Enantiospecific synthesis of (S)-(-)-8-oxoxylopinine

Article abstract of DOI:10.1016/j.tetasy.2015.01.002

The enantiospecific synthesis of (S)-(-)-8-oxoxylopinine 1 was performed using a lateral metallation strategy, in which (S)-alaninol or (S)-phenylalaninol was applied as chiral auxiliary and building block. (4S)-3-(4,5-Dimethoxy-2-methylbenzoyl)-2,2,4-tri

Full text of DOI:10.1016/j.tetasy.2015.01.002

Tetrahedron: Asymmetry 26 (2015) 225–229
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Enantiospecific synthesis of (S)-(À)-8-oxoxylopinine
⇑
Zofia Meissner, Maria Chrzanowska
Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiospecific synthesis of (S)-(À)-8-oxoxylopinine 1 was performed using a lateral metallation
strategy, in which (S)-alaninol or (S)-phenylalaninol was applied as chiral auxiliary and building block.
(4S)-3-(4,5-Dimethoxy-2-methylbenzoyl)-2,2,4-trimethyl-1,3-oxazolidine 12 was synthesized starting
from veratraldehyde 13. The addition reaction of benzylic anion generated in situ from chiral amide
12 into 6,7,-dimethoxy-3,4-dihydroisoquinoline 7a proceeded with simultaneous cyclization leading to
the protoberberine alkaloid with high enantioselectivity.
Received 19 December 2014
Accepted 5 January 2015
Available online 27 January 2015
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
high regiochemical control for the synthesis of heterocyclic com-
pounds including protoberberines.
8-Oxoxylopinine 1 can be considered as a precursor of xylopi-
nine 2, a protoberberine alkaloid.1 There are several well-known
methods described in the literature for the reduction of 8-oxoxy-
lopinine 1 to xylopinine 2 both in the synthesis of the racemate2
and in the stereoselective synthesis.3
To date, several syntheses of racemic 8-oxoxylopinine ( )-1
have been published,2 while three examples of the synthesis of
non-racemic 8-oxoxylopinine 1 have been reported.3 In 1997,
Comins et al.3a used compound 3, which contained a chiral auxil-
2. Results and discussion
In continuation of our studies on stereoselective synthesis of
isoquinoline alkaloids6 based on the addition of chiral nucleophiles
to imines, we have used the lateral metallation approach for the
synthesis of protoberberine alkaloids.7–9 Initially we performed
the asymmetric synthesis of both enantiomers of 2,3-dimethoxy-
8-oxoberbine 9 and 2,3-methylenedioxy-8-oxoberbine 10, com-
pounds which do not possess an oxygenated substituent on ring
D. Oxazolidines 8 derived from commercially available aminoalco-
hols, (1R,2R)-norephedrine, or (S)- or (R)-phenylalaninol, respec-
tively, were used as chiral auxiliaries and building blocks. The
key step of the synthesis, in which a new stereogenic center at
C13a was created, involved the addition of laterally lithiated chiral
o-toluamide of type 8 into imine 7. This addition proceeded stere-
oselectively and was accompanied by simultaneous cyclization to
directly afford protoberberine alkaloids 9 or 10 (Fig. 2).
To apply the same methodology to the synthesis of 8-oxoxylop-
inine 1,3 a protoberberine alkaloid with oxygenated substituents at
ring D, an amide with methoxy substituents in the aromatic ring
was needed. Thus, we performed the synthesis of two homochiral
o-toluamides (4S)-2,2-dimethyl-3-(4,5-dimethoxybenzoyl)-4-ben-
zyl-1,3-oxazolidine 11 and (4S)-3-(4,5-dimethoxybenzoyl)-2,2,4-
trimethyl-1,3-oxazolidine 12 starting with veratraldehyde 13 and
commercially available amino alcohols: (S)-(À)-phenylalaninol
and (S)-(+)-alaninol, respectively (Scheme 1). We have already
published10 the synthesis of oxazolidine 11, which is based on the
transformation of veratraldehyde 13 into carboxylic acid 14 and
the reaction of its acid chloride with (S)-phenylalaninol, followed
iary derived from (+)-trans-(a-cumyl)cyclohexyl chloroformate
and vinyl ether derivative, 2-bromo-4,5-dimethoxy-1-(2-methoxy-
ethenyl)benzene 3a, as the aldehyde equivalent in the asymmetric
Pictet–Spengler reaction. The intermediate chiral benzyltetrahy-
droisoquinoline (79% de) was further transformed into (S)-(À)-8-
oxoxylopinine 1 (Fig. 1). A few years later Davis and Mohanty3b
used enantiopure sulfinimine 4 and the laterally lithiated o-tol-
unitrile of 5 as substrates and next transformed the resulting cyano
sulfinamide adduct into the protoberberine system (S)-(À)-1. In
2007, Iwao and Fukuda3c developed a synthesis of both enantio-
mers of protoberberine 1 and ent-1 via the addition of laterally
lithiated (S)-4-isopropyl-2-(o-tolyl)oxazoline
6 into 6,7-dime-
thoxy-3,4-dihydroisoquinoline 7a to give diastereomeric adducts
with modest diastereoselectivity. After their chromatographic
separation and acid catalyzed lactamization, both enantiomeric
alkaloids (S)-1 and (R)-ent-1 were obtained with 98% ee and 96%
ee, respectively. These two last examples confirmed the usefulness
of the lateral metallation methodology,5 which proceeded with
⇑
Corresponding author. Tel.: +48 61 8291317; fax: +48 61 8291555.
E-mail address: marylch@amu.edu.pl (M. Chrzanowska).
http://dx.doi.org/10.1016/j.tetasy.2015.01.002
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

226
Z. Meissner, M. Chrzanowska / Tetrahedron: Asymmetry 26 (2015) 225–229
H3CO
H3CO
H3CO
H3CO
N
N
O
H
H
OCH3
OCH3
1
2
OCH3
OCH3
H3CO
H3CO
H3CO
H3CO
OTBDMS
N
O
H
H
O
N
pTolyl
Ph
S
3
4
O
OCH3
H3CO
H3CO
N
H3CO
H3CO
Br
H3CO
CN
i-Pr
O
OCH3
3a
5
6
Figure 1. (S)-(À)-8-Oxoxylopinine 1, (S)-(À)-xylopinine 2 and compounds used in its asymmetric synthesis.
4
5
recrystallized from methanol/diethyl ether to yield a crystalline
3
2
RO
RO
RO
RO
20 = À5.9 (c 0.97,
6
compound with an mp of 133-135 °C and [
CHCl3); [
rotation [
a
]
R1
O
D
B
∗
A
7
20 = +6.4 (c 1.2, MeOH). The low value of the specific
N
N
C
O
8
a
a
]
]
D
∗
N
13a
13
∗
R2
1
measured for amide 15, and the changes in sign of
D
7a R = CH3
7b R+R =CH2
O
9
the specific rotation depending on the solvent used (CHCl3 or
MeOH) prompted us to undertake additional experiments to verify
the enantiomeric purity of 15. For this purpose, we prepared a
sample of racemic compound ( )-15 according to the same syn-
thetic route as depicted in Scheme 1, using acid 14 and ( )-alaninol
as substrates. A sample of racemic amide ( )-15 was analyzed on
HPLC Chiralcel OD-H column and the result was compared with
a chromatogram of chiral amide 15 to confirm the enantiomeric
purity of this compound. Next, homochiral compound 15 was
transformed into the desired oxazolidine derivative 12, prepared
in 73% yield in the reaction with 2,2-dimethoxypropane (DMP),
catalyzed by p-toluene sulfonic acid, in benzene at reflux and
under an argon atmosphere. Pure oxazolidine 12 was obtained
after column chromatography separation and crystallization from
D
12
10
11
8a R1 = CH3, R2 = Ph
8b
9
R = CH3
R
1 = CH2Ph, R2 = H
10 R+R = CH2
Figure 2. Starting compounds and products in asymmetric syntheses of
8-oxoberbines 9, 10.
by cyclization to afford the oxazolidine. According to the same
procedure, the synthesis of (4S)-3-(4,5-dimethoxybenzoyl)-2,
2,4-trimethyl-1,3-oxazolidine 12 was carried out, in which
2-methyl-4,5-dimethoxybenzoic acid 14 and (S)-(+)-alaninol were
used as substrates (Scheme 1).
Acid 14 was obtained in its pure form from veratraldehyde 13
according to a literature procedure10,11a involving bromination,
exchange of the bromine substituent for the methyl group and oxi-
dation of the aldehyde group to a carboxylic acid. From acid 14, the
acid chloride was prepared in situ with thionyl chloride and then
reacted with (S)-alaninol to give amide 15 in 70% yield. It was then
diisopropyl ether, mp 85–86 °C, [a]
20 = +46.8 (c 0.55, CHCl3). For
D
the sake of comparison, we prepared a sample of racemic com-
pound ( )-12 from ( )-15 following the same synthetic route as
depicted in Scheme 1. HPLC analysis confirmed the enantiomeric
purity of chiral oxazolidine 12. In addition, the correctness of the
structures and purity of amide 15 and oxazolidine 12 obtained
O
O
O
H3CO
H3CO
H3CO
H3CO
H3CO
H
OH
a
N
H
OH
H3CO
13
14
15
b
Ph
O
O
O
H3CO
H3CO
H3CO
N
N
O
H3CO
11
12
Scheme 1. Synthesis of oxazolidine 12.

Z. Meissner, M. Chrzanowska / Tetrahedron: Asymmetry 26 (2015) 225–229
227
were confirmed by spectroscopic characteristics and elemental
analysis. Since compounds 15 and 12 were prepared from (S)-(+)-
alaninol, we were able to assign an (S) absolute configuration for
the enantiomers. On HPLC analysis, amide 15 was characterized
by a longer retention time, while oxazolidine 12 by a shorter reten-
tion time.
We started with the synthesis of racemic 8-oxoxylopinine ( )-1
to obtain a sample for HPLC comparison, also employing the lateral
metallation methodology. For this purpose, we tried to prepare
N,N-diethyl-4,5-dimethoxy-2-methylbenzamide 16 from the
commercially available 2-bromo-4,5-dimethoxybenzoic acid 17
(Scheme 2). The acid chloride of compound 17 was prepared
1.5 equiv of n-butyllithium at À72 °C. After the addition
of 6,7-dimethoxy-3,4-dihydroisoquinoline 7a and subsequent
work-up, the addition/cyclization product, racemic 8-oxoxylopinine
( )-1 was isolated as a crystalline compound, mp 193–197 °C (lit.4a
mp 191–192 °C) although with a low yield of 13%. Thus, we
obtained a sample of ( )-1 for confirmation of the correctness of
its structure and evaluation of HPLC conditions for the determina-
tion of the enantiomeric excess of samples of 1. We attempted to
optimize the conditions of the addition using, for example, a higher
excess of amide 16 (4 equiv), t-BuLi instead of n-BuLi for deproto-
nation of amide 16 or BF3ÁEt2O for the activation of imine 7a, but
these changes did not improve the yield of the final product.
O
O
H3CO
H3CO
H3CO
H3CO
OH
N
a
a
b
13
16
14
Br
Br
17
18
H3CO
H3CO
N
RLi
N
O
H3CO
H3CO
O
7a
THF
N
R = n-Bu, t-Bu
OCH3
OCH3
rac-1
OCH3
OCH3
16
Scheme 2. Synthesis of ( )-8-oxoxylopinine 1.
in situ with thionyl chloride and treated with diethylamine to give
amide 18 with 82% yield.12 The bromine substituent in amide 18
was exchanged for a methyl group in the reaction with n-butyllith-
ium and methyl iodide. However the crude product 16 needed
purification by repeated column chromatography, finally
supplying pure amide 16 in only 34% yield. Thus, we decided to
prepare compound 16 starting with veratraldehyde 13, via
2-methyl-4,5-dimethoxybenzoic acid 14, which was converted
into N,N-diethylamide 16 by treatment with diethylamine with
98% yield.
Crystallization from methanol/diethyl ether led to pure
crystalline amide 16 showing an mp of 58–60 °C. The key step of
the synthesis of 8-oxoxylopinine ( )-1 was the addition of the
benzylic anion generated from N,N-diethyl-4,5-dimethoxy-2-
methylbenzamide 16 to the imine 6,7-dimetoxy-3,4-dihydroiso-
quinoline 7a (Scheme 2). During this addition, a spontaneous
cyclization to the protoberberine system took place. The carbanion
was generated from amide 16 (1.3 equiv) with the aid of
With this information in hand we carried out the asymmetric
synthesis of 1 by the addition of the benzylic anion generated
in situ from chiral amide 11, in one series of experiments, or 12,
in another series of experiments, into 6,7-dimethoxy-3,4-dihydro-
isoquinoline 7a (Scheme 3). In both series of experiments we
checked the influence of different parameters on the stereoselec-
tivity and yield of the addition step to 3,4-dihydroisoquinoline
7a, in particular the types of bases used for the generation of the
benzylic anion from amides 11 and 12. We also examined different
stoichiometries of the substrates, time of carbanion generation,
and the presence of additive such as TMEDA.
Our attempts to deprotonate benzyloxazolidine 11 with n-BuLi,
which was used successfully for the deprotonation of (4S)-4-ben-
zyl-2,2-dimethyl-3-o-toluoyl-1,3-oxazolidine 8b,7 failed. Increasing
the amounts of amide 11 to 2 equiv gave only trace amounts of the
desired product 1 in the reaction mixture. Using s-BuLi or s-BuLi
with the addition of TMEDA or
a different molar ratio of
s-BuLi to amide 11 did not lead to the formation of desired product
H3CO
H3CO
N
N
O
H3CO
H3CO
RLi
R1
H
O
7a
H3CO
H3CO
N
OCH3
O
(S)-1
OCH3
11 R1 = CH2Ph
12 R1 = CH3
Scheme 3. Synthesis of (S)-(À)-8-oxoxylopinine 1.

228
Z. Meissner, M. Chrzanowska / Tetrahedron: Asymmetry 26 (2015) 225–229
1. Finally, with t-BuLi (2 equiv) in THF 8-oxoxylopinine 1 was
isolated with 74% ee and in 5% yield after column chromatography.
It should be mentioned that the 4-benzyl group present in
oxazolidine 8b was proven to be a good chiral auxiliary in the
synthesis of 8-oxoberbines 9 and 10 but for oxazolidine 11, the pres-
ence of methoxy substituents in the aromatic ring made this process
more complicated, which has also been reported by others.13,14 This
explained the low yield of racemic ( )-1 obtained from amide 16.
The process of the deprotonation of methyloxazolidine 12 was
more effective than that of compound 11. The addition of benzyl
anion of 12 generated with n-BuLi (1.1 equiv) into 6,7-dime-
thoxy-3,4-dihydroisoquinoline 7a (1 equiv) led to product 1 with
76% ee and in 5% yield. The use of 3 equiv of amide 12 under sim-
ilar reaction conditions led to a product with lower ee (56%) and
did not increase the chemical yield of the reaction. Using LDA for
the deprotonation of amide 12 led to product 1 with 51% ee. The
use of s-BuLi or t-BuLi increased the stereoselectivity of this pro-
cess, affording product 1 with 90% ee and 84% ee, respectively.
When t-BuLi was used, there was a smaller amount of by-products
in the reaction mixture, which permitted a simpler isolation of
pure alkaloid 1 from the reaction mixture with 13% yield. Enantio-
merically pure 8-oxoxylopinine 1 was isolated from the crude
reaction product by column chromatography and additionally
crystallized from dichloromethane/diethyl ether. Recrystallization
of the enantiomerically enriched product led first to a product with
a lower ee but from the mother liquor, enantiomerically pure
compound 1 was obtained (>99% ee), mp 194–197 °C (lit.3a mp
spectra: Varian 4000 GC/MS. Optical rotations: Perkin–Elmer
polarimeter 242B at 20 °C. Elemental analyses: Vario EL III. Merck
DC-Alufolien Kieselgel 60254 was used for TLC and Kieselgel 60
(70–230 mesh ASTM) for column chromatography. Analytical
HPLC: Waters HPLC system with Daicel Chiralcel OD-H column;
flow rate: 0.5 mL/min. All compounds were purchased from
Aldrich Chemical Co. and used as received. THF was freshly
distilled from LiAlH4, benzene, and toluene—from sodium wire.
4.2. (2S)-2-(4,5-Dimethoxy-2-methylbenzamide)-1-propanol 15
The acid chloride was prepared in situ from 2-methyl-4,5-
dimethoxybenzoic acid 14 (2.596 g, 13.2 mmol) which was
refluxed with SOCl2 (9 mL) and a drop of DMF for 1 h. After the
mixture was cooled to room temperature, the excess of SOCl2
was removed in vacuo to afford a white precipitate. The acid chlo-
ride was dissolved in CH2Cl2 (25 mL) and then carefully added to a
mixture of (S)-(+)-alaninol (0.992 g, 13.2 mmol) in CH2Cl2 (120 mL)
and 0.5 M KOH (86 mL) at 0 °C. The mixture was stirred intensively
for 1.5 h and then left overnight at room temperature. The phases
were then separated. The aqueous phase was extracted with
CH2Cl2 (3 Â 30 mL). Combined extracts were dried over Na2SO4.
The solvent was evaporated in vacuo to afford a light oil that quickly
solidified. Pure product 15 was crystallized from MeOH/Et2O
20
yielding 2.34 g (70%) of white crystals. Mp 133–135 °C. [
a
]
=
D
À5.9 (c 0.97, CHCl3), [
a]
20 = +6.4 (c 1.2, MeOH). IR (KBr)
m :
cmÀ1
D
3350 (NH), 3287 (OH), 1633 (C@O). 1H NMR (CDCl3) d: 1.25
(d, J = 6.7 Hz, 3H, CH3), 2.38 (s, 3H, ArCH3), 3.31–3.34 (m, 1H,
disappears on treatment with D2O, OH) 3.59–3.61 (m, 1H, CH2),
3.70–3.75 (m, 1H, CH2), 3.84 (s, 3H, CH3O), 3.87 (s, 3H, CH3O),
4.17–4.22 (m, 1H, CH), 6.13 (d, J = 7.2 Hz, 1H, NH), 6.64 (s, 1H,
ArH), 6.91 (s, 1H, ArH). 13C NMR (CDCl3) d: 17.00 (CH3), 19.57
(ArCH3), 48.05 (CH), 55.81 (CH3O), 56.06 (CH3O), 66.88 (CH2),
110.60 (CH), 113.62 (CH), 127.89 (C), 128.66 (C), 146.59 (C),
149.94 (C), 170.28 (C@O). GCMS (tR = 13.67 min), m/z (%): 253
(M+, 5), 235 (43), 220 (49), 192 (15), 179 (100), 165 (10), 151
(20), 136 (10), 107 (10), 77 (15). Anal. Calcd for C13H19NO4 Â
1/3H2O: C, 60.22; H, 7.64; N, 5.40. Found: C, 60.41; H, 7.80;
N, 5.42. HPLC for chiral 15 [hexane/propan-2-ol = 4:1] tR = 21.57 -
min. HPLC for ( )-15 [hexane/propan-2-ol = 4:1] tR = 18.73 min
and tR = 21.32 min.
187–188 °C). The specific rotation measured was [
a
]
20 = À301.8
D
(c 0.115, CHCl3), lit.3b
[a
]D = À297.1 (c 0.42, CHCl3). HPLC analysis
confirmed the high enantiomeric purity of 1; only one peak
corresponding to a longer retention time tR of 35.18 min was pres-
ent in the chromatogram. On the basis of a comparison of the sign
of the specific rotation with the literature data, the (S)-absolute
configuration of our synthetic compound 1 (characterized by a
longer retention time in HPLC chromatogram) could be postulated.
3. Conclusions
Herein, we have reported on the enantiospecific synthesis of
(S)-(À)-8-oxoxylopinine 1 using the lateral metallation methodol-
ogy. The addition reaction of oxazolidine 11 or 12, incorporating
(S)-phenylalaninol or (S)-alaninol as the chiral auxiliary and build-
ing block, respectively, into 3,4-dihydroisoquinoline 7a was
accompanied by simultaneous cyclization to directly afford lactam
(S)-1. Although the yield of (S)-(À)-1 is low (13%), this is overcome
somewhat by the simplicity of the process. The steric outcome of
the synthesis made with (S)-alaninol or (S)-phenylalaninol as the
chiral auxiliary was comparable with that of the reactions with
other aminoalcohols, such as norephedrine and phenylalaninol,
which have been used previously in the synthesis of 8-oxoberbines
9 and 10. In conclusion, the configuration of the C4 stereogenic
center in the oxazolidine ring turned out to be an important factor
for the stereochemical outcome of the reaction. We also noticed
that the absolute configuration of the newly created stereogenic
center depends on the configuration of the C-4 atom in the oxazol-
idine ring. From oxazolidines 11 and 12 with a (4S)-configuration, a
new stereogenic center with an (S) configuration in 1 was created,
which is in agreement with our earlier experiments.7–9
4.3. (4S)-3-(4,5-Dimethoxy-2-methylbenzoyl)-2,2,4-trimethyl-
1,3-oxazolidine 12
To amide 15 (1.999 g, 7.9 mmol) in dry benzene (110 mL), 2,2-
dimethoxypropane (13.146 g, 126.4 mmol) and p-toluenesulfonic
acid monohydrate (0.390 g, 2.1 mmol) were added and the mixture
was refluxed for 2 h. Next the mixture was cooled to room temper-
ature and washed with 1% NaOH. The organic phase was dried over
Na2SO4 and the solvent was evaporated in vacuo. The crude prod-
uct was chromatographed on silica gel (hexane/ethyl acetate
90:10, 80:20, and 75:35, v/v) yielding 1.69 g (73%) of product 12.
An analytical sample was crystallized from i-Pr2O yielding white
crystals, mp 85–86 °C; [
m
a]
20 = +46.8 (c 0.55, CHCl3). IR (KBr)
D
cmÀ1: 1629 (C@O). 1H NMR (CDCl3) d: 1.03 (d, J = 6.3 Hz, 3H,
CH3), 1.70 (s, 3H, CH3), 1.81 (s, 3H, CH3), 2.27 (s, 3H, ArCH3), 3.67
(d, J = 1.5 Hz, 2H, CH2), 3.87 (s, 3H, CH3O), 3.88 (s, 3H, CH3O),
4.02–4.07 (m, 1H, CH), 6.68 (s, 1H, ArH), 6.73 (s, 1H, ArH). 13C
NMR (CDCl3) d: 18.33 (ArCH3), 20.54 (CH3), 23.28 (CH3), 26.92
(CH3), 54.54 (CH), 55.82 (CH3O), 56.10 (CH3O), 69.60 (CH2), 95.25
(C(CH3)2), 109.14 (CH), 113.14 (CH), 125.96 (C), 129.94 (C),
146.85 (C), 149.00 (C), 167.66 (C@O). GCMS (tR = 17.39 min), m/z
(%): 293 (M+, 7), 235 (5), 220 (5), 179 (100), 151 (9), 136 (6), 120
(3), 107 (2), 93 (2). Anal. Calcd for C16H23NO4 Â 4/5H2O: C, 62.44;
H, 8.06; N, 4.55. Found: C, 62.13; H, 8.25; N, 4.18. HPLC for
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, with TMS as the internal standard. Mass

Z. Meissner, M. Chrzanowska / Tetrahedron: Asymmetry 26 (2015) 225–229
229
(+)-12 [hexane/propan-2-ol = 9:1] tR = 35.23 min HPLC for ( )-12
[hexane/propan-2-ol = 9:1] tR = 35.11 min and tR = 51.23 min.
to À72 °C and R-Li was added. The resulting dark purple solution
indicated the formation of the benzyl anion. The mixture was stir-
red for 3–25 min (depending on color changes) and treated with a
solution of 6,7-dimethoxy-3,4-dihydroisoquinoline 7a (1 equiv) in
THF (7 mL for 0.7 mmol). After 1 h, the reaction mixture was
quenched at À72 °C with 5% HCl. When the temperature of the
reaction mixture reached room temperature, the phases were sep-
arated and the organic phase was washed a few times with 5% HCl
until it became colorless. The organic phase was dried over Na2SO4.
The solvent was evaporated in vacuo to afford an oil which was
chromatographed on silica gel (hexane/ethyl acetate 73:30 and
60:40, v/v). The product was obtained as a light beige solid and
crystallized from CH2Cl2/Et2O. ( )-1 mp 193–197 °C (lit.4a mp
191–192 °C) HPLC for ( )-1 [hexane/propan-2-ol = 65:35]
tR = 33.60 min (R)-1, tR = 39.31 min (S)-1. (S)-(À)-1 mp 194–
4.4. N,N-Diethyl-4,5-dimethoxy-2-bromobenzamide 18
The acid chloride was prepared in situ from 2-bromo-4,5-
dimethoxybenzoic acid 17 (2.089 g, 8.0 mmol) refluxed with SOCl2
(8 mL) and a drop of DMF for 1 h. After the mixture was cooled to
room temperature, the excess of SOCl2 was removed in vacuo to
afford a white precipitate. The acid chloride was dissolved in
CH2Cl2 (20 mL) and then carefully added to a mixture of diethyl-
amine (0.585 g, 8.0 mmol) in CH2Cl2 (60 mL) and 0.5 M KOH
(52 mL) at 0 °C. The mixture was then stirred intensively for
1.5 h. The phases were separated and the aqueous phase was
extracted with CH2Cl2 (3 Â 30 mL). Organic phases were dried over
Na2SO4. Solvent was evaporated in vacuo to afford a light yellow
oil, which was crystallized from MeOH/Et2O to afford 2.070 g
crystals of pure product 18 (82%). Mp 103–104 °C (lit.12 mp 104–
105 °C). 1H NMR d (ppm): 1.08 (t, J = 7.2 Hz, 3H, CH3), 1.27 (t,
J = 7.1 Hz, 3H, CH3), 3.19 (q, J = 7.1 Hz, 4H, CH2), 3.86 (s, 3H,
CH3O), 3.88 (s, 3H, CH3O), 6.76 (s, 1H, ArH), 7.00 (s, 1H, ArH). GCMS
(tR = 15.45 min) m/z (%): 316 (M+, 35), 302 (8), 243 (100), 236 (48),
214 (8), 165 (13), 157 (8), 108 (10), 94 (5), 77 (12), 56 (7).
197 °C (lit.3a mp 187–188 °C); [
a]
20 = À301.8 (c 0.115, CHCl3), lit.3b
D
[a
]
D = À297.1 (c 0.42, CHCl3); 1H NMR (CDCl3): d (ppm): 2.71–2.97
(m, 4H, CH2), 3.15 (dd, J = 3.84, 15.66 Hz, 1H, CH2), 3.90 (s, 3H,
CH3O), 3.91 (s, 3H, CH3O), 3.95 (s, 3H, CH3O), 3.96 (s, 3H, CH3O),
4.84 (dd, J = 3.71, 13.46 Hz, 1H, CH2), 4.97–5.00 (m, 1H, CH), 6.70
(s, 1H, ArH), 6.72 (s, 1H, ArH), 6.73 (s, 1H, ArH), 7.65 (s, 1H, ArH).
13C NMR (CDCl3): d (ppm): 29.22 (CH2), 37.65 (CH2), 38.65 (CH2),
55.24 (CH), 55.89 (CH3O), 56.02 (CH3O), 56.08 (CH3O), 56.10
(CH3O), 108.70 (CH), 109.13 (CH), 110.68 (CH), 111.39 (CH),
121.62 (C), 127.30 (C), 127.71 (C), 130.94 (C), 147.87 (C), 147.93
(C), 148.17 (C), 151.85 (C), 164.69 (C@O). GCMS (tR = 26.99 min),
m/z (%): 369 (72, M), 354 (35), 338 (23), 207 (7), 178 (60), 150
(100), 107 (12), 77 (23). HPLC for (S)-1 [hexane/propan-2-
ol = 65:35] tR = 35.18 min.
4.5. N,N-Diethyl-4,5-dimethoxy-2-methylbenzamide 16
4.5.1. Synthesis from N,N-diethyl-4,5-dimethoxy-2-bromobenz-
amide 18
Amide 18 (0.979 g, 3.1 mmol) was dissolved in dry THF (25 mL),
after which n-BuLi (1.7 equiv, 1.6 M solution in hexanes, 3.3 mL,
5.28 mmol) was added at À72 °C under an argon atmosphere. The
mixture was stirredfor 10 min and then a solution of CH3I was added
(2.083 g, 14.7 mmol) in THF (10 mL). After stirring for 2.5 h, the mix-
ture was allowed to warm up to À30 °C and 20% NH4Cl was added.
When the reaction mixture reached room temperature, the phases
were separated. The aqueous phase was extracted with Et2O
(3 Â 15 mL). The combined organic extracts were dried over Na2SO4.
The solvents were evaporated in vacuo to afford an orange oil, which
was chromatographed on silica gel (CH2Cl2/MeOH, 200:1 and 100:1,
v/v) to give 0.266 g (34%) of pure product 16.
Acknowledgements
This work was supported by the research grant from the Minis-
try of Sciences and Higher Education (MNI Grant No. N204 032 32/
0794, 2007–2010) and by the research grant from the National Sci-
ence Centre (NCN) – Poland No. 2011/01/D/ST5/06627.
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4.5.2. Synthesis from 4,5-dimethoxy-2-methylbenzoic acid 14
The acid chloride was prepared in situ from 2-methyl-4,5-dim-
ethoxybenzioc acid 14 (0.981 g, 5.0 mmol), which was refluxed with
SOCl2 (5 mL) and a drop of DMF for 1 h. After the mixture was cooled
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CH3), 2.23 (s, 3H, ArCH3), 3.16 (q, J = 7.1 Hz, 2H, CH2), 3.84–3.90
(m, 2H, CH2), 3.85 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 6.69 (s, 2H,
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4.6. 8-Oxoxylopinine 1: general procedure
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Amide 16, 11, or 12 was dissolved in dry THF (15 mL for
0.7 mmol) under an argon atmosphere. The solution was cooled