30
(m, 8H, ArH); 13C NMR (CD3OD) d: 16.0 (CH3S),
19.7 (CH3Ar), 58.4 (C-2), 62.7 (C-3), 72.3 (C-1),
126.5 (CH), 127.4 (2C, CH) 127.9 (3C, CH) 130.6
(CH), 131.5 (CH), 136.6 (C), 137.9 (C), 138.8 (C),
140.7 (C), 173.0 (C@O); MS m=z (%): 331(M þ, 0.5),
161 (33), 153 (14), 152 (12), 119 (100), 91 (31);
talline 8 (3.004 g, 91%); mp 125–126 ꢁC; ½aŠ ¼ þ84.7 (c
D
1.005, MeOH); IR m: 3354 (OH, NH), 1616 (C@O), 1526
1
1
(NH) cmÀ1; H NMR d: 2.21(s, 3H, ArCH ), 2.46 (s,
Anal. Calcd for C18H21NO3S · 4H2O: C, 64.36; H, 6.45;
N, 4.17; S, 9.55. Found: C, 64.70; H, 6.10; N, 4.10; S,
9.33.
3
3H, SCH3), 3.29 and 3.84 (br s, 1H each, OH, disap-
peared with D2O), 3.89 (d, J ¼ 3:3 Hz, 2H, CH2O),

1118
M. Chrzanowska et al. / Tetrahedron: Asymmetry 15 (2004) 1113–1120
4.3. (1S,2S)-2-o-Toluamide-1-[4-(methylthio)phenyl]-1,3-
O-isopropylidenepropane 4a
with D2O), 2.36 (s, 3H, SCH3), 2.48–2.60 (m, 2H, CH2),
2.67–2.85 (m, 2H, CH2), 2.89–3.05 (m, 2H, CH2), 3.97
(dd, J ¼ 1:9, 12.1 Hz, 1H, CH2O), 4.12 (dd, J ¼ 3:0,
9.2 Hz, 1H, ArCHN), 4.32 (dd, J ¼ 1:9, 12.1 Hz, 1H,
CH2O), 4.54 (dd, J ¼ 1:9, 9.1Hz, 1H, C H(NHCO)),
5.25 (d, J ¼ 1:9 Hz, 1H, ArCHO), 5.97 (ABq,
J ¼ 1; 4 Hz, 2H, OCH2O), 6.55 (s, 1H, ArH), 6.67 (s,
1H, ArH), 7.02–7.11 (m, 3H, ArH), 7.18–7.33 (m, 5H,
ArH), 8.03 (d, J ¼ 9:1Hz, 1H, CONH, disappeared
with D2O); MS m=z (%): 546 (Mþ, 0.6), 292 (6), 264 (2),
176 (100), 118 (6), 90 (3). The fraction containing pure
diastereomer 9 with a longer retention time (tR 56.9 min)
was isolated as a colourless solid (80 mg, 15%); 1H NMR
(signals different from those for the first diastereoisomer
9) d: 1.47 (s, 3H, C(CH3)2), 1.60 (s, 3H, C(CH3)2), 1.80
(br s, 1H, NH, disappeared with D2O), 2.33 (s, 3H,
SCH3), 3.68 (dd, J ¼ 3:0, 9.2 Hz, 1H, ArCHN), 4.52
(dd, J ¼ 1:9, 9.1Hz, 1H, C H(NHCO)), 5.92 (ABq,
J ¼ 1; 4 Hz, 2H, OCH2O), 6.53 (s, 1H, ArH), 6.71 (s,
1H, ArH), 7.86 (d, J ¼ 9:0 Hz, 1H, CONH, disappeared
with D2O).
Amide 8 (2.94 g, 8.9 mmol) was dissolved in dry acetone
(35 mL) after which 2,2-dimethoxypropane (5.44 g,
52 mmol) and concentrated sulfuric acid (0.35 mL) were
added. Stirring was continued for 2 h. The solution was
neutralized with 10% aqueous Na2CO3 (3 mL). Acetone
was removed in vacuo and the remaining aqueous phase
extracted with dichloromethane (3 · 10 mL). The com-
bined organic extracts were dried and the solvents
removed in vacuo yielding 3.282 g of a colourless oil,
which was then purified by column chromatography
(dichloromethane
and
dichloromethane/methanol;
200:1 fi 100:1) to afford a pure oily compound 4a
(1.612 g, 49%). ½aŠ ¼ þ119.8 (c 1.065, CHCl3); IR m:
D
3428 (NH), 1661 (C@O), 1296 (COC), 1199 (COC)
1
cmÀ1; H NMR d: 1.52 (s, 3H, C(CH3)2), 1.60 (s, 3H,
C(CH3)2), 2.08 (s, 3H, ArCH3), 2.45 (s, 3H, SCH3), 3.99
(dd, J ¼ 1:92, 12.1 Hz, 1H, CH2O), 4.35 (dd, J ¼ 1:9,
12.1 Hz, 1H, CH2O), 4.46 (dddd, J ¼ 1:9, 1.9, 1.9,
9.6 Hz, 1H, CHNH), 5.26 (d, J ¼ 1:9 Hz, 1H, ArCHO),
6.34 (d, J ¼ 9:6 Hz, 1H, NH), 7.02–7.05 (m, 1H, ArH),
7.09–7.14 (m, 2H, ArH), 7.22–7.32 (m, 5H, ArH); 13C
NMR d: 16.2 (CH3S), 18.6 (CH3C), 19.3 (CH3Ar), 29.8
(CH3C), 46.2 (C-2), 64.7 (C-3), 71.6 (C-1), 99.6 (CH3C),
125.5 (CH), 125.6 (2C, CH), 126.5 (CH), 126.6 (2C,
CH), 129.6 (CH), 130.0 (CH), 135.3 (C), 135.8 (C), 136.1
(C), 137.5 (C), 169.2 (C@O); MS m=z (%): 371(M þ, 1.3),
160 (29), 151 (50), 119 (100), 91 (35); Anal. Calcd for
4.5. Cyclization of addition product 9 to 5,6,13,13a-
tetrahydro-2,3-methylenedioxy-8H-dibenzo[a,g]quinol-
izin-8-one (2,3-methylenedioxy-8-oxoberbine) 1
4.5.1. Cyclization of crude reaction product. Crude
product 9 (373 mg, 0.7 mmol) was refluxed under argon
in dry toluene (15 mL) for 22 h. After cooling to room
temperature, it was evaporated to dryness and the
remaining oil (370 mg) dissolved in diethyl ether (30 mL)
and extracted with 5% aqueous HCl (4 · 2 mL). The
organic phase was dried and evaporated yielding 200 mg
of an oil, which was purified by repeated column chro-
matography (dichloromethane) to yield pure 2,3-
methylenedioxy-8-oxoberbine 1 (110 mg, 49%) with 34%
ee of the enantiomer with a longer retention time
by HPLC [hexane/propan-2-ol¼4:1, 0.5 mL/min; tR
28.4 min, tR 30.0 min (major)]; mp 175–178 ꢁC (diethyl
ether). The acidic aqueous phase was alkalized with
KOH pellets, reextracted with diethyl ether (3 · 1 0 mL),
dried and evaporated to give a yellow oil (96 mg), which
consisted of unreacted 6,7-methylenedioxy-3,4-dihydro-
isoquinoline 5 and thiomicamine 6, according to TLC
and HPLC analysis.
1
C21H25NO3S · 2H2O: C, 66.29; H, 6.89; N, 3.68; S, 8.43.
Found: C, 66.50; H, 6.85; N, 3.58; S, 8.16.
4.4. Addition product 9
Amide 4a (371mg, 1mmol) was dissolved in dry THF
(10 mL) under an argon atmosphere and the mixture
cooled to À72 ꢁC. n-BuLi (1.6 M solution in hexanes,
1.4 mL) was introduced and the carbanion generated for
30 min at À72 ꢁC. A solution of 6,7-methylenedioxy-3,4-
dihydroisoquinoline 516 (175 mg, 1 mmol) in dry THF
(10 mL) was added and the mixture kept at À72 ꢁC for
4 h and then treated at this temperature with 20%
aqueous NH4Cl (6 mL). When the reaction mixture
reached room temperature, the phases were separated
and the aqueous one extracted with diethyl ether
(3 · 10 mL). The combined organic extracts were dried
and solvents removed under reduced pressure yielding a
yellow foam (549 mg). HPLC analysis of the crude
reaction product indicated the presence of two new
compounds {diastereoisomers of amine 9 in a ratio
55:45 [hexane/propan-2-ol¼9:1, 0.5 mL/min; tR 53.2 min
(major), tR 56.9 min]} together with unreacted amide 4a
and imine 5. The crude product was purified by column
chromatography (dichloromethane/methanol, 50:1)
yielding diastereomerically enriched and pure fractions
of compound 9 (312 mg, 57%). The fraction containing
pure diastereomer 9 with a shorter retention time (tR
53.2 min) was isolated as a colourless solid (120 mg, 22%
yield). Spectral data for pure diastereoisomer 9: IR m:
4.5.2. Cyclization of pure 9 with a shorter retention time.
The fraction consisting of only one diastereomer of 9
with a shorter retention time (120 mg, 0.2 mmol) was
refluxed under argon in dry toluene (10 mL) under the
same conditions as that for crude product 9. After work-
up the neutral fraction, isolated as a yellow foam (45 mg,
77%), consisted of (À)-2,3-methylenedioxy-8-oxober-
bine 1, 97% ee (by HPLC), the enantiomer with longer
retention time. From the amine fraction thiomicamine 6
(21mg) was recovered.
4.5.3. Cyclization of pure 9 with longer retention time.
(R)-(+)-5,6,13,13a-Tetrahydro-2,3-methylenedioxy-8H-di-
benzo[a,g]quinolizin-8-one (2,3-methylenedioxy-8-oxober-
bine) 1. The fraction consisting of the diastereomer 9
1
1656 (C@O) cmÀ1; H NMR d: 1.52 (s, 3H, C(CH3)2),
1.60 (s, 3H, C(CH3)2), 1.62 (br s, 1H, NH, disappeared
with a longer retention time (80 mg, 0.15 mmol)

M. Chrzanowska et al. / Tetrahedron: Asymmetry 15 (2004) 1113–1120
1119
was cyclized under the same conditions as described
above. After work-up and recrystallization, pure
4.8. (S)-(À)-5,6,13,13a-Tetrahydro-2,3-methylenedioxy-
8H-dibenzo[a,g]quinolizin-8-one (2,3-methylenedioxy-8-
oxoberbine) 1 and addition product 12
dextrorotatory amide 1 (27 mg, 61%) was isolated
with >99% ee, mp 194–196 ꢁC (methanol); ½aŠ ¼
D
þ415:3 (c 0.77, CHCl3).
Oxazolidine 4b (309 mg, 1mmol) was dissolved in dry
THF (10 mL) under an argon atmosphere and the solu-
tion cooled to À72 ꢁC. n-BuLi (1.6 M solution in hex-
anes, 0.7 mL) was added and the carbanion generated for
30 min at À72 ꢁC. A solution of 6,7-methylene- dioxy-
3,4-dihydroisoquinoline 516 (175 mg, 1 mmol) in dry
THF (8 mL) was introduced dropwise and the mixture
kept at À72 ꢁC for 3 h, then treated at this temperature
with 20% aqueous NH4Cl (6 mL). When the reaction
mixture reached room temperature, the phases were
separated and the aqueous one extracted with diethyl
ether (3 · 10 mL). The combined organic extracts were
dried and solvents removed under reduced pressure
yielding an oily product (484 mg). HPLC analysis of the
crude reaction product indicated the presence of mainly
one enantiomer of 2,3-methylenedioxy-8-oxoberbine 1
with a longer retention time, accompanied by the addi-
tion product 12 [hexane/propan-2-ol¼4:1, 0.5 mL/min;
tR 36.8 min]. The crude product was dissolved in diethyl
ether (30 mL) and extracted with 5% aqueous HCl
(3 · 2 mL). The organic phase was dried and evaporated
in vacuo yielding an oily product (119 mg), which was
purified by column chromatography (dichloromethane)
to give pure (À)-2,3-methylenedioxy-8-oxoberbine 1,
(98 mg, 33%) 81% ee by HPLC. Recrystallization from
methanol furnish a sample of 1 with >99% ee, mp 195–
4.6. (1R,2S)-2-o-Toluamide-1-phenylpropanol 11
To (1R,2S)-2-amino-1-phenylpropanol 10 (0.775 g,
5 mmol) dissolved in dichloromethane (67 mL) aqueous
KOH (33 mL, 0.5 M) was added, and o-toluoyl chloride
7 (0.770 g, 5 mmol) then introduced dropwise at 0 ꢁC.
After 30 min, the cooling bath was removed and the
mixture was stirred at room temperature. After 2 h, the
reaction had gone to completion according to TLC
analysis. The white precipitate of 11 was filtered off
(1.338 g, 99%). An analytical sample was crystallized
from dichloromethane/methanol/diethyl ether yielding
crystalline 11, mp 152–154 ꢁC; ½aŠ ¼ À99.7 (c 1.02,
D
CHCl3); IR m: 3379 (OH), 3281(NH), 6137 (C @O)
1
cmÀ1; H NMR d: 1.12 (d, J ¼ 7:1Hz, 3H; CHC H3),
2.44 (s, 3H, ArCH3), 3.64 (br s, 1H, OH, disappeared
with D2O), 4.46–4.57 (m, 1H, CHCH3), 4.93 (d,
J ¼ 3:3 Hz, 1H, CHOH), 5.92 (d, J ¼ 8:0 Hz, 1H, NH,
disappeared with D2O), 7.16–7.41 (m, 9H, ArH); 13C
NMR d: 14.8 (C-3), 19.8 (CH3Ar), 51.3 (C-2), 76.5 (C-
1), 125.6 (CH), 126.2 (2C, CH), 126.4 (CH), 126.6 (CH),
127.5 (CH), 128.1 (CH), 129.9 (CH), 130.9 (CH), 135.8
(C), 135.9 (C), 140.6 (C), 170.4 (C@O); MS m=z (%): 270
(Mþ, 0.2), 163 (31); 162 (22), 119 (100), 91 (26); Anal.
Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20.
Found: C, 75.78; H, 6.95; N, 5.13.
197 ꢁC, (lit.1 mp 250–251 ꢁC); ½aŠ ¼ À432.6 (c 0.80,
D
CHCl3); {lit.1 ½aŠ ¼ À345 (c 0.018, CHCl3)}; UV kmax
D
(MeOH): 209, 229, 289 nm; IR m: 1637 (C@O), 1330 (CN)
1
1
cmÀ1: H NMR and 2D H–1H NMR COSY d: 2.70–
2.80 (m, 1H, H-5), 2.82–3.02 (m, 3H, H-5, H-6, H-13),
3.18 (dd, J ¼ 3:7, 15.6 Hz, 1H, H-13), 4.83 (dd, J ¼ 3:7,
13.3 Hz, 1H, H-13a), 4.93–4.99 (m, 1H, H-6), 5.96 (s, 2H,
OCH2O), 6.67 (s, 1H, H-4), 6.71 (s, 1H, H-1), 7.24 (d,
J ¼ 7:4 Hz, 1H, H-12), 7.34–7.40 (m, 1H, H-10), 7.41–
7.49 (m, 1H, H-11), 8.13 (d, J ¼ 7:4 Hz, 1H, H-9); 13C
4.7. (4S,5R)-2,2,4-Trimethyl-3-o-toluoyl-5-phenyloxaz-
olidine 4b
To compound 11 (1.076 g, 4 mmol) in dry benzene
(50 mL), 2,2-dimethoxypropane (6.8 g, 65 mmol) was
added under an argon atmosphere followed by catalytic
amounts of p-toluenesulfonic acid (0.2 g). The reaction
mixture was stirred at reflux for 2 h and allowed to reach
room temperature. The reaction mixture was then
washed with 1% aqueous NaOH solution (3 · 2 mL),
dried and the solvent evaporated. The crude reaction
product was chromatographed (dichloromethane and
dichloromethane/methanol 200:1 fi 100:1) to give pure
oxazolidine 4b (1.192 g, 96%). Recrystallization from
diethyl ether gave white crystals of 4b; mp 117–119 ꢁC;
1
NMR and DEPT and H–13C NMR COSY d: 29.6 (C-
5), 38.1 (C-13), 38.7 (C-6), 55.2 (C-13a), 101.1 (OCH2O),
105.8 (C-1), 108.6 (C-4), 126.6 (C-12), 127.3 (C-10), 128.5
(C-13b), 128.6 (C-9), 128.8 (C-4a), 129.0 (C-12a), 131.8
(C-11), 137.2 (C-8a), 146.5, 146.9 (C-2, C-3), 164.5 (C-8);
MS m=z (%): 293 (Mþ, 47), 276 (17), 204 (6), 174 (15), 119
(26), 118 (69), 90 (100); HRMS calcd for C18H15NO3
293.1052, found 293.1034.
The acidic aqueous phase was alkalized with KOH
pellets, reextracted with diethyl ether (3 · 10 mL), dried
and evaporated to give a yellow oil (288 mg), which
consisted mainly of one diastereoisomer of the addition
product 12, by HPLC [hexane/propan-2-ol¼4:1, 0.5 mL/
min; tR 36.8 min]. The oily product was purified by
chromatography (dichloromethane/methanol 100:1 fi
50:1) to give pure 12 (151 mg, 31% yield). IR m: 1633
½aŠ ¼ þ22.9 (c 0.995, CHCl3); IR m: 1619 (C@O) cmÀ1
;
D
1H NMR d: 0.59 (d, J ¼ 6:6 Hz, 3H, CHCH3); 1.86 (s,
3H, C(CH3)2), 1.94 (s, 3H, C(CH3)2), 2.39 (s, 3H,
ArCH3), 3.79 (br s, 1H, CHN), 5.29 (d, J ¼ 4:9 Hz, 1H,
CHO), 7.22–7.38 (m, 9H, ArH); 13C NMR d: 16.4
(CH3C-4), 18.9 (CH3Ar), 23.8 (CH3C-2), 27.5 (CH3C-2),
58.4 (C-4), 78.5 (C-5), 94.6 (C-2), 125.6 (CH), 125.7
(CH), 126.0 (2C, CH), 127.7 (CH), 128.2 (2C, CH),
128.7 (CH), 130.3 (CH), 135.9 (2C, C), 137.6 (C), 167.7
(C@O); MS m=z (%): 294 (MþÀCH3, 10), 203 (51), 148
(36), 119 (100), 91 (45); Anal. Calcd for C20H23NO2: C,
77.64; H, 7.49; N, 4.53. Found: C, 77.94; H, 7.13; N,
4.54.
(C@O) cmÀ1
;
1H NMR d: 0.58 (d, J ¼ 5:8 Hz, 3H,
CHCH3); 1.86 (s, 3H, C(CH3)2), 1.92 (s, 1H, NH, dis-
appeared with D2O) 2.00 (s, 3H, C(CH3)2), 2.61–2.79
(m, 2H, CH2), 2.86–3.08 (m, 2H, CH2), 3.12–3.19 (m,
2H, CH2), 3.85–3.87 (br m, 1H, CHNCH3), 4.33 (d,
J ¼ 9:3 Hz, 1H, ArCHN), 5.27 (d, J ¼ 4:4 Hz, 1H,

1120
M. Chrzanowska et al. / Tetrahedron: Asymmetry 15 (2004) 1113–1120
4. Reimann, E.; Grasberger, F.; Polborn, K. Monatsh. Chem.
2003, 134, 991–1014.
CHO), 5.91(d, J ¼ 1:4 Hz, 2H, OCH2O), 6.56 (s, 1H,
ArH), 6.77 (s, 1H, ArH), 7.19–7.39 (m, 9H, ArH); MS
m=z (%): 484 (Mþ, 0.9), 292 (6), 264 (9), 176 (100), 118
(4), 91(4). HRMS calcd for C 30H32N2O4 484.2362,
found 484.2365.
ꢀ
ꢀ
5. Brozda, D.; Chrzanowska, M.; Głuszynska, A.; Rozwa-
dowska, M. D.; Sulima, A. Ann. Polish Chem. Soc. 2001,
264–268.
6. Clark, R. D.; Jahangir, A. Org. React. (N.Y.) 1995, 47,
1–314.
4.9. Cyclization of amine 12 to (À)-5,6,13,13a-tetrahydro-
2,3-methylenedioxy-8H-dibenzo[a,g]quinolizin-8-one (2,3-
methylenedioxy-8-oxoberbine) 1
7. Singh, K. N. Tetrahedron Lett. 1998, 39, 4391–4392.
8. Warrener, R. N.; Liu, L.; Russel, R. A. Chem. Commun.
1997, 2173–2174.
9. Liu, L. Synthesis 2003, 1705–1706.
10. Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67,
1290–1296.
11. Rozwadowska, M. D. Tetrahedron: Asymmetry 1998, 9,
1615–1618.
To a solution of amine 12 (49 mg, 0.1mmol) in dry THF
(10 mL) at À72 ꢁC, n-BuLi (1.6 M solution in hexanes,
0.06 mL) was added under an argon atmosphere. The
reaction mixture was allowed to warm up to ambient
temperature and quenched by the addition of an aque-
ous solution of 20% NH4Cl. Extractive work-up yielded
(À)-2,3-methylenedioxy-8-oxoberbine 1, which was
purified by column chromatography to give pure amide
1, in 50% yield and with 98% ee by HPLC.
12. Rozwadowska, M. D. Tetrahedron: Asymmetry 1993, 4,
1619–1624.
ꢀ
ꢀ
13. Brozda, D.; Chrzanowska, M.; Głuszynska, A.; Rozwa-
dowska, M. D. Tetrahedron: Asymmetry 1999, 10, 4791–
4796.
ꢀ
14. Głuszynska, A.; Rozwadowska, M. D. Tetrahedron:
Asymmetry 2000, 11, 2359–2366.
15. Chrzanowska, M. Tetrahedron: Asymmetry 2002, 13,
2497–2500.
16. MacLean, D. B.; Marsden, R. Can. J. Chem. 1987, 62,
1392–1399.
Acknowledgements
This work was supported by a research grant from the
State Committee for Scientific Research in the years
2003–2006 (KBN grant no 4T09A 07824).
17. Naito, T.; Katsumi, K.; Tada, Y.; Ninomiya, I. Hetero-
cycles 1983, 20, 779–782.
18. Chrzanowska, M.; Dreas, A.; Rozwadowska, M. D.
Application of (þ)-thiomicamine in the diastereoselective
synthesis of isoquinoline alkaloids. Program and
Abstracts, BOS 2002 International Conference on Organic
Synthesis, Vilnius, PO13.
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