Synthesis of (S)-(-)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz-Fritsch-Bobbitt methodology

Article abstract of DOI:10.1016/j.tetasy.2005.07.025

Laterally lithiated (S)-(-)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz-Fritsch-Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (-)-7 along with acyclic products, (-)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (-)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(-)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.

Full text of DOI:10.1016/j.tetasy.2005.07.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2954–2958
Synthesis of (S)-(À)- and (R)-(+)-O-methylbharatamine using
a diastereoselective Pomeranz–Fritsch–Bobbitt methodology
Maria Chrzanowska,* Agnieszka Dreas and Maria D. Rozwadowska
Faculty of Chemistry, A. Mickiewicz University, ul. Grunwaldzka 6, 60-780 Poznan´, Poland
Received 12 July 2005;accepted 21 July 2005
Available online 16 August 2005
Abstract—Laterally lithiated (S)-(À)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol,
respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bob-
bitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and
(À)-7 along with acyclic products, (À)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (À)-7, followed by cyclization, affor-
ded both enantiomers of the alkaloid, (S)-(À)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and
73% ees, respectively.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tion of carbon nucleophiles to benzalamines, prochiral
29,10 or chiral 311,12 (Fig. 1).
The crucial step in the classic Pomeranz–Fritsch–Bob-
bitt synthesis of isoquinoline alkaloids,1 the construc-
tion of the tetrahydroisoquinoline ring system,
involves acid catalyzed cyclization/hydrogenolysis of
N-benzylaminoacetaldehyde acetal of type 1.2,3 In the
stereoselective modification,4 chiral non-racemic 1-
substituted N-benzylaminoacetaldehyde acetals 1 have
been used as key intermediates, and further transformed
into isoquinoline alkaloids of different types. In most
cases intermediates 1 were prepared by substitution of
benzylic oxygen into the corresponding chiral alcohols5
or epoxides6–8 with nitrogen nucleophiles5–8 or by addi-
Several reports concerning the synthesis of chiral non-
racemic benzylamines of type 1, performed by the addi-
tion of organometallic reagents to imines, 2 or 3, real-
ized in both enantio- and diastereoselective manner,
have been published.9–12
Enantioselective addition of organolithium reagents to
prochiral ÔPomeranz–Fritsch imineÕ 2 was conducted in
the presence of chiral oxazolines 4 (R = H, SCH3 and
R1, R2 = alkyl, aryl),9,10 used as external controllers of
stereochemistry as well as catalysts (Fig. 1). Addition
R2O OR2
RO
RO
H3CO
H3CO
OCH3
NH
*
N
OCH3
R1
R1
2
1
O
N
RO
RO
OH
OR2
N
R
R1
4
3
Figure 1.
*
Corresponding author. Fax: +48 61 8658008;e-mail: marylch@amu.edu.pl
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.025

M. Chrzanowska et al. / Tetrahedron: Asymmetry 16 (2005) 2954–2958
2955
H3CO
OCH3
OCH3
H3CO OCH3
H3CO
H3CO
H3CO
H3CO
N
H3CO
N
N
∗
O
∗
2
Ph
O
∗
5
7
N
O
6
Scheme 1.
product 1 (R = R1 = R2 = CH3) obtained with an ee up
to 76%,10 was then converted into alkaloids, (À)-salsol-
idine and (À)-carnegine.9
2, using the lateral metallation methodology.13–15 As a
result, a new stereogenic centre was created with high
diastereoselectivity. The retrosynthetic analysis is shown
in Scheme 1.
In diastereoselective synthesis,11,12 chiral imines 3 (R =
H, OH, OCH3;R + R = OCH 2O and R1 = C6H5,
i-C3H7), derived from aromatic aldehydes and chiral
b-aminoalcohols, were treated with Grignard reagents.
Using this method, isopavines, (À)-O-methylthalisopa-
vine and (À)-amurensinine,12 aporphine and (S)-(+)-
glaucine,11 were synthesized with high enantiomeric
purity.
2. Results and discussion
In continuation of our study on the stereoselective modi-
fication of the Pomeranz–Fritsch–Bobbitt synthesis of
isoquinoline alkaloids,9,10 and the application of chiral
o-toluamides 6 in the synthesis of isoquinoline alka-
loids,13 we became interested in extending this approach
to the addition of 6 to acyclic imine 2. At first, the reac-
tion of imine 2 with a carbanion, generated from (S)-
(À)-6 under the action of 1.1 equiv of n-butyllithium at
À72 ꢁC, was carried out. This resulted in the formation
of two compounds: the addition–partial cyclization
product, isoquinolone 7 and the acyclic addition prod-
uct 8 (Scheme 2). After chromatographic separation,
pure isoquinolone (+)-7 in 56% yield, [a]D = +36.3 (c
0.465, CHCl3), and (À)-8 in 20% yield with 97% dr
(HPLC), [a]D = À5.3 (c 0.33, CHCl3), were obtained.
Herein, we report the results of our work on another
version of the diastereoselective synthesis of the
Pomeranz–Fritsch–Bobbitt cyclization, in which two
enantiomers of protoberberine alkaloid, (S)-(À)- and
(R)-(+)-O-methylbharatamine 5 have been synthesized.
In this approach, a chiral auxiliary was introduced into
the carbon nucleophile. As such, both enantiomers of
(S)-(À)- and (R)-(+)-o-toluamide 6,13 derived from (S)-
and (R)-phenylalaninol, respectively, incorporating an
oxazolidine moiety, were prepared and added to imine
n-BuLi, THF, -72oC - rt
H3CO
H3CO
OCH3
OCH3
H3CO
H
OCH3
NH
H3CO
H
OCH3
N
H3CO
H3CO
H3CO
H3CO
Ph
2
N 2
O
3
n-BuLi
THF
O
1
N
4
Ph
O
8
7
O
5
(S)-(+)-7
LiAlH4
(S,S)-(-)-8
N
6
O
(S)-(-)-6
H3CO
H
OCH3
4
1
5
3
2
H3CO
H3CO
H3CO
H3CO
6
1) 5M HCl
2) NaBH4/TFA
2
N 7
3 N
13a
1
6
8
H
13
4
9
8
7
10
5
12
11
(S)-(-)-9
(S)-(-)-5
Scheme 2.

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M. Chrzanowska et al. / Tetrahedron: Asymmetry 16 (2005) 2954–2958
Compound (À)-8 was easily converted into isoquinolone
(+)-7 in 71% yield, upon treatment with 1 equiv of n-
butyllithium in THF at À72 ꢁC, providing an additional
14% of (+)-7.
the building blocks as well as inductors of chirality. The
key step of the synthesis, in which a new stereogenic cen-
tre was formed, involved the addition of the ÔPomeranz–
Fritsch imineÕ to benzylic carbanion, generated by the
lateral metallation methodology from enantiopure o-tolu-
amide. Reduction of the addition product, followed by a
Bobbitt cyclization furnished the synthesis. In this way
both enantiomers of O-methylbharatamine 5 were pre-
pared in satisfactory overall yield and with high enantio-
meric excess.
The (S)-configuration of the newly created stereocentre
in (S)-(+)-7 and (S)-(À)-8 was established in the final
stage of the synthesis, in which (S)-(À)-O-methylbharat-
amine 5 of known stereochemistry13 was formed. The
stereoselectivity of the addition step was determined
for (À)-8 by HPLC (97% dr), while for 7, analytical sep-
aration of the enantiomers using standard techniques
(chiral HPLC, NMR with various shift reagents) failed.
4. Experimental
4.1. General
To complete the synthesis, cyclization to the tetrahydro-
isoquinoline ring system and reduction of the lactam
carbonyl were needed. Unfortunately, isoquinolone 7
turned out to be very difficult to cyclize. When hydro-
genated in 5 M aqueous hydrochloric acid (the Bobbitt
et al. modification2) or reduced with NaBH4/CF3-
COOH11 in refluxing dioxane, it was transformed either
into a tetrahydroisoquinoline in very poor yield or into
a mixture of products. Reduction of the carbonyl group
in 7 prior to the cyclization was then undertaken. LAH
reduced the dextrorotatory isoquinolone (+)-7 to the
levorotatory tetrahydroisoquinoline (À)-9, in 84% yield,
[a]D = À43.6 (c 0.49, CHCl3). This cyclization occurred
after stirring in 5 M aqueous hydrochloric acid for 18 h
at room temperature, followed by reduction with
sodium borohydride in trifluoroacetic acid, without
isolation of the intermediate products. From the crude
reaction mixture, after purification by column chromato-
graphy, (S)-(À)-O-methylbharatamine 5 was isolated in
54% yield with 88% ee, as estimated by HPLC.
IR spectra: Bruker FT-IR IFS 113V. NMR spectra:
Varian Gemini 300 with TMS as the internal standard.
Mass spectra (EI): instrument AMD 402. Optical rota-
tions: Perkin–Elmer polarimeter 242B, at 20 ꢁC. Merck
Kieselgel 60 (70–230 mesh) and Merck aluminium oxide
90 active neutral (70–230 mesh) were used for column
chromatography;Merck DC-Alufolien Kieselgel 60
254
for TLC. Analytical HPLC: Waters HPLC system with
Mallinkrodt–Baker Chiralcel OD-H column.
THF and diethyl ether were freshly distilled from
LiAlH4. Imine 216 and o-toluamides 613 were prepared
as previously described.
4.2. General procedure for addition reaction of
o-toluamide 6to imine 2
o-Toluamide 6 (309 mg, 1 mmol) was dissolved in dry
THF (6 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 imine 2 (253 mg,
1 mmol) in dry THF (6 mL) was introduced dropwise
and the mixture allowed to warm-up to +10 ꢁC, then
treated at this temperature with 20% aqueous NH4Cl
(7 mL). When the temperatue of 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 the solvents removed under reduced pressure. The
resulting oil was dissolved in diethyl ether (20 mL) and
extracted with 5% aqueous HCl (3 · 2 mL). The organic
phase was dried and evaporated, yielding isoquinolone
7, purified by column chromatography (dichlorometh-
ane/methanol, 200:1).
Following the same reaction sequence, the synthesis of
the opposite enantiomer, (R)-(+)-O-methylbharatamine
5 was performed starting with imine 2 and (R)-(+)-o-
toluamide 6. The addition step also afforded two prod-
ucts: isoquinolone (À)-7, in 57% yield, [a]D = À39.2 (c
0.665, CHCl3) and the addition product, (+)-8, in 28%
yield, [a]D = +5.4 (c 0.22, CHCl3), which could easily
be cyclized to (À)-7 in 74% yield. Further transforma-
tion, involving LAH-reduction of (À)-7 to give (+)-9
{80% yield, [a]D = +49.1 (c 0.375, CHCl3)} and cycliza-
tion–hydrogenolysis, resulted in formation of the alka-
loid, (R)-(+)-5, in 65% yield, with 73% ee (HPLC).
The absolute configuration and enantiomeric excess of
the final products, (S)-(À)-5 and (R)-(+)-5, were estab-
lished by comparison with samples of enantiomerically
pure alkaloids, (S)-(À)- and (R)-(+)-O-methylbharat-
amine 5 synthesized in our laboratory, whose absolute
configuration was known.13
The acidic aqueous phase was rendered alkaline with
KOH pellets, re-extracted with diethyl ether (3 ·
10 mL), dried and evaporated to give addition product
8 as an oil, which was further purified by column chro-
matography (dichloromethane/methanol, 100:1).
3. Conclusion
In summary, we have developed a convenient, syntheti-
cally useful procedure for the preparation of protoberb-
erine alkaloids with reasonable enantiomeric purity,
using stereoselective Pomeranz–Fritsch–Bobbitt cycliza-
tion as the synthetic strategy and chiral o-toluamides as
4.2.1. (3S)-(+)-N-(2,2-Dimethoxyethyl)-3-(3,4-dimethoxy-
phenyl)-3,4-dihydro-1-(2H)-isoquinolone 7. Yield 56%,
solidifying oil, [a]D = +36.3 (c 0.465, CHCl3);IR
1
(KBr) m: 2937, 2834, 1649 (C@O), 1516, 1260 cmÀ1; H
NMR (CDCl3) d: 2.81 (dd, J = 7.7, 13.7 Hz, 1H,

M. Chrzanowska et al. / Tetrahedron: Asymmetry 16 (2005) 2954–2958
2957
NCH2), 2.98 (dd, J = 1.9, 15.6 Hz, 1H, H-4), 3.43 (s,
3H, CHOCH3), 3.48 (s, 3H, CHOCH3), 3.68 (dd,
J = 6.6, 15.6 Hz, 1H, H-4), 3.69 (s, 3H, ArOCH3), 3.79
(s, 3H, ArOCH3), 4.31 (dd, J = 3.3, 13.7 Hz, 1H,
NCH2), 4.67 (dd, J = 3.3, 7.7 Hz, 1H, CHOCH3), 4.99
(dd, J = 1.9, 6.6 Hz, 1H, H-3), 6.52 (d, J = 1.9 Hz, 1H,
ArH), 6.58 (dd, J = 1.9, 8.2 Hz, 1H, ArH), 6.68 (d,
J = 8.2 Hz, 1H, ArH), 7.02 (dd, J = 2.2, 6.5 Hz, 1H,
ArH), 7.31–7.39 (m, 2H, ArH), 8.11 (dd, J = 2.2,
to ambient temperature and quenched by the addition
of 20% aqueous NH4Cl (5 mL). The aqueous phase
was extracted with diethyl ether (3 · 10 mL) washed
with 5% aqueous HCl (4 · 2 mL) and the organic phase
was dried and evaporated, to yield isoquinolone 7.
4.3.1. Isoquinolone (S)-(+)-7. Yield 71%, solidifying
oil, [a]D = +35.4 (c 0.48, CHCl3).
1
6.0 Hz, 1H, H-8); 13C NMR and DEPT and H–13C
4.3.2. Isoquinolone (R)-(À)-7. Yield 74%, solidifying
oil, [a]D = À37.0 (c 0.54, CHCl3).
COSY (CDCl3) d: 35.8 (C-4), 48.5 (NCH2), 54.5
(CHOCH3), 55.6 (ArOCH3), 55.7 (ArOCH3), 56.1
(CHOCH3), 60.3 (C-3), 103.7 (CH(OCH3)2), 109.3
(CH), 110.8 (CH), 118.6 (CH), 127.1 (CH), 127.4 (C-
8), 127.7 (CH), 129.2 (C-4a), 132.0 (CH), 132.4 (C),
135.5 (C-8a), 148.3, 148.9 (C-3, C-4), 164.9 (C-1);MS
m/z (%): 371 (M+, 9), 340 (11), 284 (14), 283 (42), 267
(16), 151 (28), 133 (23), 75 (100);HRMS calcd for
C21H25NO5: 371.17328. Found: 371.17274.
4.4. General procedure for reduction of isoquinolone 7
To a solution of isoquinolone 7 (108 mg, 0.29 mmol), in
dry THF (15 mL), LiAlH4 (108 mg) was added portion-
wise with stirring. The mixture was heated under reflux
for 2 h and left to reach ambient temperature. The
excess of the reducing agent was decomposed with
water (2.5 mL) and 20% aqueous NaOH (0.8 mL) and
extracted with diethyl ether (15 mL). The organic solu-
tion was dried, the solvent evaporated to give an oil,
which after column chromatography on aluminium oxide
(dichloromethane), gave pure tetrahydroisoquinoline 9.
4.2.2. (3R)-(À)-N-(2,2-Dimethoxyethyl)-3-(3,4-dimeth-
oxyphenyl)-3,4-dihydro-1-(2H)-isoquinolone
7. Yield
57%;solidifying oil, [ a]D = À39.2 (c 0.665, CHCl3).
4.2.3. Addition product (S,S)-(À)-8. Yield 20%, solidi-
fying oil, 97% dr by HPLC [hexane/propan-2-ol = 4:1,
0.5 mL/min; tR 15.8 min, tR 17.4 min (major)];
[a]D = À5.3 (c 0.33, CHCl3);IR (KBr) m: 3014, 2936,
4.4.1. (S)-(À)-N-(2,2-Dimethoxyethyl)-3-(3,4-dimethoxy-
phenyl)-1,2,3,4-tetrahydroisoquinoline 9. Yield 84%,
solidifying oil, [a]D = À43.6 (c 0.49, CHCl3);IR (KBr)
1
2834, 1636, 1510, 1402, 1257, 750 cmÀ1
;
1H NMR
m: 2933, 2832, 1510, 1261 cmÀ1; H NMR (CDCl3) d:
(DMSO-d6 at 50 ꢁC) d: 1.65 (s, 3H, C(CH3)2), 1.73 (s,
3H, C(CH3)2), 1.86 (s, broad, 1H, NH), 2.34 (t,
J = 4.9, 2H), 2.56–2.59 (m, 1H), 2.73–2.91 (m, 2H),
3.07 (d, J = 4.5 Hz, 1H), 3.12 (s, 3H, CHOCH3), 3.13
(s, 3H, CHOCH3), 3.58–3.62 (m, 2H), 3.65 (s, 3H, Ar-
OCH3), 3.67 (s, 3H, ArOCH3), 3.69–3.79 (m, 1H),
3.80–3.94 (m, 1H), 4.23 (t, J = 5.3 Hz, 1H), 6.47–6.50
(m, 2H, ArH), 6.77–6.80 (m, 2H, ArH), 6.83–6.89 (m,
1H, ArH), 7.10–7.12 (m, 3H, ArH), 7.28–7.39 (m, 4H,
ArH); 13C NMR and DEPT and 1H–13C COSY (CDCl3)
d: 22.9 (C(CH3)2), 26.9 (C(CH3)2), 40.2 (CH2Ph), 43.0
(ArCH2CH(NH)Ar), 48.7 (NHCH2CH(OCH3)2), 53.4
(CHOCH3), 53.7 (CHOCH3), 55.7 (ArOCH3), 55.8 (Ar-
OCH3), 61.0 (NCHCH2O), 63.3 (ArCH2CH(NH)Ar),
66.1 (OCH2), 95.3 (C(CH3)2), 103.4 (CHO(CH3)2),
109.9 (CH) 110.8 (CH), 119.2 (CH), 126.2 (C), 126.5
(CH), 126.6 (2CH), 128.6 (3CH), 128.9 (3CH), 130.8
(C), 137.4 (C), 138.0 (C), 147.0 (C), 148.8 (C), 167.7
(C@O);MS m/z (%): 563 (M++1, 0.8), 400 (19), 255
(17), 254 (100), 222 (36), 91 (13), 75 (22);HRMS calcd
for C33H43N2O6: 563.31213. Found: 563.31148.
2.31 (dd, J = 5.4, 13.5 Hz, 1H, NCH2), 2.76 (dd,
J = 5.4, 13.5 Hz, 1H, NCH2), 2.97–3.01 (m, 1H, H-4),
3.09–3.19 (m, 1H, H-4), 3.23 (s, 3H, CHOCH3), 3.30
(s, 3H, CHOCH3), 3.67 (dd, J = 4.7, 9.6 Hz, 1H, H-3),
3.71–3.80 (m, 1H, H-1), 3.86 (s, 3H, ArOCH3), 3.88 (s,
3H, ArOCH3), 4.22 (d, J = 15.9 Hz, 1H, H-1), 4.50 (t,
J = 5.4 Hz, 1H, CHOCH3), 6.81 (d, J = 8.1 Hz, 1H,
ArH), 6.87 (d, J = 8.1 Hz, 1H, ArH), 6.98 (d,
J = 2.1 Hz, 1H, ArH), 7.07–7.10 (m, 2H, ArH), 7.12–
1
7.16 (m, 2H, ArH); 13C NMR and DEPT and H–13C
COSY (CDCl3) d: 36.9 (C-4), 52.9 (CHOCH3), 53.8
(CHOCH3), 55.3 (C-1), 55.7 (ArOCH3), 55.8 (ArOCH3),
55.8 (NCH2), 64.1 (C-3), 103.6 (CH(OCH3)2), 110.5
(CH), 110.6 (CH), 120.1 (CH), 125.7 (CH), 126.1 (CH),
126.2 (CH), 128.0 (CH), 134.1 (C), 134.3 (C), 135.1
(C), 148.1, 149.0 (C-3, C-4);MS m/z (%): 357 (M+, 7),
283 (20), 282 (100), 254 (13), 253 (52), 252 (13), 223
(10), 222 (11), 151 (16), 115 (19), 75 (14);HRMS calcd
for C21H27NO4: 357.19400. Found: 357.19253.
4.4.2. (R)-(+)-N-(2,2-Dimethoxyethyl)-3-(3,4-dimethoxy-
phenyl)-1,2,3,4-tetrahydroisoquinoline 9. Yield 80%,
solidifying oil, [a]D = +49.1 (c 0.375, CHCl3).
4.2.4. Addition product (R,R)-(+)-8. Yield 28%, solidi-
fying oil, [a]D = +5.4 (c 0.22, CHCl3). For this com-
pound only one peak was observed on HPLC
chromatogram [hexane/propan-2-ol = 9:1, 0.5 mL/min;
tR 28.7 min].
4.5. General procedure for cyclization of tetrahydroiso-
quinoline 9
A
solution of tetrahydroisoquinoline 9 (131 mg,
4.3. General procedure for the cyclization of 8
0.37 mmol) and 5 M aqueous HCl (3.7 mL) was stirred
overnight at rt. The mixture was basified with 20% aque-
ous NaOH (4 mL) and extracted with dichloromethane
(3 · 15 mL). The combined organic extracts were dried
and the solvent evaporated under reduced pressure.
The resulting oil was dissolved in dichloromethane
To a solution of compound 8 (372 mg, 0.66 mmol) in
dry THF (10 mL), n-BuLi (1.6 M solution in hexanes,
0.46 mL) was added at À72 ꢁC under an argon atmo-
sphere. The reaction mixture was allowed to warm-up

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M. Chrzanowska et al. / Tetrahedron: Asymmetry 16 (2005) 2954–2958
(15 mL) and treated with a mixture of NaBH4 (165 mg,
4 mmol) and TFA (2.7 mL, 35 mmol) in dichlorometh-
ane (6 mL), 0 ꢁC. The reaction mixture was stirred at
rt for 6 h, and then the solvent and TFA were removed
under reduced pressure. The resulting slurry was dis-
solved in water (10 mL), basified with 20% aqueous
NaOH (4 mL) and extracted with dichloromethane
(3 · 10 mL). The organic extracts were dried and evapo-
rated to yield O-methylbharatamine 5, which was puri-
fied by column chromatography (dichloromethane).
References
1. (a) Shamma, M. The Isoquinoline Alkaloids, Chemistry and
Pharmacology;Academic Press: New York, 1972;(b)
Shamma, M.;Moniot, L. Isoquinoline Alkaloid Research
1972–1977;Plenum Press: New York, 1978;(c) Bentley, K.
W. The Isoquinoline Alkaloids;Harwood Academic Pub-
lishers: Amsterdam, 1998.
2. Bobbitt, J. M.;McNew Kiely, J.;Khanna, K. L.;
Eberman, R. J. J. Org. Chem. 1965, 30, 2247–2250.
3. Bobbitt, J. M.;Steinfeld, A. S.;Weisgraber, K. H.;Dutta,
S. J. Org. Chem. 1969, 34, 2478–2479.
4.5.1. (S)-(À)-2,2-Dimethoxy-5,8,13,13a-tetrahydro-6H-
dibenzo[a,g]quinolizine (O-methylbharatamine) 5. Yield
54%, solidifying oil, 88% ee by HPLC [hexane/propan-
2-ol = 9:1, 0.5 mL/min; tR 23.9 min (major), tR
49.1 min]. The product obtained was identical to (S)-
(À)-O-methylbharatamine in terms of spectral data as
well as TLC and HPLC comparisons.13
4. Chrzanowska, M.;Rozwadowska, M. D. Chem. Rev.
2004, 104, 3341–3370.
5. Ponzo, V. L.;Kaufman, T. S. Tetrahedron Lett. 1995, 36,
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4.5.2. (R)-(+)-2,2-Dimethoxy-5,8,13,13a-tetrahydro-6H-
dibenzo[a,g]quinolizine (O-methylbharatamine) 5. Yield
65%, solidifying oil, 73% ee by HPLC [hexane/propan-
2-ol = 9:1, 0.5 mL/min; tR 24.1 min, tR 46.5 min
(major)]. The product obtained was identical to (R)-
(+)-O-methylbharatamine in terms of TLC and HPLC
comparisons.13
´
9. Głuszynska, A.;Rozwadowska, M. D.
Tetrahedron:
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´
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This work was supported by research grants from the
State Committee for Scientific Research in the years
2003–2006 (KBN Grant No. 4T09A 07824) and the
Ministry of Sciences and Information Society Technolo-
gies in the years 2005–2006 (MNI Grant No. 3 TO9A
102 28).
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