The Polonovski-Potier reaction of berbine N-oxides. Synthesis of 8-hydroxymethyl and 8-methylberbines

Article abstract of DOI:10.1016/S0040-4020(00)00945-5

The Polonovski-Potier reaction of trans and cis berbines N-oxides was studied. The 8-cyano derivative obtained from trans N-oxides were used to synthesize 8-hydroxymethyl and 8-methyl berbines. This procedure was applied to the stereocontroled synthesis of (8R, 14S)-(-)-8-methylcanadine from (14S)-(-)-canadine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00945-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9713±9723
The Polonovski±Potier Reaction of Berbine N-Oxides. Synthesis
of 8-Hydroxymethyl and 8-Methylberbines
*
Rafael Suau, Francisco Najera and Rodrigo Rico
Â
   Â
Departamento de Quõmica Organica, Facultad de Ciencias, Universidad de Malaga, 29071 Malaga, Spain
Received 5 June 2000; revised 22 September 2000; accepted 5 October 2000
AbstractÐThe Polonovski±Potier reaction of trans and cis berbines N-oxides was studied. The 8-cyano derivative obtained from trans
N-oxides were used to synthesize 8-hydroxymethyl and 8-methyl berbines. This procedure was applied to the stereocontroled synthesis of
(8R, 14S)-(2)-8-methylcanadine from (14S)-(2)-canadine. q 2000 Elsevier Science Ltd. All rights reserved.
The protoberberines are a class of isoquinoline alkaloids
characterized by the dibenzo[a,g]quinolizidine ring system,
with oxygenated substituents at rings A and D. A number of
this class of alkaloids with alkyl substituted in ring C are
also known.1 Various tetrahydroprotoberberine alkaloids
(berbines) with a C-8 substituent have been isolated as
minor components from plants, including corytenchirine
(1, RˆH) from Corydalis ochotensis,2 solidaline (2) from
Corydalis solida,3 malacitanine (3) from Ceratocapnos
heterocarpa4 and the benzylberbinol 4 from Aristolochia
constricta (Fig. 1).5
occurring tetrahydroprotoberberine alkaloids to enantiopure
C-8 alkyl substituted protoberberines may be the selective
oxidation to the 7,8-dehydro derivative and insertion of the
substituent as a nucleophile (Scheme 2).
The partial oxidation of berbines (tetrahydroprotober-
berines) to the corresponding 7,8-dehydroberbines with
iodine is of limited use since only berbines substituted at
position 1, with a preferred cis-B/C-quinolizidine confor-
mation, give the reaction.9 Predictably, functionalization
The total syntheses of C-8 substituted berbines has been
accomplished by formation of ring C from benzylisoquino-
line using a biogenetic approach.4,6 Also, partial syntheses
of racemic C-8 alkyl substituted berbines have been
achieved by inserting the substituent on aromatic ber-
berinium salts in two different ways: (i) by addition of
carbon nucleophiles at the suf®ciently electrophilic position
8 [in this way, (^)-8-methylcanadine, (^)-6, was synthe-
sized from berberine chloride (5) by reaction with MeMgI,
followed by reduction with NaBH4];7 (ii) and by hydroxy-
methylation of berberinium salts by photoinduced single
electron transfer and reduction as in the recently reported
synthesis of (^)-solidaline (2) from palmatine chloride.8
The asymmetric synthesis of (8R, 14S)-(2)-8-methyl-
canadine [(2)-6)] was accomplished by regioselective
complexation of enantiopure (2)-canadine [(2)-7] to
Cr(CO)3, separation of the diasteroisomers, silylation at
position 11 (followed by a stereoselective deprotonation at
C-8) and addition of MeI (Scheme 1).7
One alternative approach to transforming chiral, naturally
Keywords: alkaloids; isoquinolines; Polonovski reaction; protoberberines.
* Corresponding author. Tel.: 134-95-213-1934; fax: 134-95-213-1941;
e-mail: suau@uma.es
Figure 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00945-5

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R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
Scheme 1.
The Polonovski±Potier reaction of trans-berbine
N-oxides
The trans N-oxides, with a rigid trans-B/C-quinolizidine
junction (I),12 possess three hydrogens (H-6ax, H-8ax and
H-14) in an anti-periplanar arrangement with respect to the
oxygen in the N-oxide function, so they could yield three
different iminium salts in the Polonovski reaction (Fig. 3).
Scheme 2.
of C-8 berbines is also possible by the Polonovski±Potier
reaction (viz. the modi®ed Polonovski reaction), by which
an N-oxide is converted into an iminium ion intermediate.10
In this paper, we report on the differential behavior of cis-
and trans-berbines N-oxides towards the modi®ed Polo-
novsky reaction.11 The synthetic applications of the reaction
leading to 8-hydroxymethyl and 8-methyl berbines are also
described.
The reaction of trans-canadine N-oxide under Polonovski±
Potier conditions (TFAA 15 equiv., in CHCl3, at 2308C for
30 min and then allowing to rise to 258C) was monitored by
1H and 13C NMR. After complete disappearance of the
N-oxide, only two products were formed, in a 37:63 ratio,
the structures of which were tentatively assigned as 7,8-
1
dehydrocanadine (14) and 7,14-dehydrocanadine (15). H
NMR data for 15 matched those for the protonated 13,14-
dehydrocanadine (1TFA). A low-®eld singlet (9.25 ppm)
and a benzyl iminium carbon (163.3 ppm) suggested struc-
ture 14. NaBD4 reduction of the mixture of iminium salts 14
and 15 gave a mixture of 8-d-canadine and 14-d-canadine as
inferred from the retro Diels±Alder fragmentation in the
mass spectra (Scheme 3).
Results and Discussion
The 9,10-substituted, readily accessible, trans- and cis-
canadine N-oxides [(2)-8, (^)-8 and (^)-9], the 10,11-
substituted trans-(^)-xylopinine N-oxide (11) and trans-
(^)-thalictricavine N-oxide (10), were selected for this
study (Fig. 2).12,13
A similar behavior was observed in the other trans
N-oxides. Thalictricavine N-oxide (10) underwent H-14
elimination to a much greater extent (18:82 ratio) than
H-8 elimination; on the other hand xylopinine N-oxide
(11) yielded the 7,8-dehydroxylopinine as the main product
(64:36 ratio), probably re¯ecting the substantial effect of the
substituent on C-9 on the course of the reaction. In all cases,
(^)-Canadine [(^)-7] was prepared by reduction of berber-
ine chloride (5). Enantiomer (2)-7 was obtained by resolu-
tion of racemic canadine by fractional crystalization with
(1)-di-O,O0-p-toluoyl-d-tartaric acid.14 (^)-Xylopinine
(12) was synthesized by cyclization of N-norlaudanosine.15
(^)-Thalictricavine (13), a 13-methyl canadine with a trans
stereochemistry relative to H-14, was obtained by methyl-
ation of 13,14-dehydrocanadine, available from the partial
reduction of 5.16 The corresponding N-oxides were prepared
by reaction with mCPBA. Only in the case of (^)-canadine
was a large enough amount of the cis isomer available to
study its reactivity.
Figure 3.
Figure 2.

R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
9715
Scheme 3.
1
Table 1. Regioselectivity of the Polonovski reaction of trans-berbine N-oxides as determined by H NMR
Activating agent
Temperature (8C)
Reaction time (h)
(^)-8
(^)-10
7,8-dehydro/7,14-dehydro ratio
(^)-11
TFAA
AcCl
MsCl
230 to 125
25
60
1
2
2
37/63
39/61
18/82
20/80
49/51a
64/36
50/50
58/32a
84/16a
a Characterized as the corresponding protoberberinium salt.
the absence of 6,7-dehydro derivatives was signi®cant; it
probably resulted from the weak acidity of H-6 and the
lower stability of the corresponding iminium ion.
H-8 (Fig. 4). A cis-B/C-quinolizidine conformation was
inferred from the 13C NMR signals at 55.1 (C-14), 48.9
(C-6) and 36.4 ppm (C-13).18
Acetyl chloride as activating agent provided quite similar
results; the reaction however, was slower. Mesyl chloride
required heating at 608C for the reaction to start. The prefer-
ential formation of the 7,8-dehydro derivatives may be due
to a concomitant intramolecular syn-elimination of H-8eq
together with the normal anticoplanar H-8ax elimination
(Table 1).17
The high diastereoselectivity observed, with the cyano
group in an axial position, reveals that the attack on the
Re face is favored, a ®nding that is not unprecedented.19
Semi-empirical calculations (PM3) for both 8-cyanocana-
dine diastereoisomers indicate that the cis isomer (16) is
2.3 kcal more stable than the trans isomer, which suggests
that the reaction is thermodynamically controlled.20
7,8- and 7,14-Dehydroberbines proved highly prone to
oxidation (particularly the latter, which aromatized easily
to the protoberberinium salt); attempts at isolating them
were unsuccessful. Therefore, the Polonovski±Potier reac-
tion was conducted under the conditions described above,
with the ®nal addition of KCN in a saturated aqueous solu-
tion of NaOAc to trap the iminium ion formed. After the
reaction of (^)-8 with TFAA, addition of cyanide and
preparative TLC afforded berberine (5) and crystalline
(8Rp, 14Sp)-(^)-8-cyano-canadine [(^)-16, 29%]. The
absence of the 14-cyano derivative can be ascribed to
the reaction pH rising upon addition of the KCN/NaOAc
solution, the 7,14-dehydro iminium ion (15) tautomerizing
to the enamine (13,14-dehydrocanadine), which is readily
oxidized.
The Polonovski±Potier reaction of trans-(^)-xylopinine
N-oxide (11) (TFAA), with subsequent addition of KCN,
Although two 8-cyanoderivatives were to be expected from
the addition of KCN to 7,8-dehydrocanadine (14), only
diastereoisomer (16), with a cis arrangement between
H-14 and the cyano group, was observed. The stereo-
chemistry of 16 was established from the observed nOe
between H-8 and both hydrogens of the methylene group
at C-6, and also from the absence of nOe between H-14 and
Figure 4.

9716
R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
Two elimination processes could therefore be expected to
occur leading to the 6,7- and 7,8-dehydro derivatives.
The Polonovski±Potier reaction of (^)-9 with TFAA,
followed by H NMR, suggested a much complex process
1
than with the trans isomer: the 7,8-dehydrocanadine was the
only product identi®ed in the complex mixture. Neutrali-
zation of the reaction crude and chromatography allowed
the isolation of two tertiary bases that were characterized as
(^)-5a-hydroxycanadine (19), and its C-5 epimer, (^)-5b-
hydroxycanadine (20) (in 9 and 10% yield, respectively).
When the reaction was performed with ®nal addition of
KCN, 16 (15%) was isolated together with 19 (9%) and
20 (11%) (Scheme 4).
Figure 5.
The relative stereochemistry of the hydroxy group in 19 and
20 was derived from the H NMR signal for H-5. In the
1
a-isomer 19, H-5 gives a broad singlet at 4.48 ppm; in the
b-isomer 20, the H-5 signal appears down®eld (4.81 ppm),
as a dual doublet (J5,6axˆ7.5 Hz and J5,6eqˆ4.0 Hz). These
data are in agreement with those reported for other synthetic
5-hydroxy protoberberines.22
Scheme 4.
There is at least one precedent of an analogous incorpora-
tion of a hydroxyl group in the Polonovski±Potier reaction
of a cis-quinolizidine N-oxide. Thus, the reaction of Na,O-
di-Boc-Z-geissoschizine cis-Nb-oxide with TFAA afforded
Na,O-di-Boc-6a-hydroxy-Z-geissoschizine in a 3% yield;
no explanation for the process was proposed, however.23
gave (8Sp, 14Sp)-(^)-8-cyanoxylopinine (17) in a 49%
yield, together with pseudopalmatine, the quaternary form
of xylopinine. Compound 17 also exhibits a cis-B/C-quino-
lizidine conformation with the cyano group cis to H-14.
trans-(^)-Thalictricavine N-oxide (10) was reacted with
MsCl to give the corresponding cyanide, 18, after work up.
The formation of these unexpected compounds suggests that
the C-5 becomes an electrophilic site. The simplest possible
process would start with the expected elimination of H-6
leading to the key intermediate 6,7-dehydrocanadine (21)
(Scheme 5). Tautomeric equilibrium with the enamine
(22) and reprotonation at C-6 (23) induced by the oxygen
at C-2 would allow the attack of the TFA anion on C-5.
The Polonovski±Potier reaction of cis-canadine N-oxide
cis-(^)-Canadine N-oxide (9) occurs in a cis-B/C-quino-
lizidine conformation,12 so the N-oxide bond (Fig. 5) is in
a quasi-antiperiplanar arrangement respect to H-6 (II) and
H-8 (III), while H-14 is in a syn-coplanar arrangement.21
This hypothesis was tested by examining the behavior of
5,6-dehydroberbines. The most readily accessible 5,6-de-
hydroxylopinine (24) (Scheme 6), was prepared by
condensation of papaverine with DMF/POCl3 to give
5,6-dehydropseudopalmatine, followed by ring-C reduc-
tion.24 Quantitative protonation of 24 provided the 6,7-
dehydroxylopinine (25), subjection of which to Polo-
novski±Potier reaction conditions resulted in no 5-hydroxy
derivatives only the 6-cyanoxylopinine (26) was isolated.
Moreover, treating the enamine 24 with TFA-d resulted in
no incorporation of deuterium on C-6 which was to be
expected if the oxygen at C-2 were involved in the process.
These ®ndings seemingly exclude the participation of a
Scheme 5.
Scheme 6.

R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
9717
Scheme 7.
6,7-dehydroberbine as a common intermediate leading to
both the 6-cyano and the 5-hydroxy products.
(29a) and (8Sp, 14Sp)-8-hydroxymethylxylopinine (29b) in
70% and 91% yield, respectively (Fig. 6).
It does not seem unreasonable to postulate a mechanism
involving aromatic ring A (Scheme 7). The loss of tri¯uor-
acetate from the N-oxide may be assisted by the oxygen at
C-3 to yield the aziridinium dication IV, the deprotonation
of which would give the aziridinium monocation V, from
which compounds 19 and 20 can be obtained.
The addition of MeMgBr at C-8 of berberine chloride,
followed by hydride reduction, is highly diastereoselective;
entry of the hydride occurs exclusively from the less
hindered face away from the substituent.7 We realized that
this sequence could be used with cyanide as the nucleophile,
thus opening alternative access to 8-hydroxymethylberbines
in a 8Rp, 14Sp-con®guration.
A
similar mechanism was tentatively proposed by
Danishefsky to explain the anomalous results of the
Polonovski reaction of mitosane derivatives.25 More
recently, Potier also described an unusual intramolecular
oxygen transfer in the Polonovski reaction of the
Amarillidaceae alkaloid galanthamine N-oxide, a process
that neither involves an iminium ion as intermediate.26
In fact, addition of KCN to a methanolic solution of ber-
berine chloride (5) gave 8-cyano-13,14-dehydrocanadine
(30) quantitatively; however, addition of NaBH4 was
found to remove the substituent and cause the reduction to
(^)-7. Elimination of the substituent was avoided by a
previous transformation to the amide 31.
As expected, reduction of (^)-8-carbamoyl-13,14-dehydro-
canadine (31) gave (8Rp, 14Sp)-(^)-8-carbamoylcanadine
(32) with the predicted stereochemistry. The nOe observed
between H-8, H-6ax and H-14, and the down®eld appearance
of C-14 in the 13C NMR spectra suggested a trans-B/C-
quinolizidine conformation with trans arrangement between
H-14 and the carbamoyl group, for the amide 32. Trans-
formation into the methyl ester 33 and reduction afforded
the epimeric (8Rp, 14Sp)-(^)-8-hydroxymethylcanadine
(34) (Scheme 8).8
Synthetic applications
We recently found the photoaddition of methanol to proto-
berberinium ions to take place in a regioselective manner at
position 8, with subsequent stereoselective reduction
yielding (8Rp, 14Sp)-hydroxymethylberbines with a trans
arrangement between H-14 and the substituent.8 As stated
above, the Polonovski±Potier reaction of the trans-berbine
N-oxides gave the corresponding cis-cyanides; conse-
quently, the reaction could be used to prepare (8Sp, 14Sp)-
8-hydroxymethylberbines such as 29a and 29b, which are
epimeric with those provided by the photochemical
approach.
8-Methylberbines can be synthesized by conversion of the
cyano derivatives into 7,8-dehydroberbinium ions, followed
by addition of methyl magnesium iodide. However, direct
treatment of the cyano derivatives with the Grignard reagent
gave higher yields, in a stereoselective reaction where the
The reaction sequence involved in these transformation is as
follows:27 (i) rigorously controlled hydrolysis of the cyano
derivatives 16 and 17 (conc HCl at 08C) to afford the
8-carbamoylberbines (27a and 27b, in 50% and 75%
yields); (ii) quantitative conversion of these amides to the
methyl ester derivatives 28a and 28b by use of the acid resin
Amberlitew IR-120 in methanol; and (iii) reduction with
LiAlH4 to obtain (8Sp, 14Sp)-8-hydroxymethylcanadine
Figure 6.
Scheme 8.

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R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
photometer and IR spectra on a Perkin±Elmer 883 spectro-
photometer. Low resolution mass spectra were recorded on
a HP-MS 5988a, and high resolution MS were recorded on a
Kratos MS 50 or a VG Autospec M spectrometers, operating
at 70 eV. NMR spectra were obtained on Bruker WP-200
SY at 200 MHz for 1H, and at 50.3 MHz for 13C. 1H Chemical
shifts (dH) are given relative to residual CHCl3 (dH
7.24 ppm) in deuteriochloroform. Jˆvalues are in Hz. 13C
Chemical shifts (dC) are given relative to CDCl3 (dC
77.0 ppm) in deuteriochloroform. TLC analyses were
performed on silica gel 60 F 256 plates, and column
chromatography was carried out on silica gel 60 (70±230
mesh).
(^)-Canadine, (^)-7. Was prepared by NaBH4 reduction
of a methanolic solution of berberine chloride obtained from
roots of Berberis vulgaris subsp australis.29 White crystals;
mp 167±1688C (MeOH), [lit: 169±1708C].1
(2)-Canadine, (2)-7. Was obtained by fractional crystal-
lization of an equimolecular mixture (1)-Di-O,O0-p-
toluoyl-d-tartaric acid and (^)-canadine, dissolved in the
minimum amount of MeOH. White crystals; mp 131±
1328C (MeOH); [a]2D0ˆ2306 (c 1.0, CHCl3) [lit: 131±
1328C (MeOH), [a]2D0ˆ2298 (c 1.05, CHCl3)].14
Scheme 9.
methyl group retained the con®guration of the cyano
group.28 In this way, O-methylcorytenchirine (1, RˆMe)
was prepared in a 80% yield.
(^)-Xylopinine, 12. Was synthesized by re¯uxing (^)-N-
norlaudanosine hydrochloride and 35% aqueous formalde-
hyde; mp 146±1488C (MeOH), [lit: 148±1498C].1
The stereoselective nature of the reaction implies that the
chirality at C-14 guides the nucleophile entry at C-8. As a
result, Polonovski±Potier reaction of homochiral tetra-
hydroprotoberberines could be used to prepare C-8 alkyl-
ated derivatives, provided the chirality at C-14 is not
affected during the reaction (Scheme 9). In order to test
this possibility, the trans-N-oxide (2)-8 was treated,
under Polonovski±Potier conditions, to afford (8S, 14S)-
(2)-8-cyanocanadine, (2)-16, in a 39% yield. Treatment
of (2)-16 with TFA gave (14S)-7,8-dehydrocanadine,
which was reduced with NaBH4 to obtain (2)-canadine
([a]2D0ˆ2323 (c 0.9, CHCl3)), thus showing that the
chirality at C-14 is retained in the reaction. Thus, the treat-
ment of (2)-16 with MeMgI/Et2O afforded (8R, 14S)-(2)-
8-methylcanadine, (2)-6, in a 80% yield and a high purity
([a]2D0ˆ2236 (c 1.0 CHCl3)).7
(^)-Thalictricavine, 13. Partial reduction of vacuum-dried
berberine choride (NaBH4/dry pyridine) gave 13,14-de-
hydrocanadine as a yellow amorphous powder of mp
148±1508C [lit: 152±1588C].30 Alkylation of the enamine
with 40% formaldehyde in AcOH/NaOAc gave 13-methyl-
berberine iodide, yellow crystals mp 201±2038C (MeOH)
[lit: 185±1958C (H2O)dec.],31 which was reduced (NaBH4/
MeOH) to give (^)-thalictricavine, white crystals, mp 203±
2058C (MeOH) [lit: 204±2068C].1
trans-Berbine N-oxides
A CHCl3 solution of the tertiary bases was stirred with
mCPBA (1:1.1 mmol) at room temperature overnight. The
reaction mixture was washed with 10% aqueous Na2CO3,
dried and the solvent evaporated. The residue was puri®ed
by vacuum column chromatography (1:1 MeOH/EtOAc).
In summary, trans-berbine N-oxides undergo anti-peri-
planar elimination as their major mechanism for the Polo-
novski±Potier reaction. The easy access to 8-cyanoberbines
without affecting the chirality of C-14, together with the
preferential nucleophilic attack on the Re face, make an
effective asymmetric approach to the synthesis of enantio-
pure C-8 alkylated berbines. cis-Berbine N-oxides undergo
a more complex Polonovski reaction involving a non-
stereoselective hydroxylation at C-5, a process that is
currently being investigated by our group.
(^)-trans-Canadine N-oxide, (^)-8. Yield 81%, white
crystals; mp 2178C (MeOH), [lit: 203±2048C].12
(2)-trans-Canadine N-oxide, (2)-8. White crystals; mp
1818C (acetone); [Found: C, 66.35; H, 6.06; N, 3.86.
C20H21NO5 1/3H2O requires C, 66.47; H, 6.04; N, 3.88%];
[a]2D0ˆ2166 (c 1, MeOH); HRMS (EI) M1, found
355.1431. C20H21NO5 requires 355.1420.
Experimental
(^)-trans-Thalictricavine N-oxide, 10. Yield 80%, white
crystals; mp 198±2008C (acetone) [lit: 206±2088C (CHCl3±
EtOAc)].13
General methods
Mps were determined on a Gallenkamp instrument
(MFB595010M) and are given uncorrected. UV spectra
were recorded on a Hewlett-Packard 8452A spectro-
(^)-trans-Xylopinine N-oxide, 11. Yield 55%, white

R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
9719
crystals; mp 158±1598C (acetone) [lit: 167±1688C
190 (35), 164 (100%); HRMS (EI) M1, found 380.1738.
C22H24N2O4 requires 380.1736.
(MeOH± CHCl3)].12
(^)-cis-Canadine N-oxide, (^)-9. (^)-7 Was dissolved in
CH2Cl2/MeOH (3:1) and excess aqueous H2O2 (30% w/v)
was added and allowed to stand at rt for 7 days. Pd/C was
added to destroy excess H2O2 and the solution was ®ltered,
washed with water, dried and the solvent evaporated. The
syrup obtained was separated by vacuum column chroma-
tography (MeOH/EtOAc 1:1). Yield 9%; white crystals; mp
1458C (acetone), [lit: 1448C (acetone)].13
Modi®ed Polonovski reaction of 10
To a solution of trans-(^)-thalictricavine N-oxide (10,
70 mg, 0.2 mmol) in dry CH2Cl2 (10 mL), MsCl (0.3 mL,
3.6 mmol) was added dropwise, the solution being warmed
at 608C and stirred for 2 h. KCN (10 mg, 0.2 mmol) in a
aqueous saturated solution of NaOAc was added and the
mixture stirred for 30 min, followed by extraction with
CHCl3, washing with 10% Na2CO3, drying and solvent
evaporation to obtain a syrup. Preparative TLC (CHCl3/
MeOH 25:1) of the residue afforded (8Sp, 13Rp, 14Sp)-
(^)-8-cyanothalictricavine, 18: yield 21%; white crystals;
mp 1678C (MeOH); nmax (KBr) cm21 2937, 2228 (CN), lmax
nm (log e) CHCl3: 242 (3.80), 288 (3.88); dH (CDCl3) 6.92
(d, 1H, Jˆ8.5 Hz, H-12), 6.86 (d, 1H, Jˆ8.5 Hz, H-11),
6.63 (s, 1H, H-1), 6.57 (s, 1H, H-4), 5.92 (m, 2H,
OCH2O), 5.13 (s, 1H, H-8), 4.09 (brd, 1H, Jˆ3.2 Hz,
H-14), 4.01 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.09 (dq,
1H, Jˆ6.8, 3.2 Hz, H-13), 3.03 (m, 3H, H-5ax, H-6ax,
H-6eq), 2.64 (m, 1H, H-5eq), 0.85 (d, 3H, Jˆ6.8 Hz, C13-
Me); dC (CDCl3) 150.0, 146.5, 145.9, 145.1 (C2, C3, C9,
C10), 134.5, 128.7, 128.5, 123.2 (C4a, C8a, C12a, C14a),
117.1 (CN), 124.2, 113.4, 108.2, 105.8 (C1, C4, C11, C12),
100.8 (OCH2O), 60.4 (OMe), 58.8 (C14), 56.0 (OMe), 53.8
(C8), 48.5 (C6), 38.4 (C13), 29.6 (C5), 17.9 (C13-Me); m/z
(EI) 378 (M1, 54), 358 (43), 203 (100), 176 (87%); HRMS
(EI): M1 found 378.1563. C22H22N2O4 requires 378.1579.
Polonovski±Potier reaction of trans-(^)-berbine
N-oxides (^)-8 and 11
A solution of (0.3 mmol) trans-(^)-berbine N-oxide in dry
CH2Cl2 (10 mL) was cooled at 2308C under an N2
atmosphere. TFAA (0.75 mL, 5.4 mmol) was added
dropwise and the mixture stirred for 30 min, with the
temperature kept at 2308C; then the temperature was
allowed to rise to room temperature. KCN (26 mg,
0.4 mmol) in an aqueous saturated solution of NaOAc was
added and the mixture stirred at rt for 30 min, and extracted
with CHCl3. Extracts were washed with a 10% Na2CO3
solution, dried and the solvent evaporated to obtain a
residue from which the corresponding (8Sp, 14Sp)-(^)-8-
cyanoberbines were separated by preparative TLC
(CHCl3/MeOH, 9:1).
(8Sp,14Sp)-(^)-8-Cyanocanadine, (^)-16. Yield 29%;
white crystals; mp 1538C (MeOH); [Found: C, 69.06; H,
5.46; N, 7.55. C21H20N2O4 requires C, 69.22; H, 5.53; N,
7.69%]; nmax (KBr) cm21 2842, 2224 (CN); lmax nm (log e)
MeOH: 228 (4.04), 288 (3.81); dH (CDCl3) 6.90 (d, 1H,
Jˆ8.5 Hz, H-12), 6.81 (d, 1H, Jˆ8.5 Hz, H-11), 6.67 (s,
1H, H-1), 6.56 (s, 1H, H-4), 5.90 (s, 2H, OCH2O), 5.15 (s,
1H, H-8), 4.01 (s, 3H, OMe), 3.95 (m, 1H, H-14), 3.82 (s,
3H, OMe), 3.17 (dd, 1H, Jˆ16.5, 4.5 Hz, H-13eq), 3.05 (m,
2H, H-6eq, H-13ax), 2.70 (m, 3H, H-5ax, H-5eq, H-6ax); dC
(CDCl3) 150.2, 146.3, 146.1, 145.2 (C2, C3, C9, C10),
129.6, 127.3, 127.1, 123.6 (C4a, C8a, C12a, C14a), 123.9,
113.3, 108.3, 105.7 (C1, C4, C11, C12), 116.7 (CN), 100.8
(OCH2O), 60.4 (OMe), 55.9 (OMe), 55.1 (C14), 53.3 (C8),
48.9 (C6), 36.4 (C13), 29.4 (C5); m/z (EI) 364 (M1, 11), 338
(M12CN, 33), 337 (100), 322 (50), 307 (42), 278 (30%);
m/z (FAB): 365 (100%, MH1); HRMS (EI) M1, found
364.1432. C21H20N2O4 requires 364.1423.
Polonovski±Potier reaction of cis-(^)-canadine N-oxide,
(^)-9
A solution of (^)-9 (200 mg, 0.6 mmol) in dry CH2Cl2
(10 mL) under an N2 atmosphere was cooled to 2308C.
TFAA (0.5 mL, 3.6 mmol) was added dropwise and the
temperature was kept at 2308C for half an hour, after
which the reaction mixture was allowed to reach rt. The
mixture was then washed with 10% Na2CO3 and dried.
Solvent evaporation afforded a syrup consisting of a mixture
of two 5-hydroxycanadines which were separated by
preparative TLC (CHCl3/MeOH 9:1).
(^)-5a-Hydroxycanadine, 19. Yield 9%; yellowish crys-
tals; mp 1708C (MeOH); [Found: C, 66.49; H, 5.72; N, 3.92.
C20H21NO5 1/4 H2O requires C, 66.75; H, 6.02; N, 3.89%];
nmax (KBr) cm21 3455 (OH); lmax nm (log e) MeOH: 212
(4.24), 228 (3.98), 286 (3.57), 336 (2.96); dH (CDCl3) 6.88
(d, 1H, Jˆ9.5 Hz, H-12), 6.82 (s, 1H, H-4), 6.79 (d, 1H,
Jˆ9.5 Hz, H-11), 6.73 (s, 1H, H-1), 5.94 (s, 2H, OCH2O),
4.48 (brs, 1H, H-5), 4.19 (d, 1H, Jˆ15.5 Hz, H-8eq), 3.84 (s,
6H, 2£OMe), 3.59 (d, 1H, Jˆ15.5 Hz, H-8ax), 3.52 (m, 1H,
H-14), 3.24 (m, 2H, H-6eq, H-13eq), 2.83 (m, 2H, H-6ax,
H-13ax); dC (CDCl3) 150.4, 147.8, 146.4, 145.0 (C2, C3,
C9, C10), 131.3, 130.1, 128.3, 127.2 (C4a, C8a, C12a,
C14a), 123.8, 111.2, 109.2, 105.3 (C1, C4, C11, C12),
101.1 (OCH2O), 66.8 (C5), 60.2 (OMe), 59.5 (C14), 58.5
(C6), 55.9 (OMe), 53.4 (C8), 36.4 (C13); m/z (EI) 355 (M1,
18), 338 (M1217, 19), 164 (100), 149 (97%); HRMS (EI)
M1, found 355.1410. C20H21NO5 requires 355.1419.
(8Sp, 14Sp)-(^)-8-Cyanoxylopinine, 17. Yield 49%; white
crystals; mp 1508C (MeOH); [Found: C, 68.52; H, 6.31; N,
7.23. C22H24N2O4 1/3 MeOH requires C, 68.58; H, 6.53; N,
7.16%]; nmax (KBr) cm21 2839, 2224 (CN); lmax nm (log e)
MeOH: 216 (4.26), 286 (3.83); dH (CDCl3) 6.70 (s, 1H,
H-1), 6.69 (s, 1H, H-12), 6.65 (s, 1H, H-4), 6.60 (s, 1H,
H-9), 4.89 (s, 1H, H-8), 4.09 (dd, 1H, Jˆ10.5, 4.0 Hz,
H-14), 3.89, 3.88 (2£s, 12H, 4£OMe), 3.22 (dd, 1H,
Jˆ15.5, 4.0 Hz, H-13eq), 2.90±3.10 (m, 2H, H-5eq,
H-6eq), 2.60-2.90 (m, 3H, H-5ax, H-6ax, H-13ax); dC
(CDCl3) 149.3, 147.7 (C1, C4, C10, C11), 126.9, 126.0,
121.1, (C4a, C8a, C12a, C14a), 116.9 (CN), 111.5, 111.3,
109.4, 108.7 (C1, C4, C9, C12), 57.5 (C8), 56.1 (2£OMe),
55.9 (2£OMe), 55.0 (C14), 49.2 (C6), 36.6 (C13), 29.0
(C5); m/z (EI) 380 (M1, 8), 354 (M12CN, 18), 352 (50),
(^)-5b-Hydroxycanadine, 20. Yield 10%; yellowish

9720
R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
crystals; mp 1818C (MeOH); [Found: C, 66.84; H, 5.90; N,
3.89. C20H21NO5 1/5 H2O requires C, 66.91; H, 6.01; N,
3.90%]; nmax (KBr) cm21: 3453 (OH); lmax nm (log e)
MeOH: 212 (4.23), 228 (3.97), 286 (3.53), 322 (2.74); dH
(CDCl3) 7.05 (s, 1H, H-4), 6.81 (d, 1H, Jˆ9.5 Hz, H-12),
6.78 (d, 1H, Jˆ9.5 Hz, H-11), 6.65 (s, 1H, H-1), 5.92 (s, 2H,
OCH2O), 4.81 (dd, 1H, Jˆ7.5, 4.0 Hz, H-5), 4.15 (d, 1H,
Jˆ16.6 Hz, H-8eq), 3.87 (s, 6H, 2£OMe), 3.75 (d, 1H,
Jˆ16.6 Hz, H-8ax), 3.68 (dd, 1H, Jˆ12.5, 4.5 Hz, H-14),
3.35 (dd, 1H, Jˆ11.5, 4.0 Hz, H-6eq), 3.07 (dd, 1H, Jˆ16.0,
12.5 Hz, H-13eq), 2.71 (dd, 1H, Jˆ16.0, 12.5 Hz, H-13ax),
2.52 (dd, 1H, Jˆ11.5, 7.5 Hz, H-6ax); dC (CDCl3) 150.4,
147.2, 146.6, 145.2 (C2, C3, C9, C10), 131.6, 131.2, 127.8,
127.0 (C4a, C8a, C12a, C14a), 123.8, 111.1, 106.8, 105.2
(C1, C4, C11, C12), 101.0 (OCH2O), 66.8 (C5), 60.2
(OMe), 58.6 (C14), 57.7 (C6), 55.9 (OMe), 52.8 (C8),
34.4 (C13); m/z (EI) 355 (M1, 18), 338 (M1217, 20), 164
(100), 149 (94%); HRMS (EI): M1 found 355.1413.
C20H21NO5 requires 355.1419.
dH (CDCl31CD3OD) 6.81 (d, 1H, Jˆ8.6 Hz, H-12), 6.76 (d,
1H, Jˆ8.6 Hz, H-11), 6.55 (s, 1H, H-1), 6.53 (s, 1H, H-4),
5.85 (s, 2H, OCH2O), 4.69 (s, 1H, H-8), 4.33 (dd, 1H,
Jˆ11.0, 5.2 Hz, H-14), 3.85 (s, 3H, OMe), 3.79 (s, 3H,
OMe), 2.93 (dd, 1H, Jˆ16.7, 5.2 Hz, H-13eq), 2.98-2.69
(m, 5H, H-5ax, H-5eq, H-6ax, H-6eq, H-13ax); m/z (EI)
382 (M1, 2), 338 (M1244, 100), 322 (15%).
(8Sp, 14Sp)-(^)-8-Carbamoylxylopinine, 27b. Yield 75%;
white crystals; mp 1978C (acetone); [Found: C, 64.80; H,
6.44; N, 6.88. C22H26N2O5 1/2 H2O requires C, 64.85; H,
6.68; N, 6.88%]; nmax (KBr) cm21 3409 (NH), 3216 (NH),
2841, 1663 (CO), 1515, 1256; lmax nm (log e) MeOH: 214
(4.28), 286 (3.83); dH (CDCl3) 7.41 (brd, 1H, Jˆ4.6 Hz,
CONH2), 6.99 (s, 1H, H-9), 6.63 (s, 1H, H-4), 6.57 (s, 1H,
H-1), 6.52 (s, 1H, H-12), 5.50 (brd, 1H, Jˆ4.6 Hz, CONH2),
4.24 (s, 1H, H-8), 4.16 (dd, 1H, Jˆ11.2, 5.8 Hz, H-14), 3.88
(s, 3H, OMe), 3.85 (s, 6H, 2£OMe), 3.82 (s, 3H, OMe), 3.12
(m, 4H, H-5ax, H-5eq, H-6ax, H-6eq), 3.04 (dd, 1H,
Jˆ16.6, 5.8 Hz, H-13eq), 2.81 (dd, 1H, Jˆ16.6, 11.2 Hz,
H-13ax); dC (CDCl3) 174.2 (CONH2), 148.3, 147.8, 147.2,
147.1 (C2, C3, C10, C11), 130.5, 125.3, 125.1, 122.1 (C4a,
C8a, C12a, C14a), 112.8, 111.6, 110.6, 109.3 (C1, C4, C9,
C12), 66.9 (C8), 56.0 (OMe), 55.9 (2£OMe), 55.8 (OMe),
52.6 (C14), 45.3 (C6), 31.1 (C13), 29.2 (C5); m/z (EI) 398
(M1, 2), 354 (M1244, 100), 338 (14), 355 (23%); m/z (CI,
CH4) 399 (100%, MH1); HRMS (EI) M1, found 398.1838.
C22H26N2O5 requires 398.1842.
(^)-6-Cyanoxylopinine, 26
To a solution of 5,6-dehydroxylopinine (24)24 (200 mg) in
dry CH2Cl2 (10 mL), a mixture of TFA and TFAA was
added, followed by standing at rt for 1 h. Excess KCN in
an aqueous saturated solution of NaOAc was then added, the
mixture being stirred at rt for 30 min, extracted with CHCl3,
washed with 10% Na2CO3 and dried, the solvent being
evaporated to obtain 26: yield 89%; white crystals; mp
1568C (MeOH); [Found: C, 68.52; H, 6.31; N, 7.23.
C22H24N2O4 1/4 H2O requires C, 68.64; H, 6.42; N,
7.28%]; nmax (KBr) cm21 2840, 2224 (CN); dH (CDCl3)
6.52 (s, 1H, H-1), 6.40 (s, 1H, H-9), 6.33 (s, 1H, H-12),
6.30 (s, 1H, H-4), 3.87 (d, 1H, Jˆ14.7 Hz, H-8eq), 3.78
(dd, 1H, Jˆ11.2, 3.6 Hz, H-14), 3.56 (brd, 1H, Jˆ5.4 Hz,
H-6), 3.53, 3.52, 3.50, 3.46 (4£s, 3H, OMe), 3.42 (d, 1H,
Jˆ14.7 Hz, H-8ax), 3.05 (dd, 1H, Jˆ15.6, 5.4 Hz, H-5),
3.00 (dd, 1H, Jˆ15.5, 3.6 Hz, H-13ax), 2.77 (dd, 1H,
Jˆ15.5, 11.2 Hz, H-13eq), 2.50 (brd, 1H, Jˆ15.6 Hz,
H-5); dC (CDCl3) 148.3, 147.9, 147.8, 147.6 (C2, C3,
C10, C11), 128.1, 125.6, 125.0, 121.8 (C4a, C8a, C12a,
C14a), 116.6 (CN), 111.3, 111.2, 108.8, 108.4 (C1, C4,
C9, C12), 55.9, 55.8, 55.7 (4£OMe, C6, C14), 51.5 (C8),
36.9 (C13), 32.3 (C5); m/z (EI) 380 (M1, 5), 353 (M12CN,
12), 164 (100%); HRMS (EI) M1, found 380.1728.
C22H24N2O4 requires 380.1736.
A methanolic solution of 27a and 27b (0.1 mmol in 10 mL)
was stirred with 0.2 g of Amberlitew IR-120 at 608C for
12 h. The resin was washed with MeOH and suspended in
5 mL of MeOH/Et3N (3:1) for 48 h, followed by ®ltering
and solvent evaporation to quantitatively obtain the corre-
sponding (8Sp, 14Sp)-(^)-8-methoxycarbonylberbines (28a
and 28b). Without further puri®cation, a THF solution
(5 mL) of the esters 28a and 28b was dropped at room
temperature over a solution of LiAlH4 in dry THF
(0.3 mmol in 5 mL) and stirred for 2 h. The reaction was
quenched by addition of a water-saturated Et2O solution
(5 mL) and stirred for 1 h before Celitew was added and
the reaction mixture was ®ltered. Removal of the organic
solvent and preparative TLC (CHCl3/MeOH 25:1) of the
residue afforded the corresponding (8Sp, 14Sp)-(^)-8-
hydroxymethylberbines, 29a and 29b.
(8Sp, 14Sp)-(^)-8-Methoxycarbonylcanadine, 28a. Color-
less syrup, nmax (®lm) cm21 2854, 1734 (CO); lmax nm
(log e) MeOH: 210 (4.27), 226h (4.01), 288 (3.64); dH
(CDCl3) 6.87 (d, 1H, Jˆ8.8 Hz, H-12), 6.82 (d, 1H,
Jˆ8.8 Hz, H-11), 6.65 (s, 1H, H-1), 6.55 (s, 1H, H-4),
5.89 (s, 2H, OCH2O), 4.83 (s, 1H, H-8), 4.33 (dd, 1H,
Jˆ11.0, 3.92 Hz, H-14), 3.82 (s, 3H, OMe), 3.80 (s, 3H,
OMe), 3.70 (s, 3H, COOMe), 3.10 (dd, 1H, Jˆ16.0,
3.9 Hz, H-13eq), 2.73 (dd, 1H, Jˆ16.0, 11.0 Hz, H-13ax),
3.26±2.62 (m, 4H, H-5ax, H-5eq, H-6ax, H-6eq); dC
(CDCl3) 171.5 (CO), 150.0, 146.0, 145.8, 145.5 (C2, C3,
C9, C10), 131.2, 128.0, 127.3, 126.5 (C4a, C8a, C12a,
C14a), 124.0, 112.3, 108.4, 106.1 (C1, C4, C11, C12),
100.7 (OCH2O), 63.2 (C8), 59.9 (OMe), 55.9 (C14), 52.5
(OMe), 51.6 (COOMe), 47.8 (C6), 36.2 (C13), 30.1 (C5);
m/z (EI) 338 (M1259, 100), 322 (9%); HRMS (EI) M1,
found 397.1510. C22H23NO6 requires 397.1525.
Synthesis of (8Sp, 14Sp)-(^)-8-hydroxymethylberbines,
29a,b
The (8Sp, 14Sp)-(^)-8-cyanoberbines (^)-16 and 18 were
dissolved in the minimum amount of concentrated HCl at
08C and kept at 58C for 48 h. Then, they were made
alkaline with concentrated aqueous NH3 extracted with
CHCl3 and dried, the solvent being ®nally evaporated.
Preparative TLC (CHCl3/MeOH 9:1) of the syrups thus
obtained afforded the corresponding (^)-8-carbamoyl-
berbines, 27a and 27b.
(8Sp, 14Sp)-(^)-8-Carbamoylcanadine, 27a. Yield 50%;
white crystals mp 1908C (acetone); [Found: C, 66.00; H,
5.82; N, 7.49. C21H22N2O5 requires C, 65.96; H, 5.80; N,
7.33%]nmax (KBr) cm21 3400 (NH), 3220 (NH), 1665 (CO);

R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
9721
(8Sp, 14Sp)-(^)-8-Hydroxymethylcanadine, 29a. Yield
70%; yellowish crystals; mp 1578C (MeOH); [Found: C,
68.02; H, 6.34; N, 4.02. C21H23NO5 requires C, 68.28; H,
6.28; N, 3.79%]; nmax (®lm) cm21 3455 (OH); lmax nm
(log e) MeOH: 226 (4.00), 288 (3.55); dH (CDCl3) 6.78
(s, 2H, H-11, H-12), 6.58 (s, 1H, H-1), 6.55 (s, 1H, H-4),
5.90 (s, 2H, OCH2O), 4.14 (m, 2H, H-8, H-14), 3.87 (dd, 1H,
Jˆ10.4, 5.2 Hz, CH2OH), 3.86 (s, 3H, OMe), 3.83 (s, 3H,
OMe), 3.47 (t, 1H, Jˆ10.4 Hz, CH2OH), 2.91 (dd, 1H,
Jˆ17.1, 11.1 Hz, H-13ax), 2.75 (brd, 1H, Jˆ17.1 Hz,
H-13eq), 3.26-2.65 (m, 4H, H-5ax, H-5eq, H-6ax, H-6eq);
dC (CDCl3) 150.5, 146.4, 146.2, 145.8 (C2, C3, C9, C10),
126.6, 126.5 (C4a, C8a, C12a, C14a), 123.9, 111.7, 108.8,
106.6 (C1, C4, C11, C12), 100.8 (OCH2O), 62.3 (C8), 61.4
(CH2OH), 60.7 (OMe), 55.8 (OMe), 50.0 (C14), 45.7 (C6),
30.3 (C13), 29.7 (C5); m/z (EI) 338 (M1231, 100), 322
(10%).
20), 336 (M1226, 100), 320 (41%); HRMS (EI) M1, found
362.1256. C21H18N2O4 requires 362.1266.
(^)-8-Carbamoyl-13,14-dehydrocanadine, 31. Yield
67%; dH (CDCl3) 7.09 (s, 1H, H-1), 6.75 (d, 1H, Jˆ
8.4 Hz, H-12), 6.69 (d, 1H, Jˆ8.4 Hz, H-11), 6.55 (s, 1H,
H-4), 6.25 (brs, 1H, CONH2), 5.89 (s, 2H, OCH2O), 5.76 (s,
1H, H-13), 5.58 (brs, 1H, CONH2), 5.19 (s, 1H, H-8), 3.94
(s, 3H, OMe), 3.81 (s, 3H, OMe), 3.55 (ddd, 1H, Jˆ10.6,
5.4 Hz, H-6eq), 3.19 (ddd, 1H, Jˆ11.1, 4.3 Hz, H-5ax), 2.84
(m, 2H, H-5eq, H-6ax); dC (CDCl3) 172.1 (CO), 149.8,
147.3, 146.5, 143.9 (C2, C3, C9, C10), 140.3, 128.9,
127.7, 125.0 (C4a, C8a, C12a, C14a), 119.5 (C14), 119.1,
112.6, 107.7, 104.3 (C1, C4, C11, C12), 100.9 (OCH2O),
93.7 (C13), 61.4 (C8), 60.8 (OMe), 55.8 (OMe), 47.5 (C6),
30.0 (C5); m/z (EI) 380 (M1, 3), 336 (M1244, 100), 320
(20%).
(8Sp, 14Sp)-(^)-8-Methoxycarbonylxylopinine, 28b. IR,
(8Rp, 14Sp)-(^)-8-Carbamoylcanadine, 32. Yield 95%;
white crystals; mp 2078C (MeOH); [Found: C, 65.70; H,
5.64; N, 7.07. C21H22N2O5 requires C, 65.96; H, 5.80; N,
7.33%]; nmax (KBr) cm21 3400 (NH), 3220 (NH), 1665
(CO); lmax nm (log e) MeOH: 212 (4.26), 226h (4.05),
288 (3.67); dH (CDCl31CD3OD) 6.87 (d, 1H, Jˆ9.2 Hz,
H-12), 6.82 (d, 1H, Jˆ9.2 Hz, H-11), 6.68 (s, 1H, H-1),
6.54 (s, 1H, H-4), 5.87 (s, 2H, OCH2O), 4.26 (s, 1H, H-8),
3.83 (s, 3H, OMe), 3.81 (s, 3H, OMe), 3.56 (brd, 1H,
Jˆ11.0, 2.8 Hz, H-14), 3.43 (dd, 1H, Jˆ11.0, 4.4 Hz,
H-6eq), 3.13 (dd, 1H, Jˆ15.5, 2.8 Hz, H-13eq), 2.93 (m,
1H, H-5ax), 2.81 (dd, 1H, Jˆ15.5, 11.0 Hz, H-13ax), 2.60
(m, 2H, H-5eq, H-6ax); dC (CDCl31CD3OD) 176.7 (CO),
150.3, 145.9, 145.8 (C2, C3, C9, C10), 129.9, 128.3, 127.5,
126.5 (C4a, C8a, C12a, C14a), 123.5, 112.2, 107.8, 105.2
(C1, C4, C11, C12), 100.5 (OCH2O), 68.3 (C8), 59.2 (C14),
58.2 (OMe), 55.5 (OMe), 48.5 (C6), 36.6 (C13), 29.4 (C5);
m/z (EI) 338 (M1244, 100), 336 (17), 322 (14%); m/z (CI,
CH4) 383 (100%, MH1).
1
UV, H NMR, 13C NMR and EI-MS identical with those
for an authentic sample obtained by condensation of
N-norlaudanosine with glyoxylic acid.4
(8Sp, 14Sp)-(^)-8-Hydroxymethylxylopinine, 29b. IR,
1
UV, H NMR, 13C NMR and EI-MS identical with those
for an authentic sample.4
Synthesis of (8Rp, 14Sp)-(^)-8-hydroxymethylcanadine,
34
To a suspension of berberine chloride (5, 1 g, 2.7 mmol) in
MeOH (50 mL) was added KCN (175 mg dissolved in the
minimum amount of water). The yellow precipitate that
immediately appeared was ®ltered and identi®ed as (^)-8-
cyano-13,14-dehydrocanadine (30). Hydrolysis of 30 with
conc. HCl (5 mL) at 08C was carried out as above to obtain
(^)-8-carbamoyl-13,14-dehydrocanadine (31), that proved
to be rather unstable and was immediately dissolved in
methanol (25 mL) and reduced with excess NaBH4. The
reaction was followed by TLC and worked up in the usual
way to afford (8Rp, 14Sp)-(^)-8-carbamoylcanadine (32).
The reaction sequence which includes methanolysis of
the amide 32 to the methyl ester 33 and reduction to the
target (8Rp, 14Sp)-(^)-8-hydroxymethylcanadine (34), was
carried out as above.
(8Rp, 14Sp)-(^)-8-Methoxycarbonylcanadine, 33. Yield
80%; white crystals; mp 206±2088C (MeOH); nmax (KBr)
cm21 2854, 1732 (CO), 1439, 1280; lmax nm (log e) MeOH:
210 (4.27), 228h (4.01), 288 (3.64); dH (CDCl3) 6.89 (d,
1H, Jˆ8.5 Hz, H-12), 6.83 (d, 1H, Jˆ8.5 Hz, H-11), 6.71
(s, 1H, H-1), 6.55 (s, 1H, H-4), 5.89 (s, 2H, OCH2O), 4.32 (s,
1H, H-8), 3.83 (s, 3H, OMe), 3.78 (s, 3H, OMe), 3.74 (s, 3H,
COOMe), 3.60 (brd, 1H, Jˆ11.3 Hz, H-14), 3.31 (dd, 1H,
Jˆ11.1, 3.8 Hz, H-6eq), 3.14 (dd, 1H, Jˆ15.3, 3.6 Hz,
H-13eq), 3.08 (m, 1H, H-5ax), 2.90 (dd, 1H, Jˆ15.3,
11.3 Hz, H-13ax), 2.57 (m, 2H, H-5eq, H-6ax); dC
(CDCl3) 172.8 (CO), 150.4, 146.1, 146.0, 145.5 (C2, C3,
C9, C10), 130.3, 128.3, 128.1, 127.1 (C4a, C8a, C12a,
C14a), 123.8, 112.1, 108.2, 105.5 (C1, C4, C11, C12),
100.8 (OCH2O), 67.3 (C8), 59.8 (OMe), 59.1 (C14), 55.9
(OMe), 52.4 (Me), 49.1 (C6), 36.6 (C13), 29.7 (C5); m/z
(EI) 397 (M1, 3), 338 (M1259, 100), 322 (9%); HRMS (EI)
M1, found 397.1518. C22H23NO6 requires 397.1525.
(^)-8-Cyano-13,14-dehydrocanadine, 30. Yield 95%;
yellowish crystals; mp 1748C (MeOH); [Found: C,68.88;
H, 4.89; N, 7.61. C21H18N2O4 1/4 H2O requires C, 68.75;
H, 5.08; N, 7.64%]; nmax (KBr) cm21 2837, 2224 (CN); lmax
nm (log e) CHCl3: 276 (4.07), 368 (4.29); dH (CDCl3) 7.15
(s, 1H, H-1), 6.88 (d, 1H, Jˆ8.4 Hz, H-12), 6.82 (d, 1H,
Jˆ8.4 Hz, H-11), 6.58 (s, 1H, H-4), 6.13 (s, 1H, H-13),
5.95 (d, 2H, Jˆ2.1 Hz, OCH2O), 5.73 (s, 1H, H-8), 3.96
(s, 3H, OMe), 3.85 (s, 3H, OMe), 3.41 (ddd, 1H, Jˆ15.2,
11.9, 4.0 Hz, H-6eq), 3.25 (ddd, 1H, Jˆ15.2, 4.0, 3.0 Hz,
H-5ax), 2.98 (ddd, 1H, Jˆ15.2, 11.9, 4.0 Hz, H-6ax), 2.81
(ddd, 1H, Jˆ15.2, 3.0, 3.0 Hz, H-5eq); dC (CDCl3) 150.6,
147.7, 146.9, 144.4 (C2, C3, C9, C10), 138.4, 128.4, 126.9,
124.1 (C4a, C8a, C12a, C14a), 119.8 (C1), 117.0 (C14),
116.5 (CN), 113.8 (C4), 107.8 (C11), 104.1 (C12), 101.2
(OCH2O), 98.1 (C13), 60.9 (OMe), 56.1 (OMe), 49.9 (C8),
47.9 (C6), 29.6 (C5); m/z (EI) 362 (M1, 68), 347 (M1215,
(8Rp, 14Sp)-(^)-8-Hydroxymethylcanadine, 34. Yield
81%; yellowish crystals; mp 157±1588C (MeOH); [Found:
C, 67.99; H, 6.28; N, 3.80. C21H23NO5 requires C, 68.28; H,
6.28; N, 3.79%]; nmax (KBr) cm21 3455 (OH), 1485, 1277,
1230, 1033; lmax nm (log e) MeOH: 226 (4.07), 288 (3.75);
dH (C6D6) 6.70 (d, 1H, Jˆ8.3 Hz, H-12), 6.64 (s, 1H, H-1),

9722
R. Suau et al. / Tetrahedron 56 (2000) 9713±9723
6.53 (d, 1H, Jˆ8.3 Hz, H-11), 6.42 (s, 1H, H-4), 5.38 (s, 2H,
OCH2O), 4.03 (s, 3H, H-8, H-16, H-160), 3.73 (s, 3H, OMe),
3.49 (brd, 1H, Jˆ10.9 Hz, H-14), 3.34 (s, 3H, OMe),
3.10±2.60 (m, 5H, H-5ax, H-6eq, H-13ax, H-13eq, OH),
2.40±2.10 (m, 2H, H-5eq, H-6ax); dC (CDCl3) 150.8,
146.1, 146.0, 145.6 (C2, C3, C9, C10), 130.9, 129.9,
129.6, 128.0 (C4a, C8a, C12a, C14a), 123.2, 111.3, 108.4,
105.6 (C1, C4, C11, C12), 100.8 (OCH2O), 63.8 (C16), 61.9
(C8), 60.3 (OMe), 58.3 (C14), 55.9 (OMe), 49.0 (C6), 37.2
(C13), 30.6 (C5); m/z (EI) 369 (M1, 2), 368 (M121, 7), 338
(M1231, 100), 322 (14%); m/z (FAB) 370 (100%, MH1).
HRMS (EI) M1, found 369.1567. C21H23NO5 requires
369.1576.
(OCH2O), 60.5 (OMe), 55.8 (OMe), 50.6 (C8), 47.0 (C6),
34.9 (C13), 29.4 (C5), 16.0 (C8-Me); m/z (EI) 353 (M1, 7),
338 (M1215, 100), 178 (62), 163 (53%).
Acknowledgements
The authors wish to acknowledge ®nancial support from
Spain's DGICYT (Project PB97-1077). Professor J. Bosch
(University of Barcelona) is also gratefully acknowledged
for helpful discussion. Thanks are given to Dr M. Marcos
from the CACTI (University of Vigo) for the HRMS.
(^)-O-Methylcorytenchirine (1, RˆMe)
References
A solution of (8Sp, 14Sp)-(^)-8-cyanoxylopinine (50 mg) in
Et2O (5 mL) was added over freshly prepared MeMgI in
Et2O (5:1 excess) and the mixture re¯uxed for 2 h. The
reaction mixture was extracted with 6 M HCl, the aqueous
layer being neutralized (aqueous NH3) and extracted with
CHCl3. A syrup was obtained after evaporation of the
solvent that was chromatographed over silica gel (2:1
hexane/Et2O) to obtain (^)-O-methylcorytenchirine (1,
RˆMe).32 Yield: 80% (yellowish syrup); nmax (®lm) cm21
1509, 1275, 1145; dH (CDCl3) 6.67 (s, 1H, H-12), 6.60 (s,
1H, H-1), 6.56 (s, 2H, H-4, H-9), 4.26 (dd, 1H, Jˆ11.1,
4.8 Hz, H-14), 4.11 (q, 1H, Jˆ6.7 Hz, H-8), 3.86 (s, 3H,
OMe), 3.84 (s, 6H, 2£OMe), 3.82 (s, 3H, OMe), 3.06 (dd,
1H, Jˆ16.4, 4.8 Hz, H-13eq), 3.07-2.85 (m, 4H, H-5ax,
H-5eq, H-6ax, H-6eq), 2.79 (dd, 1H, Jˆ16.4, 11.1 Hz,
H-13ax), 1.41 (d, 3H, Jˆ6.7 Hz, C8-Me); dC (CDCl3)
147.6, 147.5, 147.4 (C2, C3, C10, C11), 131.3, 130.2,
126.2, 125.0 (C4a, C8a, C12a, C14a), 111.4, 111.1, 109.7,
109.0 (C1, C4, C9, C12), 59.3 (C8), 56.0, 58.8, 50.4
(4£OMe), 47.2 (C14), 35.5 (C13), 29.2 (C5), 18.2
(C8-Me); m/z (EI) 369 (M1, 5), 354 (M1215, 34), 178
(100), 163 (16%); HRMS (EI) M1, found 369.1926.
C22H27NO4 requires 369.1940.
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OCH2O); 4.32 (q, 1H, Jˆ6.6 Hz, H-8), 4.19 (dd, 1H,
Jˆ11.2, 4.9 Hz, H-14), 3.87 (s, 3H, OMe), 3.83 (s, 3H,
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(m, 4H, H-5ax, H-5eq, H-6ax, H-6eq), 2.72 (dd, 1H,
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C10), 132.9, 131.4, 127.1, 125.9 (C4a, C8a, C12a, C14a),
123.9, 111.3, 108.6, 106.1 (C1, C4, C11, C12), 100.8
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