Diastereoselective Pomeranz-Fritsch-Bobbitt synthesis of (S)-(-)-O-methylbharatamine using (S)-N-tert-butanesulfinimine as a substrate

Article abstract of DOI:10.1016/j.tetasy.2007.11.010

The protoberberine-type alkaloid, (S)-(-)-O-methylbharatamine, has been synthesized in six steps involving the addition of laterally lithiated o-toluamide to (S)-N-tert-butanesulfinimine as the crucial process. The target alkaloid was obtained in 24.4% overall yield with 88% ee.

Full text of DOI:10.1016/j.tetasy.2007.11.010

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2910–2914
Diastereoselective Pomeranz–Fritsch–Bobbitt synthesis of (S)-(ꢀ)-O-
methylbharatamine using (S)-N-tert-butanesulfinimine as a substrate
Agnieszka Grajewska and Maria D. Rozwadowska*
Faculty of Chemistry, A. Mickiewicz University, ul. Grunwaldzka 6, 60-780 Poznan´, Poland
Received 26 October 2007; accepted 7 November 2007
Abstract—The protoberberine-type alkaloid, (S)-(ꢀ)-O-methylbharatamine, has been synthesized in six steps involving the addition of
laterally lithiated o-toluamide to (S)-N-tert-butanesulfinimine as the crucial process. The target alkaloid was obtained in 24.4% overall
yield with 88% ee.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
So far, both enantiomers of aminoacetal 1 were used in the
synthesis of (S)-(ꢀ)- and (R)-(+)-salsolidine and (S)-(ꢀ)-
carnegine. In the enantioselective synthesis, compound
(S)-1 (R = H, R0 = CH3) was prepared from classic ‘Pom-
eranz–Fritsch’ imine 4 (R0 = CH3) by the addition of
methyl lithium in the presence of external inductors of chi-
rality of an oxazoline-type2 (Fig. 1). In the diastereoselec-
tive synthesis, chiral imines 5 were used as substrates.
Imine 5a afforded benzylamine (S)-1 (R = H, R0 = Et)
The synthesis of chiral non-racemic isoquinoline alkaloids
using the Bobbitt modification of the Pomeranz–Fritsch
methodology involves aminoacetals of types 1–3 as key
intermediates1 (Fig. 1). They are then subjected to cycliza-
tion by treatment with acids followed by reduction (cata-
lytic hydrogenation or NaBH4 reduction) to afford the
1,2,3,4-tetrahydroisoquinoline core.
R1
R'O OR'
R'O
OR'
R'O
OR'
N
CH3O
CH3O
CH3O
CH3O
CH3
N
N
∗
R
R
R2O
R
OR3
OR1
CH3
OBn
3
2
1
OCH3
R1O
R'O
OR'
CH3
R2O
CH3O
CH3O
CH3O
CH3O
OH
NR*
N
OR3
R1
4
5
6
OBn
R*
R1
H
a
b
c
(R)-S(O)t-Bu
(R)-S(O)t-Bu
CH3
H
(S)-CH(Ph)CH2OH
Figure 1.
*
Corresponding author. Tel.: +48 61 8291322; fax: +48 61 8658008; e-mail: mdroz@amu.edu.pl
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.010

A. Grajewska, M. D. Rozwadowska / Tetrahedron: Asymmetry 18 (2007) 2910–2914
2911
when subjected to a series of transformations involving the
addition of methylmagnesium bromide, removal of the
chiral auxiliary from the addition product and N-alkyl-
ation with the bromoacetaldehyde acetal; this was further
cyclized to (S)-(ꢀ)-salsolidine.3 The enantiomer (R)-1
(R = H, R0 = Et) was obtained by hydride reduction of
imine 5b and transformed into (R)-(+)-salsolidine accord-
ing to the same reaction scheme.4
tives;12–14 however, only in a few cases3,4,15–19 have they
found application in the syntheses of isoquinoline alka-
loids. Ellman et al.,15 using N-tert-butanesulfinimine as a
substrate performed the synthesis of pavine and iso-
pavine-type alkaloids, in the eight-step reaction sequence,
by applying the Pomeranz–Fritsch cyclization as the final
step. Davis et al.16–19 via the addition of laterally lithiated
o-toluamides, o-tolunitriles and phthalide to chiral N-p-tol-
uenesulfinimines obtained several mono- and disubstituted
tetrahydroisoquinolines, which are important building
blocks for alkaloid synthesis,16–18 for example, for
(S)-(ꢀ)-xylopinine.19
In a similar fashion, chiral imine 5c, incorporating (S)-phen-
ylglycinol,5–7 was converted into several aminoacetals of
type 2, differing in substituents in the aromatic rings. These
were then transformed into benzylisoquinolines,5 iso-
pavines,6 and (+)-glaucine.7
In our synthesis (S)-sulfinaldimine ent-5a was used as a chi-
ral starting material (Scheme 2). It was prepared by the
condensation of 3,4-dimethoxybenzaldehyde with (S)-tert-
butanesulfinamide in the presence of Ti(OEt)4, according
to Ellman’s procedure,20 in 91% yield, mp 77–78 ꢁC,
[a]D = +19.8, showing spectral characteristics correspond-
ing to those of the (R)-enantiomer, 5a (lit.3 mp 77–78 ꢁC,
[a]D = ꢀ19.1).
Aminoacetals of type 3, which were prepared from the
corresponding benzyl alcohols 6 (R1, R2, R3 = alkyl, allyl)
(Fig. 1) either by treatment with N-tosylated aminoacetal-
dehyde acetal to give the corresponding 3 (R = Ts),8 or
via azidolysis, catalytic hydrogenation and reaction with
glyoxal monoacetal to give the corresponding compound
3 (R = H),9,10 were used as important building blocks in
the synthesis of b-adrenergic receptor antagonist
MY336-a8 as well as of ecteinascidin 7439 and cribrostatin
IV.10
The addition of laterally lithiated N,N-diethyl-o-toluamide
8 to the sulfinimine C@N double bond was the key step of
the synthesis. The amide carbanion was best generated
with t-BuLi at ꢀ72 ꢁC affording addition product 9 as
an oil in 93% yield, [a]D = ꢀ18.3. The diastereoselectivity
of this step could not be established either by chiral HPLC
Herein, we report the synthesis of (S)-(ꢀ)-O-methylbharat-
amine 14, a protoberberine alkaloid, by applying chiral
(S)-N-tert-butanesulfinimine ent-5a and o-toluamide 8 as
building blocks.
1
analysis, run under various conditions, or by H NMR
spectroscopy (amide functionalities). The (S)-configura-
tion of sulfinamide 9 was finally postulated at the end of
the synthesis on the basis of the negative sign of the spe-
cific rotation of the target alkaloid, O-methylbharatamine
14, for which the (S)-configuration had been previously
established.21 It also could be deduced from a transition
state postulated by Davis et al.16 for a similar reaction,
in which the lithium cation of the lithiated o-toluamide
was chelated to the sulfinimine and amide oxygen atoms
to form a less crowded chair-like six-membered system
with the carbanion approaching from the less hindered
Si site (Fig. 2).
2. Results and discussion
As a contribution to our study on the stereoselective mod-
ification of the Pomeranz–Fritsch–Bobbitt synthesis of iso-
quinoline alkaloids, in a previous paper,11 we have
described the synthesis of both enantiomers of O-methyl-
bharatamine 14 of good enantiomeric purity, using achiral
imine 4 and both enantiomers of o-toluamide 7 as sub-
strates (Scheme 1). Herein, we report on a complementary
diastereoselective synthesis of (S)-(ꢀ)-O-methylbharata-
mine 14, starting with chiral sulfinaldimine ent-5a and achi-
ral o-toluamide 8 (Scheme 1).
Removal of the N-sulfinyl auxiliary from sulfinamide 9
occurred with concentrated hydrochloric acid in methanol
at room temperature for 1 h. Amine 10 was isolated as an
oil (93%) and characterized as its hydrochloride salt,
10ÆHCl, mp 189–191 ꢁC, [a]D = +36.6.
Chiral sulfimines are known to be excellent substrates for
the asymmetric synthesis of amines and their deriva-
CH3
O
O
CH3O
N(Et)2
+
N
CH3O
S
CH3O
CH3O
O
ent-5a
8
N
∗
Ph
CH3
R'O
OR'
CH3O
CH3O
+
N
∗
N
O
O-Methylbharatamine 14
4
7
Scheme 1.

2912
A. Grajewska, M. D. Rozwadowska / Tetrahedron: Asymmetry 18 (2007) 2910–2914
CH3O
CH3O
CH3O
CH3O
N
S
H
N
NH2
ent-5a
O
CH3O
S
O
CH3O
+
O
9
10
CH3
O
O
N(Et)2
N(Et)2
N(Et)2
8
EtO
OEt
N
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
H
N
H
N
O
H
H
H
12
13
11
CH3O
CH3O
N
H
O-Methylbharatamine 14
Scheme 2.
CH3
14, while HPLC analysis established the enantiomeric ex-
cess to be 88%.
N
O
S
Li
3. Conclusion
O
N
CH3O
In conclusion, the asymmetric synthesis of (S)-(ꢀ)-O-meth-
ylbharatamine 14 from readily available chiral sulfinaldi-
mine ent-5a and o-toluamide 8 is described. The key
process, during which a new stereogenic center was created,
involved the addition of laterally lithiated o-toluamide to
the imine C@N double bond. The final step of the synthe-
sis, the formation of the protoberberine ring system was
accomplished via a Pomeranz–Fritsch–Bobbitt cycliza-
tion/reduction to afford the target alkaloid in 24.4% overall
yield and with enantiomeric excess of 88%.
Figure 2.
In the next step of the synthesis, amine 10, upon treatment
with 1 equiv of n-BuLi in THF at ꢀ70 ꢁC, cyclized easily
into isoquinolone 11 in 96% yield and with 85% ee (by
HPLC analysis). Attempts to increase ee by crystallization
failed, for example, a sample crystallized from ethyl acetate
showed only 72% ee (mp 149–150 ꢁC, [a]D = ꢀ76.2).
4. Experimental
4.1. General
Crude isoquinolone 11 of 85% ee was then reduced with
boron reducing agents, BH3ÆS(CH3)2 or BH3ÆTHF in
THF. Better yields (85% vs 66%) were obtained with
the latter reagent in reaction carried out at reflux for
28 h, giving pure tetrahydroisoquinoline 12, mp 123–
125 ꢁC, [a]D = ꢀ83.0. Its N-alkylation with bromoacetal-
dehyde in DMF/sodium hydride led to aminoacetal 13,
which could not be isolated in pure form because of its
instability during both crystallization and chromato-
graphic separation. Therefore crude 13 was used in the
final step of the synthesis in which it was treated with
5 M hydrochloric acid for 12 h at room temperature and
then reduced with sodium borohydride/TFA in methylene
chloride, producing (S)-(ꢀ)-O-methylbharatamine 14,
[a]D = ꢀ264.5 (lit.21 [a]D = ꢀ285.5 for a sample of 99%
ee) in 38% yield. The negative sign of the specific rotation
indicated an (S) configuration of the product synthesized
Melting points: determined on a Koffler block and are
uncorrected. IR spectra: Perkin–Elmer 180 in KBr pellets.
NMR spectra: Varian Gemini 300, with TMS as internal
standard. Mass spectra (EI): instrument AM D402. Spe-
cific rotation: Perkin–Elmer polarimeter 243B at 20 ꢁC.
Analytical HPLC: Waters HPLC system with Mallink-
rodt-Baker Chiralcel OD-H column. Merck DC-Alufolien
Kieselgel 60254 was used for TLC. Merck Kieselgel 60
(70–230 mesh) was used for column chromatography.
THF was freshly distilled from LiAlH4. 3,4-Dimethoxy-
benzaldehyde, Ti(OEt)4, tert-butanesulfinamide, t-BuLi,
n-BuLi, BH3ÆS(CH3)2, BH3ÆTHF, bromoacetaldehyde
diethyl acetal and TFA were purchased from Aldrich and
used as received.

A. Grajewska, M. D. Rozwadowska / Tetrahedron: Asymmetry 18 (2007) 2910–2914
2913
4.2. (S)-(+)-N-(3,4-Dimethoxybenzylidene)-2-methylpro-
panesulfinamide ent-5a
4.51 (dd, J = 6 Hz, 9 Hz, 1H, CH2CH), 6.84–7.23 (m,
7H, ArH), 8.71 (s, 3H, disappears on treatment with
D2O, NHþ). 13C NMR (DMSO-d6) d: 12.86, 13.74,
3
To a solution of 3,4-dimethoxybenzaldehyde (332 mg,
2 mmol) and (S)-tert-butanesulfinamide (242 mg, 2 mmol)
in anhydrous THF (4 ml), Ti(OEt)4 (0.84 ml, 4 mmol)
was added. The mixture was heated at reflux for 4 h under
an argon atmosphere. Water (5 ml) was added with rapid
stirring and the reaction mixture was filtered through a
pad of Celiteꢂ and the filter cake was washed with CH2Cl2.
The phases were separated, the organic solution washed
with brine, dried over Na2SO4, and the solvents were evapo-
rated. The residue was crystallized from i-Pr2O to give
pure ent-5a, mp 77–78 ꢁC, [a]D = +19.8 (c 0.57, CH2Cl2).
Additional amounts (total yield 91%) were obtained from
mother liquors after silica gel column chromatography
with CH2Cl2. The spectral characteristics of ent-5a corre-
sponded to that of 5a.3
38.32, 42.20, 54.66, 55.48, 55.61, 111.07, 111.32, 120.13,
125.47, 126.68, 128.50, 129.47, 130.37, 132.55, 137.35,
148.66, 148.78, 169.21. EI MS m/z (%): 356 (M+ꢀHCl,
2), 190 (6), 166 (100), 139 (5), 124 (6). Anal. Calcd for
C21H29ClN2O3Æ1/2H2O: C, 62.74; H, 7.53; N, 6.97. Found:
C, 62.78; H, 7.61; N, 6.82.
4.5. (S)-(ꢀ)-3-(3,4-Dimethoxyphenyl)-1,2,3,4-tetra-
hydroisoquinolone 11
To the addition product 10 (53 mg. 0.15 mmol) dissolved in
THF (3 ml), n-BuLi (1.6 M solution in hexanes, 0.09 ml,
0.15 mmol) was added at ꢀ70 ꢁC. After 20 min, 20%
NH4Cl (2 ml) was added at this low temperature. When
the solution reached room temperature, the phases were
separated, and the aqueous one extracted with Et2O
(3 · 10 ml). The combined organic extracts were dried over
Na2SO4 and the solvent evaporated to give 11 (41 mg, 96%)
in 85% ee [HPLC hexane/2-propanol 85:15; 0.5 ml/min;
tR = 55 min (major), tR = 63 min (minor)]. Recrystalliza-
tion from EtOAc afforded crystalline 11 (72% ee), mp
149–150 ꢁC, [a]D = ꢀ76.2 (c 0.28, MeOH). IR (KBr)
cmꢀ1: 3339, 1662. 1H NMR (CDCl3) d: 3.08 (dd,
J = 4.6 Hz, 15.6 Hz, 1H, CHHCH), 3.20 (dd,
J = 11.3 Hz, 15.3 Hz, 1H, CHHCH), 3.88 (s, 3H, OCH3),
3.89 (s, 3H, OCH3), 4.80 (dd, J = 4.6 Hz, 11.5 Hz, 1H,
CH2CH), 6.1 (s, 1H, disappears on treatment with D2O,
NH), 6.84–7.49 (m, 6H, ArH), 8.11 (d, 1H, ArH). 13C
NMR (CDCl3) d: 37.64, 55.88, 55.91, 55.96, 109.13,
111.16, 118.77, 127.24, 127.28, 127.98, 128.26, 132.47,
133.36, 137.63, 148.95, 149.26, 166.29. EI MS m/z (%):
283 (M+, 64), 252 (48), 224 (5), 164 (7), 146 (7), 118
(100). Anal. Calcd for C17H17NO3: C, 72.05, H, 6.05, N,
4.95. Found: C, 71.74, H, 5.98, N, 4.75.
4.3. Addition of o-toluamide 8 to sulfinimine ent-5a
o-Toluamide 8 (132 mg, 0.69 mmol) was dissolved in dry
THF (3 ml) under an argon atmosphere and the solution
cooled to ꢀ72 ꢁC. tert-BuLi (1.7 M solution in pentane,
0.4 ml, 0.69 mmol) was added and the carboanion (red)
was generated for 10 min at ꢀ72 ꢁC. A solution of imine
ent-5a (80 mg, 0.29 mmol) in THF (1 ml) was introduced
dropwise and, after 40 min, 20% NH4Cl (3 ml) was added
at this low temperature. When the solution was warmed-
up to room temperature, the phases were separated and
the aqueous one was extracted with Et2O (3 · 5 ml). The
combined organic extracts were dried over Na2SO4 and
the solvents were evaporated to yield a yellow oil, from
which, after silica gel column chromatography with
CH2Cl2/MeOH (100:0.3), oily 9 (89 mg, 93%) was eluted,
[a]D = ꢀ18.3 (c 0.95, MeOH). IR (KBr) cmꢀ1: 3243,
1613, 1518. 13C NMR (CDCl3) d: 12.89, 14.06, 22.44,
22.74, 39.24, 41.95, 43.05, 55.87, 55.92, 60.94, 110.16,
111.07, 118.67, 125.35, 126.43, 128.95, 129.70, 135.37,
136.85, 148.16, 148.91, 171.03. FAB-MS m/z (%): 461
(M++H). Anal. Calcd for C25H36N2SO4: C, 65.18; H,
7.88; N, 6.09; S, 6.95. Found: C, 65.23; H, 7.95; N, 6.06;
S, 7.01.
4.6. (S)-(ꢀ)-3-(3,4-Dimethoxyphenyl)-1,2,3,4-tetrahydroiso-
quinoline 12
4.6.1. Reduction with BH3ÆS(CH3)2. In a distillation set
supplied with a Vigreux column and a receiver containing
30% hydrogen peroxide, a solution of compound 11
(102 mg, 0.35 mmol) of 85% ee in THF (10 ml) was placed.
Then BH3ÆS(CH3)2 (0.25 ml, 1.25 mmol) was added and the
mixture was kept at 65 ꢁC for 4 h under a strong stream of
argon. It was then cooled to 0 ꢁC, treated slowly with 10%
hydrochloric acid (4 ml) and warmed to 65 ꢁC for 0.5 h.
Then, at room temperature, 20% NaOH (5 ml) was added,
phases were separated and the basic solution extracted with
Et2O (4 · 5 ml). The organic extracts were washed with
10% hydrochloric acid (10 ml), and the phases were sepa-
rated. The organic extract was dried over Na2SO4 and con-
centrated to give the starting compound 11 (45 mg, 44%).
The aqueous layer was basified with 20% NaOH and re-
extracted with Et2O (3 · 10 ml) to give, after drying over
Na2SO4 and solvent evaporation, pure 12 (63 mg, 66%).
4.4. (S)-(+)-N,N-Diethyl-2-[2-amino-2-(3,4-dimethoxy-
phenyl)ethyl]benzamide hydrochloride 10ÆHCl
Sulfinamide 9 (577 mg, 1.25 mmol) was dissolved in MeOH
(7.6 ml) and the solution was cooled to 0 ꢁC. Concentrated
hydrochloric acid (0.23 ml, 2.77 mmol) was added and the
reaction mixture stirred at room temperature for 1 h. The
solvent was evaporated, water (5 ml) added and the mix-
ture extracted with Et2O. Phases were separated and the
aqueous one was basified with solid NaOH and extracted
with CH2Cl2 until the Dragendorff test was negative. The
organic solution was dried over Na2SO4 and the solvent
evaporated to leave oily 10 (416 mg, 93%). It was charac-
terized as the hydrochloride salt, 10ÆHCl, mp 189–191 ꢁC,
[a]D = +36.6 (c 1.14, EtOH). IR (KBr) cmꢀ1: 2905. 1H
NMR (DMSO-d6) d: 0.93 (t, J = 6 Hz, 3H, CH2CH3),
1.19 (t, J = 6.8 Hz, 3H, CH2CH3), 2.88, 3.04, 3.55 (3m,
6H, 3 · CH2), 3.70 (s, 3H, OCH3), 3.73 (s, 3H, OCH3),
4.6.2. Reduction with BH3ÆTHF. To compound 11
(292 mg, 1.03 mmol) of 85% ee in dry THF (11 ml),
BH3ÆTHF (1 M solution in THF, 3 ml, 3 mmol) was added

2914
A. Grajewska, M. D. Rozwadowska / Tetrahedron: Asymmetry 18 (2007) 2910–2914
and the mixture heated at reflux for 15 h under an argon
atmosphere. After that time, an additional amount of the
reducing agent (3 ml, 3 mmol) was introduced and heating
continued for 13 h. This was then cooled to room temper-
ature and 10% hydrochloric acid (6 ml) added dropwise.
The mixture was heated at 65 ꢁC for 1 h, then basified with
20% NaOH and extracted with Et2O (4 · 10 ml). The
organic phase was treated with 15% hydrochloric acid
(3 · 6 ml) and the acidic aqueous phase was basified with
20% NaOH and extracted with CH2Cl2 (5 · 10 ml). The
organic solution was dried over Na2SO4 and the solvent
evaporated yielding pure 12 (237 mg, 85%), mp 123–
tR = 50 min (minor)] was isolated by silica gel column chro-
matography with CH2Cl2. [a]D = ꢀ264.5 (c 0.55, CHCl3),
lit.21 for a sample of (S)-(ꢀ)-14 showing 99% ee:
[a]D = ꢀ285.5 (c 0.51, CHCl3). Spectral characteristics of
our sample corresponded to those of the literature for
(S)-(ꢀ)-14.21
Acknowledgment
This work was supported by a research grant from the
Ministry of Science and Higher Education in the years
2007–2008 (MNiSW Grant No. N204 073 32/2021).
125 ꢁC, [a]D = ꢀ83.0 (c 1.17, CH2Cl2). IR (KBr) cmꢀ1
:
1
3262, 2929, 2787, 1517. H NMR (CDCl3) d: 1.92 (s, 1H,
disappears on treatment with D2O, NH), 2.97 and 2.99
(2s, 2H, CH2CH), 3.88 (s, 3H, OCH3), 3.90 (s, 3H,
OCH3), 3.96 (dd, J = 6.3 Hz, 8.8 Hz, 1H, CHN), 4.23 (m,
2H, CH2N), 6.84–7.26 (m, 7H, ArH). 13C NMR (CDCl3)
d: 37.88, 49.32, 55.91, 55.94, 58.41, 109.48, 110.94,
118.53, 125.73, 126.05, 126.15, 128.92, 134.67, 134.70,
136.87, 148.09, 148.97. EI MS m/z (%): 269 (M+, 26), 252
(12), 238 (13), 179 (6), 165 (15), 151 (20), 130 (17), 104
(100). Anal. Calcd for C17H19NO2: C, 75.80, H, 7.11, N,
5.20. Found: C, 75.54, H, 6.95, N, 5.05.
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at 153 ꢁC for 1 h under an argon atmosphere. Bromoacet-
aldehyde diethyl acetal (0.3 ml, 2 mmol) was added and
heating was continued for 6 h. After cooling to room tem-
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4.8. (S)-(ꢀ)-O-Methylbharatamine 14
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A solution of the crude amino acetal 13 (240 mg) in 5 M
hydrochloric acid (3.4 ml) was stirred for 12 h at room tem-
perature. The mixture was basified with 20% NaOH and
extracted with CH2Cl2 (4 · 10 ml). The combined organic
extracts were dried and the solvent evaporated. The oily
residue (166 mg) was dissolved in CH2Cl2 (16 ml) and trea-
ted with NaBH4 (151 mg, 4 mmol) followed by the drop-
wise addition of TFA (3 ml, 38 mmol) in CH2Cl2 (6 ml)
at 0 ꢁC. The mixture was stirred at room temperature for
6 h, then the solvent and TFA were removed under reduced
pressure. To the resulting slurry water (3 ml) and 20%
NaOH were added and the mixture was extracted with
CH2Cl2 (3 · 10 ml). The organic extracts were dried over
Na2SO4 and the solvent was evaporated to yield an oily res-
idue (100 mg), from which pure (S)-(ꢀ)-O-methylbharat-
amine 14 (45 mg, 38%) of 88% ee [HPLC hexane/
2-propanol 90:10; 0.5 ml/min; tR = 24 min (major),