7,7-Dimethyl-6,8-dioxabicyclo[3.3.0]oct-3-en-2-one as a synthetic equivalent of ketodicyclopentadiene: A new route to (-)-physostigmine, (-)-physovenine, and (-)-aphanorphine

Article abstract of DOI:10.1016/S0040-4039(00)02171-7

A new diastereocontrolled route to three alkaloids having a quaternary benzylic stereogenic center, (-)-physostigmine, (-)-physovenine, and (-)-aphanorphine, has been developed using enantiopure 7,7-dimethyl-6,8-dioxabicyclo[3.3.0]oct-3-en-2-one as a synthetic equivalent of chiral cyclopentadienone.

Full text of DOI:10.1016/S0040-4039(00)02171-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1049–1052
7,7-Dimethyl-6,8-dioxabicyclo[3.3.0]oct-3-en-2-one as a synthetic
equivalent of ketodicyclopentadiene: a new route to
(−)-physostigmine, (−)-physovenine, and (−)-aphanorphine
Keigo Tanaka, Takahiko Taniguchi and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 24 November 2000; accepted 27 November 2000
Abstract—A new diastereocontrolled route to three alkaloids having a quaternary benzylic stereogenic center, (−)-physostigmine,
(−)-physovenine, and (−)-aphanorphine, has been developed using enantiopure 7,7-dimethyl-6,8-dioxabicyclo[3.3.0]oct-3-en-2-one
as a synthetic equivalent of chiral cyclopentadienone. © 2001 Elsevier Science Ltd. All rights reserved.
Quite recently, we developed an efficient preparation of
enantiopure 7,7-dimethyl-6,8-dioxabicyclo[3.3.0]oct-3-
en-2-one 1 in both enantiomeric forms from cyclopen-
tadiene by employing lipase-mediated resolution in the
key step.1 Since this compound possesses a biased
framework due to the protecting group of the dihy-
droxy functionality adjacent to the enone functionality,
we are interested in utilizing it as a synthetic equivalent
of chiral cyclopentadienone similar to ketodicyclo-
pentadiene2–4 2, in which its cyclopentene moiety plays
dual roles as a protecting group of an olefin functional-
ity and as a stereocontrolling device. We also take
compound 1 as a synthetic equivalent of chiral cy-
clopentadienone, one of whose olefin functionalities
being blocked by the 1,3-dioxolane ring at the same
time brings about the molecular bias, just as the cy-
clopentene moiety of 2 does. We could, therefore, uti-
lize the former 1, which is more readily accessible, as a
substitute for the latter, provided that its 1,3-dioxolane
moiety could serve as the cyclopentene moiety in 2 (Fig.
1).
In this letter, we report an alternative route to the
Calabar bean alkaloids,6 (−)-physostigmine 8 and (−)-
physovenine 9, and the norbenzomorphan natural alka-
loid, (−)-aphanorphine7 25, from the former with its
1,3-dioxolane ring serving as the cyclopentene moiety
of the latter on the basis of the methodology8 developed
for the latter. As shown in our previous synthesis,8 the
stereochemistry of the target molecules was controlled
by the molecular bias exerted by the cyclopentene moi-
ety of the intermediate 3, obtained from the latter by
sequential 1,4-reduction and alkylation, under Fischer
indolization conditions. The Fischer indolization reac-
tion occurred diastereoselectively from the less hindered
convex-face to give the carbinolamine 6, presumably
via 4 and 5. The aminal moiety of the target molecules
is then constructed after regeneration of the olefin
functionality by retro-Diels–Alder removal of the
cyclopentene moiety (Scheme 1). The same strategy
may be applicable to the former enone 1 if it could
afford the a-methyl-ketone 12, and the resulting ketone
12 carrying the acid-sensitive 1,3-dioxolane ring could
be tolerable under Fischer indolization conditions.
O
O
O
In order to demonstrate the utilization of the former
enone 1 as a substitute for the latter enone 2 in the
synthesis of the Calabar bean alkaloids, (−)-1 was first
transformed into the a-methyl-enone (−)-11, mp 48°C,
[h]2D8 −17.7 (c 0.9, CHCl3), via the a-iodo-enone (+)-10,
mp 84°C, [h]2D9 +12.2 (c 0.9, CHCl3), by employing the
established procedure5 involving the a-iodination9 and
the palladium-mediated cross-coupling reactions.10 Cat-
alytic hydrogenation of (+)-11 yielded the a-methyl-
ketone 12 as a mixture of two epimers. Thus,
introduction of the a-methyl functionality could be
O
(–)-1
(–)-2
O
"chiral cyclopentadienone"
O
O
O
O
(+)-1
(+)-2
Figure 1.
* Corresponding author. E-mail: konol@mail.cc.tohoku.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02171-7

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K. Tanaka et al. / Tetrahedron Letters 42 (2001) 1049–1052
iii
i, ii
HO
HN
Me
HN
Me
(–)-2
OMe
HN
Me
Me
H2N
O
N
H
OMe
OMe
3
4
6
5
Me
Me
Me
MeNHC
O
MeNHC O
MeO
iv, v
O
O
and
O
N
N
Me
N
O
NAc
H
H
Me
Me
Me
7
(–)-physovenine 9
(–)-physostigmine 8
Scheme 1. Reagents and conditions: (i) Zn, AcOH. (ii) LDA, MeI, THF. (iii) 4-Methoxyphenylhydrazine hydrochloride, aqueous
pyridine (1:10), reflux. (iv) Ac2O, pyridine. (v) NaH, MeI, THF–DMF (1:1).
O
O
O
O
i
iii
ii
I
Me
O
Me
O
O
O
O
O
O
O
12
(–)-11
(+)-10
(–)-1
O
O
Me
OH
MeO
O
O
iv
O
Me
N
HN
OMe
HN
O
H
Me
H2N
N
H
OMe
(+)-15
13
14
Scheme 2. Reagents and conditions: (i), I2, pyridine–CCl4, rt (83%). (ii) Me4Sn, PdCl2(PhCN)2, CuI, Ph3As, N-Me-pyrrolidone,
75°C (76%). (iii) H2, 10% Pd–C, MeOH. (iv) 4-Methoxyphenylhydrazine hydrochloride, aqueous pyridine (1:10), reflux (71% from
(+)-11).
accomplished, keeping the 1,3-dioxolane moiety intact,
without employing strong basic conditions. On reflux
with 4-methoxyphenylhydrazine hydrochloride in
aqueous pyridine,8,11 12 furnished the carbinolamine
(+)-15, mp 130–132°C, [h]2D3 +6.5 (c 1.0, CHCl3), in
satisfactory yield as a single product without affecting
the dioxolane moiety. It is noteworthy that the dioxo-
lane moiety controlling the diastereoselectivity was sta-
ble under the Fischer indolization conditions employed.
Overall yield of (+)-15 from (−)-1 was 45% in four steps
(Scheme 2).
cyclopentene moiety of 2, the removal of which
required high temperature. On reduction with lithium
aluminum hydride in THF, 18 afforded the known
tricyclic aminoacetal8,13 (−)-20, mp 33°C, [h]2D3 −94.4 (c
0.7, CHCl3) [lit.8: [h]D32 −96.2 (c 0.35, CHCl3)], the key
intermediate of (−)-physovenine12 9, directly in 67%
yield by reductive cyclization. On the other hand, 18,
on condensation with methylamine followed by reduc-
tion of the resulting imine with lithium aluminum
hydride afforded (−)-19, [h]2D3 −139.0 (c 0.7, benzene)
[lit.8: [h]3D4 −134 (c 0.7, benzene)], known as eser-
methole6 and the key intermediate of (−)-physostig-
mine12 8, in 54% overall yield, by sequential reductive
amination and reductive cyclization. Thus, an alterna-
tive route to two Calabar bean alkaloids has been
developed using 7,7-dimethyl-6,8-dioxabicyclo[3.3.0]-
oct-3-en-2-one (−)-1 as the substitute for the previously
used ketodicyclopentadiene (−)-2 employing the same
methodology (Scheme 3).
Having served its dual purpose as a stereocontrolling
device and protecting group, the 1,3-dioxolane group of
(+)-15 was next hydrolysed. Thus, (+)-15 was treated
with hydrochloric acid to give the triol 16, which was
immediately treated with 37% formalin and sodium
triacetoxyborohydride, followed by sodium periodate in
aqueous sodium hydrogen carbonate solution to fur-
nish N-methyloxyindole 18, mp 116–118°C, [h]2D4 +15.7
(c 1.0, CHCl3), in 52% overall yield via the transient
N-methyltriol 17 with loss of one carbon moiety. Thus,
the dioxolane moiety of 1 played the same role as the
Enantiomeric (+)-7,7-dimethyl-6,8-dioxabicyclo[3.3.0]-
oct-3-ene (+)-1 could also be used for an alternative

K. Tanaka et al. / Tetrahedron Letters 42 (2001) 1049–1052
1051
Me
OH
Me
OH
MeO
MeO
i
(+)-15
OH
OH
OH
OH
N
Me
N
H
16
17
Me
N
MeO
ref. 8
(–)-8
(–)-9
N
Me
ii
H
Me
Me
MeO
CHO
(–)-19
N
O
iii
Me
Me
(+)-18
MeO
ref. 8
N
O
H
Me
(–)-20
Scheme 3. Reagents and conditions: (i), 2N HCl–THF (1:3), 37% formalin, NaBH(OAc)3, then NaIO4, NaHCO3 (52%). (ii)
Methylamine hydrochloride, Et3N, MgSO4, CH2Cl2, rt, then LiAlH4, THF, reflux (54%). (iii) LiAlH4, THF, 0°C (67%).
OH
Me
O
MeO
Me
Me
i
MeO
OH
OH
MeO
as Scheme 2
O
O
+
N
H
O
OH
O
O
O
(–)-15
(+)-1
22
21
Me
Me
Me
HO
MeO
MeO
ii
OTf
ref. 16
iii
NMe
O
O
H
(+)-24
(–)-aphanorphine 25
23
Scheme 4. Reagents and conditions: (i) NaNO2, H3PO2, H2O, rt. (ii) PhNTf2, Et3N, DMAP (cat.), CH2Cl2, rt. (iii) H2, 10% Pd–C,
i-Pr2NEt, MeOH, rt (56% from (−)-15).
synthesis of (−)-aphanorphine 25, the only known nor-
benzomorphan natural product isolated from the fresh-
water blue-green alga Aphanizomenon flos-aquae. Thus,
employing the exact same procedure as for the enan-
tiomeric counterpart, (+)-1 was transformed into the
enantiomeric carbinolamine (−)-15, mp 130–131°C,
[h]2D3 −5.5 (c 0.9, CHCl3), in a comparable overall yield.
Upon exposure to sodium nitrite in aqueous hypoph-
sosphorus acid,13,14 (−)-15 afforded a mixture of the
dihydroxy-ketone 21 and the diosphenol 22 by concur-
rent diazotization and reductive removal of nitrogen
with hydrolysis of the dioxolane functionality and b-
dehydration to some extent under the conditions. The
mixture without separation was triflated to give rise to
the single enol triflate 23 with concurrent b-dehydration
of the diol 21 under the conditions. Finally, catalytic
hydrogenation of 23 in the presence of Hu¨nig base15
yielded the cyclopentanone (+)-24, [h]2D5 +93.7 (c 0.8,
CHCl3) [lit.16: [h]D27 +83.2 (c 1.21, CHCl3)], previously
obtained from (−)-1 and used for the key intermediate
of the first synthesis16 of (−)-aphanorphine 25. The
overall yield of (+)-24 from the carbinolamine (−)-15
was 56% in three steps (Scheme 4).
In summary, we have demonstrated that enantiopure
7,7-dimethyl-6,8-dioxabicyclo[3.3.0]oct-3-ene could
1
serve as the substitute for enantiopure ketodicyclopen-
tadiene 2 in the enantio- and diastereo-controlled syn-
thesis of (−)-physostigmine 8, (−)-physovenine 9, and
(−)-aphanorphine 25. In the present synthesis, the for-
mer exhibited the same chemical and steric characteris-
tics as the latter as a synthetic equivalent of chiral
cyclopentadienone.
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