Stereoselective synthesis of aporphine alkaloids using a hypervalent iodine(III) reagent-promoted oxidative nonphenolic biaryl coupling reaction. Total synthesis of (S)-(+)-glaucine

Article abstract of DOI:10.1055/s-2004-816009

The aporphine alkaloid (+)-glaucine (8a) and two other analogues 8b,c have been synthesized in good yield and high ee from the appropriate 1,2-diarylethylamine derivatives, which were in turn prepared using (S)-(+)-phenylglycinol as chiral support. Next, a sequence of simple transformations: N-alkylation with bromoacetaldehyde diethyl acetal, N-methylation, Pommeranz-Fritsch cyclization, and ionic hydrogenation led to the key intermediate, optically active, 1-benzyltetrahydroisoquinolines 7a-c. The final C-ring closure step was performed by C-C biaryl bond formation by an hypervalent iodine(III) reagent promoted oxidative coupling, affording the target heterocycles 8a-c in good yields and with no racemization at the formerly created stereogenic center.

Full text of DOI:10.1055/s-2004-816009

PAPER
1093
Stereoselective Synthesis of Aporphine Alkaloids Using a Hypervalent
Iodine(III) Reagent-Promoted Oxidative Nonphenolic Biaryl Coupling
Reaction. Total Synthesis of (S)-(+)-Glaucine
T
E
otal
S
ynthesis
n
of
(
S
)-(+)-G
e
laucine ritz Anakabe, Luisa Carrillo, Dolores Badía,* Jose L. Vicario, Maite Villegas
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea, P.O.
Box 644, 48080 Bilbao, Spain
Fax +34(94)6012748; E-mail: qopbaurm@lg.ehu.es.
Received 18 December 2003; revised 11 February 2004
gic action.10 With all these circumtances in mind, the
Abstract: The aporphine alkaloid (+)-glaucine (8a) and two other
development of new and efficient synthetic procedures for
the preparation of these alkaloids in a stereocontrolled
in turn prepared using (S)-(+)-phenylglycinol as chiral support. way turns out to be a challenging field for the synthetic or-
analogues 8b,c have been synthesized in good yield and high ee
from the appropriate 1,2-diarylethylamine derivatives, which were
Next, a sequence of simple transformations: N-alkylation with bro- ganic chemist.
moacetaldehyde diethyl acetal, N-methylation, Pommeranz–Fritsch
The strategies that have been commonly employed for the
cyclization, and ionic hydrogenation led to the key intermediate, op-
synthesis of aporphines can be classified according to the
last ring built up during the synthesis (Figure 1). In this
tically active, 1-benzyltetrahydroisoquinolines 7a–c. The final C-
ring closure step was performed by C–C biaryl bond formation by
an hypervalent iodine(III) reagent promoted oxidative coupling, af- context, reports have appeared in which the B ring is the
fording the target heterocycles 8a–c in good yields and with no ra- last one to be assembled by some kind of heterocycliza-
cemization at the formerly created stereogenic center.
11
tion process, but the most frequently employed strategy
Key words: alkaloids, amino alcohols, asymmetric synthesis, relies upon formation of the C ring at the final stage of the
chiral auxiliaries, iodine
synthetic route by connecting both aromatic A and D rings
via biaryl C–C bond formation. These routes utilize an ap-
propriately functionalized 1-benzylisoquinoline as the
Aporphines are a small group of alkaloids characterized penultimate intermediate.
by the tetracyclic skeleton shown in Figure 1, in which
3
4
relevant features are the presence of an isoquinoline core,
together with a biaryl subunit, and one stereogenic center
at C-6a. Interest in natural and non-natural aporphines
arises from the diverse array of biological properties dis-
2
R
1
5
A
B
NMe
6
C
7
11
1
R'
D
9
played. In fact, plant sources of aporphines have been
10
8
used for many years in the treatment of asthma, whooping
cough, and different types of tumors like pharynx tumor
2
and uterine bleeding. Relevant examples include (+)-bol-
R
R
NHMe
NMe
dine and its non-phenolic dimethyl ether (+)-glaucine,
which display antioxidative and cytoprotective
properties and act as dopamine antagonist in vivo. (+)-
Isoteoline has shown antagonist activity at 5-HT sero-
3
4
R'
R'
2
c
5
tonergic receptors; nantenine derivatives cause an inhib- Figure 1 The aporphine skeleton with the adopted numbering sche-
6
me and the commonly employed retrosynthetic approaches to it.
itory effect on the a-adrenoceptors in the rat aorta;
apomorphine, a non-natural aporphine, acts as a dopamin-
ergic agent in the central nervous system dysfuntions,7 Related to the last topic mentioned, some syntheses of
and several others have potential uses in cancer treat- aporphines have appeared in which this biaryl C–C bond
8
ment. Interestingly, some of the above mentioned activi- formation has been attained either by cyclization of ami-
ties are structurally related to the presence of the biphenyl nophenols,12 by benzyne-mediated cyclization, or by
13
system, the nature of the substituent at C-2 and a benzylic radical- or lead tetraacetate-mediated coupling of 1-benz-
9
hydrogen neighboring a nitrogen lone electron pair, but ylisoquinolines bearing a bromo subtituent at the appro-
more detailed studies on structure-activity relationships priate position of one of the two aromatic rings to be
have also shown that the configuration of the C-6a stereo- coupled.1
4,15
However, these methodologies suffer from
genic center is of essential importance for the dopaminer- many drawbacks, such as large amounts of side-products
often isolated together with the desired tetracycles. An-
other frequently employed method in this context is the
SYNTHESIS 2004, No. 7, pp 1093–1101
x
x
.
x
x
.2
0
0
4
oxidative biaryl phenolic or non-phenolic coupling.
Among these two approaches, the former suffers from the
limitation that a 1-benzylisoquinoline bearing one hy-
Advanced online publication: 15.03.2004
DOI: 10.1055/s-2004-816009; Art ID: T13903SS
Georg Thieme Verlag Stuttgart · New York
©

1
094
E. Anakabe et al.
PAPER
droxy group at C-6 is required while in the later a hydrox- With all these circumstances in mind, and continuing our
yl group is necessary at either the C-3¢ or C-4¢ position of ongoing interest in the development of general routes for
the starting material. As a consequence, the non-phenolic the asymmetric synthesis of isoquinoline alkaloids,23 we
coupling normally affords better yields of the desired wish to present herein a highly effective and general ap-
1
6
product. Finally, another strategy which has to be men- proach for the asymmetric synthesis of aporphines. In this
tioned is the direct preparation of aporphines by acid-pro- context, we decided to explore the possibilities of enan-
1
0a,17
moted rearrangement of morphinanes,
however this tiopure 1,2-diarylethylamines of type 3 as useful chiral
methodology requires the previous preparation of synthe- starting materials for the preparation of conveniently
tically more complex precursors.
functionalized 1-benzyltetrahydrosoquinolines, which af-
terwards would afford the desired heterocycles after final
build-up of the C ring by connecting the A and D rings.
Consequently, according to the retrosynthetic analysis de-
picted in Scheme 1, N-alkylation of 1,2-diarylethy-
As already mentioned, the stereochemistry at C-6a has a
major influence on the biological activity presented by
most of the aporphines described. Surprisingly, only a few
reports have succeeded in establishing general stereose-
lective methods for the preparation of these alkaloids. In
this sense, Comins et al. have reported the synthesis of
lamines
3
with bromoacetaldehyde diethylacetal
(
BADA), followed by Pommeranz–Fritsch cyclization
should afford the corresponding 1-benzyltetrahydroiso-
quinolin-4-ols, which, after removal of the 4-OH substit-
(
+)-glaucine in which the key synthetic intermediate, a
chiral non-racemic N-acyl-1-(2¢-bromobenzyl)tetrahy-
droisoquinoline was prepared by means of a diastereose-
lective Pictet–Spengler reaction using cyclohexyl-based
uent
should
provide
the
key
1-benzyl-
tetrahydroisoquinolines, ready for the last C–C biaryl cou-
pling step. At this point, as we have previously shown that
the existent methodologies normally afford poor results,
we have explored new ways for performing this coupling,
which includes the use of recently developed hypervalent
iodine(III) reagents.24
1
8
chiral auxiliaries. Unfortunately the final radical-medi-
ated biaryl bond formation step gave a very low yield of
the desired product. Alternatively, the enantioselective
synthesis of ()-glaucine has been reported in which the
preparation of enantioenriched 1-benzylisoquinolines via
Bischler–Napieralski cyclization/reduction of phenethyl-
amides derived from a modified form of L-(+)-ascorbic
R
R
1
9
NMe
NMe
acid or D-()-tartaric acid was implicated. The final trans-
formation into the aporphine alkaloid was achieved using
chromium(III) oxide or thallium trifluoroacetate. Howev-
er, either low yields or separation of diastereomeric mix-
tures at intermediate steps of the synthesis was often
required.
R'
R'
EtO OEt
The well-known chiral formamidine method established
by Meyers, has been used by himself as a tool for reaching
a great number of chiral non-racemic isoquinoline alka-
loids, including some natural aporphines, in high enantio-
meric excess. Application of this methodology allowed
R
R
NH2
NMe
R'
R'
3
the authors to prepare the required 1-benzyltetrahydroiso- Scheme 1
quinolines which were transformed into the final com-
pounds by C-C biaryl bond formation using a non-
phenolic metal-mediated oxidative coupling, thus obtain-
ing (+)-glaucine and (+)-ocoteine with optical purities of
The synthesis of the chiral starting compounds, the 1,2-di-
arylethylamines 3a–c, was performed under conditions
previously reported by our group,2 using the reaction be-
tween freshly prepared Grignard benzylic reagents and
imines 1a–c, followed by removal of the chiral appendage
by catalytic hydrogenation. In this way, chiral non-racem-
ic amines 3a–c were obtained as highly enantioenriched
materials (>92% ee by chiral HPLC analysis under condi-
tions optimized for a racemic standard). Next, we pro-
ceeded to perform a sequential N-alkylation reaction with
bromoacetaldehyde diethylacetal (BADA) and subse-
quent N-methylation under standard conditions (HCHO,
3g
8
7% and 93%, respectively, although in moderate yields
2
0
(
40–50%). Finally, another conceptually different ap-
proach for the stereocontrolled preparation of these tetra-
cycles has been reported by Hara et al. in which a lead
tetraacetate-mediated oxidation of racemic 1-benzyltet-
rahydroisoquinolines in the presence of a chiral acid was
2
1
performed. The oxidation process furnished a diastereo-
meric mixture of two p-quinol acylates in a nearly 1:1 ra-
tio, which had to be separated, each of them being further
applied to the synthesis of the corresponding aporphines
enantiomer. Finally, it has to be mentioned that an enzy-
matic lipase-catalyzed resolution of the acetates of racem-
NaBH CN), thus obtaining the tertiary amines 5a–c in
3
good yields. At this point, it has to be mentioned that
when we inverted the order of introduction of the alkyl
chains at the nitrogen atom of the amines 3a–c, that is,
when we carried out the N-methylation step first, we ob-
served a significant decrease in the obtained yields. In ad-
dition, considerably longer reaction times were needed in
2
2
ic phenolic aporphines has also been described, although
the final compounds were obtained in moderate chemical
and optical yields.
Synthesis 2004, No. 7, 1093–1101 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (S)-(+)-Glaucine
1095
R1
the reaction in which the acetaldehyde chain was intro-
duced.
R1
OH
OH
H
N
i
R2
N
R2
Continuing with the synthesis, we focused on the forma-
tion of the future B ring of the final aporphines, which was
planned to be accomplished via standard Pommeranz–
Fritsch cyclization. Indeed, 1-benzyltetrahydroisoquino-
lin-4-ols 6a–c were cleanly obtained when amines 5a–c
were stirred in HCl–acetone. These isoquinolinols were
obtained as a 1:1 mixture of epimers, which could be sep-
arated by flash column chromatography in the case of 6a,
and were therefore completely characterized as pure iso-
mers. Anyway, the fact that the stereocenter at the 4-posi-
tion of the isoquinoline core had to be removed in the next
step, made this separation unnecessary and the derivatives
cis- and trans-6a–c were used in the next step as a mixture
of epimers.
Ph
Ph
1
a-c
R3
2a-c
R3
EtO OEt
NH
ii
R1
R2
R1
iii
NH2
R2
R3
R3
R3 4a-c
R3
3a-c
iv
R4 R5
EtO OEt
NMe
R1
R1
NMe
v
R2
R3
Next, we proceeded to carry out the reduction of these iso-
quinolinols 6a–c to the key 1-benzyltetrahydroisoquino-
lines 7a–c. In this context, the so-called ionic
R2
2
5
hydrogenation reaction is a widely employed reductive
transformation that allows the deoxygenation of alcohols
that can form stable carbocations (e.g. benzylic alcohols),
which are then transformed into the corresponding al-
kanes, as happens in our case. Among the different report-
R3
R3
R3
4
5
5a-c
R =OH, R =H: cis-6a-c
R =H, R =OH: trans-6a-c
4
5
vi
R1
ed carboxylic acid/NaBH combination of reagents
4
2
6
NMe
R2
developed for this reaction, we choose TFA as the pro-
ton source, due to its high ionizing power together with its
low nucleophilic character. In fact, we have previously
applied this methodology for the reduction of other struc-
turally related 3-aryl-1,2,3,4-tetrahydroisoquinolin-4-ols
R3
7a-c
R3
2
3a
Scheme 2 Reagents and conditions (i) ArCH MgCl, THF, 40 ºC.
2
with excellent results. Consequently, compounds 6a–c
(
ii) H , Pd/C, HCl, MeOH, r.t. (iii) BADA, K CO , MeCN, reflux. (iv)
2
2
3
were treated with a solution of NaBH in TFA, affording,
4
HCHO , NaBH CN, MeCN, r.t. (v) concd HCl/acetone 1:1, r.t. (vi)
aq.
3
after 2–3 hours, the reduced heterocycles 7a–c in excel-
lent yields after flash column chromatography purifica-
tion (Scheme 2). Remarkably, chiral HPLC analysis of the
NaBH , TFA, CH Cl , r.t.
4
2
2
crude reaction mixture indicated that the reaction pro- therefore should allow us to complete the synthesis of the
ceeded with no racemization, at the remaining stereogenic desired aporphines. As previously mentioned, among the
center at the 1-position, thus, 1-benzyl-1,2,3,4-tetrahy- methods reported for this transformation,27 one of the
droisoquinolines 7a–c were obtained as almost enantio- most promising is the non-phenolic oxidative coupling
merically pure compounds (see Table 1).
between both aromatic rings. In this context, most of the
methodologies reported in the literature involve the use of
transition metal trifluoroacetates as oxidants, which are
very often prepared in situ by treatment of the correspond-
Once the key 1-benzyltetrahydroisoquinolines were pre-
pared, we turned our attention to the final C–C biaryl cou-
pling that should build up the tetracyclic skeleton and
2
8
Table 1 Yields and Stereoselectivities Obtained in the Asymmetric Synthesis of the 1-Benzyltetrahydroisoquinolines 7a–c
R1
R2
R3
Prod Yield Prod Yield ee
Prod Yield Prod Yield Prod Yield Prod Yield ee
%)a
(%)a (%)
b
(%)a
(%)a
(%)c
(%)a (%)
d
(
OMe OMe OMe
2a
2b
2c
80e
78
3a
3b
3c
92e
80
82
95
92
94
4a
4b
4c
93
5a
5b
5c
85
6a
6b
6c
85
-
7a
7b
7c
85
94
91
93
H
OMe OCH O
78
75
82f
86f
2
H
OMe OMe
75
75
78
-
a
Yield of pure product after purification by flash column chromatography.
Determined by chiral HPLC (Chiracel OD, UV detector, hexanes–i-PrOH, 50:50 as eluent. Flow rate 0.90 mL/min.).
Global yield for both diastereoisomers cis- and trans-7.
b
c
d
e
f
Determined by chiral HPLC (Chiracel OD, UV detector, hexanes–i-PrOH, 75:25 as eluent. Flow rate 0.60 mL/min.).
23g
See ref.
Yield calculated from product 5 (2 steps).
Synthesis 2004, No. 7, 1093–1101 © Thieme Stuttgart · New York

1
096
E. Anakabe et al.
PAPER
ing metal oxides with trifluoroacetic anhydride/trifluoro- only detect starting material even after 48 hours reaction
acetic acid (TFAA/TFA). We proceeded then to test some time and reflux temperature.
of these oxidation systems, using (S)-laudanosine 7a as
the model compound (Scheme 3), with the results shown
in Table 2.
Although this ruthenium-mediated oxidative coupling
procedure afforded the desired tetracycles in good yields,
we also observed slight racemization of the stereogenic
center. This fact prompted us to find alternative proce-
MeO
MeO
MeO
MeO
dures to perform this reaction. In this context, the hyper-
valent iodine(III) reagent phenyliodine bis(trifluoro-
acetates) (PIFA) has been shown to be an alternative re-
agent for oxidative coupling of phenols and phenol
NMe
NMe
i
30
MeO
MeO
ethers, and therefore this prompted us to test this reagent
in our particular case. To our delight, the PIFA-promoted
oxidative coupling of substrate 7a proceeded cleanly, in
good yield and with no noticeable racemization at the
stereogenic center present in the starting compound
OMe
OMe
7a
(+)-Glaucine (8a)
Scheme 3 Reagents and conditions: (i) see Table 2.
(
Table 3). Additional advantages of this reaction are the
As can be seen in Table 2, the use of the Cr O afforded
no coupling product, and the starting material was recov-
ered unchanged even after prolonged reaction times (entry
2
3
considerably shorter reaction times (30 min vs 24–48 h)
and the lower temperatures used. These optimized condi-
tions were further extended to the two other 1-benzyltet-
rahydroisoquinolines 7b–c, affording the final aporphines
8b–c in good yields and as almost enantiomerically pure
compounds (Scheme 4).
1
). On the other side, when we used the Ce(OH) /TFAA/
4
TFA or the RuO /TFAA/TFA combination of reagents
2
(
entries 2–5), in the presence of a Lewis acid like
BF ·OEt , the desired aporphine, the natural product (S)-
3
2
(
+)-glaucine (8a), was obtained in variable yields, the best
R1
R1
results obtained were with the RuO /TFAA/TFA/
2
NMe
NMe
R2
i
R2
BF ·OEt system (entries 4 and 5). Remarkably, we also
3
2
noticed that the order of the addition of reagents was cru-
cial to the yield of the coupling reaction. We observed that
the yield significantly improved when the Lewis acid was
the last reagent to be added (entry 5) compared to the re-
action in which the BF ·OEt was added together with the
R3
R3
R3
R3
7
a-c
8a-c
3
2
Scheme 4 Reagents and conditions: (i) PIFA, BF ·OEt , CH Cl ,
3
2
2
2
metal oxide (entry 4), before the addition of TFAA and
TFA (see experimental part). Although the role of this
Lewis acid has not already been completely established, it
is thought that it activates the para-alkoxy substituent on
one of the aromatic rings, therefore favoring the oxidative
coupling by stabilization of the intermediate aromatic rad-
–
20 ºC.
Table 3 Synthesis of Aporphines 8a–c by PIFA-Mediated Oxida-
tive Coupling
Prod.
R1
R2
R3
Yield
(%)a
ee
2
8a,29
b
ical cationic species.
Finally, we also tested the radi-
(%)
cal-mediated coupling (entry 6) but in this case we could
8
8
8
a
b
c
OMe
H
OMe
OMe
OMe
OMe
75
75
78
94
91
93
OCH O
2
Table 2 Oxidative Coupling of 1-Benzyltetrahydroisoquinoline 7a
H
OMe
Entry Reagents
T
Yield ee
b
(ºC)
(%)a
–c
(%)
a
Yield of 8a–c after purification by flash column chromatography.
Determined by HPLC (Chiralcel OD column, UV detector, hexanes–
b
1
2
3
4
5
6
Cr O /TFAA/TFA
reflux
0ºC
r.t.
–
2
3
i-PrOH 95:5 flow rate 0.9 mL/min.).
Ce(OH) /TFAA/TFA/BF .OEt
60
93
–
4
3
2
2
10d
In summary, a very simple and efficient synthetic route to
obtain optically pure aporphine alkaloids has been devel-
oped starting from chiral 1,2-diarylethylamines, which in
turn, were obtained enantiomerically pure by using phe-
nylglycinol as the source of chirality. Then, a sequence of
transformations (N-alkylations, Pommeranz–Fritsch cy-
clization, ionic hydrogenation, and oxidative C–C biaryl
coupling) was performed to reach to the aporphine core.
Besides, this last C–C biaryl coupling has been performed
by means of a hypervalent iodine(III)-mediated reaction,
under a completely different protocol which supersedes
Ce(OH) /TFAA/TFA/BF .OEt
4
3
RuO /BF .OEt /TFAA/TFA
–10 ºC 60
–10 ºC 75
91
91
–
2
3
2
e
RuO /TFAA/TFA/BF ·OEt
2
3
2
Bu SnH/AIBN
reflux
–
3
a
Yield of 7a after flash column chromatography purification.
Determined by HPLC (Chiralcel OD column, UV detector, hex-
b
anes–i-PrOH 95:5, flow rate 0.9 mL/min.).
c
Starting material was recovered unchanged.
Over-oxidation products were obtained.
d
e
BF ·OEt was the last reagent added.
3
2
Synthesis 2004, No. 7, 1093–1101 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (S)-(+)-Glaucine
+61.2 (c 0.1, EtOH).
1097
2
0
other reported methodologies, both in terms of the yields Yield: 75%; [a]
obtained and the absence of racemization at the stereogen- IR (KBr): 3550–3250 (NH, OH) cm .
D
–
1
ic center present in the starting compounds. The useful-
ness of this methodology has been exemplified with the
synthesis of the natural aporphine (+)-glaucine (8a), but it 3.89 (m, 12 H), 6.40–6.91 (m, 6 H), 7.11–7.27 (m, 5 H).
1
H NMR: d = 2.19 (br s, 2 H), 2.90 (dd, J = 13.6, 6.7 Hz, 1 H), 2.92
dd, J = 13.6, 6.7 Hz, 1 H), 3.50 (dd, J = 10.6, 7.0 Hz, 1 H), 3.66–
(
has to be mentioned that the described protocol is interest-
ing from a synthetic point of view taking into account the
13
C NMR: d = 43.2, 55.0, 55.5, 55.7, 55.8, 61.4, 62.0, 65.1, 110.3,
10.9, 112.4, 112.7, 119.5, 121.3, 127.1, 127.3, 128.4, 129.2, 130.9,
1
large number of diarylethylamines of type 3 available by 133.5, 141.0, 145.2, 148.3, 159.4.
this method and thus should lead to the synthesis of a wide
range of naturally and unnaturally occurring aporphine
derivatives.
MS (EI): m/z (%) = 286 (100), 271 (20), 77 (9).
Cleavage of the Chiral Appendage; Typical Procedure
A solution of the amine 2b (0.39 g, 1.0 mmol) in EtOH (10 mL) was
hydrogenated (2 atm) in the presence of 10% Pd/C (0.8 g) and of
Melting points were determined in unsealed capillary tubes and are
uncorrected. IR spectra were obtained on KBr pellets (solids) or
CHCl solution (oils). NMR spectra were recorded at 20–25 ºC, and
1
6
0% HCl (8 mL). After absorption of hydrogen was complete (45–
0 h), the catalyst was filtered off and the filtrate was basified with
3
a sat. solution of NaHCO and extracted with CH Cl (2 × 20 mL).
3
2
2
1
13
were recorded at 250 MHz for H and 62.8 MHz for C in CDCl3
solution and resonances are reported in ppm relative to TMS unless
The combined organic layers were dried with Na SO and the sol-
2
4
vent was evaporated under reduced pressure. The resulting residue
was purified by flash column chromatography (EtOAc) to afford
amine 3b (0.21 g, 0.82 mmol).
1
3
otherwise stated. Assignment of individual C resonances is sup-
ported by DEPT experiments. Mass spectra were recorded under
electron impact at 70 eV. TLC was carried out with 0.2 mm. thick
silica gel plates (Merck Kiesegel GF254). Visualization was accom-
plished by UV light or by spraying with Dragendorff´s re-
(
+)-(1S)-1-(3-Methoxyphenyl)-2-(3,4-methylendioxyphen-
yl)ethylamine (3b)
3
1
agent. Flash column chromatography on silica gel was performed
20
Yield: 80%; [a]D +35.5 (c 0.2, CH Cl ).
2
2
3
2
with Merck Kiesegel 60 (230–400 mesh). Enantiomeric excesses
was determined by chiral HPLC analysis of non-crystallized sam-
ples using a Chiracel OD column with a UV detector with the elu-
ents and flow rates as indicated in each case. All solvents used in
reactions were dried and purified according to standard proce-
dures.33 Imines 1a–c, amine 2a, and 1,2-diarylethylamine 3a were
prepared according to reported procedures. All air- or moisture-
sensitive reactions were performed under argon. The glassware was
oven dried (140 ºC) overnight and purged with argon.
–
1
IR (KBr): 3210–3200 (NH ) cm .
2
1
H NMR: d = 1.66 (br s, 2 H), 2.71 (dd, J = 13.5, 8.7 Hz, 1 H), 2.91
(dd, J = 13.5, 5.0 Hz, 1 H), 3.80 (s, 3 H), 4.10 (dd, J = 8.7, 5.0 Hz,
1 H), 5.90 (s, 2 H), 6.61–6.81 (m, 4 H), 6.91–6.93 (m, 2 H), 7.20–
7.27 (m, 1 H).
2
3g
1
3
C NMR: d = 45.9, 55.0, 57.4, 100.7, 109.4, 111.7, 112.3, 118.6,
1
22.1, 129.3, 132.6, 145.9, 147.2, 147.4, 159.5.
MS (EI): m/z (%) = 254 (28), 207 (100), 135 (97).
Synthesis of Amines 2b,c; Typical Procedure
(
+)-(1S)-2-(3,4-Dimethoxyphenyl)-1-(3-methoxyphenyl)ethyl-
A solution of imine 1b (2.27 g, 8.9 mmol) in THF (35 mL) was add-
ed to a freshly prepared solution of (3,4-methylendioxybenzyl)mag-
nesium chloride (5 equiv) in the same solvent (60 mL), and the
mixture was heated at 45–50 ºC for 5 h. After cooling, the reaction
amine (3c)
Amine 3c (1.39 g, 5.93 mmol) was obtained following the typical
procedure starting from amine 2c (2.39 g, 5.91 mmol).
was quenched with a sat. solution of NH Cl (20 mL), the organic
20
4
Yield: 82%; [a]D +21.0 (c 0.4, CH Cl ).
2
2
layer was decanted, and the aqueous layer was extracted with Et O
2
–
1
IR (KBr): 3560–3360 (NH ) cm .
2
(
2 × 20 mL). The combined organic extracts were dried over
1
Na SO , and the solvent was distilled under vacuum. The residue
H NMR: d = 1.69 (br s, 2 H), 2.76 (dd, J = 13.5, 8.7 Hz, 1 H), 2.95
(dd, J = 13.5, 5.0 Hz, 1 H), 3.83 (s, 3 H), 3.84 (s, 3 H), 3.85 (s, 3 H),
4.14 (dd, J = 8.7, 5.0 Hz, 1 H), 6.60–6.94 (m, 6 H).
2
4
was purified by flash column chromatography (hexanes–EtOAc,
:1) to afford 2b (2.72 g, 6.91 mmol).
1
1
3
C NMR: d = 45.8, 55.2, 55.7, 55.8, 111.0, 112.1, 112.4, 112.4,
(
+)-(2S,1¢S)-2-(3,4-Methylendioxyphenyl)-1-(3-methoxyphen-
1
18.8, 121.2, 129.3, 131.3, 136.9, 147.2, 147.5; 148.6.
yl)-N-(2-hydroxy-1-phenylethyl)ethylamine (2b)
Yield: 78%; [a]D +65.2 (c 0.2, EtOH).
20
MS (EI): m/z (%) =136 (100), 109 (15), 94 (6).
–
1
Anal. Calcd for C H NO : C, 71.06; H, 7.37; N, 4.87. Found: C,
IR (KBr): 3540–3250 (NH, OH) cm .
17 21
3
7
1.07; H, 7.57; N, 4.87.
1
H NMR: d = 2.11 (br s, 2 H), 2.81 (dd, J = 13.5, 7.1 Hz, 1 H), 2.97
dd, J = 13.5, 6.7 Hz, 1 H), 3.50 (dd, J = 10.7, 7.0 Hz, 1 H), 3.65–
(
Synthesis of N-Alkylated Amines 4a–c; Typical Procedure
To a stirred suspension of K CO (0.97 g, 8.2 mmol) in anhyd
3
.86 (m, 6 H), 5.83 (s, 2 H), 6.42–6.80 (m, 7 H), 7.15–7.30 (m, 5 H).
2
3
1
3
C NMR: d = 43.5, 55.6, 61.7, 62.0, 65.5, 100.6, 107.9, 109.6,
10.0, 110.6, 119.2, 122.2, 127.0, 127.1, 127.3, 128.4, 132.4, 135.2,
41.3, 145.7, 147.8, 148.5.
MeCN (25 mL) was added a solution of amine 3a (0.80 g, 2.52
mmol) in the same solvent (15 mL) and the mixture was refluxed for
2 h. Then, bromoacetaldehyde diethylacetal (1.52 mL, 10.1 mmol)
was added in one portion and the reflux was continued until the con-
version was complete (3 d). After cooling, the mixture was
quenched with water (10 mL), extracted with CH Cl (3 × 10 mL)
and the combined organic fractions were dried over Na SO , filtered
and the solvent was evaporated under reduced pressure to afford, af-
ter crystallization from hexanes, pure amine 4a as a white solid
1
1
MS (EI): m/z (%) = 270 (100), 255 (20), 77 (9).
2
2
(+)-(2S,1¢S)-2-(3,4-dimethoxyphenyl)-1-(3-methoxyphenyl)-N-
(2-hydroxy-1-phenylethyl)ethylamine (2c)
2
4
Amine 2c (2.39 g, 5.90 mmol) was obtained following the typical
procedure starting from imine 1c (2.00 g, 7.80 mmol).
(1.02 g, 2.34 mmol).
Synthesis 2004, No. 7, 1093–1101 © Thieme Stuttgart · New York

1
098
E. Anakabe et al.
PAPER
(
+)-(1S)-1,2-Bis(3,4-dimethoxyphenyl)-N-(2,2-diethoxyeth-
yl)ethylamine (4a)
Yield: 93%; mp 73–75 ºC; [a]D +20.5 (c 0.4, CH Cl ).
(+)-(1S)-N-(2,2-Diethoxyethyl)-1,2-bis(3,4-dimethoxyphenyl)-
N-methylethylamine (5a)
2
0
20
Yield: 85%; [a]D +38.5 (c 0.8, CH Cl ).
2
2
2
2
–
1
IR (neat): 1130 (COC) cm–1.
IR (KBr): 3310 (NH), 1260 (COC) cm .
1
1
H NMR: d = 0.98 (t, J = 7.0 Hz, 6 H), 1.67 (br s, 1 H), 2.39–2.44
H NMR (CDCl ): d = 1.16 (t, J = 7.1 Hz, 3 H), 1.17 (t, J = 7.1 Hz,
3
(
m, 2 H), 2.69–2.74 (m, 2 H), 3.25–3.40 (m, 2 H), 3.42–3.48 (m, 2
3 H), 2.34 (s, 3 H), 2.48 (dd, J = 13.5, 5.1 Hz, 1 H), 2.68 (dd,
J = 13.5, 5.2 Hz, 1 H), 2.86 (dd, J = 13.4, 9.3 Hz, 1 H), 3.20 (dd,
J = 13.4, 5.2 Hz, 1 H), 3.41–3.62 (m, 4 H), 3.69 (s, 3 H), 3.78 (s, 3
H), 3.81–3.84 (m, 7 H), 4.52 (t, J = 5.1 Hz, 1 H), 6.46 (d, J = 1.8 Hz,
1
1
H), 3.60–3.66 (m, 1 H), 3.68 (s, 3 H), 3.72 (s, 3 H), 3.74 (s, 3 H),
3
.75 (s, 3 H), 4.39 (t, J = 5.1 Hz, 1 H), 6.49–6.78 (m, 6 H).
1
3
C NMR: d = 14.9, 44.7, 49.5, 55.4, 55.5, 61.4, 61.5, 64.2, 101.5,
09.9, 110.7, 111.0, 112.4, 119.3, 120.9, 131.2, 136.0, 147.3, 147.8,
48.5, 148.8.
H), 6.54 (dd, J = 8.1, 1.8 Hz, 1 H), 6.63–6.86 (m, 4 H).
1
1
3
C NMR (CDCl ): d = 15.2, 38.7, 39.8, 55.6, 55.7, 55.8, 56.8, 61.6,
3
6
1
1.7, 70.7, 101.9, 110.3, 110.7, 111.9, 112.5, 121.1, 132.2, 132.4,
46.9, 147.8, 148.2, 148.4.
MS (EI): m/z (%) = 301 (15), 282 (53), 236 (100), 190 (32), 151
30).
(
MS (EI): m/z (%) = 402 (3), 300 (90), 296 (100), 285 (47), 195 (52),
51 (40).
Anal. Calcd for C H NO : C, 66.49; H, 8.13; N, 3.23. Found: C,
24
35
6
1
6
6.67; H, 8.29; N, 3.14.
Anal. Calcd for C H NO : C, 67.09; H, 8.33; N, 3.13. Found: C,
2
5
37
6
(
+)-(1S)-N-(2,2-Diethoxyethyl)-1-(3-methoxyphenyl)-2-(3,4-me-
67.22; H, 8.51; N, 3.24.
thylendioxyphenyl)ethylamine (4b)
Amine 4b (0.24 g, 0.66 mmol) was obtained following the typical
procedure starting from amine 3b (0.20 g, 0.83 mmol).
(+)-(1S)-N-(2,2-Diethoxyethyl)-1-(3-methoxyphenyl)-N-methyl-
2-(3,4-methylendioxyphenyl)ethylamine (5b)
2
0
Amine 5b (0.18 g, 0.45 mmol) was obtained following the typical
procedure starting from amine 4b (0.24 g, 0.60 mmol).
Yield: 78%; [a]D +10.2 (c 0.2, CH Cl ).
2
2
–
1
IR (neat): 3300 (NH), 1260 (COC) cm .
2
0
Yield: 75%; [a]D +30.9 (c 0.1, CH Cl ).
2
2
1
H NMR: d = 1.06 (t, J = 7.1 Hz, 3 H), 1.08 (t, J = 7.1 Hz, 3 H), 1.78
br s, 1 H), 2.42–2.58 (m, 2 H), 2.70–2.89 (m, 2 H), 3.34–3.58 (m,
H), 3.70–3.73 (m, 1 H), 3.78 (s, 3 H), 4.50 (t, J = 5.2 Hz, 1 H),
.88 (s, 2 H), 6.57–6.89 (m, 6 H), 7.17–7.23 (m, 1 H).
–
1
IR (neat): 1160 (COC) cm .
(
2
5
1
H NMR: d = 1.16 (t, J = 7.1 Hz, 3 H), 1.18 (t, J = 7.1 Hz, 3 H), 2.30
(s, 3 H), 2.46 (dd, J = 13.5, 5.2 Hz, 1 H), 2.65 (dd, J = 13.5, 5.2 Hz,
1 H), 2.88 (dd, J = 13.5, 8.3 Hz, 1 H), 3.12 (dd, J = 13.5, 6.0 Hz, 1
H), 3.42–3.64 (m, 4 H), 3.76 (s, 3 H), 3.71–3.80 (m, 1 H) 4.52 (t,
J = 5.1 Hz, 1 H), 5.84 (s, 2 H), 6.48–6.78 (m, 6 H), 7.13–7.20 (m, 1
H)
1
3
C NMR: d = 15.1, 44.8, 49.7, 55.0, 61.9, 64.7, 100.7, 101.7, 108.0,
09.3, 112.3, 112.5, 119.6, 122.1, 129.1, 132.4, 145.2, 145.9, 147.5,
59.6.
1
1
MS (EI): m/z (%) = 254 (33), 206 (100), 160 (64), 135 (76).
1
3
C NMR: d = 15.2, 38.2, 39.4, 55.0, 56.7, 61.7, 61.8, 70.5, 100.5,
07.7, 109.6, 112.0, 114.6, 121.2, 122.0, 128.7, 133.4, 140.7, 145.4,
47.5, 159.1.
1
1
(
+)-(1S)-N-(2,2-Diethoxyethyl)-2-(3,4-dimethoxyphenyl)-1-(3-
methoxyphenyl)-ethylamine (4c)
Amine 4c (1.34 g, 3.62 mmol) was obtained following the typical
procedure starting from amine 3c (1.39 g, 4.86 mmol).
MS (EI): m/z (%) = 220 (100), 207 (86), 150 (64), 121 (35).
2
0
(+)-(1S)-N-(2,2-Diethoxyethyl)-2-(3,4-dimethoxyphenyl)-1-(3-
methoxyphenyl)-N-methylethylamine (5c)
Amine 5c (1.16 g, 2.80 mmol) was obtained following the typical
procedure starting from amine 4c (1.34 g, 3.60 mmol).
Yield: 75%; [a]D +18.5 (c 0.5, CH Cl ).
2
2
–
1
IR (neat): 3300 (NH), 1250 (COC) cm .
1
H NMR: d = 1.06 (t, J = 7.0 Hz, 3 H), 1.10 (t, J = 7.0 Hz, 3 H), 1.78
br s, 1 H), 2.43–2.59 (m, 2 H), 2.74–2.87 (m, 2 H), 3.34–3.43 (m,
H), 3.46–3.54 (m, 2 H), 3.68–3.74 (m, 1 H), 3.74 (s, 3 H), 3.76 (s,
H), 3.83 (s, 3 H), 4.50 (t, J = 5.3, 1 H), 6.57–6.88 (m, 6 H), 7.17–
.26 (m, 1 H).
(
20
Yield: 78%; [a]D +14.4 (c 0.7, CH Cl ).
2
2
2
3
7
–
1
IR (neat): 1120 (COC) cm .
1
H NMR: d = 1.16 (t, J = 7.0 Hz, 3 H), 1.17 (t, J = 7.0 Hz, 3 H), 2.33
(s, 3 H), 2.49 (dd, J = 13.5, 5.0 Hz, 1 H), 2.70 (dd, J = 13.5, 5.1 Hz,
1
3
C NMR: d = 15.1, 44.6, 49.6, 55.0, 55.5, 55.6, 61.7, 61.8, 64.7,
01.6, 110.8, 112.1, 112.1, 119.6, 121.0, 129.1, 131.0, 145.1, 147.0,
47.3, 148.5, 148.4, 159.5.
1
3
H), 3.20 (dd, J = 13.5, 5.1 Hz, 1 H), 3.42–3.69 (m, 4 H), 3.69 (s,
H), 3.74 (s, 3 H), 3.79 (s, 3 H), 3.63–3.84 (m, 2 H), 4.53 (t, J = 5.0
1
1
Hz, 1 H), 6.46–6.78 (m, 6 H), 7.12–7.19 (m, 1 H).
MS (EI): m/z (%) = 281 (12), 270 (54), 207 (100), 151 (49).
1
3
C NMR: d = 15.3, 38.6, 39.7, 55.1, 55.5, 55.7, 56.8, 61.6, 61.8,
0.9, 101.9, 110.6, 112.0, 119.6, 112.5, 114.7, 121.1, 121.3, 128.6,
32.1, 141.2, 146.9, 148.1, 159.1.
7
1
N-Methylation of Aminoacetals 4a–c; Typical Procedure
Aminoacetal 4a (0.25 g, 0.58 mmol) was dissolved in anhyd MeCN
(
25 mL), 35% aq HCHO (0.25 mL, 2.9 mmol), and NaBH CN (0.18
MS (EI): m/z (%) = 266 (48), 149 (100).
3
g, 2.9 mmol) was added in one portion. The solution was stirred at
r.t. until TLC analysis showed complete conversion (typically 12 h).
Then, the mixture was quenched with water (10 mL) and extracted
with CH Cl (2 × 10 mL). The organic extracts were combined,
Synthesis of 1-Benzyltetrahydroisoquinolin-4-ols cis-6a–c and
trans-6a–c; Typical Procedure
A solution of aminoacetal 5a (0.71 g, 1.6 mmol) in acetone (10 mL)
and concd HCl (5 mL) was stirred overnight at r.t. The mixture was
cooled on an ice bath, basified with 1 M NaOH and extracted with
CH Cl (3 × 25 mL). The combined organic extracts were dried
2
2
dried over Na SO and the solvent was evaporated off under re-
2
4
duced pressure. The resulting residue was purified by flash column
chromatography (hexanes–EtOAc, 2:8) to afford 5a (0.24 g, 0.54
mmol) as a colorless oil.
2
2
over Na SO and the solvent was evaporated under reduced pres-
2
4
sure to afford tetrahydroisoquinolin-4-ols 6a as a mixture of two di-
astereoisomers (0.50 g, 1.40 mmol; global yield: 85%). Both
diastereoisomers were separated by flash column chromatography
Synthesis 2004, No. 7, 1093–1101 © Thieme Stuttgart · New York

PAPER
CH Cl –MeOH, 0–2%) to afford pure oily samples of tetrahy-
Total Synthesis of (S)-(+)-Glaucine
1099
1
3
(
C NMR: d = 25.4, 40.8, 42.6, 46.9, 55.5, 55.6, 55.7, 55.8, 64.8,
110.8, 110.9, 111.0, 112.8, 121.8, 125.9, 129.1, 132.4, 146.1, 147.1,
47.2, 148.4.
2
2
droisoquinolinols cis- and trans-6a.
1
(
1
[
+)-(1S,4S)-6,7-Dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-
,2,3,4-tetrahydroisoquinolin-4-ol (cis-6a)
+
MS (EI): m/z (%) = 206 (M – 15, 100).
20
Anal. Calcd for C H NO : C, 70.56; H, 7.61; N, 3.92. Found: C,
a]D +25.0 (c 1.0, CH Cl ).
21 27
4
2
2
7
0.32; H, 7.77; N, 3.47.
–
1
IR (neat): 3500–3300 (OH) cm .
1
H NMR: d = 1.70–1.90 (br s, 1 H, OH), 2.55 (dd, J = 13.1, 9.1 Hz,
(+)-(1S)-7-Methoxy-2-methyl-1-(3,4-methylendioxybenzyl)-
1,2,3,4-tetrahydroisoquinoline (7b)
Isoquinoline 7b (0.25 g, 0.83 mmol) was obtained following the
typical procedure starting from amine 5b (0.34 g, 1.00 mmol).
1
2
3
H), 2.66 (s, 3 H), 2.77 (dd, J = 12.5, 2.8 Hz, 1 H), 3.13–3.22 (m,
H), 3.48 (s, 3 H), 3.77 (s, 3 H), 3.77–3.81 (m, 1 H), 3.84 (s, 3 H),
.87 (s, 3 H), 4.47 (br s, 1 H), 5.80 (s, 1 H), 6.48 (d, J = 1.7 Hz, 1
H), 6.54 (dd, J = 8.2, 1.7 Hz, 1 H), 6.76 (d, J = 8.2 Hz, 1 H), 6.89
20
Yield: 82% (2 steps); [a]D +75.5 (c 0.35, EtOH).
1
(
s, 1 H).
H NMR: d = 2.49 (s, 3 H), 2.47–2.63 (m, 1 H), 2.71–2.89 (m, 3 H),
.04–3.22 (m, 2 H), 3.64 (s, 3 H), 3.69–3.81 (m, 1 H), 5.91 (s, 2 H),
.28 (d, J = 2.8 Hz, 1 H), 6.55–6.97 (m, 4 H), 6.99 (d, J = 8.3 Hz, 1
1
3
C NMR: d = 34.7, 42.8, 54.3, 55.2, 55.7, 55.8, 55.9, 64.0, 65.9,
3
6
H).
1
1
10.1, 111.0, 111.2, 113.0, 122.0, 127.5, 129.5, 131.1, 147.2, 147.5,
47.9, 148.6.
MS (EI): m/z (%) = 371 (12), 222 (100), 208 (36), 190 (25), 151(61).
13
C NMR: d = 24.6, 41.1, 42.6, 46.9, 55.0, 65.3, 100.7, 107.9, 109.9,
1
12.4, 112.7, 122.4, 126.1, 129.6, 133.6, 138.3, 145.7, 147.3, 157.0.
(
1
)-(1S,4R)-6,7-Dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-
,2,3,4-tetrahydroisoquinolin-4-ol (trans-6a)
+
MS (EI): m/z (%) = 311 (M , 1), 309 (28), 266 (62), 176 (100), 174
(65).
20
[
a]D –70.4 (c 1.0, CH Cl ).
2 2
–
1
IR (neat): 3450–3200 (OH) cm .
(
+)-(1S)-1-(3,4-Dimethoxybenzyl)-7-methoxy-2-methyl-1,2,3,4-
1
H NMR: d = 2.66 (s, 3 H), 2.84–2.98 (m, 1 H), 3.02 (dd, J = 11.6,
tetrahydroisoquinoline (7c)
Isoquinoline 7c (0.20 g, 0.65 mmol) was obtained following the typ-
ical procedure starting from amine 5c (0.23 g, 0.72 mmol).
4
.0 Hz, 1 H), 3.13–3.15 (m, 2 H), 3.63 (s, 3 H), 3.77 (s, 3 H), 3.79
(
s, 3 H), 3.80 (s, 3 H), 3.77–3.82 (m, 1 H), 4.39 (br s, 1 H), 6.32 (d,
J = 1.8 Hz, 1 H), 6.50 (s, 1 H), 6.49–6.54 (m, 1 H), 6.68 (d, J = 8.2
Hz, 1 H), 6.77 (s, 1 H).
20
Yield: 86% (2 steps); [a]D +85.8 (c 0.3, EtOH).
1
H NMR: d = 2.50 (s, 3 H), 2.48–2.61 (m, 1 H), 2.70–2.86 (m, 3 H),
.08–3.19 (m, 2 H), 3.58 (s, 3 H), 3.76 (s, 3 H), 3.83 (s, 3 H), 3.70–
.90 (m, 1 H), 6.22 (d, J = 2.4 Hz, 1 H), 6.56–6.77 (m, 4 H), 6.97
1
3
C NMR: d = 39.3, 43.1, 55.6, 55.7, 55.8, 55.9, 57.4, 64.6, 65.9,
09.5, 110.5, 110.9, 113.1, 122.1, 128.3, 129.5, 129.9, 147.5, 147.7,
48.2, 148.4.
3
3
1
1
(
d, J = 8.7 Hz, 1 H).
13C NMR: 24.9, 40.8, 42.6, 47.0, 54.9, 55.5, 55.7, 65.2, 110.7,
(
2
6
1S,4R)- and (1S,4S)-1-(3,4-Methylenedioxybenzyl)-7-methoxy-
-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol (cis-6b and trans-
b) and (1S,4R)- and (1S,4S)-1-(3,4-dimethoxybenzyl)-7-meth-
1
1
12.3, 112.5, 112.6, 121.5, 126.1, 129.4, 132.2, 138.3, 147.0, 148.2,
56.8.
oxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol (cis-6c and
trans-6c)
They were prepared according to the general procedure and used di-
rectly as a mixture of diastereoisomers without further purification
in the next step of the synthesis.
MS (EI): m/z (%) = 176 (100).
Anal. Calcd for C H NO : C, 73.37; H, 7.70; N, 4.28. Found: C,
2
0
25
3
7
3.61; H, 7.64; N, 4.02.
Oxidative Coupling of 1-Benzyltetrahydroisoquinolines (7a–c);
Typical Procedure
Reduction of 1-Benzyltetrahydroisoquinolinols 6a–c; Typical
Procedure
a) Oxidation with RuO ·xH O
2
2
A solution of tetrahydroisoquinoline 7a (0.10 g, 0.28 mmol) in
A solution of diastereomeric tetrahydroisoquinolinols cis-6a and
trans-6a (0.36 g, 1.00 mmol) in CH Cl (10 mL) was dropwise add-
CH Cl (8 mL) was added over a stirred suspension of RuO ·xH O
2
2
2
2
2
2
(
(
0.15 g, 1.12 mmol) in CH Cl (17 mL), TFA (1.70 mL), and TFAA
0.88 mL) at –10 ºC under argon and then, BF ·OEt (0.2 mL, 1,58
2 2
ed over a cooled (0 ºC) suspension of NaBH pellets (0.38 g, 10
4
3
2
mmol) in TFA (4.6 mL, 60 mmol). The reaction mixture was stirred
at r.t. until complete conversion of starting materials had occured
mmol) was added in one portion. The mixture was stirred at r.t. for
4 h and then the solvent was removed under reduced pressure. H O
2
2
(typically 2–3 h) and then the volatiles were removed under reduced
(15 mL) was added, the mixture was basified to pH 9 with NH OH
4
pressure. The resulting slurry was basified with 1 M NaOH (10 mL)
and extracted with CH Cl . The combined organic fractions were
(
10 mL), extracted with EtOAc (3 × 15 mL), and washed with
2
2
brine. The combined organic fractions were collected, dried over
Na SO , filtered, and the solvent was removed under reduced pres-
collected, dried over Na SO , filtered, and the solvent was removed
2
4
2
4
under reduced pressure. The resulting residue was purified by flash
column chromatography (CH Cl –MeOH, 99:1) to afford 1-benz-
sure. The resulting residue was purified by column chromatography
CH Cl –MeOH, 99:1) to afford aporphine 8a (70 mg, 0.21 mmol);
2
2
(
2
2
yltetrahydroisoquinoline 7a (0.30 g, 0.85 mmol).
yield: 75%.
(
1
+)-(1S)-1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-2-methyl-
,2,3,4-tetrahydroisoquinoline [(+)-Laudanosine, 7a]
b) Oxidation with Ce(OH)4
20
20a
TFA (3,5 mL) and TFAA (0.60 mL) were added over a stirred sus-
pension of Ce(OH) (0.43 g, 2.06 mmol) in CH Cl (15 mL) at 0 ºC
Yield: 85%; [a] +90.0 (c 0.2, EtOH) [Lit.
EtOH].
+96.6 (c 0.41,
D
4
2
2
under argon. At this temperature BF ·OEt (0.4 mL, 3.15 mmol)
was added followed immediately by a solution of tetrahydroiso-
quinoline 7a (0.10 g, 0.28 mmol) in CH Cl (4 mL). The mixture
3
2
1
H NMR: d = 2.53 (s, 3 H), 2.58–2.61 (m, 1 H), 2.72–2.86 (m, 3 H),
3
.10–3.20 (m, 2 H), 3.56 (s, 3 H), 3.68 (dd, J = 7.7, 4.7 Hz, 1 H),
.78 (s, 3 H), 3.83(s, 3 H), 3.84 (s, 3 H), 6.1 (s, 1 H), 6.55–6.78 (m,
H).
2
2
3
4
was stirred at r.t for 48 h and, quenched with a sat. solution of
NaHCO , and extracted with CH Cl . The combined organic frac-
3
2
2
tions were collected, dried over Na SO , filtered, and the solvent
2
4
Synthesis 2004, No. 7, 1093–1101 © Thieme Stuttgart · New York

1
100
E. Anakabe et al.
PAPER
was removed under reduced pressure. The resulting residue was
purified by column chromatography CH Cl –MeOH, 99:1) to af-
2001) and the Ministerio de Ciencia y Tecnología (Project
BQU2002-00488) for financial support.
2
2
ford aporphine 8a (60 mg, 0.17 mmol); yield: 60%.
References
c) Oxidation with PIFA
A solution of PIFA (0.23 g, 0.52 mmol) in CH Cl (10 mL) was add-
ed at –20 ºC to a solution of tetrahydroisoquinoline 7a (0.15 g, 0.42
2
2
(
(
1) Bentley, K. W. Nat. Prod. Rep. 2003, 20, 342.
2) Shoji, N.; Umeyama, A.; Takemoto, T.; Ohizumi, Y. J.
Pharmacol. Sci. 1984, 73, 568.
mmol) and BF ·OEt (0.14 mL, 1.0 mmol) in CH Cl (20 mL). The
3
2
2
2
mixture was stirred for 30 min and then quenched with MeOH (5
mL). The solvent was removed under reduced pressure and the
crude reaction product was purified by column chromatography
(3) Cassels, B. K.; Asencio, M.; Conget, P.; Speisky, H.
Pharmacol. Res. 1995, 31, 103.
(
4) Loghin, F.; Chagraoui, A.; Asencio, M.; Comoy, E.;
Speisky, H.; Cassels, B. K.; Protais, P. Eur. J. Pharmacol.
(
CH Cl –MeOH, 99:1) to afford aporphine 8a (0.11 g, 0.31mmol);
2 2
yield: 75%.
2003, 18, 133.
(
5) Zhelyazkova-Savova, M. D.; Zhelyazkov, D. K. J.
Pharmacol. Sci. 2003, 55, 125.
6) Indra, B.; Matsunaga, K.; Hoshino, O.; Suzuki, M.;
Ogasawara, H.; Ohizumi, Y. Eur. J. Pharmacol. 2002, 437,
173.
(
[
1
+)-(S)-Glaucine (8a)
a]D +106.0 (c 0.2, CH Cl ) [Lit. +100 (c 3.2, CHCl3].
20
21
2
2
(
H NMR: d = 2.48–2.70 (m, 3 H), 2.53 (s, 3 H), 2.97–3.07 (m, 4 H),
.64 (s, 3 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 3.92 (s, 3 H), 6.58 (s, 1 H),
.77 (s, 1 H), 8.08 (s, 1 H).
3
6
(7) Wang, B. H.; Lu, Z. X.; Polya, G.-M. Planta Med. 1997, 63,
13C NMR: 29.2, 34.4, 44.0, 53.3, 55.7, 55.9, 60.1, 62.5, 110.3,
494.
(
(
8) Hsieh, T.-J.; Chang, F.-.; Chia, Y.-C.; Chen, C.-Y.; Lin, H.-
C.; Chiu, H.-F.; Wu, Y.-C. J. Nat. Prod. 2001, 437, 1157.
9) Raby, S.; Neumeyer, J. L.; Grigoriadis, D.; Seeman, P. J.
Med. Chem. 1989, 32, 1198.
1
1
10.7, 111.4, 124.4, 126.8, 127.0, 128.8, 129.2, 144.2, 147.4, 147.9,
51.9.
+
+
MS (EI): m/z (%) = 355 (M , 100), 354 (M – 1, 61), 340 (32).
Anal. Calcd for C H NO : C, 70.96; H, 7.09; N, 3.94. Found: C,
(10) (a) Berényi, S.; Csutorás, C.; Makleit, S.; Auth, F.;
Laszlovszky, I.; Kiss, B.; Karpati, E.; Low, M. Med. Chem.
Res. 1997, 509. (b) Gao, Y.; Baldessarini, R. J.; Kula, N. S.;
Neumeyer, J. L. J. Med. Chem. 1990, 33, 1800.
21
25
4
7
0.94; H, 7.11; N, 3.97.
(
+)-(6S)-1-Methoxy-6-methyl-9,10-methylenedioxy-5,6,6a,7-
tetrahydro-4H-dibenzo[de,g]quinoline (8b)
Aporphine 8b (0.19 g, 0.60 mmol) was obtained following the typ-
ical procedure starting from isoquinoline 7b (0.25 g, 0.80 mmol).
(11) (a) Aporphines prepared by Pomerantz–Fristch type
cyclization: Yasuda, M.; Yamashita, T.; Kojima, R.; Shima,
K. Heterocycles 1996, 43, 2513. (b) Yasuda, M.;
Hamasuna, S.; Yamano, K.; Kubo, J.; Shima, K.
20
Yield: 75%; [a]D +95 (c 0.2, CH Cl ).
2
2
Heterocycles 1992, 34, 965. (c) Aporphines prepared by Pd-
catalyzed heteroannulation of iodophenanthrylamines: Gies,
A.-E.; Pfeffer, M.; Sirlin, C.; Spencer, J. Eur. J. Org. Chem.
1999, 1957. (d) Aporphines prepared by cyclization of 1-(2-
aminoethyl)-10-oxophenanthrene derivatives: Ramana, M.
M. V.; Prashant, V. P. Tetrahedron Lett. 1996, 37, 1671.
1
H NMR: d = 2.56 (s, 3 H), 2.60–2.66 (m, 3 H), 3.00–3.07 (m, 4 H),
3
6
.86 (s, 3 H), 5.92 (s, 2 H), 6.78 (s, 1 H), 6.87 (d, J = 8.2 Hz, 1 H),
.99 (d, J = 8.2, 1 H), 7.92 (s, 1 H).
1
3
C NMR: d = 28.7, 34.2, 44.0, 53.2, 55.9, 63.2, 100.7, 110.7, 111.1,
1
12,5, 122.1, 124.7, 125.5, 127.9, 129.0, 135.7, 146.9, 147.4, 154.2;
(e) Aporphines prepared by Friedel–Crafts cyclization:
+
MS (EI): m/z (%) = 309 (M , 100), 308 (50), 294 (15).
Suau, R.; Lopez-Romero, J. M.; Rico, R. Tetrahedron Lett.
1996, 37, 9357.
Anal. Calcd for C H NO : C, 73.77; H, 6.19; N, 4.53. Found: C,
19
19
3
7
3.35; H, 5.90; N, 4.81.
(12) (a) Kupchan, S. M.; Liepa, A. J. J. Am. Chem. Soc. 1973, 95,
4062. (b) Kupchan, S. M.; Kameswaran, V.; Findlay, J. W.
(
+)-(6S)-1,9,10-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-
A. J. Org. Chem. 1972, 37, 405. (c) Fukumoto, K. J.
Heterocycl. Chem. 1971, 8, 341.
dibenzo[de,g]quinoline (8c)
Aporphine 8c (0.15 g, 0.47 mmol) was obtained following the typ-
ical procedure starting from isoquinoline 7c (0.20 g, 0.60 mmol).
(13) Spangler, R. J.; Boop, D. C.; Kim, J. H. J. Org. Chem. 1974,
39, 1368.
(
14) Radical-mediated coupling: (a) Orito, K.; Uchiito, S.; Satoh,
2
0
Yield: 78%; [a]D +23.4 (c 0.2, CH Cl ).
1
2
2
Y.; Tatsuzawa, T.; Harada, R.; Tokuda, M. Org. Lett. 2000,
H NMR: d = 2.55 (s, 3 H), 2.59–2.65 (m, 3 H), 2.99–3.07 (m, 4 H),
.86 (s, 3 H), 3.90 (s, 3 H), 3.91 (s, 3 H), 6.78 (s, 1 H), 6.87 (d,
J = 8.3 Hz, 1 H), 7.00 (d, J = 8.3 Hz, 1 H), 7.92 (s, 1 H).
2, 307. (b) Nimgirawath, S.; Podoy, P. Aust. J. Chem. 2000,
3
53, 527. (c) Orito, K.; Thakker, M.; Kanbayashi, R.;
Tokuda, M.; Suginome, H. J. Org. Chem. 1999, 64, 6583.
(d) Zhou, D.-M.; Yue, B.-Z.; Cui, J.-Q.; Cai, M.-S.; Zhang,
L.-H. Heterocycles 1997, 45, 439. (e) Wiegand, S.; Schäfer,
H. J. Tetrahedron 1995, 51, 5341. (f) Shamma, M.; Hwang,
D.-Y. Tetrahedron 1974, 30, 2279.
1
3
C NMR: d = 28.6, 34.2, 44.1, 53.3, 55.8, 55.9, 56.0, 63.2, 110.7,
11.0, 112,5, 127.8, 122.1, 124.6, 125.6, 129.1, 135.7, 146.9, 147.6,
1
1
54.3.
+
MS (EI): m/z (%) = 325 (M , 100), 324 (76), 282 (47), 251 (53).
(
15) Lead tetraacetate-mediated coupling: (a) Hoshino, O.;
Suzuki, M.; Ogasawara, H. Tetrahedron 2001, 57, 265.
(b) Ogasawara, H.; Suzuki, M.; Shiohara, T.; Hoshino, O.
Heterocycles 1998, 47, 911.
Anal. Calcd for C H NO : C, 73.82; H, 7.12; N, 4.30. Found: C,
3.64; H, 7.04; N, 4.27.
2
0
23
3
7
(
16) (a) Planchenault, D.; Dhal, R.; Robin, J.-P. Tetrahedron
Acknowledgment
1
1
993, 49, 5823. (b) Landais, Y.; Robin, J.-P. Tetrahedron
992, 48, 7185. (c) Taylor, E. C.; Andrade, J. G.; Rall, G. J.
The authors thank the Basque Government (Project PI-1999-54 and
a fellowship to E.A.), the University of the Basque Country (Sub-
vención General a Grupos de Investigación, UPV 170.310-13546/
H.; McKilllop, A. J. Am. Chem. Soc. 1980, 102, 6513.
d) Kupchan, S. M.; Liepa, A. J.; Kameswaran, V.; Bryan, R.
F. J. Am. Chem. Soc. 1973, 95, 6861.
(
Synthesis 2004, No. 7, 1093–1101 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (S)-(+)-Glaucine
1101
(
17) (a) Berényi, S.; Csutorás, C.; Gyulai, S.; Rusznyák, G. Synth.
Commun. 2001, 31, 1987. (b) Hedberg, M.; Johansson, A.
M.; Hacksell, U. J. Chem. Soc., Chem. Commun. 1992, 845.
Vishwanath, V. M.; Han, G. R.; Laikes, G. D.; Balk, M. A.
J. Org. Chem. 1985, 50, 3619. (c) Olah, G. A.; Arvanaghi,
M.; Ohannesian, L. Synthesis 1986, 770. (d) McComsey, D.
F.; Reitz, A. B.; Maryanoff, C. A.; Maryanoff, B. E. Synth.
Commun. 1986, 16, 1535. (e) Lomas, J. S.; Bru-Capdeville,
V. J. Chem. Soc., Perkin Trans. 2 1997, 2589. (f) Yato, M.;
Homma, K.; Ishida, A. Heterocycles 1998, 233. (g) Li, C.;
Rehman, A.; Dalley, N. K.; Savage, P. B. Tetrahedron Lett.
1999, 40, 1861.
(c) G ranchelli, F. E.; Filer, C. N.; Soloway, A. H.;
Neumeyer, J. L. J. Org. Chem. 1980, 45, 2275.
(
(
18) Comins, D. L.; Thakker, P. M.; Baevsky, M. F. Tetrahedron
1997, 48, 16327.
19) (a) Czarnocki, Z.; Mieczkowski, J. B.; Ziolkowski, M.
Tetrahedron: Asymmetry 1996, 7, 2711. (b) Czarnocki, Z.;
McLean, D. B.; Szarek, W. A. Can. J. Chem. 1987, 65, 2356.
20) (a) Gottlieb, L.; Meyers, A. I. J. Org. Chem. 1990, 55, 5659.
(27) Whiting, D. A. In Comprehensive Organic Synthesis, Vol.
3; Trost, B. M.; Fleming, I.; Schreiber, S. L., Eds.; Pergamon
Press: Oxford, 1991, 659.
(
(
1
b) Meyers, A. I.; Dickman, D. A.; Boes, M. Tetrahedron
987, 43, 5095.
(28) (a) Several metal oxidants: Planchenault, D.; Dhal, R.;
Robin, J.-P. Tetrahedron 1993, 49, 5823. (b) Kupchan, S.
M.; Liepa, A. J. J. Am. Chem. Soc. 1973, 95, 4062.
(c) Thallium trifluoroacetate: McKillop, A.; Turrell, A. G.;
Young, D. W.; Taylor, E. C. J. Am. Chem. Soc. 1980, 102,
6504. (d) See also: Elson, I. H.; Kochi, J. K. J. Am. Chem.
Soc. 1973, 95, 5060; see also ref. 20b. (e) Chromium(III)
trifluoroacetate: See ref. 18a. (f) Ruthenium(IV)
(
(
(
21) Hara, H.; Komoriya, S.; Miyashita, T.; Hoshino, O.
Tetrahedron: Asymmetry 1995, 6, 1683.
22) Hoshino, O.; Fuchino, H.; Kikuchi, M. Heterocycles 1994,
39, 553.
23) See for example: (a) Vicario, J. L.; Badía, D.; Carrillo, L.;
Anakabe, A. Tetrahedron: Asymmetry 2003, 14, 347.
(
b) Anakabe, E.; Vicario, J. L.; Badía, D.; Carrillo, L.; Yoldi,
V. Eur. J. Org. Chem. 2001, 4343. (c) Vicario, J. L.; Badía,
D.; Domínguez, E.; Carrillo, L. Tetrahedron: Asymmetry
trifluoroacetate: Landais, Y.; Robin, J.-P. Tetrahedron 1992,
48, 7185; See also ref. 20a. (g) VOF /TFA: Kupchan, S. M.;
3
2
000, 11, 1227. (d) Vicario, J. L.; Badía, D.; Domínguez, E.;
Dhingra, O. O.; Kim, C.-K.; Kameswaran, V. J. Org. Chem.
1978, 43, 2521.
(29) Kochi, J. H.; Tang, R. T.; Bernath, T. J. Am. Chem. Soc.
1973, 95, 7114.
(30) (a) Kita, Y.; Arisawa, M.; Gyoten, M.; Nakajima, M.;
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6625. (b) Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.;
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(c) See also:Herrero, M. T.; Tellitu, I.; Dominguez, E.;
Hernandez, S.; Moreno, I.; SanMartin, R. Tetrahedron 2002,
58, 8581.
Carrillo, L. J. Org. Chem. 1999, 64, 4610. (e) Carrillo, L.;
Badía, D.; Domínguez, E.; Anakabe, E.; Osante, I.; Tellitu,
I.; Vicario, J. L. J. Org. Chem. 1999, 64, 1115. (f) Vicario,
J. L.; Badía, D.; Domínguez, E.; Crespo, A.; Carrillo, L.
Tetrahedron: Asymmetry 1999, 10, 1947. (g) Carrillo, L.;
Badía, D.; Domínguez, E.; Vicario, J. L.; Tellitu, I. J. Org.
Chem. 1997, 62, 6716.
(
24) Reviews: (a) Stang, P. J. J. Org. Chem. 2003, 68, 2997.
(
b) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271.
(
25) (a) Kursanov, D. N.; Parnes, Z. N.; Kalinkin, M. I.; Loim, N.
M. Ionic Hydrogenation and Related Reactions; Harwood
Academic Publishers: New York, 1985. (b) Gribble, G. W.
Reductions in Organic Synthesis, ACS Symposium Series
(31) Stahl, E. Thin Layer Chromatography, 2nd ed.; Springer
Verlag: Berlin, 1969.
(32) Still, W. C.; Kann, H.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
641; Abdel-Magid, A. F., Ed.; ACS: Washington, 1996,
1
67–200. (c) Seyden-Penne, J. Reductions by the Alumino-
(33) Armarego, W. F.; Perrin, D. D. Purification of Laboratory
Chemicals, 4th ed.; Butterworth-Heinmann: Newton / MA,
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and Borohydrides in Organic Synthesis; Wiley-VCH: New
York, 1997.
(26) (a) Review: Gribble, G. W. Chem. Soc. Rev. 1998, 28, 395.
(
b) See also: Nordlander, E.; Payne, M. J.; Njoroge, F. G.;
Synthesis 2004, No. 7, 1093–1101 © Thieme Stuttgart · New York