Regio- and stereoselective stevens rearrangement of benzyltetrahydroprotoberberinium salts

Article abstract of DOI:10.1002/ejoc.200400443

8-(Arylmethyl)berbines are conveniently obtained through a Stevens rearrangement of the corresponding N-arylmethylberbinium salts with sodium methylsulfinylmethylide in DMSO. This procedure has provided two new nonnatural 8-benzylcanadines stereoselectively, without competition from the Hofmann elimination. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400443

SHORT COMMUNICATION
Regio- and Stereoselective Stevens Rearrangement of
Benzyltetrahydroprotoberberinium Salts
Maria Valpuesta,*[a] Amelia Diaz,[a] Rafael Suau,[a] and Gregorio Torres[a]
´
Dedicated to the memory of Dr. Fidel Jorge Lopez Herrera
Keywords: Rearrangement / Alkaloids / Ylides / Elimination / Conformation
8-(Arylmethyl)berbines are conveniently obtained through a
benzylcanadines stereoselectively, without competition from
Stevens rearrangement of the corresponding N-arylmethyl- the Hofmann elimination.
berbinium salts with sodium methylsulfinylmethylide in
DMSO. This procedure has provided two new nonnatural 8-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Tetrahydroprotoberberine alkaloids substituted in ring
position 8 constitute an uncommon group of isoquinoline
alkaloids that have been isolated from several sources. The
substitution pattern at the A or D rings is diverse and all
of the 8-substituted tetrahydroprotoberberines possess one
or more phenolic group at the D ring. However, only the
methyl, hydroxymethyl, and benzyl substituents at the C-8
position have been characterised from natural sources (Fig-
ure 1). 8-Methylberbines such as (Ϫ)-corytenchirine and
(Ϫ)-lienkonine were isolated from Corydalis spp. a long time
ago,[1] and more recently, four new 8-methyl derivatives
have been isolated from Aniba canelilla[2] and Croton Hemi-
argyreus.[3] (Ϫ)-Malacitanine is the first tetrahydroprotob-
erberine alkaloid described that contains a hydroxymethyl
substituent at the C-8 position;[4] (Ϯ)-solidaline also pos-
sesses this group, but the oxygen atom is bridged to the C-
14[5] in this case. Theoneberine constitutes a unique ex-
ample of a brominated 8-benzyltetrahydroprotoberberine
isolated from a marine organism, exhibiting antimicrobial
and cytotoxic activities.[6] Several 8-benzyltetrahydroproto-
berberines have been isolated from plant sources such as
Aristolochia sp.[7] or Gnetum parvifolium.[8] Javaberine A, re-
cently isolated from Talinum paniculatum, presents a 3,4-
dioxysubstituted benzyl moiety at C-8 and exhibits a strong
inhibitory activity on the lipopolysaccharide-induced tu-
mour necrosis factor.[9]
Figure 1. Structure of relevant 8-substituted tetrahydroprotober-
berine alkaloids
action of 1-benzyltetrahydroisoquinoline with aldehydes
under acidic conditions (disconnection a) constitutes a
classical route for systems with an activated C ring, but this
reaction lacks regio- and stereoselectivity.[4,10] This discon-
nection has also been exploited by the N-acylation of
1-benzylisoquinolines and subsequent acid catalysis[11] or
by photochemical cyclisation.[12] An alternative pathway
(disconnection
b),
based
on
the
classical
BischlerϪNapieralski[13] or PictetϪSpengler[14] cyclisations,
has been employed for 1-substituted N-(phenylethyl)tetra-
hydroisoquinoline to yield 8-alkyl- and 8-arylberbines. The
imminium annelation of C2Ј-functionalized 3-arylisoquino-
lines (disconnection c) has proved to be efficient for the syn-
thesis of 8-substituted tetrahydroprotoberberine based on a
double cyclization approach.[15] Finally, disconnection d,
Figure 2 shows the different strategies for the synthesis
of 8-substituted berbines. The intramolecular Mannich re-
[a]
´
´
Departamento de Quımica Organica, Facultad de Ciencias,
´
Universidad de Malaga,
´
Campus de Teatinos s/n Malaga, Spain
Fax (internat.): ϩ34-952-13-19-41
E-mail: mvalpuesta@uma.es
Eur. J. Org. Chem. 2004, 4313Ϫ4318
DOI: 10.1002/ejoc.200400443
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4313

M. Valpuesta, A. Diaz, R. Suau, G. Torres
SHORT COMMUNICATION
based on the introduction of the C-8 substituent, has also viously reported,[23] the signals for C-13 and N-CH2Ar are
been applied once the isoquinoline skeleton is formed. In shifted downfield for the cis configuration relative to those
this last case, protoberberinium salts[16] or 8-oxoprotober- for the trans salt, while the C-6 signal exhibits an upfield
berine alkaloids,[17] easily available through classical meth- shift. The reason for this behaviour is the influence of the
ods, are treated with organometallic reagents to yield the γ-gauche effect on the 13C NMR chemical shift.[24] These
corresponding 8-substituted berbines. The introduction of shifts can be used to assign the cis or trans configuration
substituents at C-8 can also be performed by photochemical to a berbinium salt, independent of the alkyl substituent
hydroxymethylation[18] or through the PolonovskiϪPotier introduced at the quaternary nitrogen atom.
reaction of berbine N-oxides.[19] A parallel strategy for the
insertion of a substituent at C-8 is based on Stevens re-
arrangement. This reaction has been used by Kametani et
al. for the synthesis of (Ϯ)-8β-methylcanadine and (Ϯ)-xilo-
pinine starting from the corresponding N-methyltetrahydro-
protoberberinium salts.[20] However, in this case, two path-
ways compete to yield spirobenzylisoquinoline as the major
product besides the 8-substituted berbine. In contrast, Tak-
emoto et al.[21] reported that base treatment of the N-meth-
ylcanadinium salt exclusively yields ochotensane-type alka-
loids and Hofmann elimination products.
Figure 3. Relevant 13C NMR spectroscopic data of the N-arylme-
thylcanadinium salts
When treated with a base, these salts may react through
two competitive pathways: Hofmann elimination and/or
Stevens rearrangement. The Hofmann elimination occurs
by hydrogen removal at C-5 and C-13 to provide 3-aryliso-
quinolines 7, 8 and dibenzoazecines 5, 6 in a ratio that
strongly depends on the base and solvent employed. Other-
Figure 2. Strategies for the synthesis of 8-substituted berbines
wise, the Stevens rearrangement exclusively yields 8-arylme-
As part of our studies on the synthesis of 8-substituted
berbines, we describe herein the use of the Stevens re-
arrangement to synthesise 8-benzylberbines.
thylberbines 3 and 4 (Figure 4) derived from a nitrogen yl-
ide formed at C-8.
Results and Discussion
The syntheses of N-benzyl- and N-(p-methoxybenzyl)-
canadinium bromide (1, 2; Figure 4) was achieved following
standard methods; both products were obtained as a mix-
ture of cis and trans diastereomers (cis-1/trans-1, 8:1; cis-2/
trans-2, 4:1). Typically, iodomethylation of tetrahydroproto-
berberines yields the trans diastereomer as the major prod-
uct, but in the benzylation reaction, the cis diastereoisomer
is the major product, probably due to steric and/or elec-
tronic factors. Both diastereomers were separated by frac-
tional crystallisation. Although analogous benzyl deriva-
tives have recently been described as sodium, potassium and
calcium ion channel inhibitors,[22] no spectroscopic data for
the pure diastereomers have been reported. We character-
Figure 4. Reaction of benzylcanadinium salts under basic medium
In Table 1 the yields obtained by treating N-benzylcanad-
ised these structures by standard spectroscopic methods. inium bromide (1) with different bases and solvents are
The H,H-NOESY experiment concludes that the trans salts shown. As can be seen, the elimination products 5 ϩ 7 are
possess a unique configuration, while the cis salts are in strongly favoured in hydroxylic solvents with medium bases,
equilibrium between two conformations of the B/C quinoli- while strong bases and highly polar nonprotic solvents fav-
zidine moiety, namely cis-1 and cis-2. The most significant our the Stevens rearrangement pathway. The behaviour of
13C NMR chemical shift of both configurations is shown N-(p-methoxybenzyl)canadinium bromide (2) was also
in Figure 3. Similarly to those for the N-methyl salts pre- evaluated following the same pattern. The most advan-
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Eur. J. Org. Chem. 2004, 4313Ϫ4318

Stevens Rearrangement of Benzyltetrahydroprotoberberinium Salts
SHORT COMMUNICATION
tageous conditions for the generation of the 8-benzyl- or 8- signals for C-6 and C-13 at δ ϭ 46.8 ppm and δ ϭ
(p-methoxybenzyl)canadine (3 or 4) make use of dimsylsod- 31.9 ppm, respectively, thus validating the major contri-
ium in DMSO; under these circumstances, no elimination bution of the cis-B/C quinolizidine conformation.
product was detected.
Table 1. Yields of 3 and 5 ϩ 7 under different conditions (esti-
1
mation based on the H NMR spectrum)
Base
Solvent
Percentage [%]
3
5 ϩ 7
tBuOH
THF
DMSO
tBuOH
THF
DMSO
Hexane
Benzene
THF
Ϫ
ഠ 50
ഠ 60
Ϫ
ഠ 50
ഠ 60
10
Ͼ 90
ഠ 50
ഠ 40
Ͼ 90
ഠ 50
ഠ 40
90
MeONa
tBuOK
HNa
Figure 6. a) Observed NOE effect for trans-3 and trans-4; b) Ob-
served NOE effect for cis-3 and cis-4
Under identical conditions, the trans-N-benzylcanadin-
ium salt (trans-1) yields only one product (trans-1) with a
trans-B/C quinolizidine junction, according to its nuclear
15
55
85
45
DMSO
NaCH2SOCH3 DMSO
70
100
30
Ϫ
magnetic resonance and infrared (Bohlmann’s bands[25]
)
spectra (see Table 2). This compound exhibits three intense
NOE effects between H-14, H-6 and H-8, proving a trans
relative configuration between the substituent at C-8 and
H-14 (Figure 6, b). The stereoselectivity of this rearrange-
ment is confirmed using trans-2 as a substrate.
When the optimized conditions for the Stevens re-
arrangement were used, the diastereomeric salts 1 or 2
yielded a mixture of diastereomers 3 or 4, respectively, that
can easily be separated by column chromatography. As is
expected, the diastereomers were isolated in a ratio similar
to the cis/trans ratio of the starting material as predicted by
stereochemical control of the rearrangement. In order to
confirm the stereochemical behaviour, we evaluated the re-
action with the diastereomerically pure derivatives. Thus,
treatment of the cis-(8-arylmethyl)canadinium salts (cis-1 or
cis-2) with dimsylsodium in DMSO stereoselectively yielded
the 8-arylmethylcanadine (cis-3 or cis-4) derivatives with a
cis configuration between H-14 and the substituent at C-
8 (Figure 5).
Table 2. Relevant spectroscopic data for the rearranged products
trans-3
trans-4
cis-3
cis-4
δ (H-14) [ppm]
δ (C-14) [ppm]
δ (C-6) [ppm]
δ (C-13) [ppm]
3.47
58.9
50.2
36.8
3.46
58.9
50.1
36.9
4.41
50.5
46.8
31.9
4.38
50.1
47.0
31.9
IR Bohlmann bands 2800, 2771 2802, 2768 absent absent
[cmϪ1
]
The great efficiency of these results reveals a high reactiv-
ity of the C-8 carbanion α to the quaternary nitrogen atom
relative to other potential ylides that can be produced at C-
14 or C-α. Once the nitrogen ylide is generated at C-8, the
subsequent step in the Stevens rearrangement implies the
generation of an imminium ion or an imminium radical in-
side a solvent cage.[26] Any of these pathways generate 7,8-
dehydrocanadine as the most stable imminium ion or rad-
ical, yielding the corresponding 8-substituted berbines. In
addition, no spirobenzylisoquinoline or benzazepine struc-
Figure 5. Stevens rearrangement of 1cis and 2cis
The H,H-NOESY experiment proves the relative configu- tures are detected, demonstrating that the C-8 ylide is the
ration between H-14 and H-8 by the presence of two intense only reactive species present in the reaction mixture. This
NOE effects between H-8 and H-6a and between H-14 and result differs from that previously reported,[20] which ac-
one hydrogen atom of the benzyl group (Figure 6, a). The counts for a C-14 ylide formation leading to spirobenzyliso-
quinolizidine moiety of berbine alkaloids can be present in quinoline as the major compound. The difference in reactiv-
three different conformations, which are in equilibrium in ity could be ascribed to the presence of the benzyl group,
solution. As a rule of thumb, in tetrahydroprotoberberines that probably assists C-8 hydrogen abstraction.
a high-field chemical shift for carbon atoms C-14, C-6 and
Furthermore, the observed diastereoselectivity indicates
C-13, as well as a deshielding of H-14 suggest a major con- that the rearrangement takes place to yield the product that
tribution of the cis-1 conformation to the equilibrium.[23] In requires minimum movement, retaining the initial configu-
our case, the spectrum for 8-benzylcanadine (cis-1) exhibits ration of the salt. Remarkably, when the reaction mixture
a signal for H-14 at δ ϭ 4.41 ppm (J ϭ 10.3, 6.1 Hz), and was quenched with deuterium oxide no deuterated com-
Eur. J. Org. Chem. 2004, 4313Ϫ4318
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Valpuesta, A. Diaz, R. Suau, G. Torres
SHORT COMMUNICATION
(12), 174 (12), 164 (38), 149 (41), 91 (100). FAB HRMS:
C27H28NO4 calcd. 430.2018; found 430.2007.
pound was isolated, suggesting that the C-8 ylide is present
at a very low concentration due to its high reactivity.
(؎)-cis-N-Benzylcanadinium Bromide (cis-1): White solid (2.5 g,
84%). M.p. 199Ϫ201°C (CH3COCH3). IR (KBr): ν˜ ϭ 1600, 1496,
1483, 1456, 1278 cmϪ1. UV (MeOH): λmax. (log ε) ϭ 206 (4.04),
236 (3.30), 290 (3.02) nm. 1H NMR (400 MHz, CDCl3): δ ϭ
7.6Ϫ7.5 (m, 2 H, H-2Ј, H-6Ј), 7.5Ϫ7.4 (m, 3 H, H-3Ј, H-4Ј, H-5Ј),
Conclusion
In conclusion, we have developed an efficient and short
approximation to the synthesis of 8-arylmethylberbines by
using a Stevens rearrangement in a diastereoselective ap-
proach through treatment of the corresponding N-(arylme-
thyl)berberinium salts with dimsylsodium in DMSO. This
method avoids the competition of alternative reactions such
as Hofmann elimination, to yield products that are derived
from a nitrogen ylide at C-8. Ongoing work in our labora-
tory involves the use of this reaction in the synthesis of
natural products containing this substitution pattern and
will be reported in due course.
3
6.85 (d, 3J ϭ 8.5 Hz, 1 H, H-11), 6.80 (d, J ϭ 8.5 Hz, 1 H, H-12),
6.73 (s, 2 H, H-1, H-4), 6.00, 5.99 (two s, 2 H, OCH2O), 5.46, 5.05
(two d, 3J ϭ 12.9 Hz, 1 H each, H-α, H-αЈ), 5.27 (dd, 3J ϭ 8.9,
3
6.0 Hz, 1 H, H-14), 4.98, 4.81 (two d, J ϭ 15.6 Hz, 1 H each, H-
8, H-8Ј), 4.6Ϫ4.4 (m, 1 H, H-6), 3.89, 3.80 (two s, 3 H each, 2 ϫ
OMe), 3.6Ϫ3.5 (m, 2 H, H-5, H-6Ј), 3.44 (dd, 3J ϭ 18.3, 6.0 Hz, 1
H, H-13), 3.15 (m, 1 H, H-5Ј), 3.11 (dd, 3J ϭ 18.3, 8.9 Hz, 1 H,
H-13Ј) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 151.3, 148.6, 147.4,
145.9 (C-2, C-3, C-9, C-10), 133.3 (C-2Ј, 6Ј), 130.7 (C-4Ј), 129.2
(C-3Ј, 5Ј), 126.7, 124.7, 121.9, 120.3, 119.8 (C-1Ј, C-4a, C-8a, C-
12a, C-14a), 123.3 (C-12), 113.2 (C-11), 109.1, 106.7 (C-1, C-4),
101.6 (OCH2O), 62.7 (C-14), 62.4 (CH2Ph), 61.3, 55.9 (2 ϫ OMe),
53.6 (C-8), 49.5 (C-6), 33.2 (C-13), 23.7 (C-5) ppm. EI MS: m/z ϭ
339 (22) [M Ϫ 91], 338 (15), 174 (16), 164 (47), 149 (49), 91 (100).
FAB HRMS: C27H28NO4 calcd. 430.2018; found 430.2001.
Experimental Section
General Remarks: Melting points were determined with a Gallenk-
amp instrument and are given uncorrected. UV spectra were re-
corded with a HewlettϪPackard 8452A spectrophotometer and IR
spectra with a PerkinϪElmer 883 spectrophotometer. EI MS were
recorded with a HP-MS 5988A spectrometer operating at 70 eV.
HRMS were recorded with a VG Autospec spectrometer. EI
HRMS were recorded with m-nitrobenzyl alcohol as the matrix.
NMR spectra were obtained with a Bruker WP-200 SY instrument
(؎)-trans-N-(p-Methoxybenzyl)canadinium
Bromide
(trans-2):
White solid (472 mg, 15%). M.p. 194Ϫ195°C. IR (KBr): ν˜ ϭ 1610,
1514, 1500, 1460, 1280 cmϪ1. UV (MeOH): λmax. (log ε) ϭ 208
(4.04), 224 (3.45), 290 (3.18) nm. 1H NMR (400 MHz,
3
CDCl3ϩTFA): δ ϭ 7.12 (d, J ϭ 8.5 Hz, 1 H, H-12), 7.06 (d, 3J ϭ
3
8.8 Hz, 2 H, H-2Ј, H-6Ј), 7.03 (d, J ϭ 8.5 Hz, 1 H, H-11), 6.93 (d,
3J ϭ 8.8 Hz, 2 H, H-3Ј, H-5Ј), 6.83, 6.75 (two s, 1 H each, H-1, H-
at 200 MHz for H and 50.3 MHz for 13C. H chemical shifts are
given relative to residual CHCl3 (δ ϭ 7.24 ppm) in deuteriochloro-
form. 13C chemical shifts are given relative to CDCl3 (δ ϭ
77.0 ppm) in deuteriochloroform.
1
1
3
4), 6.01, 5.99 (two s, 2 H, OCH2O), 5.59 (dd, J ϭ 12.5, 5.8 Hz, 1
3
H, H-14), 4.88, 4.68 (two d, J ϭ 15.9 Hz, 1 H each, H-8, H-8Ј),
4.2Ϫ4.1 (m, 1 H, H-6), 4.03 (s, 2 H, H-α, H-αЈ), 4.0Ϫ3.9 (dd, 3J ϭ
17.4, 5.8 Hz, 1 H, H-13), 3.92, 3.84, 3.83 (three s, 3 H each, 3 ϫ
OCH3), 3.55 (m, 1 H, H-6Ј), 3.45 (m, 1 H, H-5), 3.30 (m, 1 H, H-
5Ј), 3.24 (dd, 3J ϭ 17.4, 12.5 Hz, 1 H, H-13Ј) ppm. 13C NMR
(50 MHz, CDCl3ϩTFA): δ ϭ 161.6 (C-4Ј), 151.6, 148.6, 148.1,
145.0 (C-2, C-3, C-9, C-10), 133.3 (C-2Ј, 6Ј), 124.7 (C-12), 123.1,
122.1, 121.6, 120.1, 116.7 (C-1Ј, C-4a, C-8a, C-12a, C-14a), 115.1
(C-3Ј, 5Ј), 113.6 (C-11), 108.5, 105.5 (C-1, C-4), 101.8 (OCH2O),
66.8 (C-14), 61.3, 55.8, 55.5 (3 ϫ OMe), 56.7 (C-8), 55.9 (C-6), 51.5
(CH2Ph), 29.0 (C-13), 24.3 (C-5) ppm. EI MS: m/z ϭ 339 (16) [M
Ϫ 91], 338 (12), 174 (12), 164 (38), 149 (41), 91 (100). FAB HRMS:
C28H30NO5 calcd. 460.2124; found 460.2102.
Preparation of 1 and 2: The corresponding benzyl bromide
(8.3 mmol) was added to
a solution of (Ϯ)-canadine (2 g,
5.90 mmol) in dried acetone (200 mL) under argon . After stirring
at room temperature for 12 h, a mixture of cis/trans isomers was
obtained. The solution was filtered, and the solid was recrystallized
twice in chloroform to yield the pure trans diastereoisomer. The
organic phases were concentrated under vacuum to yield the cis
diastereoisomer.
(؎)-trans-N-Benzylcanadinium Bromide (trans-1): White solid
(241 mg, 8%). M.p. 188Ϫ189°C (CHCl3). IR (KBr): ν˜ ϭ 1610,
1500, 1460, 1280 cmϪ1. UV (MeOH): λmax. (log ε) ϭ 208 (4.04),
(؎)-cis-N-(p-Methoxybenzyl)canadinium Bromide (cis-2): White
228 (3.55), 290 nm (3.18). 1H NMR (400 MHz, CDCl3ϩTFA): δ ϭ solid (2.2 g, 70%). M.p. 177Ϫ178°C. IR (KBr): ν˜ ϭ 1610, 1500,
3
3
7.50 (t, J ϭ 8.0 Hz, 1 H, H-4Ј), 7.44 (t, J ϭ 8.0 Hz, 2 H, H-3Ј, 1460, 1285 cmϪ1. UV (MeOH): λmax. (log ε)ϭ 206 (4.02), 230
H-5Ј), 7.14 (d, 3J ϭ 8.0 Hz, 2 H, H-2Ј, H-6Ј), 7.12 (d, 3J ϭ 8.6 Hz, (3.35), 290 (3.06) nm. H NMR (400 MHz, CDCl3): δ ϭ 7.49 (d,
1 H, H-12), 7.03 (d, J ϭ 8.6 Hz, 1 H, H-11), 6.84, 6.76 (two s, 1
1
3
3
3J ϭ 8.7 Hz, 2 H, H-2Ј, H-6Ј), 6.90 (d, J ϭ 8.7 Hz, 2 H, H-3Ј, H-
3
H each, H-1, H-4), 6.01, 5.98 (two s, 1 H each, OCH2O), 5.68 (dd, 5Ј), 6.83, 6.77 (two d, J ϭ 8.5 Hz, 1 H each, H-11, H-12), 6.71 (s,
3
3J ϭ 11.7, 5.3 Hz, 1 H, H-14), 4.99 (d, J ϭ 16.0 Hz, 1 H, H-8),
2 H, H-1, H-4), 6.0Ϫ5.9 (m, 2 H, OCH2O), 5.33, 4.94 (two d, 3J ϭ
3
3
4.69 (d, J ϭ 16.0 Hz, 1 H, H-8Ј), 4.31 (m, 1 H, H-6), 4.09, 4.05 13.1 Hz, 1 H each, H-α, H-αЈ), 5.12 (dd, J ϭ 9.3, 6.0 Hz, 1 H, H-
3
3
(two d each, J ϭ 13.7 Hz, 1 H, H-α, H-αЈ), 3.97 (dd, J ϭ 17.7,
14), 4.91, 4.79 (two d, 3J ϭ 15.9 Hz, 1 H each, H-8, H-8Ј), 4.38
5.3 Hz, 1 H, H-13), 3.91, 3.83 (two s, 3 H each, 2 ϫ OCH3), (m, 1 H, H-6), 3.88, 3.79, 3.77 (three s, 3 H each, 3 ϫ OMe),
3
3.55Ϫ3.44 (m, 2 H, H-5, H-6Ј), 3.30 (m, 1 H, H-5Ј), 3.22 (dd, 3J ϭ 3.55Ϫ3.45 (m, 2 H, H-5, H-6Ј), 3.41 (dd, J ϭ 18.4, 6.0 Hz, 1 H,
17.7, 11.7 Hz,
1
H, H-13Ј) ppm. 13C NMR (50 MHz, H-13), 3.15 (m, 1 H, H-5Ј), 3.08 (dd, 3J ϭ 18.4, 9.3 Hz, 1 H, H-
CDCl3ϩTFA): δ ϭ 151.6, 148.6, 148.0, 145.1 (C-2, C-3, C-9, C-
13Ј) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 161.2 (C-4Ј), 151.3,
10), 132.1 (C-2Ј, C-6Ј), 131.2 (C-4Ј), 129.8 (C-3Ј, C-5Ј), 125.4, 148.5, 147.3, 145.7 (C-2, C-3, C-9, C-10), 134.7 (C-2Ј, 6Ј), 124.7,
123.2, 122.2, 121.6, 120.2 (C-1Ј, C-4a, C-8a, C-12a, C-14a), 124.7 122.0, 120.4, 119.9, 118.3 (C-1Ј, C-4a, C-8a, C-12a, C-14a), 123.2
(C-12), 113.6 (C-11), 108.6, 105.7 (C-1, C-4), 101.8 (OCH2O), 67.3 (C-12), 114.5 (C-3Ј, 5Ј), 113.2 (C-11), 109.1, 106.6 (C-1, C-4), 101.6
(C-14), 61.6, 56.0 (2 ϫ OMe), 57.4, (C-8), 56.2 (C-6), 52.0 (CH2Ph),
(OCH2O), 62.4 (C-14, CH2Ph), 61.2, 55.8, 55.3 (3 ϫ OMe), 53.4
29.2 (C-13), 24.5 (C-5) ppm. EI MS: m/z ϭ 339 (16) [M Ϫ 91], 338 (C-8), 49.6 (C-6), 33.3 (C-13), 23.7 (C-5) ppm. EI MS: m/z ϭ 339
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Eur. J. Org. Chem. 2004, 4313Ϫ4318

Stevens Rearrangement of Benzyltetrahydroprotoberberinium Salts
(24) [M Ϫ 121], 174 (16), 164 (47), 149 (46), 121 (100). FAB (C-4), 106.6 (C-1), 100.6 (OCH2O), 63.1 (C-8), 60.3, 55.8, 55.1 (3
SHORT COMMUNICATION
HRMS: C28H30NO5 calcd. 460.2124; found 460.2117.
ϫ OMe), 50.1 (C-14), 47.0 (C-6), 39.6 (C-α), 31.9 (C-13), 29.9 (C-
5) ppm. EI MS: m/z ϭ 459 (0.3) [Mϩ], 458 (0.3), 339 (23), 338 (100),
121 (23). EI-HRMS: C28H29NO5 calcd. 459.2046; found 459.2047.
General Method for the Stevens Rearrangement: A solution of HNa
(3.71 mmol) in DMSO (5 mL, 65 mmol) was stirred for 90 minutes
at 80°C. Once the dimsylsodium was formed, the corresponding
canadinium salt (0.49 mmol) was added, and the mixture stirred
for 5 h. The reaction was monitored by 1H NMR spectroscopy and
TLC. The reaction mixture was poured onto ice, the white precipi-
tate was filtered off, and the corresponding 8-substituted canadine
purified by column chromatography (CHCl3). The yields of isolated
product decreased to a great extent due to the lability of these de-
(8S*,14S*)-8-(p-Methoxybenzyl)canadine (trans-4): Yellowish solid
(43% after purification). M.p. 137Ϫ138°C. IR (CHCl3): ν˜ ϭ 3027,
3011, 2957, 2936, 2909, 2802, 2768, 1606, 1509, 1484, 1245, 1235
3
cmϪ1
.
1H NMR (400 MHz, CDCl3): δ ϭ 6.88 (d, J ϭ 8.2 Hz, 2
3
H, H-2Ј, H-6Ј), 6.73, 6.69 (two d, J ϭ 8.5 Hz, 1 H each, H-11, H-
12), 6.60 (d, J ϭ 8.2 Hz, 2 H, H-3Ј, H-5Ј), 6.67 (s, 1 H, H-1), 6.56
3
(s, 1 H, H-4), 5.87 (s, 2 H, OCH2O), 4.16 (bs, 1 H, H-8), 3.94, 3.87,
3
1
3.70 (three s, 3 H each, 3 ϫ OMe), 3.46 (d, J ϭ 11.3 Hz, 1 H, H-
rivatives, although the crude H NMR spectrum exhibited a pure
14), 3.05 (dd, 3J ϭ 13.4, 3.0 Hz, 1 H, H-α), 2.91 (dd, 3J ϭ 13.4,
5.4 Hz, 1 H, H- αЈ), 3.1Ϫ2.9 (m, 2 H, H-5, H-6), 2.82 (d, 3J ϭ
14.0 Hz, 1 H, H-13), 2.56 (m, 1 H, H-6Ј), 2.46 (m, 1 H, H-5Ј), 2.18
(dd, 3J ϭ 14.0, 11.3 Hz, 1 H, H-13Ј) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 157.6 (C-4Ј), 150.7 (C-10), 145.8, 145.7, 145.3 (C-2,
C-3, C-9), 131.8, 131.6 (C-1Ј, C-4a, C-8a), 130.8 (C-12a), 127.6 (C-
14a), 131.2 (C-2Ј, C-6Ј), 122.8 (C-12), 112.6 (C-3Ј, C-5Ј), 110.4 (C-
11), 108.4 (C-4), 105.5 (C-1), 100.6 (OCH2O), 62.0 (C-8), 60.4
(OMe), 58.9(C-14), 55.9, 55.1 (2 ϫ OMe), 50.1 (C-6), 41.4 (C-α),
36.9 (C-13), 30.7 (C-5) ppm. EI MS: m/z ϭ 459 (0.1) [Mϩ], 458
(0.3), 339 (22), 338 (100), 121 (21).
product resulting from the Stevens rearrangement.
(8R*,14S*)-8-Benzylcanadine (cis-3): White solid (45% after purifi-
cation). M.p. 120Ϫ121°C. IR (CHCl3): ν˜ ϭ 3027, 3007, 2960, 2908,
1
1603, 1502, 1485, 1277, 1232 cmϪ1. H NMR (400 MHz, CDCl3):
δ ϭ 7.34 (d, 3J ϭ 7.5 Hz, 2 H, H-2Ј, H-6Ј), 7.24 (dd, 3J ϭ 7.5,
3
7.0 Hz, 2 H, H-3Ј, H-5Ј), 7.16 (t, J ϭ 7.0 Hz, 1 H, H-4Ј), 6.78 (s,
2 H, H-11, H-12), 6.65 (s, 1 H, H-1), 6.54 (s, 1 H, H-4), 5.90 (s, 2
H, OCH2O), 4.41 (dd, 3J ϭ 10.3, 6.1 Hz, 1 H, H-14), 4.19 (dd,
3J ϭ 9.4, 1.8 Hz, 1 H, H-8), 3.90, 3.86 (two s, 3 H each, 2 ϫ OMe),
3.03 (dd, 3J ϭ 14.1, 9.4 Hz, 1 H, H-α), 2.92 (dd, 3J ϭ 14.1, 1.8 Hz,
1 H, H-αЈ), 2.90Ϫ2.70 (m, 4 H, H-6, H-13, H-13Ј, H-5), 2.57Ϫ2.51
(m, 2 H, H-5Ј, H-6Ј) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 150.4
(C-10), 145.9 (C-9), 145.7, 145.6 (C-2, C-3), 142.0 (C-1Ј), 132.6,
132.3 (C-4a, C-8a), 129.4 (C-2Ј, C-6Ј), 127.9 (C-3Ј, C-5Ј), 127.6,
127.0 (C-12a, C-14a), 125.8 (C-4Ј), 123.8 (C-12), 111.7 (C-11),
108.9 (C-4), 106.0 (C-1), 100.6 (OCH2O), 62.9 (C-8), 60.5, 56.0 (2
ϫ OMe), 50.5 (C-14), 46.8 (C-6), 40.4 (C-α), 31.9 (C-13), 30.0 (C-
5) ppm. EI MS: m/z ϭ 429 (0.1) [Mϩ], 428 (0.1), 339 (22), 338 (100),
91 (20). EI HRMS: C27H27NO4 calcd. 429.1940, found 429.1922.
Acknowledgments
This work was supported by the DGES (PB97Ϫ1077). Thanks to
University of Vigo (C.A.C.T.I.) for providing EI and FAB HRMS
analysis.
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(C-10), 145.8, 145.7, (C-2, C-3), 145.3 (C-9), 139.5 (C-1Ј), 131.8 (C-
4a, C-8a), 130.7 (C-12a), 128.6 (C-14a), 130.4 (C-2Ј, C-6Ј), 127.2
(C-3Ј, C-5Ј), 125.5 (C-4Ј), 122.7 (C-12), 110.3 (C-11), 108.4 (C-4),
105.5 (C-1), 100.6 (OCH2O), 62.0 (C-8), 60.4 (OMe), 58.9 (C-14),
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3
(dd, J ϭ 9.9, 7.3 Hz, 1 H, H-14), 4.15 (dd, J ϭ 9.2, 3.1 Hz, 1 H,
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4318
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4313Ϫ4318