The asymmetric synthesis of (R)-(+)- and (S)-(-)-O-methylbharatamine

Article abstract of DOI:10.1016/j.tetasy.2004.06.038

The asymmetric syntheses of (R)-(+)- and (S)-(-)-O-methylbharatamine were performed using the lateral metallation strategy, in which (R)- and (S)-phenylalaninol were applied as chiral auxiliaries. The addition reaction of chiral o-toluamide carbanion to 6

Full text of DOI:10.1016/j.tetasy.2004.06.038

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2561–2567
The asymmetric synthesis of (R)-(+)- and
(S)-(–)-O-methylbharatamine
Maria Chrzanowska* and Agnieszka Dreas
´
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
Received 10 June 2004; accepted 28 June 2004
Available online 3 August 2004
Abstract—The asymmetric syntheses of (R)-(+)- and (S)-(ꢀ)-O-methylbharatamine were performed using the lateral metallation
strategy, in which (R)- and (S)-phenylalaninol were applied as chiral auxiliaries. The addition reaction of chiral o-toluamide carb-
anion to 6,7-dimethoxy-3,4-dihydroisoquinoline proceeded with a simultaneous cyclization reaction, giving both enantiomers of 2,3-
dimethoxy-8-oxoberbine in good yield (76%) with high enantioselectivity (99% ee). Lithium aluminum hydride reduction of each
enantiomer led to (R)-(+)- and (S)-(ꢀ)-O-methylbharatamine without loss of enantioselectivity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
5
4
A
1
3
2
CH3O
HO
6
Bharatamine 1, a protoberberine alkaloid, has been iso-
lated in its racemic form from the seeds of Alangium
lamarackii Thw. (Alangiaceae) in 1983 by Pakrashi
et al.1 Its structure as 2-hydroxy-3-methoxy-5,8,13,13a-
tetrahydro-6H-dibenzo[a,g]quinolizine 1 elucidated on
the basis of the spectral data analysis of the natural
product was confirmed by an unequivocal synthesis.1
Bharatamine 1 is a protoberberine alkaloid, which does
not have the two oxygenated substituents at ring D,
always present in this class of alkaloids. It has been
postulated that compound 1 is biogenetically derived
from loganin, a monoterpenoid precursor, on a plausi-
ble biogenetic route involving deacetylipecoside or its
equivalent.1 According to Shamma et al.,2 bharatamine
1 has also been classified as an emetine type alkaloid
because its lower half (C and D rings) is very probably
of a terpenoidal origin. The O-methylated derivative
of compound 1, O-methylbharatamine 2, served for
many years as the model compound in designing new
methods of synthesis of the protoberberine skeleton
(Fig. 1).3–12
B
N
C
8
13a
13
9
D
12
10
11
Bharatamine 1
Figure 1.
a protoberberine skeleton, a growing interest in the lat-
eral metallation methodology18 has been observed over
the last decade. In 1998, the regioselective addition–
cyclization reaction of achiral o-tolyl oxazoline with
3,4-dihydroisoquinoline was applied by Singh16 for the
synthesis of racemic bharatamine 1. Warrener et al.,19
performed the asymmetric synthesis of 2,3-dimethoxy-
8-oxoberbine 3 by incorporation of chiral amines into
o-toluamides. Recently, an efficient enantioselective syn-
thesis of lactam 3 based upon the (ꢀ)-sparteine-medi-
ated addition of nonchiral o-toluamides to 3,4-
dihydroisoquinoline has been reported by Liu.20
Until now, only racemic bharatamine 1 has been synthe-
sized13–17 with no synthesis of this protoberberine alka-
loid in its optically active form being published. Among
the different methods developed for the construction of
To continue our study on stereoselective syntheses of
isoquinoline alkaloids,21–25 including protoberberine
system,26 based on the addition of carbon nucleophiles
to imines, we have performed the first asymmetric syn-
thesis of (R)-(+)- and (S)-(ꢀ)-O-methylbharatamine 2.
Our concept of the asymmetric synthesis is based on
*
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.2004.06.038

2562
M. Chrzanowska, A. Dreas / Tetrahedron: Asymmetry 15 (2004) 2561–2567
CH3O
CH3O
CH3O
CH3O
CH3O
N
CH3O
∗
N
∗
N
O
4
+
O
R*
2
3
N
R1
5
Scheme 1.
the lateral metallation methodology involving the addi-
tion of a carbon nucleophile derived from optically ac-
tive o-toluamide 5 to 3,4-dihydroisoquinoline 4. A new
stereogenic center created at C-13a leads to the optically
active 2,3-dimethoxy-8-oxoberbine 3,27 which is further
transformed to O-methylbharatamine 2 by LiAlH4
reduction. The retrosynthetic analysis of this synthesis
is illustrated in Scheme 1.
including the enantioselective synthesis of isoquinoline
alkaloids21–25 and diastereoselective synthesis of proto-
berberine alkaloid,26 as well. Our initial synthesis started
with optically active amide 5a, prepared from thiomic-
amine 6 and o-toluoyl chloride 8 as according to litera-
ture procedure.26
The reaction of lithiated o-toluamide 5a with 6,7-dimeth-
oxy-3,4-dihydroisoquinoline 428 activated with boron tri-
fluoride etherate29 and subsequent work-up provided an
addition product 9 as a diastereomeric mixture (23% de
by 1H NMR) in 60% yield. In the cyclization step, crude
product9washeated inrefluxingtoluene togive thelaevo-
rotatory enantiomer (S)-(ꢀ)-3 in 77% yield with 13% ee
(by HPLC) along with recovered thiomicamine 6
(Scheme 2). The spectral data of lactam 3 corresponded
to those reported for racemic ( )-3 in literature.30 Due
to the low enantiomeric purity, this compound was used
as our reference sample of ꢀracemicꢁ amide 3 for the deter-
mination of the enantiomeric excess by HPLC.
2. Results and discussion
In our synthesis we have placed the chiral auxiliary in
the amine part of the carbon nucleophile. For this pur-
pose chiral amines, commercially available, enantiomer-
ically pure, (+)-thiomicamine 6 and (R)- and (S)-
phenylalaninol 7, ent-7 have been chosen. Thiomicamine
6, an industrial waste product, has been used success-
fully by our research group, as a source or promoter
of stereochemistry in many types of organic synthesis,
4
+
CH3O
CH3O
CH3O
O
PhCH3
N
O
n-BuLi
NH
O
O
CH3O
O
O
H
N
H
∆
THF
O
N
H
(S)-(-)-3
9
SCH3
77%, 13% ee
SCH3
60%, 23% de
5a
1. Column chromatography
∆
2. PhCH3,
OH
OH
CH3O
CH3O
H
N
H
N
H
O
SCH3
(R)-(+)-3
82%, 61% ee
Thiomicamine 6
Scheme 2.

M. Chrzanowska, A. Dreas / Tetrahedron: Asymmetry 15 (2004) 2561–2567
2563
In another experiment, crude product 9 was chromato-
graphed on a silica gel column to give the diastereomer-
ically enriched fractions of the more polar diastereomer,
78% de (HPLC), which was cyclized to afford the dex-
oxoberbine 3 with ee >99% was obtained, showing mp
169–171ꢁC, and [a]D = +420.1 (c 0.359, chloroform),
{lit.19 [a]D = +366.6 (c 0.359, chloroform), 96% ee}.
Amine 11 was readily converted to lactam (R)-3 (99%
ee) under basic conditions (n-BuLi) providing an addi-
tional 9% of (R)-3 (Scheme 4).
trorotatory 2,3-dimethoxy-8-oxoberbine
3
{[a]D =
+172.2 (c 0.6, chloroform)} in 82% yield. The enantio-
meric excess of this compound, established by HPLC,
was 61%. The absolute configuration of the product
was postulated as (R) on the basis of the sign of the spe-
cific rotation, which corresponded to that reported for
this compound by Ninomiya31 and Warrener et al.19
The synthesized dextrorotatory (R)-enantiomer was
characterized on HPLC as that showing the shorter
retention time in comparison with our reference ꢀrace-
micꢁ sample of 3 with 13% ee.
The same synthesis carried out with oxazolidine ent-5b
incorporating (S)-phenylalaninol ent-7, and imine 4 led
to (S)-8-oxoberbine 3 in 60% yield with 82% ee (HPLC)
along with the addition product, amine ent-11 (98% de).
Recrystallization of (S)-3 from diethyl ether/methanol
led to pure 2,3-dimethoxy-8-oxoberbine 3 with ee >99%,
mp 169–172ꢁC, and [a]D = ꢀ413.8 (c 0.359, chloroform),
{lit.19 [a]D = ꢀ372.4 (c 0.359, chloroform), 97% ee}. The
cyclization reaction of ent-11 provided an additional
11% of 8-oxoberbine (S)-3 with 99% ee (Scheme 4).
To improve the diastereoselectivity of the addition step,
we decided to prepare an amide without hydrogen at the
nitrogen atom, which is supposed to be responsible for
lowering the selectivity in such additions.19 Therefore,
we replaced (+)-thiomicamine 6 with both enantiomers
of phenylalaninol, 7 and ent-7 realizing a possibility of
protection of NH and OH groups in the form of an
oxazolidine ring. Thus, the reaction of (R)-phenylalani-
nol 7 with o-toluoyl chloride 8 gave amide 10 in 89%
yield. The functional NH and OH groups in compound
10 were converted into oxazolidine derivative 5b. This
was prepared in 68% yield, in the reaction of amide 10
with 2,2-dimethoxypropane catalyzed by p-toluenesulf-
onic acid, in refluxing benzene under an argon atmo-
sphere and followed by column chromatography
purification (Scheme 3).
Lithium aluminum hydride reduction of (R)-and (S)-2,3-
dimethoxy-8-oxoberbine 3 led to (R)-and (S)-O-meth-
ylbharatamine 2. The reaction was carried out in THF
at reflux and no loss of enantioselectivity was observed
(Scheme 5).
CH3O
CH3O
CH3O
CH3O
N
O
N
LiAlH4
THF
H
H
(S)-(-)-3
(S)-(-)-2
99% ee
89%, 99% ee
O
Ph
O
Scheme 5.
Cl
KOH
(0.5 M)
N
8
H
OH
The reduction reaction of dextrorotatory lactam (R)-3
(99% ee) led to dextrorotatory (R)-O-methylbharat-
amine 2 in 90% yield with >99% ee by HPLC, and
[a]D = +282.3 (c 0.32, chloroform). The free base (R)-
(+)-2 was converted to its hydrochloride salt with hydro-
chloric acid in methanol to give crystalline (R)-2ÆHCl,
mp 223–225ꢁC (dec).
CH2Cl2
+
10
89%
Ph
(CH3)2C(OCH3)2
Benzene
H2N
p-CH3C6H4SO3H
OH
Phenylalaninol 7
Ph
Laevorotatory lactam (S)-3 (99% ee) was transformed to
laevorotatory (S)-O-methylbharatamine 2 in 89% yield
with >99% ee (HPLC), showing [a]D = ꢀ285.5 (c 0.51,
chloroform). The free base (S)-(ꢀ)-3 was converted to
its hydrochloride salt (S)-2ÆHCl, mp 206–207ꢁC (dec).
The spectral data of our synthetic product 2 corre-
sponded to those reported for racemic amine ( )-2 in
the literature.6,7,12
O
N
O
5b
68%
Scheme 3.
The carbanion was generated from oxazolidine 5b with
the aid of 1.1equiv of n-butyllithium at ꢀ72ꢁC. After
the addition of 6,7-dimethoxy-3,4-dihydroisoquinoline
4 and subsequent work-up, the cyclization product, dex-
trorotatory (R)-8-oxoberbine 3 was isolated in 67% yield
with 92% ee (HPLC) along with the addition product,
amine 11 (98% de). After recrystallization of (R)-3 from
diethyl ether/methanol, a sample of 2,3-dimethoxy-8-
3. Conclusion
Herein, we have reported the first asymmetric synthesis
2
of (R)-(+)- and (S)-(ꢀ)-O-methylbharatamine
obtained as enantiomerically pure compounds. The high
enantioselectivity has been achieved in the addition reac-
tion of o-toluamide 5b and ent-5b, incorporating (R)-
and (S)-phenylalaninol, 7 and ent-7 as a chiral auxiliary,

2564
M. Chrzanowska, A. Dreas / Tetrahedron: Asymmetry 15 (2004) 2561–2567
CH3O
CH3O
CH3O
CH3O
Ph
n-BuLi
NH
N
O
4
5b
+
O
H
H
+
N
THF
O
(R)-(+)-3
11
11%, 98% de
67%, 92% ee
n-BuLi, THF, -72oC - rt
CH3O
CH3O
Ph
N
O
NH
n-BuLi
4
+ ent-5b
CH3O
H
CH3O
O
+
H
N
THF
O
ent-11
12%, 98% de
(S)-(-)-3
60%, 82% ee
n-BuLi, THF, -72oC - rt
Scheme 4.
respectively, to 3,4-dihydroisoquinoline 4. This process
was accompanied by simultaneous cyclization directly
affording optically active lactams (R)-3 and (S)-3 in
67% and 60% yield, respectively. We would like to point
out the simplicity of this process and the high enantio-
selectivity achieved. We were also able to isolate the
addition product 11 (and ent-11, respectively), and con-
vert it into enantiomerically pure lactam (R)-(+)-3 [and
(S)-(ꢀ)-3, respectively], which increased by ca. 10% the
total yield of the product.
III. Merck Kieselgel 60 (70–230mesh) was used for col-
umn chromatography and Merck DC-Alufolien Kiesel-
gel 60254 for TLC. Analytical HPLC: Waters HPLC
system with Mallinkrodt–Baker Chiracel OD-H
column.
THF and diethyl ether were freshly distilled from
LiAlH4, benzene, and toluene––from sodium wire and
acetone––from KMnO4. Unless stated otherwise, all
reagent were purchased from commercial sources and
used without additional purification. 6,7-Dimethoxy-
3,4-dihydroisoquinoline 4 was prepared as previously
described.28
The key intermediates in the synthesis, lactams (R)-(+)-3
and (S)-(ꢀ)-3, were obtained with high yield and with
>99% ee. The enantiomeric excess was established by
HPLC using a Chiracel OD-H column. The values of
the specific rotation measured for both pure enantio-
mers with >99% ee reached [a]D = +420.1 (c 0.359, chlo-
roform) for (R)-(+)-3 and [a]D = ꢀ413.8 (c 0.359,
chloroform) for (S)-(ꢀ)-3. These differ from those re-
ported in literature:19 [a]D = +366.6 (c 0.359, chloro-
form), and [a]D = ꢀ372.4 (c 0.359, chloroform), which
were claimed to represent 96% ee for (R)-(+)-3 and
97% ee for (S)-(ꢀ)-3, respectively.
4.2. Addition product 9
Amide 5a26 (371mg, 1mmol) was dissolved in dry THF
(5mL) under an argon atmosphere and the mixture
cooled to ꢀ72ꢁC. n-BuLi (1.6M solution in hexanes,
1.4mL) was introduced and the carbanion generated
for 30min at ꢀ72ꢁC. A solution of 6,7-dimethoxy-3,4-
dihydroisoquinoline 428 (191mg, 1mmol), activated
with borontrifluoride etherate29 (156mg, 1.1mmol) in
dry THF (5mL) was added and the mixture kept at
ꢀ72ꢁC for 4h and treated at this temperature with
20% aqueous NH4Cl (6mL). When the reaction mixture
reached room temperature, the phases were separated
and the aqueous one extracted with diethyl ether
(3·10mL). The combined organic extracts were dried
and the solvents removed under reduced pressure to give
a yellow foam of compound 9 (546mg) with 23% de by
1H NMR. The crude product 9 was purified by column
chromatography (dichloromethane/methanol, 100:1!
50:1) yielding diastereomerically enriched fractions
(337mg, 60% yield). IR (KBr) m: 3441, 3299 (NH amine,
4. Experimental
4.1. General
Melting points were determined on a Koffler block and
are uncorrected. IR spectra: Bruker FT-IR IFS 113V.
NMR spectra: Varian Gemini 300 in CDCl3, with
TMS as the internal standard. Mass spectra (EI): instru-
ment AM D402. Optical rotations: Perkin–Elmer pola-
rimeter 242B at 20ꢁC. Elemental analyses: Vario EL

M. Chrzanowska, A. Dreas / Tetrahedron: Asymmetry 15 (2004) 2561–2567
2565
1
amide), 1653 (C@O) cmꢀ1; H NMR (more polar dia-
4.4. Synthesis of 2-o-toluamide-3-phenylpropanol
stereoisomer 9, 67% de) d: 1.47, 1.54, 1.60 (3s, 6H,
C(CH3)2), 1.75 (br s, 1H, NH, disappeared with D2O),
2.32, 2.36 (2s, 3H, SCH3), 2.55–2.95 (m, 5H, CH2),
3.17, 3.28 (2dd, J = 3.85, 13.7Hz, 1H, CH2), 3.70, 4.16
(2dd, J = 3.85, 8.5Hz, 1H, ArCH(NH)), 3.87, 3.88,
3.89, 3.90 (4s, 6H, OCH3), 4.00 (dd, J = 1.92, 12.0Hz,
1H, CH2O), 4.32 (dd, J = 1.92, 12.0Hz, 1H, CH2O),
4.52 (dd, J = 2.2, 9.1Hz, 1H, CH(NHCO)), 5.26 (d,
J = 2.2Hz, 1H, ArCHO), 6.55, 6.60, 6.69, 6.73 (4s, 2H,
ArH isoquinoline ring), 6.95, 7.06 (2d, J = 8.5Hz, 1H,
ArH), 7.03–7.11 (m, 1H, ArH), 7.18–7.32 (m, 5H,
ArH), 7.89, 8.25 (2d, J = 8.8Hz, 1H, CONH, disap-
peared with D2O); MS m/z (%): 562 (M+, 3), 560
(M+ꢀ2, 5), 308 (25), 307 (11), 306 (15), 305 (16), 292
(11), 264 (4), 193 (13), 192 (100), 176 (8), 152 (12), 118
(11), 90 (9); HRMS calcd for C32H36N2O5S2
560.23242. Found 560.23450.
4.4.1. (2R)-2-o-Toluamide-3-phenylpropanol 10. To
(R)-(ꢀ)-2-amino-3-phenylpropanol 7 (0.755g, 5mmol)
dissolved in dichloromethane (60mL) aqueous 0.5M
KOH solution (32.5mL) was added and then o-toluoyl
chloride 8 (0.77g, 5mmol) introduced dropwise with
stirring at 0ꢁC. After 30min, the cooling bath was re-
moved and the stirring continued at room temperature
for 1h. The phases were separated and the aqueous
one extracted with dichloromethane (3 · 20mL). The
combined organic phases were dried and the solvent re-
moved under reduced pressure yielding a white precipi-
tate of amide 10 (1.369g, 89% yield); mp 125–127.5ꢁC
(EtOH); [a]D = +36.4 (c 1.055, chloroform); IR (KBr)
m: 3368, 3286 (OH, NH), 1640 (C@O) 1540 (NH)
1
cmꢀ1; H NMR d: 2.31 (s, 3H, ArCH3), 2.88–3.03 (m,
3H, ArCH2, OH, 1H disappeared with D2O), 3.64–
3.81 (m, 2H, CH2OH), 4.33–4.43 (m, 1H, CH(NH)),
6.05 (d, J = 7.4Hz, 1H, NH, disappeared with D2O),
7.10–7.37 (m, 9H, ArH); 13C NMR d: 19.7 (CH3Ar),
37.0 (C-3), 53.1 (C-2), 64.4 (C-1), 125.6 (CH), 126.5
(CH), 126.6 (CH), 128.6 (2C, CH), 129.1 (2C, CH),
129.8 (CH), 130.8 (CH), 135.9 (C), 136.0 (C), 137.4
(C), 170.5 (C@O); MS m/z (%): 269 (M+, 4), 238 (4),
178 (49), 119 (100), 91 (44); Anal. Calcd for
C17H19NO2 · 1/8 H2O: C, 75.18; H, 7.14; N, 5.16.
Found; C, 75.32; H, 7.03; N 4.98.
4.3. Cyclization of addition product 9 to 5,6,13,13a-
tetrahydro-2,3-dimethoxy-8H-dibenzo[a,g]quinolizin-8-
one (2,3-dimethoxy-8-oxoberbine) 3
4.3.1. Cyclization of crude reaction product 9. Crude
product 9 (453mg, 0.7mmol) was refluxed in dry toluene
(15mL) for 20h. After cooling to room temperature, it
was evaporated to dryness and the remaining oil purified
by repeated column chromatography (dichloromethane)
to yield pure 2,3-dimethoxy-8-oxoberbine 3 (193mg,
77% yield) with 13% ee of the enantiomer with longer
retention time by HPLC [hexane/propan-2-ol = 4:1,
0.5mL/min; tR 27.4, 32.0min (major)]; mp 137–139ꢁC
(diethyl ether), (lit.4 mp 142ꢁC,10 140–141ꢁC,12 144–
4.4.2.
(2S)-2-o-Toluamide-3-phenylpropanol
ent-10.
The reaction was run in the same way as described in
Section 4.4.1 using (S)-(ꢀ)-2-amino-3-phenylpropanol
ent-7 (2.265g, 15mmol), dichloromethane (200mL),
aqueous 0.5M KOH solution (97.5mL) and o-toluoyl
chloride 8 (2.35g, 15mmol), yielding a white precipitate
of amide ent-10 (4.005g, 99% yield); mp 124–127ꢁC;
[a]D = ꢀ36.0 (c 1.13, chloroform).
1
145ꢁC,30 136ꢁC); IR (KBr) m: 1653 (C@O) cmꢀ1; H
NMR d: 2.75–2.83 (m, 1H, H-5), 2.94–3.03 (m, 3H,
H-5, H-6, H-13), 3.23 (dd, J = 3.6, 15.7Hz, 1H, H-13),
3.90 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.88 (dd,
J = 3.6, 13.2Hz, 1H, H-13a), 5.00–5.30 (m, 1H, H-6),),
6.71 (s, 1H, H-4), 6.73 (s, 1H, H-1), 7.26–7.29 (m,
1H, ArH), 7.38–7.50 (m, 2H, ArH), 8.15 (d, J =
7.7Hz, 1H, H-9); MS m/z (%): 309 (M+, 100), 308
(81), 294 (40), 278 (32), 190 (19), 176 (11), 118 (54), 90
(59).
4.5. Synthesis of 2,2-dimethyl-3-o-toluoyl-4-
benzyloxazolidine
4.5.1. (4R)-2,2-Dimethyl-3-o-toluoyl-4-benzyloxazolidine
5b. To compound 10 (1.369g, 5.09mmol) in dry benz-
ene (40mL), 2,2-dimethoxypropane (8.50g, 81.7mmol)
was added under an argon atmosphere followed by cat-
alytic amounts of p-toluenesulfonic acid (0.25g). The
reaction mixture was stirred at reflux for 3.5h and
allowed to reach room temperature. Then the reaction
mixture was washed with 1% aqueous NaOH solution
(3 · 2mL), dried and the solvent evaporated. The crude
reaction product was chromatographed (dichlorometh-
ane and dichloromethane/methanol 200:1) to give the
pure oxazolidine 5b (1.074g, 68% yield) as an oil;
[a]D = +32.6 (c 1.115, chloroform); IR (film) m: 1642
4.3.2. Cyclization of diastereomerically enriched 9. (R)-
(+)-5,6,13,13a-Tetrahydro-2,3-dimethoxy-8H-dibenzo-[a,
g]quinolizin-8-one (2,3-dimethoxy-8-oxoberbine) 3. The
diastereomerically enriched 9 consisting mainly of the
more polar diastereomer of 9 (TLC) diastereomeric ratio
8:1 (by HPLC), (201mg, 0.36mmol) was refluxed in dry
toluene (10mL) for 20h. After cooling to room tempera-
ture, it was evaporated to dryness and the remaining oil
(198mg) dissolved in diethyl ether (30mL) and extracted
with 5% aqueous HCl (4 · 2mL). The organic phase was
dried and evaporated yielding pure 2,3-dimethoxy-8-
oxoberbine 3 (90mg, 82% yield) with 61% ee of the
enantiomer with shorter retention time by HPLC [hex-
ane/propan-2-ol=4:1, 0.5mL/min; tR 27.4min (major),
tR 32.0min]; [a]D = +172.2 (c 0.6, chloroform). The
acidic aqueous phase was alkalized with KOH pellets,
reextracted with diethyl ether (3 · 10mL), dried and
evaporated to give an oil (66mg), which consisted of thio-
micamine 6, according to TLC and HPLC analysis.
1
(C@O) cmꢀ1; H NMR d: 1.72 (s, 3H, C(CH3)2), 1.87
(s, 3H, C(CH3)2), 2.36 (s, 3H, ArCH3), 2.58–2.74 (m,
2H, ArCH2), 3.62 (br s, 1H, CH(CH2O)), 3.76–3.84 (m,
2H, CH2O), 6.48–6.53 (m, 2H, ArH), 7.11–7.18 (m,
3H, ArH), 7.26–7.42 (m, 4H, ArH); 13C NMR d: 18.9
(CH3Ar), 23.1 (CH3C-2), 27.0 (CH3C-2), 40.2 (CH2Ph),
61.0 (C-4), 66.2 (C-5), 95.4 (C-2), 125.6 (CH), 125.9
(CH), 126.5 (CH), 128.5 (2C, CH), 128.8 (2C, CH),
128.9 (CH), 130.5 (CH), 137.4 (2C, C), 137.7 (C), 167.7

2566
M. Chrzanowska, A. Dreas / Tetrahedron: Asymmetry 15 (2004) 2561–2567
(C@O); MS m/z (%): 309 (M+, 0.9), 218 (38), 119 (100),
91 (33); Anal. Calcd for C20H23NO2 · 1/4H2O: C,
76.52; H, 7.55; N, 4.46. Found C, 76.74; H, 7.77; N, 4.43.
run in the same way as described in Section 4.6.1. using
oxazolidine ent-5b (331mg, 1.07mmol), dry THF
(17mL), n-BuLi (0.74mL), and 6,7-dimethoxy-3,4-di-
hydroisoquinoline 4 (200mg, 1.05mmol). Extractive
4.5.2. (4S)-2,2-Dimethyl-3-o-toluoyl-4-benzyloxazolidine
ent-5b. The reaction was run in the same way as de-
scribed in Section 4.5.1 using amide ent-10 (2.138g,
7.9mmol), dry benzene (60mL), 2,2-dimethoxypropane
(13.43g, 129mmol) and p-toluenesulfonic acid
(0.295g). The crude reaction product was chromato-
graphed (dichloromethane and dichloromethane/metha-
nol 200:1) to give the pure oxazolidine ent-5b (1.731g,
71% yield) as an oil; [a]D = ꢀ31.8 (c 0.99, chloroform).
work-up yielded (ꢀ)-2,3-dimethoxy-8-oxoberbine
3
(195mg, 60% yield) with 82% ee by HPLC [hexane/pro-
pan-2-ol = 4:1, 0.5mL/min; tR 27.4, 32.0min (major)].
After recrystallization from diethyl ether/methanol, a
sample with >99% ee was obtained, mp 169–172ꢁC,
[a]D = ꢀ413.8 (c 0.359, chloroform); {lit.19 [a]D =
ꢀ372.4 (c 0.359, chloroform), 97% ee}.
Additionally amine ent-11, with high diastereomeric
purity (98% de) by HPLC [hexane/propan-2-ol = 4:1,
0.5mL/min; tR 52.6min (major), tR 95.0min] was ob-
tained, which was further purified by column
chromatography.
4.6. Addition reaction of oxazolidine 5b (ent-5b) to
imine 4
4.6.1. (R)-(+)-5,6,13,13a-Tetrahydro-2,3-dimethoxy-8H-
(2,3-dimethoxy-8-oxober-
dibenzo[a,g]quinolizin-8-one
4.6.3. Cyclization of amine 11 to (R)-(+)-2,3-dimethoxy-
8-oxoberbine 3. To a solution of pure amine 11 (56mg,
0.11mmol) in dry THF (10mL), n-BuLi (1.6M solution
in hexanes, 0.08mL) was added at ꢀ72ꢁC under an
argon atmosphere. The reaction mixture was allowed
to warm-up to ambient temperature and quenched by
the addition of an aqueous solution of 5% HCl (2mL).
Extractive work-up yielded (+)-2,3-dimethoxy-8-oxo-
berbine 3 (17mg, 50% yield) with 99% ee by HPLC. This
provided an additional 9% yield of lactam 3.
bine) 3 and addition product 11. Oxazolidine 5b
(309mg, 1mmol) was dissolved in dry THF (6mL)
under an argon atmosphere and the solution cooled to
ꢀ72ꢁC. n-BuLi (1.6M solution in hexanes, 0.7mL)
was added and the carbanion generated for 30min at
ꢀ72ꢁC. A solution of 6,7-dimethoxy-3,4-dihydroiso-
quinoline 4 (191mg, 1mmol) in dry THF (7mL) was
introduced dropwise and the mixture kept at ꢀ72ꢁC
for 3h, then treated at this temperature with 5% aqueous
HCl solution (3mL). When the reaction mixture reached
room temperature, the phases were separated and the
organic one extracted with 5% aqueous HCl
(3 · 2mL). The organic phase was dried and evaporated,
yielding 2,3-dimethoxy-8-oxoberbine 3, (208mg, 67%
yield) with 92% ee by HPLC [hexane/propan-
2-ol = 4:1, 0.5mL/min; tR 27.4min (major), tR 32.0
min]. After recrystallization from diethyl ether/metha-
nol, a sample of 2,3-dimethoxy-8-oxoberbine 3 with
ee >99% was obtained, showing mp 169–171ꢁC, [a]D =
+428.1 (c 0.359, chloroform); {lit.19 [a]D = +366.6 (c
0.359, chloroform), 96% ee}.
4.6.4. Cyclization of amine ent-11 to (S)-(–)-2,3-dimeth-
oxy-8-oxoberbine 3. The reaction was run in the same
way as described in Section 4.6.3 using amine ent-11
(109mg, 0.2mmol), dry THF (20mL) and n-BuLi
(1.6M solution in hexanes, 0.3mL). Extractive
work-up yielded (S)-(ꢀ)-2,3-dimethoxy-8-oxoberbine 3,
(35mg, 57% yield) with >99% ee by HPLC. This pro-
vided an additional 11% yield of lactam 3.
4.7. Reduction reaction of 8-oxoberbine 3 to 2,2-dimeth-
oxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]guinolizine
(O-methylbharatamine) 2
The acidic aqueous phase was alkalized with KOH pel-
lets, re-extracted with diethyl ether (3 · 10mL), dried
and evaporated to give an oil, consisting of addition
product 11 with high diastereomeric purity (98% de)
by HPLC [hexane/propan-2-ol = 4:1, 0.5mL/min; tR
37.0, 62.9min (major)]. Amine 11 was purified by col-
umn chromatography (dichloromethane/methanol,
50:1!20:1) yielding pure amine 11 (56mg, 11% yield).
4.7.1. (R)-(+)-O-Methylbharatamine 2. To a solution
of (R)-(+)-3 (70mg, 0.23mmol, >99% ee by HPLC) in
dry THF (15mL), LiAlH4 (70mg) was added portion-
wise with stirring. The mixture was refluxed for 30min
and left to reach ambient temperature. The excess of
the reducing agent was decomposed with water
(0.7mL) and 20% aqueous NaOH solution (0.2mL).
The ether was decanted and the solid material extracted
with diethyl ether (3 · 10mL). The combined ether
extracts were dried and evaporated to give a yellow
oil, which was purified by column chromatography
(dichloromethane). Pure (R)-(+)-O-methylbharatamine
2 (60mg, 90% yield) was obtained with >99% ee by
HPLC [hexane/propan-2-ol = 4:1, 0.5mL/min; tR
35.4min]; [a]D = +282.3 (c 0.32, chloroform). The free
base 2 was converted to its hydrochloride salt with
hydrochloric acid in methanol, mp 223–225ꢁC (dec).
1
IR (film) m: 3416 (NH), 1631 (C@O) cmꢀ1; H NMR
d: 1.73 (s, 3H, C(CH3)2), 1.93 (s, 3H, C(CH3)2), 2.45–
2.83 (m, 5H, CH2, NH, 1H disappeared with D2O),
2.91–2.96 (m, 2H, CH2), 3.03–3.27 (m, 2H, CH2),
3,74–3.95 (m, 3H, CH, CH2) 3.81 (s, 3H, OCH3), 3.85
(s, 3H, OCH3), 4.37 ( br s, 1H, CH), 6.48–6.51 (m,
2H, ArH), 6.57 (s, 1H, ArH), 6.59–6.71 (m, 1H, ArH),
7.08–7.16 (m, 3H, ArH), 7.27–7.48 (m, 4H, ArH); MS
m/z (%): 500 (M+, 0.6), 310 (2), 206 (10), 193 (14), 192
(100), 148 (2), 118 (2).
4.6.2. S)-(–)-5,6,13,13a-Tetrahydro-2,3-dimethoxy-8H-
dibenzo[a,g]quinolizin-8-one (2,3-dimethoxy-8-oxober-
bine) 3 and addition product ent-11. The reaction was
4.7.2. (S)-(–)-O-Methylbharatamine 2. The reaction
was run in the same way as described in Section 4.7.1
using (S)-(ꢀ)-3 (60mg, 0.19mmol, >99% ee by HPLC),

M. Chrzanowska, A. Dreas / Tetrahedron: Asymmetry 15 (2004) 2561–2567
2567
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dry THF (20mL) and LiAlH4 (60mg). After work-up
and column chromatography, pure (S)-(ꢀ)-O-methyl-
bharatamine 2 (51mg, 89% yield) was obtained with
>99% ee by HPLC [hexane/propan-2-ol = 4:1, 0.5mL/
min; tR 18.5min]; [a]D = ꢀ285.5 (c 0.51, chloroform).
1
IR (KBr) m: 2751, 1644, 1610, 1512cmꢀ1; H NMR d:
2.60–2.70 (m, 2H, H-5, H-6), 2.91 (dd, J = 11.2,
16.1Hz, 1H, H-13), 3.10–3.20 (m, 2H, H-5, H-6), 3.33
(dd, J = 3.8, 16.1Hz, 1H, H-13), 3.63 (dd, J = 3.8,
11.2Hz, 1H, H-13a), 3.75 (d, J = 14.9Hz, 1H, H-8),
3.88 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.01 (d,
J = 14.9Hz, 1H, H-8), 6.63 (s, 1H, ArH isoquinoline
ring), 6.76 (s, 1H, ArH, isoquinoline ring), 7.08–7.12
(m, 1H, ArH), 7.14–7.17 (m, 3H, ArH); 13C NMR and
DEPT and 1H–13C NMR COSY d: 29.1 (C-5), 36.9
(C-13), 51.4 (C-6), 55.8 (OCH3), 56.1 (OCH3), 58.6 (C-
8), 59.6 (C-13a), 108.4, 111.2 (C-1, C-4), 125.7 (C-9),
126.0 (C-10), 126.1 (C-11), 126.6, 129.6 (C-4a, C-13b),
128.6 (C-12), 134.2, 134.3 (C-8a, C-12a), 147.2, 147.3
(C-2, C-3); MS m/z (%): 295 (M+, 77), 294 (100), 280
(13), 191 (11), 190 (26), 176 (10),105 (15), 104 (16).
17. Hu, Y.; Zhou, Q.; Bai, D. Zhongguo Yaowu Huaxue Zazhi
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Free base 2 was converted to its hydrochloride salt with
hydrochloric acid in methanol, mp 206–207ꢁC (dec).
22. Rozwadowska, M. D. Tetrahedron: Asymmetry 1993, 4,
1619–1624.
Acknowledgements
´
´
23. Brozda, D.; Chrzanowska, M.; Głuszynska, A.;
Rozwadowska, M. D. Tetrahedron: Asymmetry 1999, 10,
4791–4796.
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).
´
24. Głuszynska, A.; Rozwadowska, M. D. Tetrahedron:
Asymmetry 2000, 11, 2359–2366.
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