Total synthesis of (-)-12,13-epi-obtusenyne

Article abstract of DOI:10.1246/cl.2007.278

The stereoselective total synthesis of (-)-12,13-epi-obtusenyne is described. The oxonene skeleton possessing cis-orientated alkyl substituents at the α.α′-positions to ether linkage was stereoselectively constructed via cyclization of the corresponding h

Full text of DOI:10.1246/cl.2007.278

278
Chemistry Letters Vol.36, No.2 (2007)
Total Synthesis of (À)-12,13-epi-Obtusenyne
Toshio Suzuki,ꢀ1 Nobuyuki Yoshino,2 Toshiyuki Uemura,2 Hisahiro Hagiwara,2 and Takashi Hoshi1
1Faculty of Engineering, Niigata University, 2-8050 Ikarashi, Niigata 950-2181
2Graduate School of Science and Technology, Niigata University, 2-8050 Ikarashi, Niigata 950-2181
(Received November 15, 2006; CL-061340; E-mail: suzuki@eng.niigata-u.ac.jp)
CH3
The stereoselective total synthesis of (ꢁ)-12,13-epi-obtuse-
9
H
H
8
H3C
O
H
nyne is described. The oxonene skeleton possessing cis-orientat-
ed alkyl substituents at the ꢀ,ꢀ0-positions to ether linkage was
stereoselectively constructed via cyclization of the correspond-
ing hydroxy epoxide promoted by Eu(fod)3.
H
O
O
O
H
O
H
H
OBn
OTBS
H
H
H
O
R
H
H
3
H
O
OH
O
O
O
O
(+)-1
O
Red algae of the genus Laurencia produce a wide variety
of C15 metabolites containing medium-sized cyclic ethers as
distinctive members of marine natural products.1 In view of
the synthetic challenge entailed in the construction of strained
medium-sized cyclic ether systems, much synthetic effort has
been directed towards these metabolites.2 Among them are
nine-membered cyclic ethers represented by (+)-obtusenyne
(1).3 In 1991, an analogue of (+)-1 was isolated by Norte’s
group and its structure was proposed to be the C13-epimer of
(+)-1 with undefined configuration of C12.4 The full structure
was finally determined to be (ꢁ)-12,13-epi-obtusenyne (2) by
the Fujiwara and Murai group via total synthesis of both isomers
regarding C12 (Figure 1).5
OBn
O
OBn
OTBS
H
H
H
H
H
OTBS
4
5
H
H
9
H
8
PO
H
OH
12
TIPSO
TIPSO
R2
H
13
O
OMPM
OTES
O
H
OMPM
OTES
H
H
O
H
H
R1
H
H
6
7
Scheme 1.
OTIPS
OTIPS
e, f
O
a, b, c, d
OMTM
OBOM
OH
8
9
10
We have developed an efficient method towards the stereo-
selective construction of medium-sized cyclic ethers by cycliza-
tion of hydroxy epoxides promoted by Eu(fod)3,6 and applied it
to the synthetic studies of Laurencia metabolites.7 Herein,
we describe the total synthesis of (ꢁ)-2 as a part of our research
program.
+
OTIPS
O
g
h, i, j
k, l
OH
OMPM
OTES
11
OMTM
OMPM
OTES
12
OTIPS
TIPSO
m
6
13
Recently, we have accomplished the total synthesis of (+)-
1.7d In the synthesis of (+)-1, conformation of ꢀ,ꢀ0-trans-
oxonene 3 was important for the stereoselective introduction
of the homoallylic ꢁ-alcohol moiety in 5 starting from ꢀ-
selective epoxidation of 3 (Scheme 1). The trans-fused bicyclic
system was essential for obtaining the appropriate conformation,
whereas the diol part generated by deprotection of the acetonide
made subsequent route circuitous. Based on the results, we set
ꢀ,ꢀ0-cis-oxocene 6 as an intermediate for the synthesis of (ꢁ)-
2. Conformation analysis of 6 showed steric circumstances
around the C8–C9 double bond analogous to that of 3, and the
stereoselective conversion of 6 into 7 might proceed in the same
manner to that of 3 into 5. In addition, 7, possessing the ethyl and
discriminated hydroxy groups, could be converted to (ꢁ)-2 via
a straightforward route without the selective protection–depro-
tection sequence of the hydroxy groups required in the synthesis
of (+)-1.
OMPM
O
OMPM
O
OH
H
H
OH
NOE
13
6
Scheme 2. Reagents and conditions: (a) BOMCl, i-Pr2NEt, n-
Bu4NI, DCE, 50 ꢂC; (b) H2, Pd/C, AcOEt, 74% (two steps); (c)
propargyl bromide, Mg, HgCl2, Et2O, ꢁ50 to ꢁ15 ꢂC, 71%; (d) TIP-
SOTf, 2,6-lutidine, CH2Cl2, 100%; (e) MeSTMS, ZnI2, n-Bu4NI,
ꢂ
.
DCE, 95%; (f) DMSO, Ac2O, AcOH, 70 C, 78%; (g) n-BuLi, BF3
OEt2, THF, ꢁ78 ꢂC, 92%; (h) MsCl, TEA, DMAP, CH2Cl2, 100%;
(i) AcOH, H2O, THF, 50 ꢂC, 94%; (j) K2CO3, MeOH, CH2Cl2,
98%; (k) MeI, sat. NaHCO3, acetone, 40 ꢂC, 99%; (l) H2, Lindlar
cat., quinoline, AcOEt, 99%; (m) Eu(fod)3, xylenes, 120 ꢂC, 65%.
The synthesis of hydroxy epoxide 5 was investigated at the
outset of this research (Scheme 2). Epoxy alcohol 8, prepared
from 1,4-pentadien-3-ol by the reported procedure,8 was con-
verted to acetylene 9 via the following sequence: (i) protection
of the hydroxy group as its BOM ether, (ii) hydrogenation of
the double bond, (iii) addition of 2-propynylmagnesium bro-
mide, (iv) protection of the resulting hydroxy group as its TIPS
ether. All steps proceeded in good yields. The BOM group in 9
was displaced with the MTM group to provide acetylene 10.
Coupling of acetylene 10 with epoxide 11, derived from (ꢁ)-
diethyl tartrate by our reported procedure,9 was easily achieved
by the Yamaguchi method.10 Mesylation of the resulting hy-
droxy group followed by cleavage of the TES ether gave the
12
13
12
Br
Cl
Br
Cl
13O
O
H
H
H
H
(+)-obtusenyne (1)
(–)-12,13-epi-obtusenyne (2)
Figure 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.2 (2007)
279
OH
H
O
NOE
e
a, b
c, d
H
TIPSO
OAc
OMPM
TIPSO
OAc
OMPM
a, b
c, d
8
7
6
TIPSO
TIPSO
TIPSO
O
O
6
H
H
H
H
O
O
OMPM
OTES
Br
OMPM
OTES
H
H
H
17
18
14
15
m, n
k, l
f, g, h,
i, j
TIPSO
Cl
(−)-2
TIPSO
OAc
O
i
e, f
O
H
O
TIPSO
OH
H
H
H
g, h
O
O
OMPM
OMPM
OTES
H
H
H
H
20
OTES
19
TBS
TBS
16
7
Scheme 4. Reagents and conditions: (a) Ac2O, TEA, DMAP,
CH2Cl2, 98%; (b) AcOH, H2O, THF, 93%; (c) Tf2O, pyridine,
CH2Cl2; (d) n-Bu4NBr, toluene, 50 ꢂC, 85% (two steps); (e) n-
Bu3SnH, Et3B, toluene, 0 ꢂC, 74%; (f) DDQ, pH 7.4 buffer, CH2Cl2,
88%; (g) DMP, NaHCO3, CH2Cl2, 91%; (h) CBr4, HMPT, THF,
0 ꢂC, 99%; (i) n-Bu3SnH, Pd(PPh3)4, benzene, 81%; (j) (TBS)acety-
lene, Pd(PPh3)4, CuI, i-Pr2NH, benzene; (k) K2CO3, MeOH, 89%
(two steps); (l) CCl4, n-Oct3P, TEA, 1-methylcyclohexene, toluene;
(m) TBAF, THF, 70% (two steps); (n) CBr4, n-Oct3P, TEA, 1-meth-
ylcyclohexene, toluene, 80 ꢂC, 62%.
Scheme 3. Reagent and conditions: (a) TESCl, AgNO3, pyridine,
CH3CN, 99%; (b) MCPBA, sat. NaHCO3, CH2Cl2, 0 ꢂC, 94%; (c)
(PhSe)2, NaBH4, EtOH, n-BuOH, reflux; (d) H2O2, pyridine, 2-
methyl-2-butene, CH2Cl2, 62% (two steps); (e) MCPBA, CH2Cl2,
0 ꢂC, 86%; (f) MsCl, TEA, DMAP, CH2Cl2, 97%; (g) (PhSe)2,
NaBH4, EtOH, n-BuOH, 50 ꢂC; (h) H2O2, pyridine, 2-methyl-2-
butene, CH2Cl2, 38% (two steps); (i) n-BuLi, DIBAL, toluene, 59%.
corresponding alcohol, which was treated with a base to afford
epoxide in high yield.
Deprotection of the MTM group followed by partial hydro-
genation provided 13. With the key precursor 5 for the cycliza-
tion reaction in hand, the crucial step in this synthesis was exam-
ined. Treatment of 13 with Eu(fod)3 resulted in 9-exo cyclization
to provide ꢀ,ꢀ0-cis-oxonene 6 in 65% yield. The cis relationship
was confirmed by the existence of NOE between C6-H and
C13-H.
droxy group was brominated16 with inversion of configuration to
furnish (ꢁ)-2. The synthetic material was identical in all respects
(1H NMR, 13C NMR, ½ꢀꢃD) to those reported for natural4 and
synthetic (ꢁ)-2.5
In conclusion, the total synthesis of (ꢁ)-2 was accomplished
with high stereoselectivity via the efficient route base on the
confirmation analysis of intermediate 6.
Base on the above discussion, the stereoselective conversion
of 6 to homoallylic ꢁ-alcohol 7 was examined by the same
sequence employing in the synthesis of (+)-1 (Scheme 3). As ex-
pected, epoxidation of TES ether, derived from 6, was proceeded
stereoselectively from ꢀ-side and provided 14 in 98% yield. Its
stereochemistry was confirmed by an NOE correlation between
C6-H and C8-H. Regioselectivity of opening of the epoxide with
a phenylselenyl anion was unpredictable. Fortunately, the reac-
tion proceeded at the C8 position, and subsequent oxidative
elimination provided allyl alcohol 15. In the reaction, the prod-
uct arising from the C9-opening isomer was not detected. Anti-
selective epoxidation of 15 with MCPBA directed by the neigh-
boring hydroxy group11 provided ꢁ-epoxide as a single isomer.
Subsequent dehydration via oxidative elimination of the phenyl-
selenyl group afforded allyl epoxide 16 in a moderate overall
yield. Treatment of 16 with n-BuLi/DIBAL12 resulted in open-
ing of the epoxide mainly from the allylic position to afford
homoallylic alcohol 7 (59%) along with its regioisomer (32%).
Next, installation of the Z-enyne terminus and two halogen
functionalities was examined via a simplified route (Scheme 4).
Alcohol 7 was converted to bromide 17 in high yield via a
protection–deprotection sequence followed by bromination.
Reduction of 17 was performed with n-Bu3SnH/Et3B at 0 ꢂC.
Deprotection of the MPM group in 18 followed by oxidation
gave the corresponding aldehyde. The Z-enyne terminus was
installed by the sequence applied to synthesis of the natural com-
pound5 with slight modifications: (i) treatment with CBr4 and
HMPA in THF,7b,13 (ii) stereoselective hydrogenolysis of 1,1-di-
bromoalkene by Uenishi’s method,14 (iii) Sonogashira coupling
of the resulting Z-1-bromoalkene with (t-butyldimethylsilyl)-
acetylene.15 Deprotection of the acetyl group in 19 followed
by chlorination gave chloride 20 with inversion of configuration.
Two silyl groups were deprotected, and finally, the resulting hy-
This work was partially supported by Grant-in-Aid for
Scientific Research on Priority Area (18032031 for H.H.)
from The Ministry of Education, Culture, Sports, Science and
Technology (MEXT).
References
1
a) K. L. Erickson, in Marine Natural Products, ed. by P. J. Scheuer,
Academic Press, New York, 1983, Vol. 5, pp. 131–257. b) D. J. Faulkner,
Nat. Prod. Rep. 2001, 18, 1.
2
a) K. Albizati, V. A. Martin, M. R. Agharahimi, D. A. Stolze, in Bioorgan-
ic Marine Chemistry, ed. by P. J. Scheuer, Springer-Verlag, Berlin, 1992,
Vol. 6, pp. 69–84. b) M. C. Elliott, Contemp. Org. Synth. 1994, 1, 457.
c) K. Fujiwara, in Topics in Heterocyclic Chemistry, ed. by H. Kiyota,
Springer-Verlag, Berlin, 2006, Vol. 5, pp. 97–148.
¨
3
4
a) T. J. King, S. Imre, A. Oztunc, R. H. Thomson, Tetrahedron Lett. 1979,
1453. b) B. M. Howard, G. R. Schulte, W. Fenical, B. Solheim, J. Clardy,
Tetrahedron 1980, 36, 1747.
M. Noite, A. G. Gonzales, F. Cataldo, M. L. Rodrıgues, I. Brito, Tetra-
hedron 1991, 47, 9411.
´
5
6
D. Awakura, K. Fujiwara, A. Murai, Chem. Lett. 1999, 461.
T. Saitoh, T. Suzuki, N. Onodera, H. Sekiguchi, H. Hagiwara, T. Hoshi,
Tetrahedron Lett. 2003, 44, 2709.
7
a) T. Suzuki, R. Matsumura, K. Oku, K. Taguchi, H. Hagiwara, T. Hoshi,
M. Ando, Tetrahedron Lett. 2001, 42, 65. b) R. Matsumura, T. Suzuki,
H. Hagiwara, T. Hoshi, Tetrahedron Lett. 2001, 42, 1543. c) T. Saitoh,
T. Suzuki, M. Sugimoto, H. Hagiwara, T. Hoshi, Tetrahedron Lett.
2003, 44, 3175. d) T. Uemura, T. Suzuki, N. Onodera, H. Hagiwara, T.
Hoshi, Tetrahedron Lett., in press.
8
9
S. Hatakeyama, K. Sakurai, S. Takano, J. Chem. Soc., Chem. Commun.
1985, 1759.
R. Matsumura, T. Suzuki, K. Sato, K. Oku, H. Hagiwara, T. Hoshi, M.
Ando, V. P. Kamat, Tetrahedron Lett. 2000, 41, 7701.
10 M. Yamaguchi, I. Hirano, Tetrahedron Lett. 1983, 24, 391.
11 T. Itoh, K. Jitsukawa, K. Kaneda, S. Teranishi, J. Am. Chem. Soc. 1979,
101, 159.
12 S. Kim, K. H. Ahn, J. Org. Chem. 1984, 49, 1717.
13 E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 3769.
14 J. Uenishi, R. Kawahama, O. Yonemitsu, J. Org. Chem. 1996, 61, 5716.
15 K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467.
16 K. Tsushima, A. Murai, Tetrahedron Lett. 1992, 33, 4345.
Published on the web (Advance View) January 18, 2007; doi:10.1246/cl.2007.278