Stereoselective synthesis of pinnamine, an alkaloidal marine toxin from Pinna muricata

Article abstract of DOI:10.1016/S0040-4039(01)01583-0

Pinnamine, an alkaloidal marine toxin isolated from the bivalve Pinna muricata, was synthesized from N-Z-pyroglutamic acid in 16 steps.

Full text of DOI:10.1016/S0040-4039(01)01583-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7469–7471
Stereoselective synthesis of pinnamine, an alkaloidal marine
toxin from Pinna muricata
Hideo Kigoshi,a,* Norimitsu Hayashib and Daisuke Uemurab
aDepartment of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
bDepartment of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Received 25 July 2001; accepted 24 August 2001
Abstract—Pinnamine, an alkaloidal marine toxin isolated from the bivalve Pinna muricata, was synthesized from N-Z-pyroglu-
tamic acid in 16 steps. © 2001 Elsevier Science Ltd. All rights reserved.
Pinnamine (1), an alkaloidal marine toxin, was isolated
from the Okinawan bivalve Pinna muricata.1 The abso-
lute stereostructure of 1 was determined by spectral
analysis including CD measurement. The structural fea-
tures of 1 are a 9-azabicyclo[4.2.1]nonane moiety and a
dihydro-g-pyrone structure. Although pinnamine (1)
exhibits characteristic toxic symptoms such as scurry,
the scarcity of its natural supply has prevented further
biological studies of it. We describe herein the enan-
tioselective synthesis of pinnamine (1).
yield because of the instability of the Z protecting
group during the coupling reaction.
To avoid strongly basic conditions during homologa-
tion, the Wittig reaction and the Claisen condensation
were employed. Alcohol 5 was oxidized with SO3–pyri-
dine to give aldehyde 8, the Wittig reaction of which
afforded the conjugated ester 9 (87% yield in two steps).
Conjugated reduction of the a,b-unsaturated ester
group in 9 with NaBH4–CuCl5 quantitatively provided
saturated ester 10, which was hydrolyzed to carboxylic
acid 11 in 84% yield. Carboxylic acid 11 was converted
into the corresponding imidazolide, which was con-
densed with tert-butyl acetate to give b-ketoester 12a in
62% yield.
O
H
N
O
pinnamine (1)
Lewis acid treatment6 of the silyl enol ether of 12a
provided the bicyclo compound 13 in 78% yield, which
was stereoselectively reduced with NaBH4 to give alco-
hol 14 (90% yield). Compounds 13 and 14 were
obtained as single products, and their stereochemistry
was deduced by comparison of the coupling constants
of a hydrogen to the carbo-t-butoxy group in 14 with
those simulated using computer-calculated models with
four possible types of stereochemistry, 14A–14D (Fig.
1).7 The stereochemistry of 13 could be explained by the
formation of a chelated tin enolate intermediate and the
cyclization via a product-like transition state (Fig. 2).
The stereoselectivity of this reduction could be pre-
dicted by considering the conformation of 13 to be
attacked from the less hindered exo orientation (Fig.
2).7
Synthesis of 1 was started from N-Z-pyroglutamic acid
(2) (Scheme 1). Reduction of the carboxyl group gave
alcohol 3 in 61% yield.2,3 Alcohol 3 was further reduced
with DIBAL-H to afford hemiaminal 44 (92% yield),
the acid treatment of which in methanol provided
diastereomeric hemiaminal methyl ether 5 in 93% yield.
No pyranoside derivatives were isolated. Compound 5
was transformed into iodide 7 in two steps. Four-car-
bon homologation of 7 with the dianion of ethyl ace-
toacetate afforded the desired b-ketoester 12b in poor
Keywords: pinnamine; marine metabolite; acute toxicity;
homotropane alkaloid; synthesis.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01583-0

7470
H. Kigoshi et al. / Tetrahedron Letters 42 (2001) 7469–7471
OH
X
Z
N
Z
N
Z
N
b
c
g
O
R
HO
MeO
2 R = COOH
3 R = CH2OH
4
5 X = OH
6 X = OTs
7 X = I
d
e
a
12b
f
Z
N
Z
N
Z
N
h
i
MeO
CHO
MeO
COOMe
MeO
COOR
j
8
9
10 R = Me
11 R = H
O
O
Z
N
Z
N
l,m
n
k
t-BuOOC
MeO
COOR
12a R = t-Bu
12b R = Et
13
t-BuN
HO
HO
O
q
r
Z
N
Z
N
R
N
ROOC
O
O
14 R = t-Bu
15 R = H
16 R = Me
17
18 R = Z
R = H
s
o
p
1
Scheme 1. (a) 1. ClCO2Et, N-methylmolphorine, THF, −10°C; 2. NaBH4, MeOH, 0°C (61%); (b) DIBAL-H, CH2Cl2, −78°C
(92%); (c) p-TsOH, MeOH, rt (93%); (d) TsCl, pyridine, 0°C (90%); (e) NaI, CaCO3, DMF, 80°C (60%); (f) ethyl acetoacetate,
NaH, n-BuLi, rt (5%); (g) SO3–pyridine, Et3N, DMSO, rt; (h) Ph3PꢀCHCO2Me, THF, rt (87% in two steps); (i) NaBH4, CuCl,
MeOH, THF, 0°C (100%); (j) 1 M NaOH aq., MeOH, rt (84%); (k) 1. 1,1%-carbonyldiimidazole, THF, rt; 2. LDA, t-BuOAc, 0°C
(62%); (l) TBSCl, Et3N, THF, 40°C; (m) Sn(OTf)2, CH2Cl2, 0°C (78% in two steps); (n) NaBH4, MeOH, 0°C (90%); (o) TFA,
CH2Cl2, rt; (p) TMSCHN2, MeOH, rt (74% in two steps); (q) t-BuNꢀCHCH2CH2CH3, LDA, THF, 0°C (73%); (r) TFA, THF,
H2O, rt (91%); (s) TMSI, MeCN, 0°C (77%).
Removal of the tert-butyl group in 14 and subsequent
methylation afforded methyl ester 16 (74% yield from
14). Condensation of 16 with the lithium anion8 of
N-tert-butylbutyraldimine gave a complex mixture of
the isomeric keto imine 179 (73%). Acid treatment of 17
resulted in cyclization and concomitant epimerization
to provide Z-pinnamine (18) in 91% yield. Finally,
removal of the Z protecting group with TMSI afforded
pinnamine10 (1) in 77% yield. Synthetic 1 was found to
correspond uniquely to natural 1 by comparison of
their spectral data including their CD spectra and acute
toxicity data.11
N-Z-pyroglutamic acid (2) in 16 steps in 7% overall
yield, which confirmed the absolute stereostructure and
bioactivity of natural pinnamine (1). Further biological
studies using synthetic 1 are in progress.
Acknowledgements
This work was supported in part by Grants-in-Aid for
Scientific Research on Priority Areas ‘Targeted Pursuit
of Challenging Bioactive Molecules’ (Nos. 11175101
and 13024215) from the Ministry of Education, Science,
Sports, and Culture, Japan. We are indebted to Wako
Pure Chemical Industries, Ltd., Banyu Pharmaceutical
In conclusion, pinnamine (1), a marine alkaloid isolated
from the bivalve Pinna muricata, was synthesized from

H. Kigoshi et al. / Tetrahedron Letters 42 (2001) 7469–7471
7471
HO
H
Co., Ltd., and Suntory Institute for Bioorganic
Research, for their financial support.
5.0
Z
N
t-BuOOC
H
6.3
H
References
14
1. Takada, N.; Iwatsuki, M.; Suenaga, K.; Uemura, D.
Tetrahedron Lett. 2000, 41, 6425–6428.
HO
H
HO
H
3.9
MeOOC
10.5
R
N
R
N
2. Altmann, K.-H. Tetrahedron Lett. 1993, 34, 7721–7724.
3. Because of the resisted rotation of the urethane bond,
some NMR signals were observed as a pair with a
ratio of 1:1 for most compounds possessing the Z pro-
tecting group.
MeOOC
H
H
H
H
5.1
0.8
14A
14B
4. Satisfactory spectral (IR, 1H and 13C NMR, and mass)
and analytical (high-resolution mass analyses) data were
obtained for all new compounds.
5. Narisada, M.; Horibe, I.; Watanabe, F.; Takeda, K. J.
Org. Chem. 1989, 54, 5308–5313.
HO
H
HO
H
4.5
MeOOC
11.2
R
N
R
N
MeOOC
H
H
H
H
1.1
3.4
6. (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am.
Chem. Soc. 1981, 103, 1172–1176; (b) Nagasaka, T.;
Nishida, S.; Sugihara, S.; Kawahara, T.; Adachi, K.;
Hamaguchi, F. Heterocycles 1994, 39, 171–184.
7. Molecular mechanics calculations were performed using
the MacroModel package (ver. 6.0, MM2* force field).
8. For lithiation of N-tert-butylaldimines with LDA, see:
Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron
Lett. 1976, 7–10.
14C
14D
J in Hz
R = COOMe
Figure 1. Coupling constants observed for 14 in CDCl3 and
calculated for models with four possible types of stereochem-
istry, 14A–14D, in Hz.
Z
H
N
9. Compound 17 might be in the imine and/or enamine
form.
H
H
10. Colorless oil; [h]D27 +71.2 (c=0.0399, MeOH); IR
12a
(CHCl3) 1680 cm−1 1H NMR (800 MHz, CD3OD,
;
O-t-Bu
−15°C) l 7.47 (s, 1H), 4.89 (dd, J=10.2, 2.2 Hz, 1H),
4.26 (dd, J=13.6, 11.4 Hz, 1H), 4.15 (m, 1H), 2.89 (d,
J=13.6 Hz, 1H), 2.50 (m, 1H), 2.26 (m, 1H), 2.18 (m,
4H), 2.11 (m, 1H), 2.02 (ddd, J=13.9, 9.8, 4.4 Hz, 1H),
1.96 (br d, J=15.4 Hz, 1H), 1.85 (dd, J=15.4, 13.2
Hz, 1H), 1.05 (t, J=7.5 Hz, 3H); CD (MeOH) uext
306 nm (Dm −0.067), 273 (+0.219), 263 (+0.232),
255 (+0.197); FABMS (m-nitrobenzyl alcohol) m/z
222 [M+H]+; HRFABMS (m-nitrobenzyl alcohol) m/z
calcd for C13H20NO2 [M+H]+ 222.1494, found 222.1515
(D 2.1 mmu).
O
O
Sn
Z
H
N
H
H
14
H–
11. Acute toxicity of synthetic 1 was examined by i.p.
injection into a ddY male mouse with a dose of 0.8
mg/kg (LD99 for natural 1: 0.5 mg/kg).1 Within 5 min
after injection, the mouse was dead with the same toxic
symptoms as those of the natural sample.
COO-t-Bu
O
13
Figure 2. Plausible reaction pathway from 12a to 14.