Total synthesis of (+)-obtusenyne

Article abstract of DOI:10.1016/j.tetlet.2006.11.080

The stereoselective total synthesis of (+)-obtusenyne is described. The oxonene skeleton possessing trans-orientated alkyl substituents at the α,α′-positions was stereoselectively constructed via cyclization of the corresponding hydroxy epoxide promoted b

Full text of DOI:10.1016/j.tetlet.2006.11.080

Tetrahedron Letters 48 (2007) 715–719
Total synthesis of (+)-obtusenyne
Toshiyuki Uemura,a Toshio Suzuki,b,* Naohiro Onodera,a
Hisahiro Hagiwaraa and Takashi Hoshib
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 26 October 2006; revised 10 November 2006; accepted 10 November 2006
Available online 11 December 2006
Abstract—The stereoselective total synthesis of (+)-obtusenyne is described. The oxonene skeleton possessing trans-orientated alkyl
substituents at the a,a0-positions was stereoselectively constructed via cyclization of the corresponding hydroxy epoxide promoted
by Eu(fod)3.
Ó 2006 Published by Elsevier Ltd.
Red algae of the genus Laurencia produce a wide variety
of C15 metabolites containing medium-sized cyclic
ethers as distinctive members of marine natural prod-
ucts.1 In recent years, considerable synthetic efforts have
been made toward these systems2 in view of certain
problems incurred in assembling medium-sized cyclic
ethers as well as the stereoselective introduction of alkyl
substituents at a- and a0-positions of a cyclic ether with
cis- or trans-orientation.
isolated from Laurencia obtusa by the Imre7 and Feni-
cal8 groups independently, and its total syntheses were
reported by the Murai,9 Crimmins,10 and Holmes11
groups (Fig. 1).
Retrosynthetic analysis led to cyclization of hydroxy
epoxide 2 for straightforward access to the construction
of the oxonene skeleton 3 possessing all the required
functional groups on the cyclic ether (Scheme 1). This
attempt proved unsuccessful presumably due to the ste-
ric interaction of the internal oxygenated functionality
of the epoxide.
In the course of our synthetic efforts toward the Lauren-
cia metabolites, we have developed an efficient method
toward the stereoselective construction of medium-sized
cyclic ethers by cyclization of hydroxy epoxides pro-
moted by Eu(fod)3.3 The method has a potential advan-
tage in that stereochemistry at the a- and a0-positions
could be controlled stereospecifically since the reaction
proceeds via an SN2 process and exo mode selectivity
regardless of the configuration of the hydroxy and epox-
ide groups. The efficiency of the method was proven by
employing it in the successful synthesis of seven- and
eight-membered cyclic ethers, isolaurepinnacin,4 rogio-
loxepane A,5 and laurallene.6 In this letter, we examined
applicability of the methodology to the synthesis of
(+)-obtusenyne (1), a representative nine-membered
cyclic ether with substituents in trans-orientation, as a
part of our research program. (+)-Obtusenyne (1) was
On the basis of the result, our synthetic plan was envis-
aged in Scheme 2. Hydroxy epoxide 6, obtainable by
coupling of acetylene 8 with epoxide 9, was postulated
as a key precursor. Application of the foregoing proto-
col to 6 would result in the formation of the oxonene
skeleton 5 with the crucial a,a0-trans-orientation to the
ether linkage. Stereoselective introduction of a homo-
allylic b-alcohol moiety into 5 could arrange all the req-
uisite functionalities on the cyclic ether. Stereoselective
Br
Cl
O
H
H
Keywords: (+)-Obtusenyne; Oxonenes; Medium-ring heterocycles;
Cyclization; Hydroxy epoxides.
(+)-Obtusenyne (1)
*
Corresponding author. Tel./fax: +81 25 262 6780; e-mail: suzuki@
eng.niigata-u.ac.jp
Figure 1.
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.11.080

716
T. Uemura et al. / Tetrahedron Letters 48 (2007) 715–719
OBn
OTBS
Eu(fod)3
BnO
OTBS
OMPM
(+)-1
OMPM
O
9-exo-
cyclization
O
H
H
OH
OH
2
3
Scheme 1.
Br
Cl
MPMO
TBSO
MPMO
OH
OBn
O
O
O
H
H
H
H
OBn
H
H
OH
5
4
(+)-Obtusenyne (1)
OMPM
OMPM
Eu(fod)3
OH
TBSO
9-exo-
cyclization
OBn
O
O
O
OBn
OTBS
OH
6
7
OMPM
O
OBn
OTBS
O
+
O
8
9
Scheme 2.
introduction of the Z-enyne terminus and halogen
functionalities into 4 would complete our synthesis.
afford epoxide 12 in high yield. Epoxide 12 was con-
verted to hydroxy epoxide 6 via hydrogenation in the
presence of Lindlar catalyst and a deprotection–protec-
tion sequence. With the key precursor 6 for the cycliza-
tion reaction in hand, the crucial step in this synthesis
was examined. Hydroxy epoxide 6 was treated with
Eu(fod)3 in refluxing toluene. The reaction proceeded
smoothly to afford the corresponding cyclized product.
Since partial deprotection of the TBS group was
observed in the reaction, the product was isolated after
exposure to aqueous AcOH. Consequently, a,a0-trans-
oxonene 14 was furnished in 70% yield as the sole cyc-
lized product. Interestingly, cyclization of diol 13 under
the same conditions provided 14 in a lower yield (50%).
According to the retrosynthetic scheme, the synthesis of
acetylene 8 was investigated at the outset of this research
(Scheme 3). Alcohol 10, prepared from (+)-diethyl
tartrate by our reported procedure,5 was converted to
epoxide 11 with inversion of the configuration via the
following sequence: (i) protection of the primary alcohol
as its acetate, (ii) deprotection of the benzyl group, (iii)
mesylation of the resulting hydroxy group, (iv) treat-
ment with K2CO3 in MeOH. All steps proceeded in
good yields. Addition of 2-propynylmagnesium bromide
(77%) followed by protection of the resulting hydroxy
group as its MPM ether afforded acetylene 8 (86%).
Next, the stage was set for the stereoselective introduc-
tion of the homoallylic b-alcohol moiety on the cyclic
ether (Scheme 5). Diol 14 was converted to 15 through
a four-step sequence. Conformation analysis of 15 by
MM2 calculation suggested that the subsequent epoxi-
dation proceeds from the convex a-side. As expected,
a-epoxide 16 was obtained in 98% yield by treatment
Coupling of acetylene 8 with epoxide 9, derived from
(ꢀ)-diethyl tartrate by our reported procedure,5 was
easily achieved by the Yamaguchi method12 in 81% yield
(Scheme 4). Mesylation of the resulting hydroxy group
followed by cleavage of the TBS ether gave the corre-
sponding alcohol, which was treated with a base to
OMPM
OBn
O
e, f
a, b, c, d
OH
O
O
O
O
O
O
10
11
8
Scheme 3. Reagents and conditions: (a) Ac2O, pyridine, DMAP, CH2Cl2; (b) H2, Pd(OH)2–C, AcOEt; (c) MsCl, TEA, CH2Cl2; (d) K2CO3, MeOH,
CH2Cl2, 74% (four steps); (e) 3-bromopropyne, Mg, HgCl2, Et2O, ꢀ50 to ꢀ20 °C, 77%; (f) MPMCl, NaH, n-Bu4NI, THF, 86%.

T. Uemura et al. / Tetrahedron Letters 48 (2007) 715–719
OMPM
717
OMPM
OH
O
b, c, d
a
O
O
+
8
9
OBn
OBn
O
OBn
OTBS
O
7
12
OMPM
OMPM
g
e, f
HO
OBn
TBSO
O
OH
O
OH
13
6
h, i
MPMO
HO
O
H
H
OBn
OH
14
Scheme 4. Reagents and conditions: (a) n-BuLi, BF3ÆOEt2, THF, ꢀ78 °C, 81%; (b) MsCl, TEA, DMAP, CH2Cl2, 0 °C, 88%; (c) TBAF, THF; (d)
K2CO3, MeOH, 91% (two steps); (e) 80% aq AcOH, 89%; (f) H2, Lindlar cat., quinoline, AcOEt, 99%; (g) TBSCl, TEA, DMAP, CH2Cl2, 97%; (h)
Eu(fod)3, toluene, 120 °C; (i) AcOH, THF, H2O, 70% (two steps).
H
O
9
H
8
f, g
a, b, c, d
e
NOE
O
O
O
O
14
O
O
H
H
OBn
H
H
OBn
OTBS
OTBS
15
16
OH
OH
O
i, j, k
O
h
O
O
O
O
5
O
O
O
O
H
O
H
OBn
H
H
H
H
OBn
OTBS
OBn
OTBS
OTBS
18
19
17
l
O
O
OH
OBn
O
H
H
OTBS
20
Scheme 5. Reagents and conditions: (a) DDQ, 4A-MS, CH2Cl2, 0 °C, 95%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 96%; (c) CF3CO2H, MeOH,
58% (recovered s.m. 34%); (d) 2-methoxypropene, PPTS, CH2Cl2, 99%; (e) MCPBA, NaHCO3, CH2Cl2, 0 °C, 98%; (f) (PhSe)2, NaBH4, EtOH, n-
BuOH, reflux, 89%; (g) H2O2, pyridine, 2-methyl-2-butene, CH2Cl2, 98%; (h) MCPBA, NaHCO3, CH2Cl2, 0 °C, 85%; (i) MsCl, TEA, DMAP,
CH2Cl2, 0 °C, 92%; (j) (PhSe)2, NaBH4, EtOH, n-BuOH, 80 °C, 90%; (k) H2O2, pyridine, 2-methyl-2-butene, CH2Cl2, 93%; (l) DIBAL, n-BuLi,
toluene, 0 °C, 75%.
with MCPBA with no trace of the diastereomer. Regio-
selectivity of the subsequent opening of the epoxide
in 16 with a phenylselenyl anion was unpredictable. For-
tunately, the reaction proceeded at the C8 position
(89%), and subsequent oxidative elimination provided
allyl alcohol 17 (98%). In the latter reaction, the exis-
tence of the bulky silyloxy group at the C5 position,
which would be removed in the later stage (vide infra),
was important. The substrate in the absence of the silyl-
oxy group gave a mixture of cis- and trans-elimination
products. Anti-selective epoxidation of 17 with MCPBA
was directed by the neighboring hydroxy group13 and b-
epoxide 18 was provided in 85% yield along with a trace
amount of its a-isomer. Subsequent dehydration via oxi-
dative elimination of the phenylselenyl group afforded
allyl epoxide 19 in high yield. Regioselective cleavage
of 19 from the allylic position was attained by use of
n-BuLi/DIBAL14 to provide homoallylic b-alcohol 20
in 75% yield.
Next, alcohol 20 was converted to alcohol 21 via
a deprotection–protection sequence, and the resulting
hydroxy group was brominated to afford bromide 22
in high yield (Scheme 6). Reduction of bromide 22 was
performed with Bu3SnH and AIBN at 0 °C under the
photolytic conditions (100%).15 When the Bu3SnH

718
T. Uemura et al. / Tetrahedron Letters 48 (2007) 715–719
a, b
c
O
O
O
O
20
OTBS
OBn
OTBS
O
5
O
H
H
H
H
OBn
OH
Br
21
22
e, f, g
d
12
O
O
MPMO
HO
OTBS
OBn
OTBS
OBn
O
O
H
H
H
H
23
24
i
h
MPMO
ArSO3
MPMO
OTBS
OBn
OTBS
OBn
O
O
H
H
H
H
CF3
25
4
Ar =
CF3
Scheme 6. Reagents and conditions: (a) TBAF, THF, 100%; (b) TBSCl, imidazole, DMF, 97%; (c) CBr4, P(oct)3, TEA, 1-methyl-1-cyclohexene,
toluene, 90 °C, 97%; (d) Bu3SnH, AIBN, toluene, hm (>280 nm), 0 °C, 100%; (e) CSA, MeOH, (HOCH2)2, 78%; (f) p-anisaldehyde dimethyl acetal,
CSA, DCE, 100%; (g) DIBAL, toluene, ꢀ10 °C, 97%; (h) 3,5-bis(trifluoromethyl)benzenesufonyl chloride, TEA, DMAP, CH2Cl2; (i) MeLi, Cul,
Et2O, ꢀ12 °C, 82% (two steps).
reduction was conducted under thermolytic conditions
(i.e., 100 °C in toluene), a bicyclic compound was mainly
obtained as a result of intramolecular addition of the
radical generated at the C5 position to the double bond
on the cyclic ether. After deprotection of the acetonide
group in 23, the C12 hydroxy group was selectively
protected as its MPM ether via reductive opening of
an anisylidene acetal to afford alcohol 24 in high yield.
Homologation of the C1 unit to alcohol 24 was trouble-
some. According to the Kotsuki procedure,16 alcohol 24
was converted to the corresponding trifluoromethane-
sulfonate, which was considerably unstable and could
not be subjected to the following methylation. For
the purpose, 3,5-bis(trifluoromethyl)benzenesulfonate
ester17 was realized as a suitable leaving group having
enough stability and reactivity. Treatment of the corres-
ponding sulfonate 25 with Me2CuLi provided adduct 4
in 82% overall yield.
procedure of Murai18 with addition of 1-methyl-1-cyclo-
hexene5 furnished bromide 26 in 67% yield. The benzyl
group in 26 was deprotected with DDQ (67%), and the
resulting alcohol was converted to Z-enyne 27 by the
following sequence similar to that reported by the Murai
group:9 (i) oxidation with Dess–Martin periodinane
(83%), (ii) treatment with CBr4 and HMPT in THF
(95%),19 (iii) stereoselective hydrogenolysis of 1,1-di-
bromoalkene by Uenishi’s method (86%),20 (iv)
Sonogashira coupling of the resulting Z-1-bromoalkene
with (t-butyldimethylsilyl)acetylene (86%).21 Two TBS
groups were deprotected with TBAF (100%), and final-
ly, the resulting hydroxy group was chlorinated with
inversion of configuration by the procedure of Crim-
mins10 to furnish (+)-1 in 50% yield. The synthetic mate-
rial was identical in all respects (1H NMR, 13C NMR,
[a]D) to those reported for natural7,8 and other synthetic
(+)-1.9–11
The final stage of the synthesis required installation of
the Z-enyne terminus and two halogen groups (Scheme
7). Cleavage of the MPM ether in 4 (91%) followed by
bromination with inversion of configuration by the
In conclusion, the total synthesis of (+)-obtusenyne (1)
was accomplished with high stereoselectivity. This
synthetic study demonstrated that the cyclization of
hydroxy epoxides promoted by Eu(fod)3 is an efficient
c, d, e, f, g
a, b
h, i
Br
Br
4
(+)-1
OTBS
OBn
OTBS
O
O
H
H
H
H
27
26
TBS
Scheme 7. Reagents and conditions: (a) DDQ, benzene, pH = 7.4 buffer, 91%; (b) CBr4, P(oct)3, pyridine, 1-methyl-1-cyclohexene, toluene, 80 °C,
67%; (c) DDQ, DCE, pH = 7.4 buffer, 50 °C, 67%; (d) DMP, NaHCO3, CH2Cl2, 83%; (e) CBr4, HMPT, THF, 0 °C, 95%; (f) Bu3SnH, Pd(PPh3)4,
benzene, 86%; (g) (t-butyldimethylsilyl) acetylene, Pd(PPh3)4, CuI, i-Pr2NH, benzene, 86%; (h) TBAF, THF, 0 °C, 100%; (i) CCl4, P(oct)3, pyridine,
1-methyl-1-cyclohexene, toluene, 80 °C, 50%.

T. Uemura et al. / Tetrahedron Letters 48 (2007) 715–719
719
5. Matsumura, R.; Suzuki, T.; Hagiwara, H.; Hoshi, T.
Tetrahedron Lett. 2001, 42, 1543–1546.
approach to the stereoselective synthesis of highly
functionalized oxonenes. Further applications of this
methodology to the synthesis of related medium-sized
cyclic ethers are in progress in our laboratory.
6. Saitou, T.; Suzuki, T.; Sugimoto, M.; Hagiwara, H.;
Hoshi, T. Tetrahedron Lett. 2003, 44, 3175–3178.
¨
7. King, T. J.; Imre, S.; Oztunc, A.; Thomson, R. H.
Tetrahedron Lett. 1979, 1453–1454.
8. Howard, B. M.; Schulte, G. R.; Fenical, W.; Solheim, B.;
Clardy, J. Tetrahedron 1980, 36, 1747–1751.
9. Fujiwara, K.; Akakura, D.; Tsunashima, M.; Nakamura,
A.; Honma, T.; Murai, A. J. Org. Chem. 1999, 64, 2616–
2617.
10. Crimmins, M. T.; Powell, M. T. J. Am. Chem. Soc. 2003,
125, 7592–7595.
11. Mak, S. Y. F.; Curtis, N. R.; Payne, A. N.; Congreve, M.
S.; Francis, C. L.; Burton, J. W.; Holmes, A. B. Synthesis
2005, 3199–3201.
Acknowledgment
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).
12. Yamaguchi, M.; Hirano, I. Tetrahedron Lett. 1983, 24,
391–394.
References and notes
13. Itoh, T.; Jitsukawa, K.; Kaneda, K.; Teranishi, S. J. Am.
Chem. Soc. 1979, 101, 159–169.
14. Kim, S.; Ahn, K. H. J. Org. Chem. 1984, 49, 1717–
1724.
15. For examples of reduction of hemithio ortho esters and
xanthates with Bu3SnH/AIBN under photolytic condi-
tions, see: (a) Kahne, D.; Yang, D.; Lim, J. J.; Miller, R.;
Paguaga, E. J. Am. Chem. Soc. 1988, 110, 8716–8717; (b)
Bell, R. H.; Horton, D.; Williams, D. M.; Winter, M. E.
Carbohydr. Res. 1977, 58, 109–124.
16. Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1989,
30, 1281–1284.
17. For an example of the C–C bond formation using 3,5-
bis(trifluoromethyl)benzenesulfonate ester as a leaving
group, see: Ritter, T.; Zarotti, P.; Carreira, E. M. Org.
Lett. 2004, 6, 4371–4374.
1. For reviews, see: (a) Moore, R. E. In Marine Natural
Products; Scheuer, P. J., Ed.; Academic Press: New York,
1978; Vol. 1, pp 43–121; (b) Erickson, K. L. In Marine
Natural Products; Scheuer, P. J., Ed.; Academic Press:
New York, 1983; Vol. 5, pp 131–257; (c) Faulkner, D. J.
Nat. Prod. Rep. 2001, 18, 1–49, See also his previous
reviews in Nat. Prod. Rep.
2. For a review on the total synthesis of medium-sized cyclic
ethers from Lurencia red algae, see: (a) Fujiwara, K. In
Topics in Heterocyclic Chemistry; Kiyota, H., Ed.;
Springer-Verlag: Berlin, 2006; Vol. 5, pp 97–148; For
reviews on the synthesis of medium-sized cyclic ethers, see:
(b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127–2198; (c) Elliott, M. C. Contemp. Org. Synth. 1994,
474–475; (d) Albizati, K.; Martin, V. A.; Agharahimi, M.
R.; Stolze, D. A. In Bioorganic Marine Chemistry;
Scheuer, P. J., Ed.; Springer-Verlag: Berlin, 1992; Vol. 6,
pp 69–84.
18. Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33,
4345–4348.
19. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–
3772.
20. Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem.
1996, 61, 5716–5717.
21. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4465–4470.
3. Saitou, T.; Suzuki, T.; Onodera, N.; Sekiguchi, H.;
Hagiwara, H.; Hoshi, T. Tetrahedron Lett. 2003, 44,
2709–2712.
4. Suzuki, T.; Matsumura, R.; Oku, K.; Taguchi, K.;
Hagiwara, H.; Hoshi, T.; Ando, M. Tetrahedron Lett.
2001, 42, 65–67.