Stereoselective construction of an anti-β-alkoxy ether by Ireland-Claisen rearrangement for medium-ring ether synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.01.011

The asymmetric synthesis of an acyclic anti-β-alkoxy ether was achieved by the Ireland-Claisen rearrangement of Z-3-alkoxy-2-propenyl glycolate ester, prepared from Garner's aldehyde, a glycolic acid derivative, and ethynyl N,N-diisopropylcarbamate. The r

Full text of DOI:10.1016/j.tetlet.2009.01.011

Tetrahedron Letters 50 (2009) 1236–1239
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Tetrahedron Letters
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Stereoselective construction of an anti-b-alkoxy ether by Ireland–Claisen
rearrangement for medium-ring ether synthesis
a
Kenshu Fujiwara a, , Natsumi Kawamura , Hidetoshi Kawai a,b, Takanori Suzuki a
*
a Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
b PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric synthesis of an acyclic anti-b-alkoxy ether was achieved by the Ireland–Claisen rear-
rangement of Z-3-alkoxy-2-propenyl glycolate ester, prepared from Garner’s aldehyde, a glycolic acid
derivative, and ethynyl N,N-diisopropylcarbamate. The resulting acyclic ether was facilely converted to
seven- and eight-membered cyclic ethers via processes involving ring-closing olefin metatheses.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 1 December 2008
Revised 5 January 2009
Accepted 8 January 2009
Available online 10 January 2009
Keywords:
Stereoselective synthesis
Cyclic ethers
Ireland–Claisen rearrangement
Ring-closing olefin metathesis
Natural medium ring ether compounds, which are often bioac-
tive, have attracted synthetic interest due to their particular
structural features, such as medium-sized ring systems or stereo-
chemical complexity around the ether linkage.1 While a large
number of synthetic methods have been developed by many re-
search groups,2 ring-closing olefin metathesis (RCM)3 based ap-
proaches have been extensively explored,4,5 because RCM realizes
efficient ring-closure under mild catalytic conditions and tolerates
a wide variety of functional groups in its substrates. However, the
construction of the stereochemically complex ether linkage in the
diene substrates of RCM for medium ring ethers is still difficult.6
Therefore, approaches toward these systems have focused on the
establishment of an efficient method for the stereoselective syn-
thesis of acyclic ethers.
In our recent studies on the construction of medium ring ethers
using RCM,7 we found that the Ireland–Claisen rearrangement of
an acyclic Z-3-alkoxy-2-propenyl glycolate ester stereoselectively
produced an acyclic anti-b-alkoxy ether, corresponding to an ether
moiety of a natural trans-fused polycyclic ether.7a Here, we de-
scribe the development of an improved variant of this rearrange-
ment, which accomplishes the asymmetric synthesis of an acyclic
anti-b-alkoxy ether from easily available starting materials for effi-
cient medium ring ether synthesis.
Medium-Ring-
Formation
CO2Me
OR1
CO2Me
OR1
anti
H
H
H
H
H
H
H
H
O
O
O
(by RCM)
O
O
O
R2
trans-Fused
2
Polycyclic Ether (1)
Chirality-Transferring
Ireland-Claisen
O
OH
Rearrangement
H
H
O
O
Z
O
O
O
H
H
R2
R2
O
O
1
Z
SiR3
5
O
Z
R1O
OR1
O
O
3
H
H
4
3
R2-Assisted
OR1
Lindlar
Hydrogenation
Stereoselective
Addition
OR1
HO
R2
3 OR1
9
R2
HO
1
+
CHO
R2
Z
6
7
8
O
i-Pr
N
R3
OH
Me
H
H
Me
Cb
O
O
Boc
O
OCb
i-Pr
The goal of this project was to devise a facile method to con-
struct a terminal medium ring in a trans-fused polycyclic ether sys-
tem (1) (Scheme 1). Toward this goal, a synthetic route was
N
O
O
O
CHO
n
O
10
11
12
13: n=1, R3=CO2Me
14: n=0, R3=CH2OBn
* Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706 4924.
E-mail address: fjwkn@sci.hokudai.ac.jp (K. Fujiwara).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.011

K. Fujiwara et al. / Tetrahedron Letters 50 (2009) 1236–1239
1237
designed that relied on RCM for the ring closure of the terminal
medium ring of 1 and chirality-transferring Ireland–Claisen rear-
rangement for setting up the anti-b-alkoxy ether substrate (2) ste-
reoselectively. Based on our previous study that showed exclusive
anti selectivity in the rearrangement of a simple Z-3-alkoxy-2-pro-
penyl glycolate ester,7a 1-substituted Z-3-alkoxy-2-propenyl ester
4 was employed as a precursor of 2. We also expected that the chi-
rality at C1 of the propenyl group of 4 would be efficiently trans-
ture produced rearrangement products, which were methylated
with TMSCHN2 to afford a separable mixture of anti- and syn-
16
ethers having an E-olefin (19 and 20, respectively) in a combined
yield of 70% with 3.4:1 anti-selectivity. Diethyl malonate was
added as a scavenger of the excess base to avoid elimination of
the carbamoyloxy group from the rearrangement products. The
moderate anti-selectivity was attributed to the moderate Z-prefer-
ence in the ketene silyl acetal formation step from 18 under either
kinetic or thermodynamic conditions. Since neither the extended
time (1 h) for the deprotonation nor the addition of HMPA as a
co-solvent affected the diastereoselectivity, the equilibrium ther-
modynamic ratio of Z/E ketene silyl acetals in this reaction is sug-
gested to be 3.4:1. On the other hand, the kinetic formation of the
ketene silyl acetal of 18 by treatment with TMSCl prior to deproto-
nation with KHMDS showed a somewhat decreased anti-selectivity
(2.2:1). Thus, thanks to the thermodynamic equilibration, anti-
ether 19 was obtained in 55% isolated yield and was available for
the medium ring formation.
Next, oxane-fused eight-membered ring ethers 13 and 23 were
synthesized from 19 and 20, respectively (Scheme 3). The conver-
sion of the 3-Boc-2,2-dimethyl-1,3-oxazoline-4-yl group of 19 to a
hydroxymethyl group was first performed. A three-step process,
including acidic methanolysis of 19, oxidative cleavage of the
resulting 1,2-aminoalcohol, and Luche reduction17 produced 21
in good yield (85% from 19). Allyl alcohol 21 was transformed to
terminal alkene 22 (89%) by a modified Movassaghi’s procedure,18
in which an excess amount of 1-hexene was used as a scavenger of
free diimide generated during the reaction. Treatment of 22 with a
catalytic amount of second-generation Grubbs’ catalyst19 in reflux-
ing CH2Cl2 promoted RCM to furnish 1320 in high yield (80%). The
same five-step process from 20 also provided bicyclic ether 2320
facilely. Thus, a process for the construction of an eight-membered
ether ring in five steps after the Ireland–Claisen rearrangement
step was established. The N,N-diisopropylcarbamoyl (Cb) group
of 13 could also be removed by stepwise treatment with LiAlH4
and MeLi to produce 24 in an acceptable yield (57%).
ferred to the newly formed stereocenters of
2 via putative
transition state 3.8 Ester 4 would be prepared from polycyclic ether
5, having a glycolic acid moiety, and chiral Z-3-alkoxy-2-propenol
6. We chose to synthesize 6 by stereoselective addition of pro-
tected ynol 9 to aldehyde 8 with the assistance of the R2 group
as a chiral auxiliary, followed by Lindlar hydrogenation. Thus, the
proposed synthetic route was demonstrated by the model synthe-
sis of oxane-fused medium ring ethers 13 and 14 from oxane-con-
nected glycolic acid 109 corresponding to 5, Garner’s aldehyde
(11),10 reported to be efficient for stereoselective addition reac-
tions,11 and ethynyl N,N-diisopropylcarbamate (12),12 a stable ynol
derivative.
First, chiral Z-3-carbamoyloxy-2-propenol 17, corresponding to
6, was selectively synthesized (Scheme 2). The addition reaction of
11 with the acetylide derived from 12 in the presence of LiBr13 pro-
duced alcohol 1514 (70%) with almost complete diastereoselectivi-
ty. The configuration of the newly generated stereocenter of 15
was determined by the presence of an NOE between Ha and Hb
of 16, derived from 15 by hydrogenation and subsequent basic
treatment. Lindlar hydrogenation of 15, followed by simple filtra-
tion, quantitatively gave 1714 in an almost pure form.
The chirality-transferring Ireland–Claisen rearrangement of es-
ter 18,14 prepared by the condensation of 10 and 17 with EDCIꢀHCl
(74%), was found to proceed successfully under the following con-
ditions. After ester 18 was deprotonated with KHMDS (5 equiv)15
in THF at –78 °C for 30 min, the resulting enolate was treated suc-
cessively with TMSCl (5 equiv) and diethyl malonate (5 equiv).
Subsequent warming of the reaction mixture to ambient tempera-
The stereochemistries of 13 and 23 were determined by NMR
analysis, in which an NOE correlation H4/H10 and a large JH9–H10
(9.9 Hz) were detected in 13, and NOE correlations H5/H10 and
H9/H10 as well as a small JH9–H10 (ꢁ0 Hz) were observed in 23,
Me
Me
Me
Boc
Boc
Boc
Me
Me
Me
OCb
N
N
N
O
O
O
a
d
CHO
OCb
OH
OH OCb
11
12
15
17
CO2Me
OCb
CO2Me
OCb
O
O
b, c
a — c
d
O
Me
O
19
20
O
O
Me
N
O
O
O
O
OH
O
Me HN S
e
Cb = CN(i-Pr)2
N
O
21
22
Ha Hb
OH
O
Me
O2N
10
NOE
OCb
IPNBSH
e
16
NOEs
MeO
O
O
MeO
O
NOE
H CO2Me
H R2
O
Me
O
H
4
H
H
syn
OCb
anti
h — l
OR1
O 10
O 10
OCb
H
JH9-H10
Me
NBoc
9
4
9
OCb
f, g
1O
1O
H
5
O
O
O
+
JH9-H10
= 9.9 Hz
H
O
= ~0 Hz
O
23
13: R1 = Cb, R2 = CO2Me
NBoc
Me
NBoc
Me
f, g
O
O
24: R1 = H, R2 = CH2OH
O
CbO
Me
Me
19 (major)
20 (minor)
18
Scheme 3. Reagents and conditions: (a) 1 M HCl in MeOH, 23 °C, 3 h; (b) NaIO4, 1,4-
dioxane–pH 7 buffer (1:1), 25 °C, 1 h; (c) NaBH4, CeCl3ꢀ7H2O, MeOH, ꢂ78 °C, 10 min,
85% from 19. (d) IPNBSH, Ph3P, DEAD, THF–1-hexene (5:1), 0 °C?25 °C, 2 h, then
CF3CH2OH–H2O (1:1), 25 °C, 9 h, 89%; (e) (H2IMes)(PCy3)Cl2RuCHPh (cat.), CH2Cl2,
reflux, 3.5 h, 80%; (f) LiAlH4, THF, 0 °C?23 °C, 1.5 h; (g) MeLi, THF, 0 °C, 1.5 h, 57%
from 13; (h) TFA–CH2Cl2 (1:2), 25 °C, 10 min; (i) NaIO4, 1,4-dioxane–pH 7 buffer
(1:1), 25 °C, 2 h; (j) NaBH4, CeCl3ꢀ7H2O, MeOH, –78 °C, 10 min, 44% from 20; (k)
IPNBSH, Ph3P, DEAD, THF–1-hexene (5:1), 0 °C?25 °C, 2 h, then CF3CH2OH–H2O
(1:1), 25 °C, 9 h, 45%; (l) (H2IMes)(PCy3)Cl2RuCHPh (cat.), CH2Cl2, reflux, 3.5 h, 92%.
Scheme 2. Reagents and conditions: (a) i-Pr2NH, MeLi (including LiBr), 12, THF,
–78 °C, 30 min, then 11, –78 °C, 12 h, 70%; (b) H2, 10% Pd/C (cat.), EtOH, 24 °C, 1.5 h;
(c) NaH, DMF, 24 °C, 12.5 h, 59% from 15; (d) H2, Lindlar’s cat., PhH, 25 °C, 7.5 h,
ꢁ100%; (e) 10, EDCIꢀHCl, DMAP, CH2Cl2, 1 h, 74% from 17; (f) KHMDS (5 equiv),
–78 °C, 30 min, then TMSCl (5 equiv), 30 min, then diethyl malonate (5 equiv),
30 min, then 24 °C, 1 h; (g) TMSCHN2, MeOH, 24 °C, 10 min, 70% (19+20;
19:20 = 3.4:1) from 18.

1238
K. Fujiwara et al. / Tetrahedron Letters 50 (2009) 1236–1239
Tetrahedron 1994, 50, 3; (d) Shimizu, Y. Chem. Rev. 1993, 93, 1658; (e)
R1
CO2Me
OCb
H
H
Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1895; (f) Erickson, K. L.. In Marine
Natural Products, Chemical and Biological Perspectives; Scheuer, P. J., Ed.;
Academic Press: New York, 1983; Vol. 5, p 131; See also: (g) Blunt, J. W.;
Copp, B. R.; Munro, M. H. G.; Northcore, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2001,
18, 1. and Ref. 3a.
O
O
Grubbs II
OCb
O
O
25
c — e
2. Recent reviews, see: (a) Fujiwara, K.. In Topics in Heterocyclic Chemistry; Gupta,
R. R., Kiyota, H., Eds.; Springer: Berlin, 2006; Vol. 5, p 97; (b) Nakamura, I.;
Yamamoto, Y. Chem. Rev. 2004, 104, 2127; (c) Elliot, M. C. J. Chem. Soc., Perkin
Trans. 1 2002, 2301; (d) Elliot, M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 1
2001, 2303; (e) Yet, L. Chem. Rev. 2000, 100, 2963; (f) Hoberg, J. O. Tetrahedron
1998, 54, 12631; (g) Alverz, E.; Candenas, M.-L.; Perez, R.; Ravelo, J. L.; Martin, J.
D. Chem. Rev. 1995, 95, 1953.
3. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003.
4. For early applications to medium-ring ethers, see: (a) Linderman, R. J.;
Siedlecki, J.; O’Neil, S. A.; Sum, H. J. Am. Chem. Soc. 1997, 119, 6919; (b)
Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548.
NBoc
Me
OBn
OCb
O
Me
O
OBn
OCb
H
O
19: R1 = CO2Me
g
O
a, b
26: R1 = CH2OBn
O
H
OR2
27: R2 = H
28: R2 = Allyl
14
f
5. For recent applications to medium-ring ethers, see: (a) Marvin, C. C.; Voight, E.
A.; Suh, J. M.; Paradise, C. L.; Burke, S. D. J. Org. Chem. 2008, 73, 8452; (b) Oishi,
T.; Hasegawa, F.; Torikai, K.; Konoki, K.; Matsumori, N.; Murata, M. Org. Lett.
2008, 10, 3599; (c) Crimmins, M. T.; Ellis, J. M. J. Org. Chem. 2008, 73, 1649; (d)
Sato, K.; Sasaki, M. Angew. Chem., Int. Ed. 2007, 46, 2518; (e) Roberts, S. W.;
Rainier, J. D. Org. Lett. 2007, 9, 2227; (f) Clark, J. S.; Conroy, J.; Blake, A. J. Org.
Lett. 2007, 9, 2091; (g) Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami, A.; Ohnuma,
Y.; Kawada, Y.; Komano, K.; Yamashita, S.; Lee, N.; Hirama, M. J. Am. Chem. Soc.
2006, 128, 9352; (h) Kadota, I.; Nishii, H.; Ishioka, H.; Takamura, H.; Yamamoto,
Y. J. Org. Chem. 2006, 71, 4183; (i) Crimmins, M. T.; McDougall, P. J.; Ellis, J. M.
Org. Lett. 2006, 8, 4079; (j) Ortega, N.; Martín, T.; Martín, V. S. Org. Lett. 2006, 8,
871.
6. For related stereoselective construction of b-hydroxy ethers for cyclic ether
synthesis: (a) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591; (b)
Crimmins, M. T.; She, J. Synlett 2004, 1371; (c) Crimmins, M. T.; McDougall, P. J.;
Emmitte, K. A. Org. Lett. 2005, 7, 4033.
7. (a) Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005,
46, 3465; (b) Goto, A.; Fujiwara, K.; Kawai, A.; Kawai, H.; Suzuki, T. Org. Lett.
2007, 9, 5373; (c) Sato, D.; Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahedron Lett.
2008, 49, 1514.
Scheme 4. Reagents and conditions: (a) LiAlH4, THF, –20 °C, 1 h; (b) NaH, BnBr,
Bu4NI, THF, 0 °C?25 °C, 14 h, 87% from 19; (c) TFA–CH2Cl2 (1:2), 25 °C, 10 min; (d)
NaIO4, 1,4-dioxane–pH 7 buffer (1:1), 25 °C, 2 h; (e) NaBH4, CeCl3ꢀ7H2O, MeOH,
–78 °C, 10 min, 65% from 26; (f) NaH, allyl bromide, Bu4NI, THF, 0 °C?25 °C, 18 h,
87%; (g) (H2IMes)(PCy3)Cl2RuCHPh (cat.), CH2Cl2, reflux, 12 h, 96%.
thereby confirming the configurations of rearrangement products
19 and 20.
Construction of an oxane-fused seven-membered ring ether
from 19 was also carried out (Scheme 4). The immediate treatment
of 19 with second-generation Grubbs’ catalyst19 did not afford
RCM product 25 but gave only recovered starting material. This
suggested that steric congestion of the CbO- and the 3-Boc-2,2-di-
methyl-1,3-oxazoline-4-yl groups would inhibit the access of any
active ruthenium species to the internal olefin. Therefore, a step-
wise route from 19 including the removal of the oxazolinyl group
and a relay-RCM process,21 an effective method for the RCM of ste-
rically hindered substrates, was undertaken for the assembly of se-
ven-membered ring ether 14. After methyl ester 19 was converted
to benzyl ether 26 by reduction and subsequent benzylation (87%),
the 3-Boc-2,2-dimethyl-1,3-oxazoline-4-yl group of 26 was trans-
formed to an allyl alcohol group by the same three-step process
as described above (65%). The resulting alcohol 27 was allylated
under Williamson conditions to provide 28 (87%), which was cy-
clized with second-generation Grubbs’ catalyst19 to furnish 1420
in high yield (96%). Thus, a simple procedure was set up for the se-
ven-membered ring ether synthesis subsequent to the Ireland–Cla-
isen step.
8. McFarland, C. M.; McIntosh, M. C. In The Claisen Rearrangement; Hiersemann,
M., Nubbemeyer, U., Eds.; Wiley-VCH: Weinheim, 2007; p 117.
9. Acid 10 was prepared from known (2R,3S)-2-vinyltetrahydropyran-3-ol by a
two-step process [(i) tert-butyl bromoacetate, Bu4NHSO4, 50% NaOH–CH2Cl2
(2:1), 22 °C, 1.5 h, 54%; (ii) TFA–CH2Cl2 (1:2), 24 °C, 1.5 h, ꢁ100%]. The
synthesis of (2R,3S)-2-vinyltetrahydropyran-3-ol, see: (a) Nicolaou, K. C.;
Hwang, C. K.; Marron, B. E.; DeFrees, S. A.; Couladouros, E. A.; Abe, Y.; Carrol,
P. J.; Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 3040–3054; (b) Alvarez, E.;
Delgado, M.; Diaz, M. T.; Hanxing, L.; Perez, R.; Martin, J. D. Tetrahedron Lett.
1996, 37, 2865.
10. Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18.
11. Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001, 2136.
12. Gralla, G.; Wibbeling, B.; Hoppe, D. Org. Lett. 2002, 4, 2193.
13. The presence of LiBr enhanced the yield of 12. In order to include LiBr in the
reaction solution conveniently, acetylene 11 was deprotonated with LDA
prepared from i-Pr2NH and a commercially available ether solution of MeLi
containing LiBr (Kanto Chemical Co. Ltd).
14. The compounds 15, 17, and 18 were stable enough to be purified by silica gel
column chromatography with 5% Et3 N containing eluent.
In conclusion, the asymmetric synthesis of an acyclic anti-b-alk-
oxy ether was achieved by the Ireland–Claisen rearrangement of
Z-3-alkoxy-2-propenyl glycolate ester, prepared from Garner’s
aldehyde, a glycolic acid derivative, and ethynyl N,N-diisopropylc-
arbamate. The resulting acyclic ether was facilely converted to
seven- and eight-membered cyclic ethers via processes involving
ring-closing olefin metatheses. Further improvement of the diaste-
reoselectivity of the rearrangement step and applications to the
synthesis of natural medium ring ethers are now in progress.
15. An excess amount of KHMDS was required to obtain reproducible yields of the
products. When 18 was treated with LDA, the terminal vinylic proton adjacent
to the carbamoyloxy group was selectively deprotonated and substituted by a
TMS group. LHMDS was unreactive to 18.
16. Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981, 29, 1457.
17. Gemal, A. L.; Luche, J.-L. J Am. Chem. Soc. 1981, 103, 5454.
18. (a) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838; (b) Movassaghi,
M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Angew. Chem., Int. Ed. 2006, 45, 5859; (c)
Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507.
19. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
20. Selected spectral data: 13: ½a D25
ꢃ
+46 (c 0.035, CHCl3); IR (neat) mmax 3030, 2965,
2933, 2873, 2853, 1754, 1693, 1439, 1369, 1344, 1286, 1218, 1118, 1094, 1062,
1025, 769 cmꢂ1 1H NMR (400 MHz, C6D6) d 1.07 (6H, d, J = 6.8 Hz), 1.08 (6H, d,
;
Acknowledgments
J = 6.8 Hz), 1.19–1.38 (3H, m), 1.94–2.01 (1H, m), 2.52 (1H, ddd, J = 2.8, 6.7,
14.1 Hz), 2.67 (1H, dddd, J = 1.1, 3.5, 9.9, 14.1 Hz), 2.82–2.90 (1H, m), 3.12–3.20
(1H, m), 3.27–3.65 (1H, m), 3.40 (3H, s), 3.56–3.62 (1H, m), 3.71 (1H, br ddd,
J = 1.7, 5.0, 8.6 Hz), 3.80–4.20 (1H, m), 4.27 (1H, d, J = 9.9 Hz), 5.60–5.69 (1H,
m), 5.74 (1H, br td, J = 3.1, 9.9 Hz), 5.92 (1H, br dd, J = 5.0, 11.3 Hz); 13C NMR
(100 MHz, C6D6) d 20.8 (CH3 ꢄ 2), 21.3 (CH3 ꢄ 2), 25.7 (CH2), 30.1 (CH2), 31.5
(CH2), 45.6 (CH), 46.5 (CH), 51.6 (CH3), 67.0 (CH2), 73.7 (CH), 79.6 (CH), 79.9
(CH), 81.8 (CH), 125.1 (CH), 136.5 (CH), 154.2 (C), 171.2 (C); HR-EIMS calcd for
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi (GC–MS and
NMR Laboratory, Graduate School of Agriculture, Hokkaido Univer-
sity) for the measurements of mass spectra. This work was sup-
ported by a Global COE Program (B01: Catalysis as the Basis for
Innovation in Materials Science) and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japanese Government.
C19H31NO6 [M+]: 369.2151, found: 369.2169. Compound 23: ½a 2D5
ꢃ
+139 (c
0.050, CHCl3); IR (neat) mmax 3030, 2957, 2927, 2850, 1760, 1736, 1686, 1440,
1369, 1290, 1210, 1147, 1121, 1075, 1030, 949, 769 cm–1 1H NMR (400 MHz,
;
C6D6) d 1.00–1.42 (15H, m), 1.78–1.86 (1H, m), 1.92 (1H, tdd, J = 1.7, 7.3,
14.8 Hz), 2.81 (1H, ddd, J = 5.9, 8.2, 14.8 Hz), 2.92 (1H, br dt, J = 2.3, 12.0 Hz),
3.40–3.65 (4H, m), 3.45 (3H, s), 3.87 (1H, br s), 4.05–4.35 (1H, m), 5.67 (1H, br
d, J = 5.7 Hz), 5.69–5.77 (1H, m), 5.89 (1H, ddd, J = 1.7, 7.2, 10.9 Hz); 13C NMR
(75 MHz, CDCl3) d 20.6 (CH3 ꢄ 2), 21.3 (CH3 ꢄ 2), 26.0 (CH2), 27.3 (CH2), 31.0
(CH2), 45.3 (CH), 46.6 (CH), 52.4 (CH3), 67.9 (CH2), 74.6 (CH), 74.7 (CH), 76.4
References and notes
1. Reviews for natural cyclic ethers, see: (a) Yasumoto, T. Chem. Rec. 2001, 3, 228;
(b) Yasumoto, T.; Murata, M. Nat. Prod. Rep. 2000, 17, 293; (c) Scheuer, P. J.

K. Fujiwara et al. / Tetrahedron Letters 50 (2009) 1236–1239
1239
(CH), 78.1 (CH), 126.5 (CH), 132.0 (CH), 154.7 (C), 171.0 (C); HR-EIMS calcd for
12.8 Hz), 5.84 (1H, br td, J = 2.1, 12.8 Hz), 5.87 (1H, br qd, J = 2.4, 9.5 Hz), 7.05–
7.11 (1H, m), 7.14–7.21 (2H, m), 7.31–7.36 (2H, m); 13C NMR (100 MHz, CDCl3)
d 20.5 (CH3 ꢄ 2), 21.6 (CH3 ꢄ 2), 25.5 (CH2), 31.0 (CH2), 45.4 (CH), 46.5 (CH),
67.6 (CH2), 71.0 (CH2), 72.2 (CH2), 73.5 (CH), 80.4 (CH), 81.0 (CH), 82.7 (CH),
127.5 (CH), 127.6 (CH ꢄ 2), 128.3 (CH ꢄ 2), 130.5 (CH), 132.2 (CH), 138.4 (C),
154.2 (C); HR-EIMS calcd for C24H35NO5 [M+]: 417.2515, found: 417.2502.
21. Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc.
2004, 126, 10210.
C19H31NO6 [M+]: 369.2151, found: 369.2163. Compound 14: ½a 2D5
ꢃ
+15.8 (c
0.120, CHCl3); IR (neat) mmax 3089, 3064, 3031, 2970, 2929, 2867, 1693, 1439,
1369, 1335, 1287, 1263, 1215, 1133, 1097, 1048, 1031, 959, 769, 737, 699 cm–1
;
1H NMR (400 MHz, C6D6) d 0.86–1.26 (13H, m), 1.26–1.43 (2H, m), 1.93–2.00
(1H, m), 2.87–2.95 (1H, m), 3.21–3.29 (1H, m), 3.54–3.90 (4H, m), 3.64 (1H, dd,
J = 6.5, 10.5 Hz), 3.73 (1H, dd, J = 2.3, 10.5 Hz), 3.94 (1H, ddd, J = 2.3, 6.5, 9.5 Hz),
4.41 (1H, d, J = 12.3 Hz), 4.50 (1H, d, J = 12.3 Hz), 5.72 (1H, br td, J = 2.5,