Efficient asymmetric synthesis of oseltamivir from D-mannitol

Article abstract of DOI:10.1055/s-0028-1087941

A highly practical asymmetric synthesis of oseltamivir has been accomplished in 18 steps from D-mannitol without any chromatographic purification, which features intramolecular aldol condensation of dialdehyde with a 3-pentyl ether moiety in constructing

Full text of DOI:10.1055/s-0028-1087941

LETTER
783
Efficient Asymmetric Synthesis of Oseltamivir from D-Mannitol
Synthesisof
Os
a
eltamivir fr
d
om
D
-Manni
a
tol katsu Mandai,* Tetsuta Oshitari1
Department of Life Science, Kurashiki University of Science & the Arts, 2640, Nishinoura, Tsurajima, Kurashiki 712-8505, Japan
Fax +81(86)4401062; E-mail: ted@chem.kusa.ac.jp
Received 11 December 2008
This paper is dedicated to Professor Jiro Tsuji.
lytic amount of propionic acid (132 °C, 14 h), 3 underwent
facile orthoester Claisen rearrangement8 smoothly to give
ester 49 in 95% yield after distillation. Gratifyingly, sub-
sequent tandem acetal cleavage10 and ester reduction of 4
were effected successfully with DIBAL-H (5 mol equiv)
to afford diol 5a and its regioisomer 5b as a 10:1 insepa-
rable mixture in favor of 5a.
Abstract: A highly practical asymmetric synthesis of oseltamivir
has been accomplished in 18 steps from D-mannitol without any
chromatographic purification, which features intramolecular aldol
condensation of dialdehyde with a 3-pentyl ether moiety in con-
structing densely functionalized cyclohexene ring of oseltamivir.
Key words: anti-influenza drugs, Tamiflu, chiral pool, dihydroxy-
lations, intramolecular aldol condensation
The growing epidemics of the avian flu virus H5N1 in
Southeast Asia often evoke the pandemic life-threatening
influenza caused by the mutated forms thereof. Oselta-
mivir phosphate (1·H3PO4, TamifluTM),2 the potent anti-
influenza neuraminidase inhibitor developed by Gilead
Sciences, has been utilized clinically to avert a wide-
spread influenza. However, the current commercial pro-
duction of 1 depends upon a semisynthesis, starting from
less available shikimic acid.3 To circumvent such a supply
problem, it would be crucial to develop new routes to 1 re-
lying upon widely available commodity chemicals. Sever-
al research groups have contributed to develop the
efficient synthetic methods for 1 starting from easily
available chemicals4,5 through their own original proto-
cols, which prompted us to develop a new access to 1.
O
CO2Et
O
CHO
AcHN
AcHN
NH2
NP1P2
A
oseltamivir (1)
O
O
CHO
OH
OH
AcHN
AcHN
2 CHO
2
NP1P2
NP1P2
C
B
O
O
O
HO
OH
CO2Et
As shown by our retrosynthetic analysis (Scheme 1), we
envisioned to construct the densely functionalized cyclo-
hexene framework A by an intramolecular aldol conden-
sation of dialdehyde B with a 3-pentyl ether moiety, an
unprecedented intermediate among the hitherto reported
syntheses of 1.4
E
D
OH OH
HO
OH
O
O
OH OH
D-mannitol
CHO
Compound B could be obtained by the oxidation of diol C
with differently protected vicinal amino groups. Toward
the efficient preparation for C, we envisaged to deliver
two amino groups on alkenediol D through highly dia-
stereoselective dihydroxylation and ensuing diazide for-
mation. We envisioned that 3-pentyl ether moiety in D
could be installed by a cyclic acetal cleavage of ester E
which could be derived from the well-known aldehyde F.
F
P1, P2 = protecting group
Scheme 1 Retrosynthetic analysis of 1
It is particularly worth noting that the 3-pentyl ether moi-
ety could be installed by this reduction in a highly regio-
selective manner without use of a strong Lewis acid.2c
Protection of the crude diols 5a and 5b with 3,4-dihydro-
2H-pyran (DHP) provided di-THP ether 5c,11 which,
without further purification, was followed by asymmetric
dihydroxylation12 with AD-mix-b to furnish diol 6a as a
sole product.13 The crude diol 6a was converted into di-
mesylate 6b (MsCl, pyridine) and subsequent azide for-
mation (NaN3, DMSO) delivered diazide 7a, which pro-
duced diamine 7b through hydride reduction14 (LiAlH4,
THF). To our delight, highly regioselective protection of
the vicinal amino groups of 7b was realized with much
First, we embarked on the preparation of diol 8b
(Scheme 2). Aldehyde 2,6 easily prepared from D-manni-
tol, was transformed into allylic alcohol 37 in 88% yield
by treatment with vinylmagnesium bromide. Upon treat-
ment with triethyl orthoacetate in the presence of a cata-
SYNLETT 2009, No. 5, pp 0783–0786
x
x.
x
x.
2
0
0
9
Advanced online publication: 26.02.2009
DOI: 10.1055/s-0028-1087941; Art ID: U12408ST
© Georg Thieme Verlag Stuttgart · New York

784
T. Mandai, T. Oshitari
LETTER
aldol condensation of 9 was successfully accomplished by
heating with Bn2NH·TFA19 in toluene to provide cyclo-
hexenal 1020 as a white solid. Delightedly, the present re-
action also proceeded cleanly without formation of any
byproducts arising from elimination or aromatization.
Then, NaClO2-mediated oxidation4c,21 of 10 provided car-
boxylic acid 1122 in 86% yield. The transformation of 11
into 1 through esterification followed by deprotection re-
quired little ingenuity for a noncolumn chromatographic
process. For the solution, 11 was reduced with NaBH4 in
wet i-PrOH23 to amide 12a24 in 93% yield, which was es-
terified with a combination of EtI and K2CO3 as a base in
DMSO, affording ethyl ester 12b25 in 85% yield. Finally,
12b was treated with HCl–EtOH at room temperature for
24 hours followed by back extraction with 5% aqueous
Na2CO3, giving oseltamivir (1)26 in 83% yield.
O
O
a
b
O
O
D-mannitol
CHO
OH
2
3
O
c
d
O
O
CO2Et
RO
OH
OH
2
2
4
5a: R = H
5c: R = THP
OH
e
O
2
5b
O
O
Y
OTHP
OTHP
f
h
OTHP
OTHP
RO
g
O
CHO
2
2
O
CHO
a
b
c
OR
Y
8b
6a: R = H
7a: Y = N3
AcHN
CHO
i
AcHN
2
7b: Y = NH2
6b: R = Ms
NPhth
NPhth
10
9
O
OR
j
OR
AcHN
2
O
CO2R
OH
O
CO2H
NPhth
8a: R = THP
8b: R = H
f
d
1
k
AcHN
AcHN
NH
Scheme 2 Reagents and conditions: (a) ref. 6, 61%; (b) vinylmag-
nesium bromide (1.2 equiv), THF, 0 °C, 1 h, 88%; (c) MeC(OEt)3 (5.0
equiv), 2% EtCO2H, 132 °C, 14 h, 95%; (d) DIBAL-H (5.0 equiv), to-
luene, 0 °C, 2 h, r.t., 3 h; (e) DHP (1.2 equiv), PPTS (2 mol%),
CH2Cl2, r.t., 24 h; (f) MsNH2 (1.0 equiv), AD-mix-b (1.4 g/mmol), t-
BuOH–H2O, 0 °C, 8 h, r.t., 13 h; (g) MsCl (1.2 equiv), pyridine, 0 °C,
2 h, r.t., 8 h; (h) NaN3 (4 mol equiv), DMSO, 80 °C, 48 h; (i) LiAlH4
(1.1 equiv), THF, r.t., overnight; (j) Et3N, DMAP, PhthNCO2Et (0.9
equiv each), THF, 0 °C, 1.5 h, then Ac2O–pyridine (2.0 equiv each),
r.t., 14 h; (k) MeOH, CSA (10 mol%), r.t., 1 h, then recrystallization
from toluene, 32% from 4.
NPhth
O
11
12a: R = H
12b: R = Et
e
Scheme 3 Reagents and conditions: (a) TEMPO (10 mol%), KBr
(20 mol%), aq NaOCl, NaHCO3 (2.4 mol equiv each), CH2Cl2–H2O
(2:1), 5 °C, 15 min; (b) Bn2NH·TFA (1.1 equiv), toluene, 50 °C, 11 h,
82% for 2 steps; (c) NaClO2–NaH2PO4 (3.0 equiv each), 2-methylbut-
2-ene (10 equiv), t-BuOH–THF–H2O (4:1:1), 0 °C, 1 h, r.t., over-
night, 86%; (d) NaBH4 (5.0 mol equiv), i-PrOH–H2O (6:1), r.t., over-
night, 93%; (e) K2CO3 (1.1 equiv), EtOH–H2O (5:1), r.t., 0.5 h;
removal of the solvent; then EtI (5.0 equiv), DMSO, r.t., 40 h, 85%;
(f) 4 M HCl in 1,4-dioxane (5.0 equiv), EtOH, r.t., 24 h, then back
extraction with 5% aq Na2CO3, 83%.
success by the following one-pot procedure. That is, a so-
lution of crude 7b in THF was reacted with N-ethoxy-
carbonylphthalimide (PhthNCO2Et)15 in the presence of
Et3N and DMAP.
After the monoprotection of the less hindered amino
group had been completed (monitored by TLC), the reac-
tion mixture was treated with Ac2O–pyridine to provide
differently protected diamine 8a. After usual workup,
deprotection of THP groups (MeOH, cat. CSA) furnished
a crude diol 8b as a viscous oil. Fortunately, the pure diol
8b16 precipitated from toluene (32% overall yield from 4).
In summary, we have succeeded in developing a new
method for the synthesis of oseltamivir (1) from D-man-
nitol in 18 steps, which involves intramolecular aldol con-
densation of dialdehyde as the key reaction to construct
cyclohexene ring. Furthermore, it would be of high syn-
thetic value for the reason that no column chromatograph-
ic purification is required throughout the whole process.
We believe this synthetic protocol would contribute to
solve supply problem of 1.
The latter stage of the synthesis is shown in Scheme 3.
Oxidation of diol 8b delivered dialdehyde 917 quantita-
tively with a combination of TEMPO, KBr, and NaOCl.18
It should be noted that 9 was found to be free of a possible
eight-membered lactone and byproducts caused by
Acknowledgment
epimerization or elimination. Next, an intramolecular This work was supported financially in part by the Institute of
Nippon Chemiphar Co., Ltd.
Synlett 2009, No. 5, 783–786 © Thieme Stuttgart · New York

LETTER
Synthesis of Oseltamivir from D-Mannitol
785
7.95 Hz, 1 H), 2.43–2.36 (m, 4 H), 1.68–1.60 (m, 4 H), 1.25
(t, J = 7.0 Hz, 3 H), 0.95–0.88 (m, 6 H). 13C NMR (125
MHz, CDCl3): d = 172.7, 133.3, 128.5, 113.0, 77.3, 69.9,
60.3, 33.5, 29.9, 29.8, 27.4, 14.2, 8.1, 8.0. HRMS (EI+):
m/z calcd for C14H24O4: 256.1675; found: 256.1655.
(10) A solution of ester 4 in toluene was added dropwise to a
solution of DIBAL-H in toluene. As the relevant papers,
see: (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K.
Chem. Lett. 1983, 1593. (b) Mori, A.; Fujiwara, J.;
Maruoka, K.; Yamamoto, H. Tetrahedron Lett. 1983, 24,
4581.
(11) First we prepared a corresponding dibenzyl ether of 5a,
which proved to be cleaved in a later azide-formation step
affording a complex mixture.
(12) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa,
K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992,
57, 2768.
References and Notes
(1) Present address: School of Pharmaceutical Sciences, Teikyo
University, 1091-1 Suarashi, Sagamiko, Sagamihara, 229-
0195, Japan.
(2) (a) Kim, C. U.; Lew, W.; Williams, 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.; Postich, M. J.; Becker, M. W.; Chapman, 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) Federspiel, M.; Fischer, R.; Henning,
M.; Mair, H.-J.; Oberhauser, T.; Rimmler, G.; Albiez, T.;
Bruhin, J.; Estermann, H.; Gandert, C.; Göckel, V.; Götzö,
S.; Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.;
Röckel-Stäbler, O.; Trusssardi, R.; Zwahlen, A. G. Org.
Process Res. Dev. 1999, 3, 266. (d) Karpf, M.; Trussardi, R.
J. Org. Chem. 2001, 66, 2044. (e) Harrington, P. J.; Brown,
J. D.; Foderaro, T.; Hughes, R. C. Org. Process Res. Dev.
2004, 8, 86.
(13) The attempted dihydroxylations with OsO4/NMO and with
AD-mix-a provided a 1:1 to 1:2 mixture of diastereomers
with respect to the 3-pentyloxy group.
(14) Hydrogenolysis (10% Pd/C, EtOAc, r.t., 48 h) of 7a also
provided 7b with poor reproducibility probably owing to
poisoning by the accumulated contaminations.
(3) Farina, V.; Brown, J. D. Angew. Chem. Int. Ed. 2006, 45,
7330.
(4) (a) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc.
2006, 128, 6310. (b) Fukuta, Y.; Mita, T.; Fukuda, N.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
6312. (c) Cong, X.; Yao, Z. J. J. Org. Chem. 2006, 71, 5365.
(d) Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki,
M. Org. Lett. 2007, 9, 259. (e) Yamatsugu, K.; Kamijo, S.;
Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2007,
48, 1403. (f) Bromfield, K. M.; Graden, H.; Hagberg, D. P.;
Olsson, T.; Kann, N. Chem. Commun. 2007, 3183.
(g) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T.
Angew. Chem. Int. Ed. 2007, 46, 5734. (h) Shie, J.-J.; Fang,
J.-M.; Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. E.; Yang,
A.-S.; Hsiao, S.-C.; Su, C.-Y.; Wong, C.-H. J. Am. Chem.
Soc. 2007, 129, 11892. (i) Trost, B. M.; Zhang, T. Angew.
Chem. Int. Ed. 2008, 47, 1. (j) Zutter, U.; Iding, H.; Spurr,
P.; Wirz, B. J. Org. Chem. 2008, 73, 4895. (k) Shie, J.-J.;
Fang, J.-M.; Wong, C.-H. Angew. Chem. Int. Ed. 2008, 47,
5788. (l) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T.
Tetrahedron 2009, in press. (m) Yamatsugu, K.; Yin, L.;
Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew.
Chem. Int. Ed. 2009, 48, 1070. (n) Ishikawa, H.; Suzuki, T.;
Hayashi, Y. Angew. Chem. Int. Ed. 2009, 48, 1304.
(5) for a recent review on the synthesis of oseltamivir (1), see:
Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839; see
also ref. 3.
(6) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.
(7) The optical purity of 3 was determined as follows. The
HPLC analysis [Chiralcel OD; l = 254 nm; eluent: hexane–
EtOH (9:1); flow rate: 1.3 mL/min] of 3,5-dinitrobenzoate of
3 showed the two peaks based on their two diastereomers at
tR = 11.4 min and 22.3 min, respectively. On the other hand,
those of racemic 3, prepared from glycerol via acetalization,
Swern oxidation, and Grignard reaction, showed four peaks
at tR = 11.4 min, 14.5 min, 18.7 min, and 22.2 min,
respectively. This observation surely indicates that 2 and 3
are formed without racemization throughout the sequential
reactions.
(15) Worster, P. M.; Leznoff, C. C.; McArthur, C. R. J. Org.
Chem. 1980, 45, 174.
(16) Compound 8b: [a]D21.5 –19.2 (c 1.07, CHCl3); mp 142.1–
143.5 °C. 1H NMR (500 MHz, CDCl3): d = 7.85–7.70 (m, 4
H), 6.77 (d, J = 9.8 Hz, 1 H), 4.77–4.72 (m, 1 H), 4.60–4.54
(m, 1 H), 3.80–3.60 (m, 5 H), 3.25–3.14 (m, 2 H), 2.28–2.18
(m, 1 H), 1.98 (s, 3 H), 1.95–1.86 (m, 1 H), 1.75 (br s, 1 H),
1.55–1.30 (m, 5 H), 1.11–0.98 (m, 2 H), 0.78–0.72 (m, 6 H).
13C NMR (125 MHz, CDCl3): d = 171.7, 169.2, 134.2, 131.6,
123.3, 79.2, 75.3, 61.8, 60.4, 52.5, 51.1, 29.2, 26.1, 25.5,
25.3, 22.9, 9.39, 9.37. Anal. Calcd for C22H32N2O6: C, 62.84,
H, 7.67, N, 6.66. Found: C, 62.70, H, 7.85, N, 6.65.
(17) Dialdehyde 9 was pure enough to be used for the next step.
However, it was labile to purification on silica gel column
chromatography for combustion analysis, affording a
complex mixture involving cyclized products.
(18) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org.
Chem. 1987, 52, 2559. (b) Anelli, P. L.; Montanari, F.;
Quici, S. Org. Synth. 1990, 69, 212. (c) Leanna, M. R.;
Sowin, T. J.; Morton, H. E. Tetrahedron Lett. 1992, 33,
5029.
(19) (a) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret,
P.; Keck, G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100,
8031. (b) Snyder, S. A.; Corey, E. J. Tetrahedron Lett. 2006,
47, 2083.
(20) Compound 10: obtained as an off-white solid by washing
with hot toluene; [a]D22.5 –46.5 (c 1.10, CHCl3); mp 202.3–
202.7 °C. 1H NMR (500 MHz, CDCl3, data of a mixture of
rotamers): d = 9.55 (s, 0.13 H), 9.53 (s, 0.87 H), 7.86–7.72
(m, 4 H), 6.70 (s, 0.13 H), 6.67 (s, 0.87 H), 5.53 (d, J = 7.6
Hz, 0.87 H), 5.26 (d, J = 7.6 Hz, 0.13 H), 4.95–4.90 (m, 0.87
H), 4.75–4.71 (m, 0.87 H), 4.45–4.38 (m, 1.13 H), 4.20–4.18
(m, 0.13 H), 3.46–3.37 (m, 1 H), 3.05–2.98 (m, 1 H), 2.75–
2.65 (m, 1 H), 2.05 (s, 0.4 H), 1.78 (s, 2.6 H), 1.60–1.50 (m,
4 H), 1.00–0.85 (m, 6 H). 13C NMR (125 Hz, CDCl3, data of
a mixture of rotamers): d = 192.3, 170.3, 168.1, 147.6, 138.8,
134.2, 131.6, 128.5, 123.5, 82.5, 74.6, 54.3, 47.8, 26.3, 25.7,
25.5, 23.3, 9.7, 9.4. Anal. Calcd for C22H26N2O5: C, 66.32;
H, 6.58; N, 7.03. Found: C, 66.15; H, 6.72; N, 7.05. HRMS
(FAB+): m/z calcd for C22H27N2O5 [MH+]: 399.1920; found:
399.1925.
(8) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem.
Soc. 1970, 92, 741.
(9) Compound 4: colorless oil; [a]D21.6 +24.0 (c 1.23, CHCl3); bp
110–112 °C/6.66·10–4 bar. 1H NMR (500 MHz, CDCl3): d =
5.80 (dt, J = 15.3, 6.4 Hz, 1 H), 5.48 (dd, J = 15.3, 7.9 Hz, 1
H), 4.45 (ddd, J = 8.25, 7.95, 6.1 Hz, 1 H), 4.13 (q, J = 7.0
Hz, 2 H), 4.10 (dd, J = 7.95, 6.1 Hz, 1 H), 3.51 (dd, J = 8.25,
(21) Gonzalez-Bello, C.; Coggins, J. R.; Hawkins, A. R.; Abell,
C. J. Chem. Soc., Perkin Trans. 1 1999, 849.
Synlett 2009, No. 5, 783–786 © Thieme Stuttgart · New York

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T. Mandai, T. Oshitari
LETTER
(22) Evaporation of the volatiles and addition of a large excess of
H2O to the residue provided an off-white solid, which was
collected by filtration and washed successively with H2O
and MeOt-Bu.
H2O and MeOt-Bu to give unmingled 12b as a white solid:
[a]D23.0 –48.0 (c 1.11, CHCl3); mp 209.3–210 °C. 1H NMR
(500 MHz, CDCl3): d = 7.43–7.23 (m, 4 H), 6.73 (br s, 1 H),
4.75–4.50 (m, 2 H), 4.25–3.80 (m, 3 H), 3.37–3.33 (m, 1 H),
2.73–2.65 (m, 1 H), 2.33–2.27 (m, 1 H), 1.50–1.35 (m, 4 H),
0.86–0.77 (m, 6 H). 13C NMR (125 Hz, CDCl3): d = 171.5,
169.9, 165.9, 139.8, 137.8, 135.1, 131.2, 130.7, 129.1,
128.1, 127.9, 82.2, 75.7, 64.4, 60.9, 54.3, 48.7, 30.5, 26.2,
25.6, 22.8, 14.1, 9.6, 9.2. Anal. Calcd for C24H34N2O6: C,
Compound 11: obtained as a white solid (mp >280 °C) with
poor solubility in organic solvents such as MeOH or CHCl3:
[a]D25 –58.4 (c 0.54, DMSO). 1H NMR (500 MHz, DMSO-
d6): d = 12.6 (br s, 1 H), 7.92–7.80 (m, 4 H), 6.69 (s, 1 H),
4.38–4.20 (m, 3 H), 3.42–3.10 (m, 2 H), 2.63–2.50 (m, 1 H),
1.50–1.32 (m, 4 H), 0.86 (t, J = 7.3 Hz, 3 H), 0.75 (t, J = 7.3
Hz, 3 H). 13C NMR (125 Hz, DMSO-d6): d = 169.1, 167.6,
167.0, 137.5, 134.3, 129.0, 123.0, 81.0, 74.7, 51.5, 48.9,
26.6, 25.8, 25.1, 22.4, 9.5, 8.9. Anal. Calcd for C22H26N2O6:
C, 63.76; H, 6.32; N, 6.76. Found: C, 63.76; H, 6.45; N, 6.71.
(23) Osby, J. O.; Martin, M. G.; Ganem, B. Tetrahedron Lett.
1984, 25, 2093.
(24) Crude 12a deposited efficiently on dilution of the reaction
mixture with a large excess of diluted HCl. Filtration and
washing with water provided pure 12a as a white solid:
[a]D22.8 –79.2 (c 1.07, CHCl3–MeOH = 4:1); mp 180.4–
180.8 °C. 1H NMR (500 MHz, CD3OD): d = 7.43–7.23 (m,
4 H), 6.73 (br s, 1 H), 4.75–4.50 (m, 2 H), 4.25–3.80 (m, 3
H), 3.37–3.33 (m, 1 H), 2.73–2.65 (m, 1 H), 2.33–2.27 (m, 1
H), 1.50–1.35 (m, 4 H), 0.86–0.77 (m, 6 H). 13C NMR (125
Hz, CD3OD): d = 173.9, 172.0, 169.4, 140.9, 139.1, 136.3,
131.7, 130.7, 129.8, 128.7, 128.6, 83.8, 77.3, 63.5, 55.9,
31.5, 27.3, 26.8, 23.0, 9.9, 9.6. Anal. Calcd for C22H30N2O6:
C, 63.14; H, 7.23; N, 6.69. Found: C, 62.89; H, 7.37; N, 6.73.
(25) Dilution of the reaction mixture with a large excess of water
deposited a white solid, which was washed successively with
64.55; H, 7.67; N, 6.27. Found: C, 64.25; H, 8.03; N, 6.21.
25.0
(26) Oseltamivir (1), obtained as a white semi-solid: [a]D
–
55.8 (c 2.05, CHCl3). 1H NMR (500 MHz, CDCl3): d = 6.79
(br s, 1 H), 5.48 (d, J = 7.6 Hz, 1 H), 4.25–4.18 (m, 3 H),
3.55–3.48 (m, 1 H), 3.38–3.32 (m, 1 H), 3.27–3.20 (m, 1 H),
2.75 (dd, J = 17.9, 5.2 Hz, 1 H), 2.19–2.11 (m, 1 H), 2.04 (s,
3 H), 1.60–1.47 (m, 6 H), 1.29 (t, J = 7.1 Hz, 3 H), 0.95–0.88
(m, 6 H). 13C NMR (125 Hz, CDCl3): d = 170.9, 166.3,
137.5, 129.5, 81.6, 74.8, 60.8, 58.9, 49.2, 33.6, 26.2, 25.7,
23.6, 14.2, 9.5, 9.3. 1H NMR and 13C NMR spectra and
optical rotation value were in full accordance with those of
the authentic sample obtained through a basic extraction (sat.
aq NaHCO3–5% aq Na2CO3–CHCl3) from commercial
Tamiflu: [a]D23.0 –56.1 (c 1.24, CHCl3). 1H NMR (500 MHz,
CDCl3): d = 6.79 (br s, 1 H), 5.79 (d, J = 7.95 Hz, 1 H), 4.26–
4.17 (m, 3 H), 3.57–3.49 (m, 1 H), 3.38–3.32 (m, 1 H), 3.26–
3.18 (m, 1 H), 2.75 (dd, J = 17.9, 4.9 Hz, 1 H), 2.18–2.10 (m,
1 H), 2.04 (s, 3 H), 1.66–1.60 (m, 2 H), 1.56–1.47 (m, 4 H),
1.29 (t, J = 7.0 Hz, 3 H), 0.95–0.87 (m, 6 H). 13C NMR (125
Hz, CDCl3): d = 170.9, 166.3, 137.5, 129.5, 81.6, 74.8, 60.8,
59.0, 49.2, 33.6, 26.2, 25.7, 23.6, 14.2, 9.5, 9.3.
Synlett 2009, No. 5, 783–786 © Thieme Stuttgart · New York

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