Use of the diels-alder adduct of pyrrole in organic synthesis. Formal racemic synthesis of tamiflu

Article abstract of DOI:10.1021/jo1002856

A new synthetic route to Tamiflu was developed via the Diels-Alder reaction of pyrrole and bromoacetylene.

Full text of DOI:10.1021/jo1002856

pubs.acs.org/joc
Tamiflu was first developed by Gilead Science, and is synthe-
sized and marketed by Roche. Its production is performed
Use of the Diels-Alder Adduct of Pyrrole in Organic
Synthesis. Formal Racemic Synthesis of Tamiflu
1
starting from shikimic acid, a natural product, so that
development of a new synthesis from non-natural readily
available chemical feedstock is required. The synthesis of
Tamiflu has been investigated by many groups in the world
Akio Kamimura* and Toshiki Nakano
Department of Applied Molecular Bioscience,
Graduate School of Medicine, Yamaguchi University,
Ube 755-8611 Japan
2
and the total synthesis has been accomplished by Corey,
4
3
Shibasaki, and other groups.
Tamiflu contains ether and amino functional groups in
a cyclohexene structure, so the proper and efficient installa-
tion of these groups is very important for the synthesis. Our
synthetic strategy is illustrated in Scheme 1.
ak10@yamaguchi-u.ac.jp
Received February 15, 2010
SCHEME 1
A new synthetic route to Tamiflu was developed via the
Diels-Alder reaction of pyrrole and bromoacetylene.
To construct such a polyfunctionalized cyclohexene unit,
we were interested in the Diels-Alder adducts of pyrroles
and acetylene. This precursor may provide aminocyclohex-
ene structure by elimination reaction of the bridged amine
Recently Tamiflu (oseltamivir phosphate) has been recog-
nized as a key weapon in the combat of a new type of influ-
enza and its importance and demand are now increasing.
5
6
unit under the basic condition. The adduct, 7-azabicyclo-
[
2.2.1]heptadiene, would be a potentially useful precursor for
(
1) Federspiel, M.; Fisher, R.; Henning, M.; Mair, H. J.; Oberhauser, T.;
Rimmler, G.; Albiez, T.; Bruhin, J.; Estermann, H.; Gandert, C.; Gockel, V.;
Gotzo, S.; Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.; Rockel-
Stabler, O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res. Dev. 1999, 3,
the installation of polyfunctionalities on the cyclohexane
core. Pyrrole is an aromatic ring and it is not reactive toward
the Diels-Alder reaction. However, pyrrole derivatives
become good dienes in the Diels-Alder reaction with elec-
tron-deficient alkynes when an electron-withdrawing group
is installed at the N1 position. In this paper, we report a
formal synthesis of tamiflu from the Diels-Alder adduct of a
pyrrole and an acetylene.
2
66.
(2) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
310.
6
(
3) Fukuta, Y.; MIta, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2007, 129, 11892.
4) (a) Kim, C. U.; Lew, W.; Willimas, M. A.; Liu, H.; Zhang, L.;
(
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.;
Laver, W. G.; Stevens, R.C. J.Am. Chem.Soc. 1997, 119, 681. (b)Rohloff, J. C.;
Kent, K. M.; Positich, M. J.; Becker, M. W.; Capman, H. H.; Kelly, D. E.; Lew,
W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang,
L.J. Org.Chem. 1998, 63, 4545. (c) Karpf, M.; Trussardi, R. J.Org. Chem. 2001,
Our synthesis started from the Diels-Alder reaction of
N-boc-pyrrole (Scheme 1). A solution of bromoacetylene
carboxylate (2) in N-boc-pyrrole (1) was heated at 90 °C
for 39 h and the Diels-Alder adduct, 7-tert-butyl 2-methyl
6
6, 2044. (d) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hghes, R. C. Org.
Process Res. Dev. 2004, 8, 86. (e) Cong, X.; Yao, Z. J. J. Org. Chem. 2006, 71,
365. (f) Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tasi, K.-C.; Cheng, Y.-S. E.;
Yang, A.-S.; Hsiao, S.-C.; Su, C.-Y.; Wong, C.-H. J. Am. Chem. Soc. 2007, 129,
1892. (g) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem.,
5
3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate
1
(3), was isolated in 57% yield. An excess amount of 1, which
was used as the reaction solvent, was recovered by distilla-
tion after the reaction and reused for the preparation of
Int. Ed. 2007, 46, 5734. (h) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.;
Shibasaki, M. Tetrahedron Lett. 2007, 48, 1403. (i) Bromfield, K. M.; Graden,
H.; Hagberg, D. P.; Olsson, T.; Kann, N. Chem. Commun. 2007, 3183. (j) Mita,
T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 259.
(
k) Kipassa, N. T.; Okamura, H.; Kina, K.;Hamada, T.; Iwagawa, T.Org. Lett.
2
4
4
4
008, 10, 815. (l) Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008, 73,
895. (m) Matveenko, M.; Willis, A. C.; Banwell, M. G. Tetrahedron Lett. 2008,
9, 7018. (n) Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew. Chem., Int. Ed. 2008,
7, 5788. (o) Trost, B. M.; Zhang, T. Angew. Chem., Int. Ed. 2008, 47, 3759.
(5) (a) Lee, C. K.; Hahn, C. S.; Noland, W. E. J. Org. Chem. 1978, 43,
3727. (b) Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179. (c) Zhang, C.;
Trudell, M. L. J. Org. Chem. 1996, 61, 7189. (d) Singh, S.; Basmadjian, G, P
Tetrahedron Lett. 1997, 38, 6829. (e) Zhang, C.; Izenwasser, S.; Katz, J, L.;
Terry, D.; Trudell, M. L. J. Med. Chem. 1998, 41, 2430. (f) Nishide, K.;
Ichihashi, S.; Kimura, H.; Katoh, T.; Node, M. Tetrahedron Lett. 2001, 42,
9237. (g) Warrener, R. N.; Margetic, D.; Sun, G. Tetrahedron Lett. 2001, 42,
4263. (h) Paulvannan, K. J. Org. Chem. 2004, 69, 1207. (i) Moreno-Vargas,
A. J.; Robina, I.; Petricci, E.; Vogel, P. J. Org. Chem. 2004, 69, 4487. (j) Otani,
Y.; Futaki, S.; Kiwada, T.; Sigiura, Y.; Muranaka, A.; Kobayashi, N.;
Uchiyama, M.; Yamaguchi, K.; Ohwada, T. Tetrahedron 2006, 62, 11635.
(6) Leung-Toung, R.; Liu, Y.; Muchowski, J. M.; Wu, Y.-L. J. Org.
Chem. 1998, 63, 3235.
(p) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int, Ed. 2009, 48, 1304.
(q) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M.
Angew. Chem., Int. Ed. 2009, 48, 1070. (r) Mandai, T.; Oshitari, T. Synlett 2009,
83. (s) Oshitari, T.; Mandai, T. Synlett 2009, 787. (t) Sullivan, B.; Carrera, I.;
7
Drouin, M.; Hudlicky, T. Angew. Chem., Int. Ed. 2009, 48, 4229. (u) Nie, L.-D.;
Shi, X.-X. Tetrahedron:Asymmetry2009, 20, 124. (v)Nie, L.-D.; Shi, X.-X.; Ho,
K. H.; Lu, W.-D. J. Org. Chem. 2009, 74, 3970. (w) Karpf, M.; Trussardi, R.
Angew. Chem., Int. Ed. 2009, 48, 5760.(x)Osato, H.;Jones, I. L.;Chen, A.;Chai,
C. L. L. Org. Lett. 2010, 12, 60.
DOI: 10.1021/jo1002856
r 2010 American Chemical Society
Published on Web 04/05/2010
J. Org. Chem. 2010, 75, 3133–3136 3133

Kamimura and Nakano
JOCNote
SCHEME 2
TABLE 1. Conversion of 8 to cyclohexene 9
base
(equiv)
additive
(equiv)
temp,
time, h °C
yield
of 9, % of 8, %
recovery
a
a
entry
1
2
3
4
5
6
7
a
tBuOK (1.2)
tBuOK (2.0)
tBuLi (1.3)
LDA (1.3)
LDA (1.3)
LDA (1.3)
LDA (1.3)
40
26
1
-50
reflux
-50
-50
0
0
91
86
8
38
2
20
24
62
60
22
18
HMPA (1.5)
HMPA (3.0)
DMPU (1.5)
0.5 -78
0.5 -78
0.5 -78
21
0
Isolated yield.
SCHEME 3
further batches of 3. Treatment of 3 with mCPBA gave 5,6-
7
epoxide 4 in 46% yield. The oxidation took place in a
stereoselective manner and exo-4 was prepared as a single
isomer. The use of oxone for the conversion resulted in the
formation of a mixture of isomers. Stepwise formation of
epoxide by using aqueous NBS followed by basic treatment
8
also failed to provide the conversion to epoxide. The reac-
tion stopped after several hours and some starting material 3
was recovered even though a large excess of mCPBA was
used;even after 24 h starting material was still present.
Fortunately the recovered 3 was readily isolated from the
reaction mixture by chromatographic treatment and reused.
Finally we succeeded un improving the yield of 4 up to 64%
by repeating the reaction procedure two times.
The reduction of 4 was carried out by the hydrogenation
reaction catalyzed by Pd/C catalyst. Unfortunately the reac-
tion was accompanied by the elimination of HBr, which
induced the removal of the N-boc group after which decom-
position of the azabicylic structure occurred. Addition of base
effectively scavenged the HBr and desired 5 was isolated in
more than 80% yield, although use of simple amine bases
afforded a mixture of endo-5 and exo-5. Finally we found
that the use of 2 equiv of 2-methylpyridine as the base enhan-
ced the endo/exo selectivity to 4:1 and compound 5 was
isolated in 71% yield. Pure endo-5 was isolated by further
flash chromatography.
The next stage is the installation of the R,β-unsaturated
ester in the cyclohexane ring. The results are summarized in
Table 1. Exposure of 8 to tBuOK in THF at -50 °C resulted
in total recovery of the starting material; thus the expected
base-catalyzed elimination reaction did not take place (entry 1).
The use of an excess amount of tBuOK or refluxing condi-
tions was not effective to achieve the elimination either (entry 2).
Use of tBuLi or LDA generated the desired 9 in low yield
although some 8 was recovered (entry 3 and 4). The yield of 9
was greatly enhanced when HMPA was use as cosolvent of
the reaction, resulting in an improved yield of 9 to 62% in the
presence of 1.5 equiv of HMPA (entry 5). An excess amount
of HMPA was not effective in improving the conversion and
the yield of 9 remained at a similar level (entry 6). Unfortu-
nately, use of DMPU instead of HMPA did not afford 9 in
good yield (entry 7).
Basic hydrolysis of endo-5 yielded the corresponding
carboxylic acid, that then opened the epoxide to give tricyclic
9
lactone alcohol 6 in 89% yield in one step. The hydroxyl
group in 6 was mesylated by treatment with MsCl to give 7 in
9
11
5% yield. Compound 7 was obtained as a crystalline form
suitable for X-ray crystallographic analysis, which unambi-
guously showed the stereochemistry of 7 to be as shown in
Scheme 2. Basic hydrolysis of 7 followed by esterification
1
0
with EtI gave endoepoxide 8 in 85% yield.
(7) Hodgson, D. M.; Maxwell, G. M.; Miles, T. J.; Paruch, E.; Matthews,
I. R.; Witherington, J. Tetrahedron 2004, 60, 3611.
(10) (a) Shoji, M.; Imai, H.; Mukaida, M.; Sakai, K.; Kakeya, H.; Osada,
H.; Hayashi, Y J. Org. Chem. 2005, 70, 79. (b) Songis, O.; Didierjean, C.;
Martinez, J.; Calmes, M. Tetrahedron: Asymmetry 2008, 19, 2135.
(11) Carlier, P. R.; Lo, C. W.-S.; Lo, M. M.-C.; Wan, N. C.; Williams,
I. D. Org. Lett. 2000, 2, 2443.
(8) Cocker, W.; Grayson, D. H. Tetrahedron Lett. 1969, 51, 4451.
(9) Tran, C. H.; Crout, D. H. G. J. Chem. Soc., Perkin Trans. 1 1998,
065.
1
3
134 J. Org. Chem. Vol. 75, No. 9, 2010

Kamimura and Nakano
JOCNote
The final stage of the synthesis was performed in the
following way (Scheme 3). Installation of the 3-pentyloxy
group was achieved by treatment with 3-pentanol in the
endo-5 in 56% yield (0.070 g) and exo-5 in 14% yield (0.018 g).
The endo-5/exo-5 ratio was about 4:1. Compounds endo-5 and
exo-5 contained two rotational isomers whose ratio was about
1:1. endo-5: white solid; mp 75.5-76 °C; H NMR (270 MHz,
3
CDCl ) δ 4.58 (d, J=4.6 Hz, 0.5 H), 4.44 (d, J=4.5 Hz, 0.5 H),
1
4
j
presence of BF OEt to obtain compound 10 in 54% yield.
2
3
The epimerization at the hydroxyl group of 10 was carried
out by oxidation-reduction path way. Thus, the conversion
of 10 to the corresponding ketone was achieved by treatment
4
3
.40 (d, J = 4.8 Hz, 0.5 H), 4.25 (d, J = 4.8 Hz, 0.5 H), 3.72 (s,
H), 3.39 (d, J=3.3 Hz, 0.5 H), 3.36 (d, J=3.3 Hz, 0.5 H), 3.32
(
1
d, J=3.4 Hz, 0.5 H), 3.30 (d, J=3.4 Hz, 0.5 H), 3.20-3.06 (m,
H), 2.16 (dd, J=4.8, 11.2 Hz, 0.5 H), 2.08 (dd, J=4.5, 11.8 Hz,
0.5 H), 1.76 (dd, J=3.3, 4.7 Hz, 0.5 H), 1.72 (dd, J=3.5, 4.7 Hz,
3
with the Dess-Martin periodinane to give 11 in 87% yield.
The reduction of 11 with NaBH smoothly gave 12 in 91%
yield. The diastereoselectivity was about 3:1. The major
isomer of 12 showed an identical NMR spectrum to that of
4
1
3
0.5 H), 1.45 (s, 9 H); C NMR (68 MHz, CDCl ) δ 172.3, 157.5,
3
80.3, 58.6, 58.0, 57.4, 56.7, 52.1, 49.7, 49.3, 48.1, 45.5, 44.6, 29.1,
4
l
previously reported 12 prepared by Zutter. The conversion
28.1. Anal. Calcd for C13
Found: C, 57.76; H, 6.98; N, 5.15. exo-5: white solid; mp
5
H19NO : C, 57.98; H, 7.11; N, 5.20.
4
l
of 12 to Tamiflu has already been reported and thus con-
cludes the formal synthesis of Tamiflu from readily available
organic feedstock.
1
1
4
26.5-127 °C; H NMR (270 MHz, CDCl ) δ 4.67 (s, 0.5 H),
3
.53 (s, 0.5 H), 4.40 (d, J=4.6 Hz, 0.5 H), 4.26 (d, J=4.6 Hz, 0.5
H), 3.73 (s, 1.5 H), 3.72 (s, 1.5 H), 3.39-3.26 (m, 2 H), 2.53 (dd,
J=2.0, 4.4 Hz, 0.5 H), 2.49 (dd, J=1.8, 4.5 Hz, 0.5 H), 2.20-
In conclusion, we have successfully achieved a new for-
mal synthesis of Tamiflu in 9 steps from the Diels-Alder
adduct of N-boc-pyrrole and an alkyne dienophile. Overall
yield was 5.4%, and all of the steps proceeded in a
sufficiently stereoselective manner. We are now trying to
develop an asymmetric synthesis by using enzymatic optical
resolution of compound 6. The results will be reported in
due course.
2
.41 (m, 1 H), 1.69 (d, J=9.1 Hz, 0.5 H), 1.64 (d, J=9.2 Hz, 0.5
13
H), 1.43 (s, 9 H); C NMR (68 MHz, CDCl
57.5, 157.3, 80.0, 60.0, 59.7, 56.9, 56.2, 52.1, 50.3, 49.8, 49.2,
43.8, 42.9, 29.8, 29.4, 28.0. Anal. Calcd for C H NO : C,
3
) δ 172.6, 172.5,
1
1
3
19
5
57.98; H, 7.11; N, 5.20. Found: C, 57.95; H, 6.99; N, 5.19.
Preparation of Tricyclic Lactone 6. NaOH(aq) (10%, 6.5 mL)
was added dropwise at 0 °C to a solution of endo-5 (3.34 g, 12.45
mmol), and the resulting solution was stirred at 0 °C for 30 min
and at room temperature for 40 h to neutralize the solution, then
dilute H SO (aq) (3 M) was added. The solution was concen-
Experimental Section
2
4
Preparation of 3 via the Diels-Alder Reaction of N-Boc-
pyrrole, 1. A mixture of 1 (48 mL, 288.8 mmol) and 2 (6.3 mL,
trated in vacuo. The pH of the remaining aqueous solution was
adjusted to 2-3 by adding dilute H SO . The water solution
2
4
6
6.0 mmol) was heated at 90 °C for 39 h. After cooling, the
was extracted with CH Cl (5 ꢀ 50 mL) and the organic phase
2
2
mixture was subjected to flash chromatography (hexane-
EtOAc 30:1, 20:1, then 15:1) to give 3 in 57% yield (12.42 g).
Compound 1 was recovered in 99% (36.92 g), which was used
was dried over Na SO . Filtration and concentration of the
2 4
filtrate gave a crude product of 6 in 89% yield (2.816 g), which
was almost pure and ready to use for the next step. Mp 158-
1
1
for the reaction again. Yellow oil; H NMR (270 MHz, CDCl
3
)
158.5 °C; H NMR (270 MHz, CDCl ) δ 5.05 (t, J = 5.3 Hz,
3
δ 7.03-7.18 (m, 2 H), 5.44-5.55 (m, 1 H), 5.07-5.20 (m, 1 H),
1 H), 4.52 (d, J=5.3 Hz, 1 H), 4.34 (d, J=4.8 Hz, 1 H), 3.85 (d,
J=6.0 Hz, 1 H), 2.75 (dd, J=4.8, 11.3 Hz, 1 H), 2.28-2.11 (m,
1
3
3
1
6
4
.80 (s, 3 H), 1.41 (s, 9 H); C NMR (68 MHz, CDCl ) δ 162.4,
3
1
3
53.9, 147.4 (br), 143.5 (br), 141.0 (br), 140.4 (br), 81.1, 74.7 (br),
2 H), 1.84 (dd, J = 1.9, 13.6 Hz, 1 H), 1.47 (s, 9 H); C NMR
(68 MHz, CDCl ) δ 177.2, 155.5, 84.5, 81.7, 77.4, 62.8, 61.7,
38.2, 32.4, 28.1; HRMS (FAB þ M þ 1) m/z 256.1186. Calcd for
256.1179.
Preparation of Mesylate 7. MsCl (0.34 mL, 4.39 mmol) was
added to a solution of 6 (1.01 g, 3.96 mmol) and Et N (0.66 mL,
4.77 mmol) at room temperature and the reaction mixture was
stirred for 24 h. CH Cl (10 mL) and NaHCO (aq) (8 mL) were
added and the organic layer was separated. The water layer was
extracted with CH Cl
(5ꢀ2 mL). The combined organic phase
was washed with brine (5 mL) and dried over Na SO . After
8.4 (br), 51.4, 27.7. Anal. Calcd for C13
.88; N, 4.24. Found: C, 47.09; H, 4.66; N, 4.53.
Preparation of Epoxide 4. mCPBA (13.46 g, 77%, 60.1 mmol)
H16BrNO
4
: C, 47.29; H,
3
12 5
C H18NO
was added to a solution of 3 (16.18 g, 49.0 mmol) in Et O (100 mL)
2
at 0 °C. The mixture was stirred at 0 °C for 1 h then at room
temperature for 49 h. The mixture was concentrated and NaH-
3
CO (aq) was added. The resulting mixture was extracted with
3
2
2
3
CH Cl (3 ꢀ 20 mL). The organic phase was combined, washed
2
2
with NaHCO (aq) (20 mL) and brine (20 mL), and dried over
3
2
2
Na SO . After being filtered, the crude product was concentrated
2
4
2
4
and purified by flash chromatography (hexane-EtOAc 10:1) to
give 4 in 46% yield (7.784 g) along with recovery of 3 in 5.836 g,
which was subjected to a similar reaction conditions with use of
filtration, the filtrate was concentrated to give crude 7, which
was purified by recrystallization (acetone-hexane 1:3) in 95%
1
(1.25 g) yield. White solid; mp 178.5-179 °C; H NMR (270
mCPBA (5.942 g, 26.5 mmol) in CH
yield (3.011 g). The combined yield of the two manipulations was
4%. Compound 4consisted of a stereoselective endoisomer, which
Cl
2 2
(30 mL) to give 4 in 49%
3
MHz, CDCl ) δ 5.14 (t, J = 4.6 Hz, 1 H), 4.80 (d, J = 5.0 Hz,
1 H), 4.67 (d, J= 4.9 Hz, 1 H), 4.62 (s, 1 H), 3.10 (s, 3 H), 2.80
(dd, J=4.8, 10.3 Hz, 1 H), 2.31 (ddd, J=5.1, 11.3, 13.8 Hz, 1 H),
6
1
13
1.93 (dd, J = 1.9, 13.8 Hz, 1 H), 1.47 (s, 9 H); C NMR
contained two rotational isomers whose ratio was about 1:1. Oil; H
NMR (270 MHz, CDCl ) δ 5.06 (s, 0.5 H), 4.91 (s, 0.5 H), 4.81 (s,
.5 H), 4.67 (s, 0.5 H), 3.82 (s, 1.5 H), 3.81 (s, 1.5 H), 3.77-3.67 (m,
3
(68 MHz, CDCl
38.8, 37.8, 32.6, 28.1. Anal. Calcd for C H NO S: C, 46.84; H,
3
) δ 176.0, 154.0, 82.7, 82.5, 81.9, 61.4, 60.8,
0
2
1
1
3
19
7
1
3
H), 1.56 (s, 4.5 H), 1.47 (s, 4.5); C NMR (68 MHz, CDCl
61.9, 161.8, 155.1, 155.0, 139.6, 139.3, 138.8, 138.6, 80.9, 80.8, 69.8,
9.3, 63.5, 62.7, 56.11, 55.9, 55.8, 55.5, 51.9, 27.8; HRMS (EIþ M)
m/z 345.0217. Calcd for C H NO Br 345.0212.
3
) δ
5.74; N, 4.20. Found: C, 46.99; H, 5.75; N, 4.19.
Preparation of Endoepoxide 8. KOH (103.0 mg, 1.836 mmol)
was added to a solution of 7 (103.0 mg, 0.309 mmol) in DMF
(5 mL). The reaction mixture was stirred at room temperature
for 30 h. EtI (0.2 mL, 2.49 mmol) was added to the solution and
the reaction mixture was stirred for 24 h. A mixed solution of
6
13
16
5
Hydrogenation of 4 To Prepare Compound 5. A sample of 10%
Pd/C (16 mg) was added to a solution of 4 (0.160 g, 0.462 mmol)
and 2-methylpyridine (0.086 g, 0.923 mmol) in MeOH (8 mL).
Under hydrogen atmosphere, the mixture was stirred vigorously
at room temperature for 50 h. Pd/C was removed over Celite pad
and the filtrate was concentrated. The residue was purified by
flash chromatography (hexane-EtOAc 4:1 then 2:1) to give
NH Cl(aq) and dilute HCl (5:1, 5 mL) was added and the aque-
4
ous phase was extracted with EtOAc (7ꢀ10 mL). The combined
organic phase was washed with brine (2ꢀ5 mL) and dried over
2 4
Na SO . Filtration followed by concentration of the filtrate in
vacuo gave crude product, which was purified by flash chroma-
J. Org. Chem. Vol. 75, No. 9, 2010 3135

Kamimura and Nakano
JOCNote
tography (hexane-EtOAc 4:1) to give 8 in 85% yield (74 mg) as
a colorless oil. Compound 8 contained two rotational isomers
(m, 1 H), 2.30-2.10 (m, 1 H), 1.58-1.47 (m, 4 H), 1.45 (s, 9 H),
1.28 (t, J=7.1 Hz, 3H), 0.93 (t, J=7.4 Hz, 6 H); C NMR (68
1
3
1
whose ratio was about 1:1. H NMR (270 MHz, CDCl
3
) δ
MHz, CDCl
60.9, 50.2, 30.5, 28.4, 26.4, 26.1, 14.2, 9.5; HRMS (EIþ M) m/z
371.2324. Calcd for C19 371.2308.
3
) δ 166.4, 156.6, 136.8, 129.4, 82.0, 80.0, 77.8, 73.9,
4
.45-4.51 (m, 1 H), 4.28-4.10 (m, 3 H), 4.03-3.95 (m, 1 H),
3
.91 (dd, J = 3.1, 4.4 Hz, 1 H), 2.91-2.79 (m, 1 H), 2.06-1.92
m, 2 H), 1.57 (s, 4.5 H), 1.44 (s, 4.5 H), 1.28 (t, J=7.2 Hz, 3 H);
C NMR (68 MHz, CDCl
0.6, 60.1, 58.4, 44.2, 29.1, 28.2, 14.2. Anal. Calcd for C H -
H
33NO
6
(
Oxidation to Ketone 11. A mixture of Dess-Martin periodate
(88.7 mg, 0.209 mmol) and compound 10 (38.4 mg, 0.103 mmol)
in CH Cl (2 mL) was stirred at room temperature for 2 h.
1
3
3
) δ 172.0, 155.0, 80.7, 63.2, 63.0,
6
NO
1
4
21
2
2
5
: C, 59.35; H, 7.47; N, 4.94. Found: C, 59.49; H, 7.19; N, 4.78.
Filtration followed by flash chromatography (hexane-EtOAc
9:1) gave 11 in 87% yield (33.1 mg). Pale yellow oil; H NMR
1
Conversion to Cyclohexene Epoxide 9. A solution of LDA was
generated from a solution of iPr NH (0.31 mL, 2.2 mmol) in
(270 MHz, CDCl ) δ 6.79 (t, J=2.9 Hz, 1 H), 5.50 (d, J=7.1 Hz,
2
3
THF (10 mL) by adding HMPA (0.29 mL, 1.66 mmol) and
tBuLi (1.58 M in pentane, 1.42 mmol). To the LDA solution
was added a solution of 8 (309 mg, 1.09 mmol) in THF (5 mL) at
1 H), 4.82-4.59 (m, 2 H), 4.22 (q, J=6.1 Hz, 2H), 3.52-3.35 (m,
2H), 2.46-2.22 (m, 1 H), 1.49-1.76 (m, 8 H), 1.44 (s, 9 H), 1.29
(t, J=7.1 Hz, 3 H), 0.98 (t, J=7.3 Hz, 3 H), 0.91 (t, J=7.4 Hz,
13
-
50 °C and the resulting solution was stirred for 16 h at the same
temperature. The reaction mixture was warmed to 0 °C and
NH Cl(aq) (10 mL) was added. The mixture was extracted with
CH Cl
(3 ꢀ 25 mL) and the organic phase was dried over
Na SO . Filtration followed by concentration of the filtrate in
3 H); C NMR (68 MHz, CDCl ) δ 202.6, 165.4, 155.3, 138.0,
3
130.4, 83.7, 80.2, 76.5, 61.3, 55.2, 35.0, 28.3, 26.4, 25.4, 14.1,
9.5, 9.2.
4
2
2
Preparation of Ethyl 5-(tert-Butoxycarbonylamino)-4-hydroxy-
3-(pentan-3-yloxy)cyclohex-1-enecarboxylate, 12. NaBH (14.0 mg,
2
4
4
vacuo gave crude product, which was purified by flash chroma-
tography (hexane-EtOAc 8:1 then 4:1) to give 9 in 63% yield
0.37 mmol) was added to a solution of 11 (66.9 mg, 0.18 mmol) in
MeOH at -50 °C and the reaction mixture was stirred for 30 min.
1
(
194.0 mg). White solid; mp 58-58.5 °C; H NMR (270 MHz,
NaHCO (aq) (10 mL) was added and the mixture was extracted
with CH Cl (3ꢀ25 mL). The organic phase was washed with brine
3
CDCl ) δ 7.12 (t, J = 3.3 Hz, 1 H), 4.64-4.51 (m, 1 H), 4.49-
3
2
2
4
3
1
.31 (m, 1 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.63-3.53 (m, 1 H),
.42 (t, J=4.3 Hz, 1 H), 2.69 (d, J=16.8 Hz, 1 H), 2.35 (d, J=
2 4
(10 mL) and dried over Na SO . Filtration followed by concentra-
tion gave crude product, which was purified by flash chromatog-
raphy (hexane-EtOAc 8:1 then 4:1) to give 12 in 91% yield (61.1
mg). HPLC analysis revealed the diastereomeric ratio was 3:1.
1
3
6.3 Hz, 1 H), 1.44 (s, 9 H), 1.30 (t, J=7.1 Hz, 3 H); C NMR
) δ 165.9, 155.2, 133.6, 132.0, 100.7, 61.1, 55.8,
5.8, 43.1, 28.3, 26.8, 14.1. Anal. Calcd for C14 : C,
9.35; H, 7.47; N, 4.94. Found: C, 59.04; H, 7.61; N, 5.03.
Installation of 3-Pentanyl Ether 10. Compound 9 (822 mg,
.90 mmol) was dissolved in 3-pentanol (25 mL) and BF OEt
(
68 MHz, CDCl
3
1
Colorless oil; H NMR (500 MHz, CDCl
4
5
H
21NO
5
3
) δ 6.66 (s, 1 H), 5.19 (d,
J = 9.2 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.13-4.16 (m, 1H),
4.01-4.06 (m, 1 H), 3.85 (dt, J=7.0, 10.5 Hz, 1 H), 3.48-3.35 (m,
1 H), 2.58 (dd, J=5.6, 17.8 Hz, 1 H), 2.53-2.57 (br, 1 H), 2.32 (dd,
J=10.1, 17.3 Hz, 1 H), 1.66-1.51(m, 4H),1.44(s,9H),1.28(t,J=
2
3
2
(
1.0 mL, 3.2 mmol) was slowly added to the solution at -20 °C
over 20 min. The solution was stirred for 1 h. NaHCO (aq) (30 mL)
was added to the solution at 0 °C and the resulting mixture was
extracted with CH Cl
(3ꢀ50 mL). The organic phase was dried
over Na SO and filtered. The filtrate was concentrated in vacuo
1
3
3
3
7.1Hz, 3H), 0.92(t, J=7.4 Hz, 6 H); C NMR (126 MHz, CDCl )
δ 166.2, 155.5, 135.7, 130.7, 81.7, 79.6, 73.9, 68.2, 60.9, 48.8, 28.5,
27.1, 26.4, 26.2, 14.3, 9.8, 9.4; HRMS (EIþ M) m/z 371.2309. Calcd
2
2
2
4
6
for C19H33NO 371.2308.
and the residue was purified by flash chromatography (hexane-
EtOAc 5:1, 4:1 then 3:1) to give 10 in 54% yield (1.567 mmol).
1
13
Supporting Information Available: H NMR and C NMR
spectra for compounds 3, 4, endo-5, exo-5, 6, 7, 8, 9, 10, 11, and
12 and X-ray crystallographic data for compound 7. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
Pale yellow oil; H NMR (270 MHz, CDCl
3
) δ 6.76 (s, 1 H), 4.85
(
3
d, J=7.6 Hz, 1 H), 4.20 (q, J=7.1 Hz, 2 H), 4.06-3.98 (m, 1 H),
.90-3.71 (m, 1 H), 3.60 (ddd, J=3.6, 7.0, 10.2 Hz, 1 H), 3.48
(
t, J=4.9 Hz, 1 H), 2.88 (dd, J=4.9, 18.6 Hz, 1 H), 2.70-2.59
3
136 J. Org. Chem. Vol. 75, No. 9, 2010