Asymmetric synthesis of (S)-(-)-xylopinine. Use of the sulfinyl group as an ipso director in aromatic SE

Article abstract of DOI:10.1021/jo2007237

Optically pure (S)-(-)-xylopinine 2 was prepared in three steps in 52% overall yield. Thus, condensation of the carbanion derived from (S)-4 with the (S)-(E)-sulfinylimine 5 gave a 2:1 mixture of tetrahydroisoquinolines 6a and 6b, differing only in configuration at sulfur. N-Desulfinylation of this mixture gave the diastereomeric sulfoxides which, without separation, were converted into (S)-(-)-xylopinine (2) with loss of the sulfinyl moieties under Pictet-Spengler conditions. This unprecedented ipso electrophilic substitution of a sulfinyl group may have synthetic implications beyond that described in this work.

Full text of DOI:10.1021/jo2007237

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of (S)-(ꢀ)-Xylopinine. Use of the Sulfinyl Group
as an Ipso Director in Aromatic SE
Virginia M. Mastranzo,† Francisco Yuste,*,† Benjamín Ortiz,† Rubꢀen Sꢀanchez-Obregꢀon,† Rubꢀen A. Toscano,†
and Josꢀe L. García Ruano*,‡
†Instituto de Química, Universidad Nacional Autꢀonoma de Mꢀexico, Circuito Exterior, Cd. Universitaria, Coyoacꢀan 04510, Mꢀexico D. F.
‡Departamento de Química Orgꢀanica (C-I), Facultad de Ciencias, Universidad Autꢀonoma de Madrid, Cantoblanco, 28049-Madrid,
Spain
S Supporting Information
b
ABSTRACT:
Optically pure (S)-(ꢀ)-xylopinine 2 was prepared in three steps in 52% overall yield. Thus, condensation of the carbanion derived
from (S)-4 with the (S)-(E)-sulfinylimine 5 gave a 2:1 mixture of tetrahydroisoquinolines 6a and 6b, differing only in configuration
at sulfur. N-Desulfinylation of this mixture gave the diastereomeric sulfoxides which, without separation, were converted into
(S)-(ꢀ)-xylopinine (2) with loss of the sulfinyl moieties under PictetꢀSpengler conditions. This unprecedented ipso electrophilic
substitution of a sulfinyl group may have synthetic implications beyond that described in this work.
’ INTRODUCTION
anti-1,2-amino alcohols and anti-1,2-amino sulfides starting from
the corresponding oxygen-8,9 and sulfur-containing10 carbanions.
Reactions with N-arylarylideneamines generate mixtures of syn
and anti isomers, epimers at the amine-bearing carbon, with the
stereoselectivity being dependent on the electronic effect of the
aromatic ring substituents of the acceptor.11 Given that tetra-
hydroprotoberberines contain a 2-arylethylamine fragment, we
reasoned that they could be prepared making use of this
methodology.7ꢀ11 In this paper, we report an application of this
strategy for the synthesis of (S)-(ꢀ)-xylopinine (2) (Figure 1), a
prototypical member of the tetrahydroprotoberberines isolated
from Xylopia discreta.12
Several asymmetric syntheses of (S)-(ꢀ)-xylopinine can be
found in the literature,5bꢀc,13 with that reported by Davis14 being
remarkable because it also used the N-sulfinylimine’s methodol-
ogy. However, the syntheses are not completely satisfactory
because they involve long synthetic sequences and/or require
the separation of mixture of diastereoisomers because of the
moderated stereoselectivity control of the key asymmetric trans-
formation. In our case, these problems have been avoided by
using the bond disconnection between N-7 and C-8 indicated in
Figure 2, which provides the ring-opened 1-benzylisoquinoline
6a. Further cleavage of the C-13 and C-14 bond gives two
Protoberberines are a large group of naturally occurring alka-
loids characterized by a tetracyclic ring skeleton containing an
isoquinoline core.1 These alkaloids possess a wide range of bio-
logical properties including antimicrobial, antitumor, antileuke-
mic, and antiinflammatory activities.2 The tetrahydroprotober-
berines 1 are a subclass of protoberberines occurring in at least
eight families of the plant kingdom.3 Alkoxy (methoxy, methy-
lenedioxy) or hydroxy substituents at the A ring are always
located at the same positions, whereas the substitution pattern of
the D ring is variable. Moreover, the stereogenic center at C-14
and an alkyl or hydroxyl group at C-13 are sometimes present4
(Figure 1). Among the variety of strategies developed for the
asymmetric synthesis of tetrahydroprotoberberines, two classical
procedures, the PictetꢀSpengler5 and the BischlerꢀNapieralski
cyclization/reduction,6 have been the most frequently used for
the construction of the tetrahydroisoquinoline nucleus.
Recently, one of us has reported that 2-(p-tolylsulfinyl)benzyl
carbanions are highly efficient in transferring chiral benzyl groups
to various electrophilic species. Their reaction with compounds
containing the CdN bond has provided one of the best methods
for preparing compounds containing the 2-phenylethylamine
skeleton in high optical purity. Thus, N-sulfinylaldimines7 and
N-sulfinylketimines8 react with these carbanions with complete
stereocontrol and high yields to produce anti-1,2-diarylpropyla-
mines. These reactions were also employed in the synthesis of
Received: April 6, 2011
Published: May 12, 2011
r
2011 American Chemical Society
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|

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ARTICLE
Figure 1. Natural tetrahydroprotoberberines.
Figure 2. Retrosynthetic approach to (S)-(ꢀ)-xylopinine (2).
Scheme 1. Synthesis of 6a and 6b from (S)-4 and (S)-5
fragments: the 2-p-tolylsulfinyl-4,5-dimethoxytoluene (S)-4 and
the substituted N-p-tolylsulfinylaldimine (S)-5. Nucleophilic
addition of the o-sulfinyl carbanion derived from (S)-4 with
the imine is the key step of the sequence.
as the electrophile because of the (S) configuration of the xylopin-
ine.15 The enantiopure sulfinylimine (S)-5 was obtained in 83% yield
by condensation of 2-(2-chloroethyl)-4,5-dimethoxybenzaldehyde16
with (S)-p-toluenesulfinamide17 according to Davis’procedure.18 De-
protonation of (S)-4 at the benzylic position with LDA at ꢀ78 °C,
followed by the addition of the N-sulfinylimine (S)-5 at this tem-
perature and stirring overnight at room temperature, produced a 2:1
diastereomeric mixture of 1-benzyltetrahydroisoquinolines 6a and 6b
in 88% combined isolated yield. The diastereomeric tetrahydroiso-
quinolines 6a and 6b were readily separable by flash chromatography.
The major diastereoisomer 6a was used for completing the synthetic
’ RESULTS AND DISCUSSION
The synthesis of the intermediate 6a was performed according
to the synthetic sequence depicted in Scheme 1. Compound (S)-4
was prepared in 42% yield by the Andersen synthesis from 1-bromo-
4,5-dimethoxy-2-methylbenzene 3. We chose the sulfinylimine (S)-5
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sequence because we assumed that it would have the (S)-configura-
tion at the newly created chiral center.15 This assumption was later
confirmed by the synthesis of (S)-(ꢀ)-2.
We now tried to obtain the isomer of the xylopinine, that is,
(S)-(ꢀ)-tetrahydropalmatine (9) starting from 7a by changing
the order of the steps of Scheme 2. The results are depicted in
Scheme 3. The PictetꢀSpengler cyclization applied to 7a should
generate sulfoxide 10, which would yield 9 by C-desulfinylation.
To our surprise, however, when compound 7a was subjected to
PictetꢀSpengler reaction conditions (aqueous CH2O, HCO-
OH, 90 °C, 2 h), (S)-(ꢀ)-xylopinine (2) was obtained as the only
isolable product (65% yield, Scheme 3). From a synthetic point of
view, this process for preparing (S)-(ꢀ)-xylopinine is considerably
more efficient than that shown in Scheme 2. This reaction
presumably occurs by electrophilic attack of the iminium species
on the sulfur-bearing carbon atom of the very electron-rich
aromatic ring followed by expulsion of the arylsulfinyl moiety,
perhaps as the formicꢀp-toluenesulfinic mixed anhydride
(Scheme 3). To our knowledge, this is the first example of the
participation of an arylsulfinyl group in an electrophilic ipso
aromatic substitution reaction.20 It potentially opens up a large
number of new synthetic applications of sulfoxides, particulary
with respect to the synthesis of optically pure isoquinolines via the
reaction of o-sulfinylbenzyl carbanions with imines.7ꢀ10
The synthesis of (S)-(ꢀ)-xylopinine (2) from 6a is depicted in
Scheme 2. N-Desulfinylation of 6a was performed with TFA at
0 °C in methanol, which afforded the secondary amine 7a in 90%
yield. To ensure the regioselective cyclization that would allow
the synthesis of 2, we first proceeded to eliminate the SOTol
group from 7a by reaction with 2.2 equiv of t-BuLi at ꢀ78 °C in
THF, thus producing the (S)-(ꢀ)-norlaudanosine (8) in 62%
yield. Finally, the PictetꢀSpengler cyclization of 8 afforded
(S)-(ꢀ)-xylopinine (2) in 66% yield. The spectral properties
of 2 and 8 were fully consistent with their literature values, and
their specific rotations (Scheme 2), very similar to those reported
for the corresponding natural compounds of known configura-
tion,14,19 indicated that both exhibited the (S) configuration at
their amine-bearing carbon atom. This assignment confirms that
6a and 7a also have the (S) configuration at this carbon atom.
The complete regiocontrol observed in the cyclization step is not
unexpected on the basis of electronic requirements which yield
predominantly or exclusively the 10,11-disubstituted derivatives.
In order to establish the absolute configuration of the minor
isomer 6b, obtained by reaction of 4 and 5 (Scheme 2), we
decided to sequentially eliminate the two chiral centers. First, we
removed the N-sulfinyl group with TFA/MeOH (Scheme 4) and
obtained 7b, differing from 7a in its spectroscopic parameters,
and therefore with only one of the two chiral centers being
different. C-Desulfinylation of 7b with t-BuLi afforded (S)-(ꢀ)-
norlaudanosine 8 (67% yield). The sign of the specific rotation of
821 thus obtained was identical to that reported for the (S)-
enantiomer,19 which indicated that the configuration at the
amine-bearing trisubstituted carbon atom was identical for 6a
and 6b. Thus, 7a and 7b (and therefore 6a and 6b) differ only in
the configuration of the p-TolSO group joined to the aromatic
ring.22 Partial racemization of this sulfur group must take place
during the condensation of 4 with 5 as a consequence of the
prolonged reaction time required23 (overnight) to complete the
reaction. Finally, this also indicates that reaction of the sulfiny-
limine (S)-5 with the carbanion derived from 4 is stereounique,
Scheme 2. Preparation of (S)-(ꢀ)-Xylopinine (2) from 6a
Scheme 3. Unexpected Evolution of 7a under PictetꢀSpengler Conditions
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Scheme 4. Determination of the Absolute Configuration of 6b
Scheme 5. Asymmetric Synthesis of (S)-(ꢀ)-Xylopinine in
Three Steps from (S)-4 and (S)-5
mesh ASTM). Melting points were determined in open capillary tubes
and are uncorrected. The optical rotations were measured at room
temperature (concentration in g/100 mL). The IR spectra were
recorded with an FT-IR spectrophotometer. The NMR spectra were
acquired in CDCl3 solutions at 300 and 75 MHz for 1H and 13C NMR,
respectively. J values are given in hertz. The diastereomeric excesses were
1
determined by 300 MHz H NMR spectroscopy. Mass spectra were
measured at 70 eV and 190 °C. All described compounds were over 97%
pure by NMR analysis.
(S)-(ꢀ)-1,2-Dimethoxy-4-methyl-5-(p-tolylsulfinyl)benz-
ene (S)-(4). To a stirred solution of 1-bromo-4,5-dimethoxy-2-
methylbenzene 3 (0.40 g, 1.73 mmol, 1 equiv) in THF (4 mL) cooled
at ꢀ78 °C was added dropwise a 1.6 M pentane solution of t-BuLi
(2.16 mL, 3.46 mmol, 2 equiv). After 5 min, a solution of (S)-
menthyl-p-toluenesulfinate (0.560 g, 1.90 mmol, 1.1 equiv) in THF
(4 mL) cooled at ꢀ78 °C was added via cannula. When the reaction
was completed (20 min), the mixture was hydrolyzed with saturated
aqueous NH4Cl (8 mL) at ꢀ78 °C and extracted with CH2Cl2 (3 ꢁ
20 mL). The organic phase was washed with brine and dried
(Na2SO4), and the solvent was removed under reduced pressure.
The residue was purified by flash column chromatography eluting
with hexane/EtOAc 2:1 to produce 0.212 g (42%) of (S)-4 as a white
solid: mp 123ꢀ124 °C; [R]D ꢀ23.3 (c 1, CHCl3); IR (KBr) νmax
1593, 1502, 1262, 1052 cmꢀ1; 1H NMR (CDCl3, 300 MHz) δ 2.32 (s,
3H), 2.36 (s, 3H), 3.88 (s, 3H), 3.91 (s, 3H), 6.65 (s, 1H), 7.24 and
7.45 (AA0BB0system, 4H), 7.40 (s, 1H); 13C NMR (CDCl3, 75 MHz)
δ 18.0, 21.3, 56.0, 56.1, 106.9, 113.3, 125.6, 128.6, 129.9, 133.8, 141.3,
142.0, 148.2, 150.9; EIMS m/z 290 (76, Mþ), 273 (100), 271 (23),
242 (49), 167 (34), 138 (16); HRMS-FAB m/z [M þ 1]þ calcd for
C16H19O3S 291.1055, found 291.1059.
(S)-(þ)-(E)-N-[2-(2-Chloroethyl)-4,5-dimethoxybenzylide-
ne]-4-methylbenzenesulfinamide (S)-(5). A mixture of (S)-(þ)-
p-toluenesulfinamide17 (4.93 mmol, 0.766 g, 1.01 equiv), 2-(2-chloro-
ethyl)-4,5-dimethoxybenzaldehyde16 (1.111 g, 4.88 mmol, 1 equiv), and
titanium(IV) ethoxide (4.05 mL, 19.52 mmol, 4 equiv) in CH2Cl2
(30 mL) was refluxed for 3 h. The reaction mixture cooled at 0 °C was
quenched by addition of cold water (20 mL). The mixture was filtered
through Celite, and the filtrate was washed with CH2Cl2. The phases
were separated, the aqueous phase was washed with CH2Cl2 (15 mL),
and the combined organic portions were dried (Na2SO4) and concen-
trated. The residue was purified by flash column chromatography using
hexane/EtOAc 2:1 as eluent to give 1.47 g (83%) of (S)-5 as a white
solid: mp 91ꢀ92 °C; [R]D þ46.8 (c 1, CHCl3); IR (KBr) νmax 1585,
1514, 1275, 1068 cmꢀ1; 1H NMR (CDCl3, 300 MHz) δ 2.40 (s, 3H),
3.27ꢀ3.48 (m, 2H), 3.68 (t, 2H, J 7.2), 3.89 (s, 3H), 3.93 (s, 3H), 6.75
(s, 1H), 7.31 and 7.63 (AA0BB0system, 4H), 7.39 (s, 1H), 8.84 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 21.4, 35.9, 44.8, 56.0, 56.1, 112.9, 113.9,
124.7, 129.8 (2C), 133.8, 141.6, 142.1, 148.2, 152.3, 158.2; EIMS m/z
365 (2, Mþ), 278 (16), 226 (32), 225 (32), 191 (23), 176 (100), 139
(38), 91 (22); HRMS-FAB m/z [M þ 1]þ calcd for C18H21ClNO3S
366.0931, found 366.0924.
only yielding amines with the (S) configuration at carbon, as has
been previously observed for other carbanions.7
Since the configuration at the chiral carbon of compounds 6a
and 6b is identical, we studied the synthesis of (S)-(ꢀ)-xylopi-
nine (2) from the mixture obtained in the reaction of (S)-4 and
(S)-5 (Scheme 5). N-Desulfinylation of the 2:1 mixture of 6a and
6b with TFA at 0 °C in methanol (96% yield) followed by the
PictetꢀSpengler cyclization of the resulting mixture afforded
(S)-(ꢀ)-xylopinine (2) in 61% yield, with specific rotation iden-
tical to that reported for the natural product.14
In conclusion, the synthesis of the optically pure (S)-xylopinine
(2) was performed in three steps by reaction of the o-sulfinyl
benzyl carbanion derived from (S)-4 and N-sulfinylamine (S)-5,
N-desulfinylation of the resulting mixture of products, and sub-
sequentPictetꢀSpengler cyclization. The overall isolated yield was
52%, and the optical purity of the xylopinine thus obtained is very
high or complete. The previously unreported participation of the
sulfinyl group in anipso electrophilic aromatic substitution reaction
was the key step in the reaction sequence. This observation may
well have important synthetic implications, and this possibility is
currently under investigation in our group.
’ EXPERIMENTAL SECTION
General Methods. All moisture-sensitive reactions were carried
out in flame-dried glassware under argon atmosphere and monitored by
TLC. Flash chromatography was performed with silica gel 60 (230ꢀ400
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(1S)-1-[4,5-Dimethoxy-2(S)-p-tolylsulfinyl]benzyl-6,7-
dimethoxy-2(S)-p-tolylsulfinyl)-1,2,3,4-tetrahydroisoquinoline
(6a) and (1S)-1-[4,5-Dimethoxy-2-(R)-p-tolylsulfinyl]benzyl-
6,7-dimethoxy-2-(S)-p-tolylsulfinyl)-1,2,3,4-tetrahydroiso-
quinoline (6b). To a stirred solution of diisopropylamine (0.31 g,
0.43 mL, 3.08 mmol, 1.78 equiv) in THF (10 mL) cooled at ꢀ78 °C was
added a solution 1.1 M in hexane of n-BuLi (1.73 mL, 1.90 mmol,
1.1 equiv). After30 min, a solution of the sulfoxide (S)-4(0.5 g, 1.73mmol,
1 equiv) in THF (8 mL) was added via cannula. After 1 h at ꢀ78 °C,
a solution of sulfinylimine (S)-5 (0.696 g, 1.90 mmol, 1.1 equiv) in THF
(10 mL) was added. The resulting solution was stirred at room tempera-
ture for 12 h. The reaction mixture was hydrolyzed with saturated aqueous
NH4Cl. The aqueous phase was extracted with CH2Cl2 (3 ꢁ 20 mL),
washed with brine (2 ꢁ 20 mL), dried (Na2SO4), and evaporated. The
residue was purified by flash column chromatography using EtOAc/
hexane 4:1 as eluent to give 0.942 g (88% yield) of a 2:1 diastereoiso-
meric mixture of 6a and 6b. The mixture of 6a and 6b was separated by
flash column chromatography using EtOAc/hexane 4:1 as eluent. Major
(m, 2H), 3.00ꢀ3.09 (m, 1H), 3.13ꢀ3.23 (m, 2H), 3.39 (dd, 1H, J 4.8
and 14.4), 3.79 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 4.45
(dd, 1H, J 4.8 and 8.4), 6.59 (s, 2H), 6.70 (s, 1H), 7.17 (s, 1H), 7.24 and
7.41 (AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz) δ 21.3, 28.1,
37.9, 40.0, 53.4, 55.9, 56.0 (2C), 56.1, 109.0, 109.7, 111.8, 113.7, 125.2,
126.7, 127.8, 129.9, 130.7, 134.9, 141.3 (2C), 147.5, 148.0, 148.8, 151.6;
EIMS m/z 482 (2, Mþ þ 1), 464 (18), 340 (17), 192 (100), 176 (25),
148 (10); HRMS-FAB m/z [M þ 1]þ calcd for C27H32NO5S 482.2001,
found 482.2002.
(S)-(-)-Norlaudanosine (8). To a stirred solution of 7a or 7b
(0.2 g, 0.42 mmol, 1 equiv) in THF (4 mL) cooled at ꢀ78 °C was added
a solution 1.5 M in pentane of t-BuLi (0.91 mmol, 0.61 mL, 2.17 equiv).
When the reaction was completed (15 min), the mixture was hydrolyzed
with saturated aqueous NH4Cl (2 mL) and extracted with CH2Cl2 (3 ꢁ
5 mL). The combined organic layers were dried (Na2SO4), and the
solvent was removed under reduced pressure. The residue was purified
by flash column chromatography using EtOAc/CH2Cl2/MeOH 2:2:0.5
as eluent to obtain (S)-norlaudanosine (8) as a yellow oil [0.089 g
(62%), [R]20D ꢀ20.6 (c 1, CHCl3) [lit.19 [R]20D ꢀ21.9 (c 1, CHCl3)]
product (6a): 0.621 g (58%) as a white solid; mp 104ꢀ105 °C; [R]20
D
from 7a and 0.097 g (67%) from 7b, [R]20 ꢀ13.1 (c 1, CHCl3)].
þ10.4 (c 1.0, CHCl3); IR (deposited film) νmax 1598, 1510, 1265, 1225,
1050 cmꢀ1; 1H NMR (CDCl3, 300 MHz) δ 2.36 (s, 3H), 2.39 (s, 3H),
2.52ꢀ2.60 (m, 1H), 3.05ꢀ3.42 (m, 5H), 3.75 (s, 3H), 3.76 (s, 3H), 3.83
(s, 3H), 3.91 (s, 3H), 4.99ꢀ5.05 (m, 1H), 6.39 (s, 1H), 6.58 (s, 2H),
7.16 ꢀ7.23 (m, 6H), 7.36ꢀ7.42 (m, 3H); 13C NMR (CDCl3, 75 MHz)
δ 21.2, 21.3, 29.1, 38.5, 39.4, 55.9, 56.0 (2C), 56.3, 61.4, 107.9, 109.9,
112.0, 113.6, 125.6, 126.1, 126.2, 128.2, 129.5, 130.0, 130.3, 134.8, 140.6,
141.2, 141.5, 142.1, 147.3, 148.3, 149.0, 151.2; MS-FAB m/z 620 (13,
D
Compound 8 was also obtained starting from 6a or 6b by using the same
procedure. With 2.2 equiv of t-BuLi, (S)-norlaudanosine was obtained as
a yellow oil, 37% yield from 6a [[R]20D ꢀ18.6 (c 1, CHCl3)] and 34%
yield from 6b [[R]20 ꢀ12.1 (c 1, CHCl3)]: 1H NMR (CDCl3,
D
300 MHz) δ 2.45ꢀ2.60 (br s, 1H), 2.70ꢀ278 (m, 2H), 2.87ꢀ3.00
(m, 2H), 3.12ꢀ3.26 (m, 2H), 3.81 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H),
3.87 (s, 3H), 4.19 (dd, 1H, J 4.8 and 8.4), 6.59 (s, 1H), 6.61 (s, 1H),
6.73ꢀ6.85 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 29.1, 40.8, 42.1,
55.8 (2C), 55.9, 56.0, 56.7, 109.5, 111.4, 111.9, 112.6, 121.5, 127.1,
129.8, 131.1, 147.1, 147.6, 147.8, 149.0. These data are in accordance
with the values reported in the literature.19
M
þ þ 1), 480 (100), 330 (77), 307 (32), 192 (45), 154 (87), 136 (56);
HRMS-FAB m/z [M þ 1]þ calcd for C34H38NO6S2 620.2141, found
620.2136. Minor product (6b): 0.321 g (30%) as a white solid; mp
194ꢀ195 °C; [R]20D þ154.5 (c 1.0, CHCl3); IR (deposited film) νmax
1599, 1510, 1264, 1225, 1051 cmꢀ1; H NMR (CDCl3, 300 MHz)
1
(S)-(ꢀ)-Xylopinine (2). A mixture of 37% aqueous CH2O (0.6 mL),
HCOOH (1 mL), and (S)-norlaudanosine (8) (0.044 g, 0.13 mmol) was
heated to 90 °C for 2 h. After the resulting mixture had cooled to 25 °C,
saturated aqueous NaHCO3 was added until pH > 7 was reached. The
mixture was then extracted with CH2Cl2 (3 ꢁ 15 mL). The combined
organiclayers were dried(Na2SO4), and thesolventwas evaporated under
vacuum. The residue was purified by flash chromatography using EtOAc/
NEt3 99:1 as eluent to obtain 0.031 g (66%) of (S)-xylopinine (2) as a
δ 2.34 (s, 3H), 2.38 (s, 3H), 2.56ꢀ2.65 (m, 1H), 3.08ꢀ3.50 (m, 5H),
3.77 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 3.92 (s, 3H), 5.00ꢀ5.07
(m, 1H), 6.50 (s, 1H), 6.60 (s, 1H), 6.71 (s, 1H), 7.09 ꢀ7.26 (m, 6H),
7.40ꢀ7.47 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 21.2 (2C), 29.1,
38.4, 39.1, 55.8, 55.9, 56.1, 56.2, 62.2, 107.4, 109.9, 111.9, 113.0, 125.2,
126.1, 126.4, 128.1, 129.5, 129.9, 130.3, 135.5, 140.2, 141.2, 141.3, 142.0,
147.2, 148.2, 149.1, 151.4; MS-FAB m/z 620 (7, Mþ þ 1), 480 (55), 330
(52), 307 (30), 192 (28), 154 (100), 136 (61); HRMS-FAB m/z [M þ
1]þ calcd for C34H38NO6S2 620.2141, found 620.2146.
solid: mp 177ꢀ178 °C (lit.14 177ꢀ178 °C); [R]20 ꢀ280.1 (c 0.1,
D
CHCl3) [lit.14 [R]20 ꢀ282.4 (c 0.7, CHCl3)]. This product also was
D
obtained in 65% yield starting from7a or 7b: [R]20D ꢀ283 (c 0.1, CHCl3)
(1S)-1-[4,5-Dimethoxy-2-(S)-p-tolylsulfinyl]benzyl-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline (7a) and (1S)-
1-[4,5-Dimethoxy-2-(R)-p-tolylsulfinyl]benzyl]-6,7-dimetho-
xy-1,2,3,4-tetrahydroisoquinoline (7b). To a stirred solution of
6a or 6b (0.245 g, 0.39 mmol, 1 equiv) in MeOH (6 mL) cooled at 0 °C
was added trifluoroacetic acid (91 μL, 1.18 mmol, 3 equiv). The
resulting solution was stirred at 0 °C for 3 h. The volatiles were
evaporated, and the residue was chromatographed in a SCX column
affording 0.169 g (90%) of the corresponding amine. 7a: white solid; mp
86ꢀ87 °C; [R]20D ꢀ127.3 (c 1.0, CHCl3). IR (KBr) νmax: 3459, 1602,
from 7a; [R]20D ꢀ245 (c 0.12, CHCl3) from 7b.
Synthesis of (S)-(ꢀ)-Xylopinine from a 2:1 Diastereoiso-
meric Mixture of 6a and 6b. To a stirred solution of a 2:1 mixture of
6a and 6b (0.20 g 0.32 mmol) in methanol (5 mL) cooled at 0 °C
trifluoroacetic acid (0.96 mmol, 74 μL, 3 equiv) was added. After the
mixture was stirred for 3 h at 0 °C, the solvent was evaporated, and the
residue was chromatography in a SCX column, affording 0.148 g (96%)
of a 2:1 diastereomeric mixture of amines 7a and 7b, which was heated to
90 °C during 2 h with a mixture of 37% aqueous CH2O (1.6 mL) and
HCOOH (2.5 mL). After the resulting mixture had cooled to 25 °C,
saturated aqueous NaHCO3 was added until pH > 7 was reached. The
mixture was then extracted with CH2Cl2 (3 ꢁ 15 mL). The combined
organic layers were dried (Na2SO4), and the solvent was evaporated
under vacuum. The residue was purified by flash chromatography using
1
1510, 1460, 1262, 1227, 1047 cmꢀ1; H NMR (CDCl3, 300 MHz) δ
2.37 (s, 3H), 2.62ꢀ2.81 (m, 2H), 2.89ꢀ3.03 (m, 2H), 3.13ꢀ3.22
(m, 1H), 3.32 (dd, 1H, J 3.9 and 14.1), 3.83 (s, 3H), 3.86 (s, 3H), 3.87
(s, 3H), 3.88 (s, 3H), 4.35 (dd, 1H, J 3.9 and 9.6), 6.59 (s, 1H), 6.64
(s, 1H), 6.79 (s, 1H), 7.25 and 7.49 (AA0BB0 system, 4H), 7.32 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 21.3, 29.1, 38.6, 40.7, 55.9, 56.1 (2C),
56.2, 56.3, 108.2, 109.5, 112.0, 113.5, 125.6, 127.4, 129.7, 130.0, 131.0,
134.5, 141.4, 142.2, 147.4, 147.8, 148.9, 151.3; EIMS m/z 482 (2, Mþ þ
1), 464 (12), 340 (8), 192 (100), 177 (42), 146 (33), 118 (12), 91 (7);
HRMS-FAB m/z [M þ 1]þ calcd for C27H32NO5S 482.2001,
EtOAc/NEt3 99:1 as eluent to obtain 0.067 g (61%) of (S)-xylopinine
1
(2) as a solid: mp 177ꢀ178 °C; [R]20 ꢀ281.7 (c 0.1, CHCl3); H
D
NMR (CDCl3, 300 MHz) δ 2.56ꢀ2.71 (m, 2H), 2.84 (dd, 1H, J 11.4
and 15.6), 3.08ꢀ3.19 (m, 2H), 3.24 (dd, 1H, J 3.6 and 15.6), 3.59 (dd,
1H, J 3.9 and 11.4), 3.68 (d, 1H, J 14.7), 3.85 (s, 3H), 3.86 (s, 3H), 3.87
(s, 3H), 3.89 (s, 3H), 3.92 (d, 1H, J 14.7), 6.58 (s, 1H), 6.62 (s, 1H), 6.67
(s, 1H), 6.75 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 29.1, 36.5, 51.4,
55.8, 55.9, 56.0, 56.1, 58.3, 59.6, 108.7, 109.1, 111.4, 111.5, 126.4 (2C),
found 482.2007. 7b: white solid; mp 75ꢀ76 °C; [R]20 þ110.4 (c
D
1.0, CHCl3); IR (KBr) νmax 3459, 1602, 1510, 1460, 1262, 1227,
1
1047 cmꢀ1; H NMR (CDCl3, 300 MHz) δ 2.37 (s, 3H), 2.73ꢀ2.80
5040
dx.doi.org/10.1021/jo2007237 |J. Org. Chem. 2011, 76, 5036–5041

The Journal of Organic Chemistry
ARTICLE
126.8, 129.9, 147.5 (2C), 147.6, 147.7. Analytical data were in agreement
with literature values.14
1999, 51, 2871. (c) Kametani, T.; Takagi, N.; Toyata, M.; Honda, T.;
Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1981, 2830.
(14) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67, 1290.
(15) The amine used in the synthesis of the (S)-xylopinine according
to Scheme 1 should have the (S) configuration at the amine-bearing
carbon atom. Reactions of 2-p-tolylsulfinyltoluene with N-sulfinyli-
mines, both with (S) configuration at their respective sulfur atoms,
always evolve in a completely stereoselective manner, only yielding the
amine with the (S) configuration at this carbon atom (see ref 7). Thus,
we assume that, at least, the major compound obtained in the reaction of
(S)-4 and (S)-5 would exhibit the (S) configuration at the carbon atom.
(16) Yamato, M.; Hashigaki, K.; Qais, N.; Ishikawa, S. Tetrahedron
1990, 46, 5909.
’ ASSOCIATED CONTENT
S
Supporting Information. Proton and carbon NMR spec-
b
tra for all new compounds prepared and X-ray data for com-
pound 6b. This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: (F.Y.) yustef@unam.mx; (J.L.G.R.) joseluis.garcia.ruano@
uam.es.
(17) Fanelli, D. L.; Szewczyk, J. M.; Zhang, Y.; Reddy, G. V.; Burns,
D. M.; Davis, F. A. Org. Synth. 1999, 77, 50.
(18) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli,
D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
(19) Werner, F.; Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 3911.
(20) The trimethylsilyl group has been used as an activating group
for ipso attack in the PictetꢀSpengler reaction to control the regio-
chemistry in tetrahydroisoquinoline synthesis: (a) Miller, R. B.; Tsang,
T. Tetrahedron Lett. 1988, 29, 6715. (b) Cutter, P. S.; Miller, R. B.;
Schore, N. E. Tetrahedron 2002, 58, 11471.
(21) The magnitude of the specific rotation of compound 8 obtained
from 7b is clearly lower than that reported for norlaudanosine (see
Scheme 4), which indicates that t-BuLi should produce epimerization at
the chiral carbon of 7b. It is remarkable that this epimerization was not
observed in the reaction of the diastereomer 7a with t-BuLi to form 8
(Scheme 2).
(22) This was unequivocally demonstrated by X-ray diffraction
studies of the compound 6b (see the Supporting Information), which
has the (S) configuration at the chiral carbon and at the sulfur joined to
nitrogen but the (R) configuration (the opposite to that of the starting
sulfoxide 4) at the sulfur of the diarylsulfinyl group.
(23) Racemization of sulfoxides with organolithiums has been
reported; see: Durst, T.; LeBelle, M. J.; Van del Elzen, R.; Tin, K.-C
Can. J. Chem. 1974, 52, 761. However, this problem had never been
detected in the previously studied reactions of o-sulfinylbenzyl carba-
nions with imines (see refs 7ꢀ10), probably due to the short reaction
times and low temperatures they required to be completed.
’ ACKNOWLEDGMENT
We thank M. I. Chꢀavez, E. García-Ríos, E. Huerta, R. Pati~no,
M. A. Pe~na, F. J. Pꢀerez, H. Ríos, L. Velasco, and M. N. Zavala for
their technical assistance. We also thank Dr. J. M. Muchowski for
reviewing the manuscript. Financial support from DGAPA-
UNAM (Proyecto IN206910), the Spanish Government (CTQ-
2009-12168/BQU), and Comunidad Autꢀonoma de Madrid
(AVANCAT-S2009/PPQ-1634) is gratefully acknowledged.
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