Synthetic studies of zoanthamine alkaloids. Stereoselective synthesis of the ABC ring system of norzoanthamine by an intramolecular Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(02)00079-5

Stereoselective synthesis of the ABC ring system of norzoanthamine having five asymmetric centers including two quaternary carbon atoms has been successfully accomplished by an intramolecular Diels-Alder reaction. A key intermediate for the Diels-Alder re

Full text of DOI:10.1016/S0040-4039(02)00079-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1705–1708
Synthetic studies of zoanthamine alkaloids. Stereoselective
synthesis of the ABC ring system of norzoanthamine
by an intramolecular Diels–Alder reaction
Mio Sakai, Minoru Sasaki, Keiji Tanino and Masaaki Miyashita*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 22 November 2001; revised 4 January 2002; accepted 7 January 2002
Abstract—Stereoselective synthesis of the ABC ring system of norzoanthamine having five asymmetric centers including two
quaternary carbon atoms has been successfully accomplished by an intramolecular Diels–Alder reaction. A key intermediate for
the Diels–Alder reaction was efficiently and stereoselectively synthesized by a tandem conjugate addition–aldol strategy and
subsequent photosensitized oxidation of a furan derivative. © 2002 Elsevier Science Ltd. All rights reserved.
The zoanthamine alkaloids, a family of marine metabo-
lites, not only have a unique array of structural and
stereochemical complexity but also display, inter alia,
zoanthamine (1, Fig. 1), potent inhibitory activity
toward phorbol myristate-induced inflammation in
addition to powerful analgesic effects.1,2 Recently, nor-
zoanthamine (2) isolated from the colonial zoanthid
Zoanthus sp.3,4 has been shown to suppress the loss of
bone weight and strength in ovariectomized mice.3
Interestingly, a polyketide biogenetic pathway involving
the intramolecular Diels–Alder reaction has been pro-
posed for the zoanthamine alkaloids by Uemura et al.,
although these compounds are regarded as terpenoids.3
Their unique structures as well as significant biological
activities have elicited much attention from synthetic
organic chemists.5,6 So far, however, work on the syn-
thesis of the functionalized ABC ring system of the
zoanthamine alkaloids by the biomimetic Diels–Alder
strategy towards their total synthesis has been quite
limited.5 We describe herein the stereoselective synthesis
of the functionalized ABC ring system having five
asymmetric centers including two quaternary carbon
atoms by an intramolecular Diels–Alder reaction.
The key intermediate (13) for the Diels–Alder reaction
was efficiently and stereoselectively synthesized as
shown in Scheme 1. Conjugate addition of di[(E)-4-(tri-
isopropylsilyl)oxy-2-butenyl]cupurate7
to
cyclo-
hexenone (3) cleanly occurred in the presence of
TMSCl8 in THF at −78°C to give the TMS enol ether
4 in 94% yield. The zinc enolate generated from 4 was
reacted with a furaldehyde derivative 5, which was
prepared from commercially available ketone 14 as
shown in Scheme 2,9 to provide the aldol 6 as a 1:1
epimeric mixture in excellent yield. The aldol mixture 6
was then converted to the enone 7 by acetylation
followed by treatment with DBU, wherein the enol
acetate of 7 was formed to some extent; therefore, the
crude product was treated with K2CO3 resulting in
formation of the desired enone 7 in quantitative yield.
Reduction of the enone moiety of 7 was efficiently
performed by using triethylsilane in the presence of
Wilkinson’s catalyst10 in THF at 70°C followed by
treatment of the resulting enol silyl ether with K2CO3 in
MeOH. The ketone 8 thus obtained was transformed
into the acetate 9 in two steps, in which reduction of 8
with K-Selectride afforded the b-alcohol as the sole
product. The acetate 9 was routinely converted to the
methyl ketone 11 by a four-step reaction sequence in
70% overall yield: (1) desilylation; (2) oxidation of the
O
R
H
H
O
H
O
O
N
O
Zoanthamine (1): R = Me
Norzoanthamine (2): R = H
Figure 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00079-5

1706
M. Sakai et al. / Tetrahedron Letters 43 (2002) 1705–1708
Scheme 1.
TIPSOCH2C CLi
THF
cat. AgNO3
hexane
O
TIPSO
then K2CO3, MeOH
OH
OH
TIPSO
OAc
O
87%
from 14
14
1) BuLi
TBSCl
HMPA
2) TBAF
76%
BaMnO4
benzene
HO
TBS
OHC
TBS
O
O
94%
5
Scheme 2.
allylic alcohol; (3) methylation; (4) oxidation of the
secondary alcohol. The crucial photosensitized oxida-
tion of the furan 11 was successfully performed using a
halogen lamp in the presence of rose bengal in CH2Cl2
at 0°C according to Katsumura’s protocol.11 The crude
TBS ester was hydrolyzed by a saturated NH4Cl solu-
tion, and the resulting carboxylic acid was esterified
with (trimethylsilyl)diazomethane12 giving rise to the
(Z)-g-keto unsaturated ester 12, the key intermediate in
the present synthesis, in 62% yield. Then, 12 was trans-
formed into the diene 13, the crucial intermediate for
the Diels–Alder reaction, by treatment with TBSOTf
and Et3N.
The key intramolecular Diels–Alder reaction of 13 was
carried out in toluene at 150°C using a sealed tube
(Scheme 3). As a result, three products were obtained in
75% combined yield (85% yield based on the consumed

M. Sakai et al. / Tetrahedron Letters 43 (2002) 1705–1708
1707
OAc
HF•Py
AcO
THF
H
H
H
O
toluene
150 °C, 12 h
Me Me
H
Me
isomer
13
CO2Me
75%
O
H
H
O
Me
CO2Me
(76 : 24)
OTBS
16
15
Scheme 3.
starting material), two of which were found to be
regioisomers of the enol silyl ethers 15. The stereostruc-
ture of the major product has been unambiguously
established by X-ray crystallographic analysis13 of the
keto ester 1614 (Fig. 2) derived from 15, while the
structure of the minor stereoisomer is not determined at
present. These results demonstrate that the Diels–Alder
reaction of 13 preferentially occurred via an exo transi-
tion state rather than an alternative endo transition
state (Fig. 3) as anticipated. We are further examining
the optimum conditions for the Diels–Alder reaction
including stereoselectivity.
toward total synthesis of the zoanthamine alkaloids are
in progress in our laboratory.
Acknowledgements
We thank Professor Tamotsu Inabe, Mr. Norihito
Kobayashi and Mr. Takehiro Asari (Graduate School
of Science, Hokkaido University) for their helpful X-
ray crystallographic analysis. Financial support from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan (Grant-in-Aid for Scientific
Research (A) (No. 12304042) and Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ (No. 13029003)) is
gratefully acknowledged.
In conclusion, we have achieved the stereoselective
synthesis of the ABC ring system of the zoanthamine
alkaloids bearing five asymmetric centers including two
quaternary carbon atoms by employing an intramolecu-
lar Diels–Alder reaction as the key step. Further studies
Figure 2. X-Ray structure of compound 16.
OAc
OAc
H
H
H
H
Me
Me
H
TBDMSO
Me
>
H
O
O
Me
CO2Me
CO2Me
TBDMSO
Exo T. S.
Endo T. S.
Figure 3.

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M. Sakai et al. / Tetrahedron Letters 43 (2002) 1705–1708
Hirai, G.; Oguri, H.; Moharram, S. M.; Koyama, K.;
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