Formal synthesis of (+)-isolaurepinnacin

Article abstract of DOI:10.1016/S0040-4039(00)01880-3

The stereoselective formal synthesis of (+)-isolaurepinnacin is described. The required key oxepene skeleton possessing cis-oriented alkyl substituents at the α,ω-positions was stereoselectively constructed via the cyclization of the corresponding hydroxy epoxide promoted by the (Bu₃Sn)₂O/Zn(OTf)₂ system.

Full text of DOI:10.1016/S0040-4039(00)01880-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 65–67
Formal synthesis of (+)-isolaurepinnacin
Toshio Suzuki,a,* Ryuji Matsumura,b Ken-ichi Oku,a Keiichi Taguchi,a Hisahiro Hagiwara,b
Takashi Hoshia and Masayoshi Andoa
aFaculty of Engineering, Niigata University, 2-nocho, Ikarashi, Niigata 950-2181, Japan
bGraduate School of Science and Technology, Niigata University, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Received 29 September 2000; revised 16 October 2000; accepted 20 October 2000
Abstract—The stereoselective formal synthesis of (+)-isolaurepinnacin is described. The required key oxepene skeleton possessing
cis-oriented alkyl substituents at the a,v-positions was stereoselectively constructed via the cyclization of the corresponding
hydroxy epoxide promoted by the (Bu3Sn)2O/Zn(OTf)2 system. © 2000 Elsevier Science Ltd. All rights reserved.
total synthesis of (+)-1 was reported by the Overman
Red algae of the genus Laurencia are unique in terms of
producing C15 acetogenins.1 Medium-sized oxacyclics
bearing an enyne or allenic side chain moiety and
halogen group(s) are the main structural characteristics
of this group. In addition, most of the compounds
possess alkyl substituents with cis- or trans-orientation
at the a- and v-position on the cyclic ethereal skeleton.
Owing to the synthetic challenges associated with the
unique structural features, a number of new methods
for the construction of such a system have been investi-
gated.2 Among this group, (+)-isolaurepinnacin (1),
isolated from Laurencia pinnata Yamada,3 is a represen-
tative seven-membered oxacyclic having a,v-cis-ori-
group.5
Recently, we reported the development and the syn-
thetic utility of hydroxy-epoxide cyclizations promoted
by the (Bu3Sn)2O/Zn(OTf)2 system for the stereoselec-
tive construction of the a,v-cis- and a,v-trans-disubsti-
tuted oxepane skeletons.6 The reaction proceeded via
an exo mode coupled with an SN2 process and was
independent of the stereochemistry of the hydroxy and
epoxy groups to afford the corresponding cyclic
product. In this communication, we describe a stereose-
lective formal synthesis of (+)-1 featuring the above
protocol as a key step.
ented
alkyl
substituents.
Intensive
synthetic
investigations towards (+)-1 have resulted in several
reports for the stereoselective construction of the ox-
epane core of (+)-1.4 Consequently, in 1993, the first
Our synthetic plan is envisaged in Scheme 1. Hydroxy
epoxide 4, which could be obtained by coupling of
Br
Cl
Br
Cl
MEMO
OH
H
H
H
H
H
H
OH
O
O
OBn
O
(+)-isolaurepinnacin (1)
2
3
OMEM
OMEM
O
+
OBn
OBn
O
OTBS
OH
OTBS
4
5
6
Scheme 1.
Keywords: natural products; cyclization; oxepanes; medium-ring heterocycles.
* Corresponding author. Tel./fax: +81-25-262-6780; e-mail: suzuki@eng.niigata-u.ac.jp
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01880-3

66
T. Suzuki et al. / Tetrahedron Letters 42 (2001) 65–67
acetylene 5 with epoxide 6, was postulated as a key
intermediate. Application of the earlier cited protocol
to 4 would afford the corresponding oxepene skeleton 3
possessing the desired stereochemical outcome and the
appropriate functionalities for further transformations.
Introduction of two halogens and homologation of the
side chain would give 2, which is the intermediate
reported by Overman.5 Accordingly, 2 was set as the
target molecule for our synthetic study.
With the desired oxepene 3 in hand, we turned our
investigation to modification of the side chains. Since
several attempts to introduce the required halogens into
C6 and C13 with retention of configuration were unsuc-
cessful, the reaction sequence was manipulated in the
following order to achieve the desired goal. Acetylation
of 3 (99%), followed by removal of the MEM group
generated the corresponding alcohol in 81% yield. Ex-
posure to Mitsunobu conditions9 gave 12 (82%) pos-
sessing inverted configuration at C13. The benzyl group
of 12 was deprotected by the Nicolaou method,10 and
subsequently treated with TBAF to remove the par-
tially existing TMS ether. Under the reaction condi-
tions, migration of the acetyl group occurred to give a
mixture of 13 and 14. Fortunately, the equilibrium
could be shifted almost exclusively towards 14 by expo-
sure of the mixture to silica gel in CH2Cl2. The resulting
hydroxy group was immediately mesylated to give 15,
which was subsequently treated with a base to provide
the respective epoxide in 80% yield from 12. The gener-
ated hydroxy group was protected as a TBS ether to
give 16 in 76% yield. Regioselective opening of the
epoxy moiety with lithiated acetonitrile (74%), followed
by introduction of the chlorine functionality with
According to the synthetic plan, we started with effi-
cient preparation of the epoxide 6 and the acetylene 5
from (−)- and (+)-2,3-O-isopropylidenthreitol, respec-
tively. Successive introduction of benzyl (76%) and
tosyl groups (88%) to the hydroxy groups of (−)-7 led
to 8 (Scheme 2). Hydrolytic deprotection of 8 (67%),
followed by treatment with K2CO3 in MeOH–CH2Cl2
furnished the corresponding epoxide in 87% yield. Re-
protection of the hydroxy group with a TBS group was
effected with TBSCl, AgNO3 and pyridine in
acetonitrile7 to afford the epoxide 6 in 96% yield. On
the other hand, the acetylene 5 was synthesized as
follows. Benzyl ether 9, which is an antipode of 8
derived from (+)-7, was methylated with Me2CuLi
(89%) and then converted into 10 in high yield via an
analogous sequence to the synthesis of the epoxide 6
(Scheme 3). After protection with an MEM group
(89%), the epoxide was reacted with lithium acetylide in
DMSO (91%); subsequently, the resulting hydroxy
group was protected as a TBS ether to provide the
acetylene 5 in 79% yield.
11
(Oct)3P and CCl4 in the presence of pyridine resulted
in formation of 17 (51%) with inversion of configura-
tion at C6. Removal of the TBS group with HF·Py,
followed by exposure to the bromination conditions
reported by Murai12 provided 18 (84% from 17) with
complete inversion. Finally, reduction of the cyano
group of 18 to the primary alcohol via a two-step
sequence provided 2 in 85% yield. The synthetic sample
was identical in all aspects (1H, 13C NMR, IR and [h]D)
to those reported by Overman.5a
Coupling of 5 with 6 was easily achieved by the Ya-
maguchi method8 to afford 11 in 76% yield (Scheme 4).
Mesylation of the resulting hydroxy group (99%), fol-
lowed by treatment with TBAF in THF provided the
corresponding epoxide in 85% yield. Hydrogenation in
the presence of the Lindlar catalyst gave the intermedi-
ate 4 (99%), which was then subjected to the key
cyclization reaction. For this purpose, the tin ether
prepared by reacting 4 with (Bu3Sn)2O (0.6 equiv.) was
treated with Zn(OTf)2 (0.4 equiv.) in toluene. The reac-
tion proceeded smoothly to afford the a,v-cis-oxepene
3 as the sole cyclized product in 97% yield.
In conclusion, a formal synthesis of (+)-isolaurepin-
nacin (1) was accomplished with high stereoselectivity.
The stereoselective construction of the oxepene core
was performed by employing cyclization of the hydroxy
epoxide promoted by the (Bu3Sn)2O/Zn(OTf)2 system.
This synthetic study demonstrated that this protocol is
an efficient approach to the stereoselective synthesis of
highly functionalized seven-membered oxacyclics.
O
O
O
a,b
c,d,e
HO
TsO
OBn
OTBS
OH
OBn
O
O
6
(-)-7
8
Scheme 2. Reagents and conditions: (a) BnBr, NaH, DMF, 76%; (b) TsCl, TEA, DMAP, CH2Cl2, 88%; (c) Amberlyst 15, MeOH,
67%; (d) K2CO3, MeOH, CH2Cl2, 87%; (e) TBSCl, AgNO3, Py, CH3CN, 96%.
O
OMEM
OH
f,g,h
a,b,c,d,e
TsO
OBn
O
O
OTBS
10
9
5
Scheme 3. Reagents and conditions: (a) Me2CuLi, Et2O, −78°C–rt, 89%; (b) H2, Pd(OH)2, AcOEt, 92%; (c) TsCl, TEA, DMAP,
CH2Cl2; (d) Amberlyst 15, MeOH, 85% (two steps); (e) K2CO3, MeOH, CH2Cl2, 94%; (f) MEMCl, i-Pr2NEt, DMAP,
CH2ClCH2Cl, 50°C, 89%; (g) ꢀLi·EDA, DMSO, 0°C, 91%; (h) TBSCl, NaH, THF, 79%.

T. Suzuki et al. / Tetrahedron Letters 42 (2001) 65–67
67
OMEM
OMEM
b,c,d
e
OH
a
5
OBn
OTBS
11
OBn
OTBS
O
OH
4
MEMO
OH
ArCOO
OAc
ArCOO
OR1
H
H
H
H
H
H
i,j
f,g,h
OBn
OBn
OR2
O
O
O
6
13
Ar:p-NO2C6H4-
3
12
13: R1=Ac, R2=H
14: R1=H, R2=Ac
k
TBSO
ArCOO
OMs
TBSO
Cl
O
H
H
H
O
H
H
H
OAc
O
m,n
o,p
O
l
CN
16
15
17
Br
Cl
Br
Cl
H
H
H
H
O
OH
O
q,r
s,t
CN
18
2
Scheme 4. Reagents and conditions: (a) n-BuLi, BF3·OEt2, THF, −78°C, then 6, 76%; (b) MsCl, Py, DMAP, CH2Cl2, 99%; (c)
TBAF, THF, 85%; (d) H2, Lindlar cat., MeOH, 99%; (e) (Bu3Sn)2O, toluene, reflux, then Zn(OTf)2, 90°C, 97%; (f) Ac2O, TEA,
DMAP, CH2Cl2, 99%; (g) ZnBr2, CH2ClCH2Cl, 81%; (h) p-NO2C6H4CO2H, DEAD, Ph3P, THF, 82%; (i) PhSTMS, ZnI2, Bu4I,
CH2Cl2; (j) TBAF, THF; (k) silica gel, CH2Cl2; (l) MsCl, TEA, DMAP, CH2Cl2; (m) K2CO3, MeOH, CH2Cl2, 80% (five steps);
(n) TBSOTf, 2,6-lutidine, CH2Cl2, −70°C, 76%; (o) LiCH2CN, THF, 0°C, 74%; (p) (Oct)3P, Py, CCl4, 50°C, 51%; (q) HF·Py,
CH2Cl2–THF (7:1), 100%; (r) (Oct)3P, CBr4, toluene, 50°C, 84%; (s) DIBAL, toluene, −78°C, 100%; (t) NaBH4, EtOH, 0°C, 85%.
Acknowledgements
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This work was financially supported in part by the
Grant-in-Aid for Scientific Research on Priority Area
No. 08245101 from the Ministry of Education, Science,
Sports and Culture, of the Japanese Government. We
thank Professor V. P. Kamat (Goa University, India)
for his helpful comments on the preparation of the
manuscript.
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