The first total synthesis of (+)-rogioloxepane A

Article abstract of DOI:10.1016/S0040-4039(00)02281-4

The first total synthesis of (+)-rogioloxepane A is described. The α,ω-trans-disubstituted oxepene skeleton was stereoselectively constructed via cyclization of the hydroxy epoxide promoted by the (Bu₃Sn)₂O/Zn(OTf)₂ system. The proposed configurations of 6R and 13R were confirmed through this synthetic study.

Full text of DOI:10.1016/S0040-4039(00)02281-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1543–1546
The first total synthesis of (+)-rogioloxepane A
Ryuji Matsumura,a Toshio Suzuki,b,* Hisahiro Hagiwara,a Takashi Hoshib and Masayoshi Andob
aGraduate School of Science and Technology, Niigata University, 2-nocho, Ikarashi, Niigata 950-2181, Japan
bFaculty of Engineering, Niigata University, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Received 9 November 2000; revised 4 December 2000; accepted 8 December 2000
Abstract—The first total synthesis of (+)-rogioloxepane A is described. The a,v-trans-disubstituted oxepene skeleton was
stereoselectively constructed via cyclization of the hydroxy epoxide promoted by the (Bu3Sn)2O/Zn(OTf)2 system. The proposed
configurations of 6R and 13R were confirmed through this synthetic study. © 2001 Elsevier Science Ltd. All rights reserved.
Red algae of the genus Laurencia produce a variety of
oxacyclic C15 acetogenins.1 In particular, medium-sized
oxacyclics are unique and characteristic compounds.
Owing to synthetic challenge, these metabolites have
been popular targets for synthetic investigation and a
number of new methodologies have been developed so
far.2 Among this group, (+)-rogioloxepane A (1), iso-
lated from L. microcladia in 1992 by Pietra’s group,3
has the particular feature of an oxepene core possessing
alkyl substituents at the a- and v-positions with trans
orientation. In addition, the configurations of the halo-
genated carbons at the side chains have remained
uncertain, although they were deduced to be 6R and
13R by comparing coupling constants obtained by
molecular-mechanics calculation.3
ented alkyl side chains. While some efficient methods
towards stereoselective synthesis of a,v-cis-oxepanes
were developed,4 few methods are available for the
a,v-trans-oxepane system found in (+)-1.4e,5 Recently,
we reported a new methodology towards the stereo-
selective construction of a,v-cis- and a,v-trans-
oxepanes.6 Our approach is a direct construction via
hydroxy–epoxide cyclization promoted by the
(Bu3Sn)2O/Zn(OTf)2 system. Subsequently, a formal
synthesis of (+)-isolaurepinnacin, which is a representa-
tive a,v-cis-disubstituted oxepene, was accomplished by
utilizing the above-mentioned protocol as a key step.7
In this communication, we examined the further appli-
cability of the methodology to the synthetic study of
(+)-1 as a part of our research program.
It is obvious that the most crucial part in the synthesis
of (+)-1 is an efficient construction of the oxepene ring
as well as the stereocontrolled introduction of trans-ori-
We designed a synthetic strategy involving hydroxy
epoxide 3 as a key precursor (Scheme 1). Application of
the foregoing protocol to 3 would result in the direct
BnO
OH
Br
Cl
H
H
H
H
OMPM
O
O
13
6
(+)-rogioloxepane A (1)
2
OBn
OBn
O
+
OMPM
OMPM
OTBS
O
OH
OTBS
5
3
4
Scheme 1.
Keywords: natural products; cyclization; oxepanes; medium-ring heterocycles.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02281-4

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R. Matsumura et al. / Tetrahedron Letters 42 (2001) 1543–1546
formation of a,v-trans-oxepene 2 possessing all of the
requisite chiral centers for manipulation of the side
chains. Stereoselective introduction of a terminal cis-
enyne moiety and two halogen substituents into 2
would complete our synthesis. In turn, the precursor 3
could be accessible from acetylene 4 and epoxide 5.
Mesylation under the usual conditions followed by
deprotection of the TBS groups and concomitant epox-
ide-formation provided hydroxy epoxide 3 in high
yield. With the key precursor 3 for the cyclization in
hand, the crucial step in this synthesis was next exam-
ined. The hydroxy epoxide
3 was treated with
(Bu3Sn)2O in refluxing toluene followed by Zn(OTf)2 at
90°C. The reaction proceeded smoothly and stereoselec-
tively as described in our previous work6 to afford the
desired oxepene 2 in 75% yield as the sole product.
According to the retro-synthetic scheme, the synthesis
of the acetylene 4 was investigated at the outset of this
research (Scheme 2). Benzyl ether 6, prepared from
(+)-diethyltartrate according to the Ohno procedure,8
was protected with a 1-methyl-1-methoxyethyl group,
and subsequently treated with LiAlH4 to give the corre-
sponding diol, which was exposed to PPTS to convert
into 1,2-acetonide 7 with a trace amount of the 1,3-iso-
mer. Homologation of 7 via the corresponding tosylate
followed by deprotection of the acetonide group
afforded diol 8. The diol moiety of 8 was stereoselec-
tively converted to epoxide 9 through a three-step
sequence: (i) selective protection of the primary
hydroxy group with a TBS ether, (ii) mesylation of the
remaining secondary hydroxy group, (iii) deprotection
of the TBS group with TBAF and spontaneous forma-
tion of an epoxide. Regioselective addition of lithium
acetylide in DMSO, and subsequent protection with a
TBS group provided the acetylene 4. All steps pro-
ceeded in excellent yields.
Next, we examined installation of the cis-enyne termi-
nus. Mesylation of the oxepene 2 followed by the
cleavage of the MPM ether with PhSH and ZnCl2 in
CH2Cl2 afforded 11 (93%) (Scheme 4). Use of DDQ10
in the latter reaction was unsuccessful because of com-
petitive deprotection of the benzyl group. After conver-
sion of the alcohol 11 into epoxide (98%), the
regioselective addition of THP propynyl ether afforded
acetylene 12 in quantitative yield. Hydrogenation of 12
with Lindlar catalyst followed by protection–deprotec-
tion sequence provided cis-olefin 13 in high yield. Con-
version of 13 into cis-enyne 14 was achieved by the
following sequence involving the modified Corey
method.11 Chemoselective oxidation of the allyl alcohol
moiety with MnO2 afforded cis-a,b-unsaturated alde-
hyde, which due to easy isomerization (vide infra) was
immediately treated with CBr4 and HMPT in THF to
provide the corresponding 1,1-dibromo-cis-diene. Use
of HMPT instead of commonly used PPh3 was a key to
the success of this conversion. Under the conditions,
Coupling of 4 with 56b was easily achieved by the
Yamaguchi method9 in 78% yield (Scheme 3). The
resulting acetylene 10 was hydrogenated in the presence
of Lindlar catalyst to afford the cis-olefinic product.
OBn
a,b,c
OBn
OBn
d,e,f
CO2Et
HO
EtO2C
O
OH
OH
O
OH
6
7
8
OBn
OBn
g,h,i
j,k
O
OTBS
9
4
Scheme 2. Reagents and conditions: (a) 2-methoxypropene, POCl3, CH2Cl2, 100%; (b) LiAlH4, THF, 0°C, 91%; (c) 2-
methoxypropene, PPTS, CH2ClCH2Cl, 60°C, 86%; (d) TsCl, TEA, DMAP, CH2Cl2, 100%; (e) Me2CuLi, Et2O, −65 to 0°C, 93%;
(f) PPTS, EtOH, 80°C, 97%; (g) TBSCl, TEA, DMAP, CH2Cl2, 60°C, 100%; (h) MsCl, TEA, DMAP, CH2Cl2, 98%; (i) TBAF,
THF, 96%; (j) ꢀLi·EDA, DMSO, 0°C, 93%; (k) TBSCl, AgNO3, Py, CH3CN, 98%.
OBn
OBn
OH
O
a
+
OMPM
OTBS
OTBS
BnO
OMPM
OTBS
OTBS
5
4
10
OH
OBn
H
H
b,c,d
OMPM
O
e
OMPM
O
OH
3
2
Scheme 3. Reagents and conditions: (a) n-BuLi, BF3·OEt2, THF, −78°C, 78%; (b) H2, Lindlar cat., quinoline, MeOH, 99%; (c)
MsCl, TEA, DMAP, CH2Cl2, 98%; (d) TBAF, THF, 50°C, 91%; (e) (Bu3Sn)2O, toluene, reflux, then Zn(OTf)2, 90°C, 75%.

R. Matsumura et al. / Tetrahedron Letters 42 (2001) 1543–1546
1545
BnO
OMs
BnO
OH
H
H
H
H
OTHP
OH
O
O
e,f,g
a,b
H
c,d
2
11
12
BnO
OAc
BnO
OH
H
H
H
OH
O
O
O
h,i,j,k
l
13
14
BnO
Cl
Br
Cl
H
H
H
H
O
13
m,n
6
15
(+)-rogioloxepane A (1)
Scheme 4. Reagents and conditions: (a) MsCl, TEA, DMAP, CH2Cl2, 100%; (b) PhSH, ZnCl2, CH2Cl2, 0°C, 93%; (c) K2CO3,
MeOH–CH2Cl2 (1:1), 98%; (d) HCꢀCCH2OTHP, n-BuLi, BF3·OEt2, −78°C, 99%; (e) H2, Lindlar cat., quinoline, AcOEt, 100%;
(f) Ac2O, TEA, DMAP, CH2Cl2, 97%; (g) PPTS, EtOH, 50°C, 98%; (h) MnO2, CHCl3–benzene (1:2); (i) CBr4, HMPT, THF, 0°C;
(j) K2CO3, MeOH; (k) n-BuLi, THF, −90 to −40°C, 56% (four steps), cis:trans=20:1; (l) CCl4, (Oct)3P, 1-methyl-1-cyclohexene,
toluene, 80°C, 49%; (m) DDQ, CH2ClCH2Cl–H2O (9:1), 50°C, 100%; (n) CBr4, (Oct)3P, 1-methyl-1-cyclohexene, toluene, 70°C,
70%.
Acknowledgements
the reaction was completed in 1 minute without isomer-
ization of the double bond in conjugation to the alde-
hyde group. Deprotection of the acetyl group followed
by treatment with n-BuLi furnished the cis-enyne 14 in
56% yield over four steps as a 20:1 mixture of Z:E
stereoisomers. The cis-enyne 14 was purified by MPLC
at this stage and subjected to further manipulations.
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 Japanese Government.
Several attempts to introduce the chlorine functionality
at C6 with inversion of configuration were unsuccessful
due to the competitive elimination. The best method
finally founded for this transformation was CCl4 and
(Oct)3P in toluene in the presence of 1-methyl-1-cyclo-
hexene to afford chloride 15 in 49% yield along with the
elimination product (24%). In the absence of 1-methyl-
1-cyclohexene, a trace amount of by-products halo-
genated on the double bond(s) were formed, separation
of which from the desired product was troublesome.
DDQ was employed for cleavage of the benzyl ether of
15 according to our earlier observation (vide supra).
Finally, the resulting hydroxy group at C13 was bromi-
nated by the procedure of Murai12 with addition of
1-methyl-1-cyclohexene to furnish (+)-1 in 70% yield
with complete inversion of configuration. The synthetic
material was identical in all respects (1H NMR, 13C
NMR, [h]D, and MS)3 to those reported for natural
(+)-1.
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In conclusion, the first total synthesis of (+)-rogiolox-
epane A (1) was accomplished with high stereoselectiv-
ity. This synthesis has established that the cyclization of
hydroxy epoxides promoted by the (Bu3Sn)2O/Zn(OTf)2
system is an efficient methodology for the synthesis of
highly functionalized seven-membered oxacyclics. In
addition, the proposed 6R and 13R configurations3
were synthetically confirmed.

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