The efficient synthesis of morphinandienone alkaloids by using a combination of hypervalent iodine(III) reagent and heteropoly acid

Article abstract of DOI:10.1002/chem.200400358

The non-phenolic coupling reaction of benzyltetrahydroisoquinolines (laudanosine derivatives) by using a hypervalent iodine(III) reagent is described. In general, chemical oxidation of laudanosine gives glaucine. In contrast to general chemical oxidizing reagent systems, the novel use of reagent combination of phenyliodine bis(trifluoroacetate) (PIFA), and heteropoly acid (HPA) afforded morphinandienone alkaloids in excellent yields. In order to achieve the coupling reaction with simple reaction procedure, the use of HPA supported on silica gel instead of HPA was demonstrated and sufficient yield was exerted again. The present reagent system, PIFA/HPA, was also applied to the oxidation of other non-phenolic benzyltetrahydroisoquinolines and the high yield conversion to morphinandienones was accomplished.

Full text of DOI:10.1002/chem.200400358

FULL PAPER
The Efficient Synthesis of Morphinandienone Alkaloids by Using a
Combination of Hypervalent Iodine(iii) Reagent and Heteropoly Acid
Hiromi Hamamoto, Yukiko Shiozaki, Hisanori Nambu, Kayoko Hata,
Hirofumi Tohma, and Yasuyuki Kita*[a]
Abstract: The non-phenolic coupling
reaction of benzyltetrahydroisoquino-
lines (laudanosine derivatives) by using
a hypervalent iodine(iii) reagent is de-
scribed. In general, chemical oxidation
of laudanosine gives glaucine. In con-
trast to general chemical oxidizing re-
agent systems, the novel use of reagent
combination of phenyliodine bis(tri-
fluoroacetate) (PIFA), and heteropoly
acid (HPA) afforded morphinandie-
none alkaloids in excellent yields. In
order to achieve the coupling reaction
with simple reaction procedure, the use
of HPA supported on silica gel instead
of HPA was demonstrated and suffi-
cient yield was exerted again. The pres-
ent reagent system, PIFA/HPA, was
also applied to the oxidation of other
non-phenolic benzyltetrahydroisoqui-
nolines and the high yield conversion
to morphinandienones was accom-
plished.
À
Keywords: alkaloids
·
C C cou-
pling · heteropoly acids · hyperva-
lent iodine reagents · spiro com-
pounds
Introduction
dienones.[7,8] Such approaches by using convenient and
stable non-phenolic substrates were found to have a signifi-
cant advantage in the synthesis of morphinandienones or
other spirodienone alkaloids.[7,8] Since then, much attention
has been focused on the chemical oxidation of non-phenolic
substrates toward morphinandienone synthesis.[9,10] Al-
though two types of efficient non-phenolic coupling reac-
tions, one leading to neospirinedienone alkaloids[9] and the
other leading to aporphinic alkaloids,[10] have been devel-
oped, the transformation into morphinandienones (see for
example Figure 1) by using chemical oxidation has not yet
been accomplished. In this report, we wish to report the suc-
cessful high-yield conversion of nonphenolic benzyltetrahy-
droisoquinoline to morphinandienones by using a combina-
tion of hypervalent iodine(iii) reagent and heteropoly acid
(HPA).
The oxidative coupling reaction of benzyltetrahydroisoqui-
nolines to morphinandienones has received considerable at-
tention for a long time, since the proposal of alkaloid bio-
synthesis through the oxidative phenolic coupling reaction
presented by Barton and Cohen in 1957.[1] A great deal of
effort was invested in devising methodology for this purpose
and several heavy metal oxidizing reagents such as thalli-
um(iii), vanadium(v), iron(iii), ruthenium(iv) salts were de-
veloped.[1–6] In the early studies, the biomimetic phenolic
coupling reaction using chemical oxidants[1b,c,2,3] or some
other synthetic methods such as the Pschorr reaction,[1b,4]
photochemical coupling reaction,[5] or benzyne reaction,[6]
were continually employed. Despite large efforts, the yields
of the coupling step were usually low and, in general, these
methodologies did not afford practical routes to morphinan-
dienone alkaloids.
However, a notable breakthrough to those low yields was
reported by Miller in 1971.[7a] They investigated an electro-
oxidative method and reported the successful conversion of
non-phenolic benzyltetrahydroisoquinoline to morphinan-
Results and Discussion
Due to the low toxicity, ready availability, easy handling,
and their reactivities similar to that of heavy metal reagents,
the use of the hypervalent iodine reagent is a dominant
method for the oxidative coupling reaction of phenolic de-
rivatives to date.[11] In continuation of our research on the
use of hypervalent iodine(iii) reagents for organic synthesis,
we originally found that the reaction of phenol ethers with
some nucleophiles in the presence of phenyliodine bis(tri-
fluoroacetate) (PIFA)/(CF3)2CHOH or PIFA/BF3·Et2O
caused nucleophilic substitution reaction.[12] These reactions
[a] Dr. H. Hamamoto, Y. Shiozaki, Dr. H. Nambu, K. Hata,
Dr. H. Tohma, Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University, 1-6 Yamada-oka, Suita
Osaka 565-0871 (Japan)
Fax : (+81)6-6879-8229
E-mail: kita@phs.osaka-u.ac.jp
Chem. Eur. J. 2004, 10, 4977 – 4982
DOI: 10.1002/chem.200400358
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4977

FULL PAPER
oxidation of tetrahydroisoquinoline derivatives, and deacti-
vation of the nitrogen atom often has an influence on the
course of the coupling reaction.[2] To reduce the basicity of
the nitrogen atom, the amount of HPA was increased and
then the successful synthesis of the morphinandienones (2a)
was achieved (entries 3, 4). Alternatively, some acid addi-
tives[15] to PIFA/H3[PW12O40] were investigated for the same
purpose. In all cases, the dominant formation of 2a was ob-
served and the exclusive formation of 2a in excellent yield
occurred by using strong acid additive such as BF3·Et2O
(entry 5). This is the first example to effectively produce
morphinandienones by using chemical oxidation. Other
commercially available HPAs, such as H3[PMo12O40],
H4[SiW12O40], and H4[SiMo12O40], were also examined for
this reaction, and all were found to give 2a in good to excel-
lent yields (entries 6–8). In order to achieve the coupling re-
action with simple reaction procedure, the novel use of HPA
supported on silica gel, which is prepared by known
method,[16] was demonstrated and sufficient yield was exert-
ed (entry 9).
Figure 1. Some important isoquinoline and related alkaloids.
proceed with the formation of a charge-transfer complex of
phenol ethers with PIFA, followed by single electron trans-
fer (SET), which leads to aromatic cation radical interme-
diates.[12a]
Recently, we developed a novel methodology for generat-
ing cation radical species using the combination of PIFA
and HPA.[13] HPA is a readily available, economical, envi-
ronmental, easy to handle, and odorless solid acid.[14] Inter-
estingly, under this reagent system, the specific formation of
spirodienones was observed
Additionally, the reaction was carried out in the absence
of HPA in wet solvent and also afforded 2a. However, the
yield of 2a decreased and an inseparable mixture was ob-
tained (entries 10, 11). This indicates that the presence of
water plays an important role in producing 2a, and the hy-
in some cases during the in-
vestigation of the intra-
molecular coupling reaction
of non-phenolic derivatives
(Scheme 1).[13b] This finding
prompts us to explore a new
efficient procedure to intro-
Scheme 1. Formation of spirodienones by treatment with PIFA/HPA.
duce morphinandienones.
The study was performed on
a commercial product, the lau-
danosine (1a) (Table 1). As for
the chemical oxidation of 1a
with heavy metals, glaucine
(3a) was usually obtained in
moderate to good yields.[10]
Similar to heavy metal oxida-
tion, the reaction of 1a with
PIFA/BF3·Et2O in CH2Cl2 gave
3a in 58% yield (entry 1).[12e]
On the contrary, application of
our prior conditions,[13b] the
combination of PIFA and tung-
Table 1. Oxidative coupling reaction of laudanosine (1a).
Entry
Additive[a]
(5.0 equiv)
HPA[b]
Solv.
T
[8C]
t
2a
3a
[mgmLÀ1
]
[h]
[%][c]
[%][c]
1
2
BF3·Et2O
none
none
25(PW)
CH2Cl2
CH 3CN
À40
0.16
–
–
67
70
58
–
–
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
À20 to 0
12
1
sto(iv)
phosphoric
acid
3
4
5BF
6
7
8
9
10
11
none
none
3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
100 (PW)
150 (PW)
25(PW)
25(PMo)
25(SiW)
25(SiMo)
PW on SiO2 (0.3 equiv)[d]
none
CH3CN
CH3CN
CH 3CN
CH 3CN
CH 3CN
CH 3CN
CH3CN
0.5% H2O/CH3CN
1%MeOH/CH2Cl2
(H3[PW12O40], ca. 0.25mol%;
20 mgmLÀ1) gave neither O-
methyl flavinantine (2a) nor
glaucine (3a) (entry 2). One
possible factor which leads to
this undesirable result is the in-
fluence of the tertiary amine.
It is well known that the basici-
ty of the nitrogen atom can
play an important role in the
1
–
0.590
–
0.584
0.571
0.566
0.587
1
–
–
–
–
41
41
–
–
none
1
[a] Further additives are given in ref. [15]. [b] PW=H3[PW12O40]; PMo=H3[PMo12O40]; SiW=H4[SiW12O40];
SiMo=H4[SiMo12O40]. [c] Yield of isolated products. [d] PW on SiO2 =20 wt% supported on silica gel (see
ref. [16]).
4978
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Chem. Eur. J. 2004, 10, 4977 – 4982

Morphinandienone Alkaloids
4977 – 4982
Table 2. Syntheses of morphinandienones.
dration water of HPA, which is
present in the vicinity of the
electrophilic site, and has a sta-
bilizing effect on the cation
radical species, due to the
greater softness of the HPA
anion,[17] may cause a prefer-
ence for efficiently yielding 2a.
A plausible reaction mecha-
nism leading to 2a and 3a is
Substrate
OR1
OR2
OR3
OR4
Product
Yield
[%][c]
envisaged
as
follows
1a
1b
1c
1d
1e
1 f
OMe
OMe
OBn
OMe
OMe
OMe
OMe
OMe
OMe
OBn
OMe
OMe
OMe
OMe
2a (O-methylflavinantine)
2b (amurine)
2c
90
90
76
85
79
82
(Scheme 2). First, SET oxida-
tion of the electron-rich aro-
matic ring leads to intermedi-
ate [A]. The formation of 2a
would be introduced by the
hydration of the intermediate
À
À
OCH2O
OMe
OMe
OBn
OMe
OMe
OMe
OMe
OBn
2d
2e (O-benzylpallidine)
2 f (O-benzylflavinatine)
[a] 25mgmL À1. [b] 5equiv. [c] Yield of isolated products.
listed in Table 2 clearly showed much preference to previous
reports.[1–6,7b]
On the other hand, the oxidation of N-protected benzylte-
trahydroisoquinoline derivatives, N-trifluoroacetylnorlauda-
nosine (1g), was also investigated (Table 3). When the reac-
tion was carried out with PIFA/BF3·Et2O, the formation of
neospirinedienone (4) was observed, similar to heavy metal
oxidation (entry 1).[9b] On the contrary, the use of novel re-
agent combination, PIFA/HPA, afforded N-trifluoroacetyl-
norsebiferine (2g) and dominant formation of 2g occurred
in wet acetonitrile (entry 3). It is noteworthy that the reac-
tion proceeds under such mild reaction conditions with a
simple experimental protocol. In order to determine the ef-
fects of water, the PIFA/HPA mediated reactions were car-
ried under anhydrous conditions and exclusive formation of
4 were encountered. We also carried out the reaction with
PIFA/BF3·Et2O in wet acetonitrile and formation of 2g was
observed (entry 5). These results therefore suggest that the
presence of water in the reaction medium plays an impor-
tant role in its selectivity.
Scheme 2. Possible reaction formation mechanism for 2a and 3a.
[B]. On the other hand, as for 3a, there are two possible
pathways: direct o–p coupling[10b] (path a) versus bridgehead
p–p coupling[18] via intermediate [B] and [C] followed by re-
arrangement (path b). In view of the isolation of 2a and the
absence of 3a in entry 11, it seems reasonable to suggest
that glaucine 3a is formed by
A plausible reaction mechanism leading to 2g and 4 is en-
visaged as follows (Scheme 3). Initial SET oxidation of the
aromatic ring reads to intermediate [D]. Nucleophilic cap-
path b.
Table 3. Oxidative coupling reaction of N-trifluoroacetylnorlaudanosine (1a).
The remarkable result ob-
tained in the reaction of lauda-
nosine (1a) prompted us to
extend our procedure to sever-
al morphinandienone synthe-
ses. The benzyltetrahydroiso-
quinoline derivatives (1b–e)
were prepared according to the
reported method.[7b] The oxida-
tion was investigated with
PIFA/HPA/BF3·Et2O and the
high yield conversion to mor-
Entry
Additive
H2O
T
[8C]
t
2g
4
[h]
[%][a]
[%][a]
1
2
3
4
BF3·Et2O[d]
none
none
2.5%
none
2.5%
À40 to 0
À20 to 0
À20 to 0
À20 to 0
0 to RT
0.50
0.563
1
0.50
3
90
32
H3[PW12O40][b]
H3[PW12O40][b]
H3[PW12O40][b]/(CF3CO)2O[c]
3·Et2O[d]
phinandienone
derivatives,
84
43
9
such as flavinantine, amurine,
and pallidine was accom-
plished. The present result
90
5BF
13
[a] Yield of isolated products. [b] ca. 30 mol%. [c] 4 equiv. [d] 2 equiv.
Chem. Eur. J. 2004, 10, 4977 – 4982
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4979

Y. Kita et al.
FULL PAPER
(63 mL, 0.50 mmol) were added at À208C to a stirred solution of laudano-
sine (1a, 35.7 mg, 0.10 mmol) in CH3CN (4.0 mL). Stirring was continued
for 30 min at À20 to 08C. The solution was filtered through a pad of alu-
mina. The filtrate was concentrated and the residue was purified by
column chromatography on silica gel (EtOAc/Et3N 20:1) to afford the O-
methyl flavinantine (sebiferine) (2a, 29.6 mg, 87%).
ture of [D] by the second aromatic ring gives intermediate
[E]. The formation of [E] into 2g occurs through the nucleo-
philic addition of H2O (path c), while 4 is formed by rear-
rangement of [E] via path d.
O-Methyl flavinantine (sebiferine) (2a):[7b,19b,19d,20,21] Colorless solid; m.p.
162–1638C (lit. [19d] 112–1138C; lit. [19b] 158–1608C; lit. [20] 161–
1628C); 1H NMR: d=1.81–1.96 (m, 2H; CH2), 2.45(s, 3H; NMe), 2.56–
2.59 (m, 2H; CH2), 3.03 (dd, J=18.0, 6.0 Hz, 1H; CH2), 3.33 (d, J=
18.0 Hz, 1H; CH2), 3.68 (d, J=6.0 Hz, 1H; CH), 3.79 (s, 3H; OMe), 3.85
(s, 3H; OMe), 3.87 (s, 3H; OMe), 6.31 (s, 1H; ArH), 6.35(s, 1H; ArH),
6.62 (s, 1H; ArH), 6.80 (s, 1H; ArH); 13C NMR: d=32.6, 41.1, 41.7, 42.2,
45.7, 55.1, 55.9, 56.3, 60.8, 108.6, 110.4, 118.8, 122.2, 128.7, 130.0, 148.0,
148.3, 151.4, 161.7, 180.9; IR (KBr):n˜ = 1668, 1643, 1620 cmÀ1; UV: lmax
(EtOH) = 283, 239 nm; HRMS-EI: m/z: calcd for C20H23NO4: 341.1627;
found: 341.1626; MS: m/z (%): 341 (100) [M +]; elemental analysis calcd
(%) for C20H23NO4: C 70.36, H 6.79, N 4.10; found: C 70.20, H 6.86, N
4.05.
Amurine (2b):[7b,19b,19d,21] Colorless solid; m.p. 1748C (lit. [21] 205–
2068C); 1H NMR: d=1.73–1.94 (2H, m; CH2), 2.45(s, 3H; NMe), 2.49–
2.59 (m, 2H; CH2), 2.99 (dd, J=17.7, 6.0 Hz, 1H; CH2), 3.30 (d, J=
17.7 Hz, 1H; CH2), 3.66 (d, J=6.0 Hz, 1H; CH), 3.79 (s, 3H; OMe), 5.91
(s, 1H; OCH2O), 5.95 (s, 1H; OCH2O), 6.29 (s, 1H; ArH), 6.31 (s, 1H;
ArH), 6.61 (s, 1H; ArH), 6.83 (s, 1H; ArH); 13C NMR: d=33.0, 41.3,
41.7, 42.5, 45.7, 55.1, 60.8, 101.2, 105.1, 107.5, 118.7, 121.2, 129.6, 131.0,
Scheme 3. Possible reaction formation mechanism for 2g and 4.
Conclusion
146.8, 146.9, 151.4, 161.4, 180.9; IR (KBr): n˜ = 1668, 1643, 1618 cmÀ1
;
UV: lmax (EtOH) = 286, 246 nm; HRMS-EI: m/z: calcd for C19H19NO4:
The efficient and useful synthesis of morphinandienone al-
kaloids upon treatment with a combination of hypervalent
iodine(iii) reagent and heteropoly acid was accomplished.
This high yielding conversion using less toxic reagent sys-
tems with simple reaction procedure may find several ad-
vantages for application to the synthesis of morphine types
of skeletons and many other types of spirodienone alkaloids.
Further applications along these lines are now in progress.
325.1314; found: 325.1314; MS: m/z (%): 325(100) [ M +].
2,3-Dimethoxy-6-benzyloxymorphinandienone (2c):[7b] Colorless solid;
m.p. 187–1898C (lit. [7b] 2278C); 1H NMR: d=1.71–1.93 (m, 2H; CH2),
2.45 (s, 3H, NMe), 2.53–2.55 (m, 2H; CH2), 3.01 (dd, 1H, J=17.7,
6.0 Hz; CH2), 3.31 (d, J=17.7 Hz, 1H; CH2), 3.63 (s, 3H; OMe), 3.67 (d,
J=6.0 Hz, 1H; CH), 3.83 (s, 3H; OMe), 5.04 (d, J=12.9 Hz, 1H; CH2),
5.24 (d, J=12.9 Hz, 1H; CH2), 6.34 (s, 1H; ArH), 6.36 (s, 1H; ArH),
6.39 (s, 1H; ArH), 6.59 (s, 1H; ArH), 7.30–7.44 (m, 5H; ArH);
13C NMR: d=32.6, 41.0, 41.7, 42.4, 45.5, 55.8, 56.1, 60.8, 70.0, 108.2,
110.2, 122.0, 122.4, 126.7 (2C), 128.0, 128.5, 128.7 (2C), 129.7, 136.3,
147.9, 148.2, 150.0, 161.2, 181.1; IR (KBr): n˜ = 1666, 1643, 1620 cmÀ1
;
HRMS-EI: m/z: calcd for C26H27NO4: 417.1940; found: 417.1936; MS: m/
z (%): 417 (15) [M +], 326 (41), 298 (38), 91 (100).
Experimental Section
O-Benzylpallidine (2e):[4c,7b,22] Colorless solid; m.p. 1738C (lit. [22] 165–
1678C; lit. [4c] 224–2258C); 1H NMR: d=1.82–1.97 (m, 2H; CH2), 2.45
(s, 3H; NMe), 2.56–2.58 (m, 2H; CH2), 2.99 (dd, J=17.7, 5.7 Hz, 1 H:
CH2), 3.29 (d, J=17.7 Hz, 1H; CH2), 3.67 (d, J=5.7 Hz, 1H; CH), 3.81
(s, 3H; OMe), 3.89 (s, 3H; OMe), 5.1 (s, 2H; CH2), 6.31 (s, 1H; ArH),
6.36 (s, 1H; ArH), 6.67 (s, 1H; ArH), 6.84 (s, 1H; ArH), 7.30–7.44 (m,
5H; ArH); 13C NMR: d=32.7, 40.8, 41.4, 42.2, 45.5, 55.1, 56.6, 60.7, 71.0,
109.5, 112.9, 118.7, 122.6, 127.3 (2C), 128.0, 128.5, 128.6 (2C), 130.5,
All melting points are uncorrected. 1H and 13C NMR spectra were re-
corded at 300 and 75MHz, respectively. All NMR spectra were recorded
in CDCl3 with either TMS or residual CHCl3 as the internal standard. IR
absorption spectra were recorded as KBr pellets. UV spectra were taken
on
a SHIMADZU 2200 UV/Vis spectrometer. Aluminum oxide 60
(basic, Merck) and silica gel 60N (Kanto Chemical Company) were used
for column chromatography. The organic layer was dried with anhydrous
MgSO4 or Na2SO4. PIFA is commercially available. H3[PW12O40] and
H3[PMo12O40] were Kanto Chemical Company products. H4[SiW12O40],
Montmorillonite K10, and Nafion NR50 (beads) were purchased from
Aldrich. H4[SiMo12O40] was purchased from Wako Pure Chemical Indus-
tries. Compound 1a is commercially available. Compounds 1b–g were
prepared by known methods.[7b] 1H NMR and 13C NMR spectra of the
amide compounds 2g and 4 exhibited the presence of two rotamers.[7d,21]
136.7, 147.7, 148.7, 151.4, 180.8; IR (KBr): n˜ = 1666, 1643, 1620 cmÀ1
;
HRMS-EI: m/z: calcd for C26H27NO4: 417.1940; found: 417.1942; MS:
m/z (%): 417 (66) [M +], 91 (100).
O-Benzylflavinantine (2 f):[4b,7b,22] Colorless solid; m.p. 173–1768C
(lit. [22] 142–1448C; lit. [7b] 203–2048C; lit. [4b] 208–2108C); 1H NMR:
d=1.81–1.92 (m, 2H; CH2), 2.45 (s, 3H; NMe), 2.52–2.55 (m, 2H; CH2),
3.00 (dd, J=18.0, 6.6 Hz, 1H; CH2), 3.33 (d, J=18.0 Hz, 1H; CH2), 3.62
(s, 3H; OMe), 3.64 (d, J=6.6 Hz, 1H; CH), 3.88 (s, 3H; OMe), 5.12 (d,
J=12.6 Hz, 1H; CH2), 5.20 (d, J=12.6 Hz, 1H; CH2), 6.08 (s, 1H; ArH),
6.29 (s, 1H; ArH), 6.65(s, 1H; ArH), 6.75(s, 1H; ArH), 7.30–7.44 (m,
5H; ArH); 13C NMR: d=32.6, 41.3, 41.7, 42.1, 45.7, 55.0, 56.0, 60.8, 72.0,
110.8, 112.5, 118.6, 122.2, 127.1 (2C), 128.0, 128.6 (2C), 129.6, 129.9,
137.3, 146.9, 149.1, 151.3, 161.6, 180.9; IR (KBr): n˜ =1666, 1643,
Typical coupling procedure leading to morphinandienone derivatives 2
by treatment with PIFA/HPA: HPA (2.8 g), PIFA (1.26 g, 2.94 mmol)
and BF3·Et2O (1.4 mL, 11.2 mmol) were added at À208C to a stirred so-
lution of laudanosine (1a, 1.00 g, 2.80 mmol) in CH3CN (112 mL). Stir-
ring was continued for 60 min at À20 to 08C. The solution was diluted
with 10% Et3N/EtOAc and then quenched with saturated aqueous
NaHCO3. The mixture was extracted with EtOAc and washed with brine.
The organic extract was concentrated and the residue was purified by
column chromatography on silica gel (EtOAc/Et3N 20:1) to afford the O-
methyl flavinantine (2a). The other laudanosine derivatives 1 were exam-
ined by a similar procedure by using 1.00 mmol of 1.
1616 cmÀ1
; HRMS-EI: m/z: calcd for C26H27NO4: 417.1940; found:
417.1941; MS: m/z (%): 417 (66) [M +], 91 (100).
Procedure for the preparation of glaucine (3a): PIFA (43.0 mg,
0.10 mmol) and BF3·Et2O (63 mL, 0.50 mmol) were added at À208C to a
stirred solution of laudanosine (1a, 35.7 mg, 0.10 mmol) in CH2Cl2
(4.0 mL). Stirring was continued for 30 min at À20 to 08C. The solution
was diluted with CH2Cl2 and then quenched with saturated aqueous
NaHCO3. The mixture was extracted with CH2Cl2 and washed with brine.
Coupling procedure leading to O-methyl flavinantine (sebiferine) (2a) by
treatment with PIFA/HPA supported on silica gel: HPA (20 wt% sup-
ported on silica gel) (500 mg), PIFA (43.0 mg, 0.10 mmol) and BF3·Et2O
4980
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Chem. Eur. J. 2004, 10, 4977 – 4982

Morphinandienone Alkaloids
4977 – 4982
The organic extract was concentrated and the residue was purified by
column chromatography on silica gel (hexane/EtOAc/Et3N 20:10:1) to
afford glaucine (3a, 20.6 mg, 58%).
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research (S)
(No.7690) from the Ministry of Education, Science, Sports and Culture,
Japan.
Glaucine (3a):[9a,19b,23] Colorless solid; m.p. 134–1378C (lit. [23] 111–
1138C; lit. [19b] 136–1388C; lit. [9a] 137–1398C); 1H NMR: d=2.50–2.55
(m, 1H; CH2), 2.57 (s, 3H; NMe), 2.58–2.70 (m, 1H; CH2), 3.00–3.43 (m,
5H; CH, CH2, CH2), 3.65(s, 3H; OMe), 3.89 (s, 3H; OMe), 3.90 (s, 3H;
OMe), 3.93 (s, 3H; OMe), 6.59 (s, 1H; ArH), 6.78 (s, 1H; ArH), 8.09 (s,
1H; ArH); 13C NMR: d=29.0, 29.3, 34.5, 44.1, 53.3, 55.7, 55.8, 60.1, 62.5,
110.3, 110.7, 111.5, 124.7, 126.9, 127.2, 128.9, 129.3, 144.3, 147.4, 147.9,
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151.8; IR (KBr): n˜ = 1597 cmÀ1
.
Procedure for the oxidative coupling reaction of N-trifluoroacetyl norlau-
danosine by treatment with PIFA/HPA: HPA (100 mg) and PIFA
(43.0 mg, 0.10 mmol) were added at À208C to a stirred solution of 1g
(0.10 mmol) in 2.5% H2O/CH3CN (4.0 mL). Stirring was continued for
60 min at À20 to 08C. The solution was dilute with AcOEt and filtered
through a pad of alumina. The filtrate was concentrated and the residue
was purified by column chromatography on silica gel (hexane/EtOAc/
Et3N 10:15:0.5) to afford N-trifluoroacetylnorsebiferine (2g) and N-tri-
fluoroacetylneospirinedioenone (4).
Procedure for the oxidative coupling reaction of N-trifluoroacetylnorlau-
danosine by treatment with PIFA/BF3·Et2O: PIFA (43.0 mg, 0.10 mmol)
and BF3·Et2O (25 mL, 0.20 mmol) were added at À208C to a stirred solu-
tion of 1g (0.10 mmol) in CH3CN (4.0 mL). Stirring was continued for
30 min at À20 to 08C. The solution was diluted with EtOAc and then
quenched with saturated aqueous NaHCO3. The mixture was extracted
with EtOAc and washed with brine. The organic extract was concentrat-
ed and the residue was purified by column chromatography on silica gel
(hexane/EtOAc/Et3N 10:15:0.5) to afford the N-trifluoroacetyl neospiri-
nedioenone (4).
Procedure for the oxidative coupling reaction of N-trifluoroacetyl norlau-
danosine by treatment with PIFA/HPA/(CF3CO)2O: HPA (100 mg) and
PIFA (43.0 mg, 0.10 mmol) was added at À208C to a stirred solution of
1g (43.9 mg, 0.10 mmol) in 1.0% (CF3CO)2O/CH3CN (4.0 mL). Stirring
was continued for 30 min at À20 to 08C. The solution was diluted with
EtOAc and then quenched with saturated aqueous NaHCO3. The mix-
ture was extracted with EtOAc and washed with brine. The organic ex-
tract was concentrated and the residue was purified by column chroma-
tography on silica gel (hexane/EtOAc/Et3N 10:15:0.5) to afford the N-tri-
fluoroacetylneospirinedioenone (4).
N-trifluoroacetylnorsebiferine (2g):[7d,21,24] Colorless solid; m.p.
182–1838C (lit. [21] 203–2048C; lit. [24] 179.4–181.58C); 1H NMR: d=
1.79–2.09 (m, 2H; CH2), 2.89–3.29 (m, 3H; CH, CH2), 3.44, 4.45(2ꢁdd,
J=, 18.3, 5.7, 14.1, 5.4 Hz, total 1H; CH2), 3.81 (s, 3H; OMe), 3.86 (s,
3H; OMe), 3.90 (s, 3H; OMe), 4.99, 5.60 (each d, J=5.4, 5.7 Hz, total
1H; CH), 6.36, 6.37 (each s, total 1H; ArH), 6.41 (s, 1H; ArH), 6.62 (s,
1H; ArH), 6.84 (s, 1H; ArH); 13C NMR: d (major)=37.9, 39.5, 41.6,
42.2, 52.0, 55.2, 55.9, 56.4, 108.7, 110.8, 117.4, 123.2, 126.7, 128.6, 148.7,
149.0, 151.9, 156.6, 180.1; d(minor)=37.0, 38.7, 41.0, 42.1, 52.0, 55.3, 55.9,
56.3, 108.7, 110.5, 117.6, 122.7, 126.4, 128.6, 148.7, 149.0, 151.8, 156.3,
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180.1; IR (KBr): n˜
= ; HRMS-EI: m/z: calcd for
1649, 1678 cmÀ1
C21H20F3NO5: 423.1293; found: 423.1292; MS: m/z (%): 423.2 (100)
[M +].
N-trifluoroacetylneospirinedioenone (4):[7d,25] Colorless solid; m.p.
250–2518C (lit. [25] 247–2488C); 1H NMR: d=1.94–2.34 (m, 4H; CH2,
CH2), 2.87, 3.10 (each dd, J=18.3, 6.3, 17.4, 3.0 Hz, total 1H; CH2), 3.21,
3.47 (each dd, J=17.4, 7.2, 18.3, 9.3 Hz, total 1H; CH2), 3.68, 3.73 (each
s, total 3H; OMe), 3.91 (s, 6H; OMe, OMe), 4.49, 4.64 (each dd, J=9.3,
6.3, 7.2, 3.0 Hz, total 1H; CH), 5.69, 5.83 (each s, total 1H; ArH), 6.60 (s,
1H; ArH), 6.65, 6.76 (each s, total 1H; ArH), 6.98, 7.07 (each s, total
1H; ArH); 13C NMR: d(major) =31.7, 41.2, 45.1, 47.4, 55.2, 56.1 (2C),
60.6, 108.0, 111.1, 116.4, 116.2 (J=287 Hz), 123.7, 125.2, 127.4, 148.7,
151.3, 151.8, 155.9 (J=37 Hz), 156.8, 180.8; d (minor) =33.3, 36.2, 45.0,
48.1, 55.2, 56.0 (2C), 60.7, 107.4, 110.5, 114.4, 116.1 (J=287 Hz), 122.6,
123.9, 127.0, 148.7, 151.8, 152.1, 154.4, 155.7(J=37 Hz), 180.7; IR (KBr):
n˜ = 1639, 1693 cmÀ1; HRMS-EI: m/z: calcd for C21H20F3NO5: 423.1293;
found: 423.1294; MS: m/z (%): 423.2 (100) [M +]; elemental analysis
calcd (%) for C21H20F3NO5: C 59.57, H 4.76, N 3.31; found: C 59.34, H
4.79, N 3.32.
Chem. Eur. J. 2004, 10, 4977 – 4982
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4981

Y. Kita et al.
FULL PAPER
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Received: April 13, 2004
Revised: May 18, 2004
Published online: August 20, 2004
4982
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4977 – 4982