Azide-free synthesis of oseltamivir from L-methionine

Article abstract of DOI:10.1055/s-0028-1087940

Highly enantioselective synthesis of oseltamivir has been achieved starting from L-methionine, in which Staudinger reaction is utilized for the alignment of three contiguous chiral centers of oseltamivir. The present method would lead to an alternative sy

Full text of DOI:10.1055/s-0028-1087940

LETTER
787
Azide-Free Synthesis of Oseltamivir from L-Methionine
Synthesisof
Os
e
eltamivir fr
t
om
L
-M
s
e
thionineuta Oshitari,1 Tadakatsu Mandai*
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.
Scheme 1, a cis-b-lactam would be a first-rate candidate
with the same 2S,3R,4S configuration as that of three con-
tiguous stereogenic centers in 3. We envisioned that such
a cis-b-lactam would be constructed in a highly stereose-
Abstract: Highly enantioselective synthesis of oseltamivir has
been achieved starting from L-methionine, in which Staudinger
reaction is utilized for the alignment of three contiguous chiral cen-
ters of oseltamivir. The present method would lead to an alternative
synthesis of oseltamivir that avoids the use of hazardous azide re- lective fashion8 by Staudinger cycloaddition reaction9 be-
agents.
tween a ketene and an imine.
Key words: anti-influenza drugs, tamiflu, Staudinger reaction,
hydroformylations, intramolecular aldol condensation
NPhth
R3O
2S
AcHN
COR1
H
H
R3O
2S
4S
R2
R2
4S
NPhth
3R
NH
3R
The recent emergence of world-shaking avian flu virus
H5N1 has prompted many nations to stock oseltamivir
phosphate (1·H3PO4, TamifluTM),2 the potent anti-influenza
drug developed by Gilead Science. The present commer-
cial production of 1, however, relies heavily on the semi-
synthesis starting from less available shikimic acid, which
would hamper to stock a sufficient amount of Tamiflu.
Given the current supply issue of 1,3 we have launched our
program directed toward the synthesis of 14,5 (Figure 1)
using commodity chemicals as the starting material and
have disclosed a novel synthetic method for 16 starting
from commercially available D-mannitol, which employs
the intramolecular condensation of dialdehyde 3 culmi-
nating in a successful construction of densely functional-
ized cyclohexenal 2 without causing any side reactions
such as epimerization, elimination, or aromatization.
O
3
Staudinger reaction
NP1P2
R3O
H
+
SMe
•
NP3
O
Scheme 1 Retrosynthetic strategy via b-lactam formation and en-
suing ring opening
Thus we commenced with the synthesis of b-lactam 910 as
illustrated in Scheme 2. First, 3-pentanol was alkylated
with bromoacetic acid11 to give 4a followed by treatment
with thionyl chloride to furnish 3-pentyloxyacetyl chlo-
ride (4b, bp 110–118 °C, 20–27 mbar, 94% yield for 2
steps). On the other hand, imine 6b as a partner was syn-
thesized as follows: hydride reduction (DIBAL-H, PhMe)
of ester 5 derived from L-methionine afforded aldehyde
6a (91% yield), which was treated with p-anisidine (0.9
equiv, MgSO4, CH2Cl2) to give crude 6b quantitatively.
Staudinger reaction between a ketene derived from 4b and
imine 6b was performed by the following procedures;
slow addition of 4b (1.5 equiv) in CH2Cl2 to a solution of
freshly prepared 6b (1 equiv) and i-Pr2NEt (4.5 equiv) in
CH2Cl2 led to the desired cis-b-lactam 7a12 (55% yield
based on p-anisidine). The enantiomeric purity of 7a thus
obtained was determined to be >99% ee by HPLC analy-
sis.13
O
CO2Et
AcHN
O
CHO
O
CHO
NH2
oseltamivir (1)
AcHN
AcHN
2CHO
NPhth
NPhth
2
3
Figure 1 Oseltamivir and key intermediates of our previous synthesis
However, our previous process reluctantly used hazard-
ous sodium azide on delivering two amino groups in 3.
Therefore, we have been exploring a safer approach,7 hav-
ing resulted in the development of an alternative access to
3 by taking advantage of a cis-b-lactam. As shown in
Then, oxidation of 7a (NCS, MeCN–EtOH–H2O) and
subsequent thermal desulfinylation of sulfoxide 7b af-
forded 8a14 (81% yield for 2 steps), whose acid-sensitive
Boc group was exchanged for a phthaloyl group to afford
8c15 (86% yield for 2 steps) via allylic amine 8b. Follow-
ing CAN-mediated oxidative cleavage of p-methoxyphe-
nyl group16 occurred smoothly to generate b-lactam 9
(80% yield) with the phthaloyl group intact.
SYNLETT 2009, No. 5, pp 0787–0789
x
x.
x
x.
2
0
0
9
Advanced online publication: 09.03.2009
DOI: 10.1055/s-0028-1087940; Art ID: U12508ST
© Georg Thieme Verlag Stuttgart · New York

788
T. Oshitari, T. Mandai
LETTER
a
O
COX
O
COSEt
NPhth
O
COX
a
b
OH
pentan-3-ol
9
4a: X = OH
4b: X = Cl
b
AcHN
2 CHO
AcHN
NPhth
10
11a: X = SEt
11b: X = H
c
NHBoc
NHBoc
c
e
H
MeO2C
SMe
SMe
Y
5
6a: Y = O
6b: Y = N-(4-MeOC6H4)
O
CHO
d
d
O
CO2Et
e
AcHN
AcHN
OMe
NRR'
NHBoc
H
H
N
H
H
N
NPhth
12
NH2
O
O
Z
g
1
MeO
O
O
OMe
OMe
t-Bu
t-Bu
7a: Z = SMe
8a: R = H, R' = Boc
8b: R, R' = H
f
h
i
7b: Z = S(O)Me
O
O
O
P
O
P
8c: R, R' = Phth
O
O
NPhth
H
H
j
O
BIPHEPHOS
NH
Scheme 3 Reagents and conditions: (a) LiHMDS (2.0 equiv), THF,
–78 °C, 15 min, AcCl (2.0 equiv), –78 °C, 1 h, then EtSH–Et3N (5
equiv each), –78 °C to –20 °C, 3.5 h, 94%; (b) Rh(acac)(CO)2 (5
mol%), BIPHEPHOS (10 mol%), CO/H2 (1:1, 6 atm), THF, 65 °C
(autoclave), 7 h, 88%; (c) 10% Pd/C, Et3SiH (5.0 equiv), CH2Cl2, r.t.,
1.5 h; (d) Bn2NH·TFA (1.1 equiv), toluene, 50 °C, 10 h, 62% for 2
steps; (e) see the preceding paper.6
O
9
Scheme 2 Reagents and conditions: (a) KH (3.3 equiv), bromoace-
tic acid (2.0 equiv), 60 °C, 20 h, quant.; (b) SOCl2 (4.0 equiv), 80 °C,
10 h, 94% for 2 steps; (c) DIBAL-H (2.0 equiv), toluene, –70 °C, 2.5
h, 91%; (d) p-anisidine (0.9 equiv), MgSO4 (10 equiv), CH2Cl2 (ca.
0.3 M), 0 °C to r.t., overnight, quant.; (e) i-Pr2NEt (4.5 equiv), 4b (1.5
equiv), CH2Cl2 (ca. 0.5 M), –15 °C to r.t., 2 h, r.t., overnight, 55%; (f)
NCS (1.1 equiv), MeCN–EtOH–H2O (20:20:1), r.t., 40 min, quant.;
(g) a-pinene–decalins (1:1), NaHCO3 (10 equiv), 155 °C, 6 h, 81%;
(h) TFA–CH2Cl2 (3:5), 0 °C to r.t., 1.5 h; (i) PhthNCO2Et (1.1 equiv),
Et3N (3.0 equiv), THF, 50 °C, 7.5 h, 86% for 2 steps; (j) CAN (3.0
equiv), MeCN–H2O (1:1), 0 °C, 1 h, 80%.
azide-free synthetic route, and (3) highly stereoselective
construction of the three contiguous chiral centers by
means of Staudinger reaction.
Acknowledgment
This work was financially assisted in part from Institute of Nippon
Chemiphar Co., Ltd.
Next, the ring-opening reaction of 9 was carried out in
one-pot operation as shown in Scheme 3; that is, acetyla-
tion of 9 (LHMDS, THF, AcCl, –78 °C) followed by treat-
ment with an excess of EtSH and Et3N (–78 °C to –20 °C)
produced thiol ester 10 (94% yield) successfully. Facile
hydroformylation17 of 10 [Rh(acac)(CO)2, BIPHE-
PHOS,18 6 atm of CO/H2 (1:1), THF] afforded aldehyde
11a (88% yield) with high regioselectivity (linear/
branched >30:1). Transformation of 11a into dialdehyde
11b was effected successfully by Fukuyama’s protocol
(Et3SiH, 10% Pd/C).19 The crude aldehyde 11b underwent
the intramolecular aldol condensation employing
Bn2NH·TFA20 (1.1 equiv, toluene, 50 °C, 10 h, 62% yield
for 2 steps) to yield enal 12, whose spectroscopic data
were in full accord with those of the authentic sample.6,21
Finally, the conversion of 12 to 1 was accomplished un-
eventfully according to our reported procedure.6
References and Notes
(1) Present address: School of Pharmaceutical Sciences, Teikyo
University, 1091-1 Suarashi, Sagamiko, Sagamihara, 229-
0195, Japan.
(2) 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.
(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,
In summary, we have succeeded in developing a new syn-
thetic pathway to oseltamivir (1) in 18 steps from abun-
dant L-methionine. The key features of the present method
are: (1) ready availability of the starting material, (2)
Synlett 2009, No. 5, 787–789 © Thieme Stuttgart · New York

LETTER
J.-M.; Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. E.; Yang, A.-
Synthesis of Oseltamivir from L-Methionine
789
with brine (2 × 30 mL), dried (MgSO4), filtered, and
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.
concentrated in vacuo. The residue was purified by flash
column chromatography (hexane–EtOAc, 1:0 to 20:1 to 10:1
to 6:1) to give olefin 8a as a white solid (1.09 g, 81% from
7a); [a]D26 –93.6 (c 1.03, CHCl3); mp 116.9–117.4 °C. 1H
NMR (500 MHz, CDCl3): d = 7.35 (d, J = 8.8 Hz, 2 H), 6.87
(d, J = 8.8 Hz, 2 H), 5.92 (ddd, J = 7.6, 10.4, 17.0 Hz, 1 H),
5.30 (d, J = 9.5 Hz, 1 H), 5.07 (d, J = 10.4 Hz, 1 H), 5.00 (d,
J = 17.0 Hz, 1 H), 4.94 (m, 1 H), 4.78 (d, J = 5.5 Hz, 1 H),
4.38 (dd, J = 5.1, 5.5 Hz, 1 H), 3.79 (s, 3 H), 3.60 (tt, J = 5.5,
5.5 Hz, 1 H), 1.72 (m, 2 H), 1.62 (m, 2 H), 1.45 (br s, 9 H),
0.95 (t, J = 7.5 Hz, 6 H). 13C NMR (125 MHz, CDCl3): d =
165.2, 156.4, 133.8, 130.7, 118.6, 114.5, 106.3, 84.4, 81.0,
79.7, 57.5, 55.5, 52.3, 28.4, 26.5, 25.5, 9.6, 9.3. For thermal
elimination of a methionine-derived sulfoxide, see:
(a) Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1984, 25,
1071. (b) For our previous protocol of thermal
(6) Mandai, T.; Oshitari, T. Synlett 2009, 783.
(7) For previously reported azide-free syntheses, see: (a)Karpf,
M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044.
(b) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes,
R. C. Org. Process Res. Dev. 2004, 8, 86.
(8) For preparation of cis-b-lactams, see: (a) Palomo, C.;
Cabré, F.; Ontoria, J. M. Tetrahedron Lett. 1992, 33, 4819.
(b) Palomo, C.; Cossío, F. P.; Cuevas, C.; Lecea, B.; Mielgo,
A.; Román, P.; Luque, A.; Martinez-Ripoll, M. J. Am. Chem.
Soc. 1992, 114, 9360.
(9) For reviews of Staudinger reaction, see: (a) Palomo, C.;
Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem.
1999, 3223. (b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.;
Oiarbide, M. Curr. Med. Chem. 2004, 11, 1837.
(10) For reviews of b-lactams as chiral synthetic building blocks,
see: (a) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004,
11, 1921. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Chem. Rev. 2007, 107, 4437.
desulfinylation, see also: Mandai, T.; Matsumoto, S.;
Kohama, M.; Kawada, M.; Tsuji, J.; Saito, S.; Moriwake, T.
J. Org. Chem. 1990, 55, 5671.
(15) Compound 8c: white solid; [a]D25 –14.4 (c 0.86 CHCl3); mp
111.6–111.8 °C. 1H NMR (500 MHz, CDCl3): d = 7.60–7.55
(br s, 4 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.39 (d, J = 8.8 Hz, 2
H), 6.20 (ddd, J = 6.1, 10.0, 17.0 Hz, 1 H), 5.33–5.26 (m, 3
H), 5.03 (dd, J = 5.2, 10.3 Hz, 1 H), 4.89 (d, J = 5.2 Hz, 1 H),
3.65 (tt, J = 5.5, 5.5 Hz, 1 H), 3.45 (s, 3 H), 1.72 (m, 2 H),
1.61 (m, 2 H), 1.02 (t, J = 7.5 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3
H). 13C NMR (125 MHz, CDCl3): d = 167.8, 166.0, 156.9,
134.2, 133.5, 131.7, 131.4, 128.1, 123.5, 122.8, 122.7,
119.0, 118.5, 114.5, 113.8, 83.3, 80.3, 57.3, 55.1, 53.0, 26.2,
25.3, 9.4, 9.2. Anal. Calcd for C26H28N2O5: C, 69.63, H,
6.29, N, 6.25. Found: C, 69.25; H, 6.10; N, 6.29.
(11) Wallace, G. A.; Scott, R. W.; Heathcock, C. H. J. Org.
Chem. 2000, 65, 4145.
(12) The desired cis-b-lactam 7a was easily purified by
trituration in cold MeOH to remove byproducts such as
minor stereoisomers (ca. 5%) and N-(4-methoxyphenyl)-
(3-pentyloxy)acetamide.
(16) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem.
1982, 47, 2765.
(17) Cuny, G. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115,
2066.
(18) 6,6¢-{[3,3¢-bis(1,1-dimethylethyl)-5,5¢-dimethoxy[1,1¢-
biphenyl]-2,2¢-diyl]bis(oxy)}bis{dibenzo[d,f][1,3,2]dioxa-
phosphepine}: (a) Billig, E.; Abatjoglou, A. G.; Bryant,
D. R. US 4668651, 1987. (b) Billig, E.; Abatjoglou, A. G.;
Bryant, D. R. US 4769498, 1988; for preparation of
BIPHEPHOS, see Supporting Information of ref. 17.
(19) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am.Chem. Soc. 1990,
112, 7050.
(20) (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.
Compound 7a: a white solid; [a]D22 –119 (c 0.99 CHCl3); mp
161.6–162.6 °C. 1H NMR (500 MHz, CDCl3): d = 7.39 (br
d, J = 8.9 Hz, 2 H), 6.87 (br d, J = 8.9 Hz, 2 H), 5.09 (br d,
J = 10.1 Hz, 1 H), 4.78 (d, J = 5.5 Hz, 1 H), 4.56 (m, 1 H),
4.40 (dd, J = 5.5, 5.8 Hz, 1 H), 3.79 (s, 3 H), 3.61 (tt, J = 5.8,
5.8 Hz, 1 H), 2.55 (ddd, J = 4.6, 8.6, 13.1 Hz, 1 H), 2.38
(ddd, J = 7.9, 8.3, 13.1 Hz, 1 H), 1.93 (m, 1 H), 1.87 (s, 3 H),
1.80 (m, 1 H), 1.72 (m, 2 H), 1.62 (m, 2 H), 1.51–1.43 (two
br s, 9 H), 1.94 (m, 6 H). 13C NMR (125 MHz, CDCl3): d =
165.3, 156.6, 155.7, 130.6, 118.4, 114.6, 84.5, 81.1, 79.6,
57.3, 55.5, 48.7, 30.9, 28.8, 28.4, 26.6, 25.5, 15.2, 9.6, 9.4.
Anal. Calcd for C24H38N2O5S: C, 61.77; H, 8.21; N, 6.00.
Found: C, 61.87; H, 8.31; N, 6.16.
(21) Compound 12: off-white solid; [a]D23.4 –44.0 (c 1.05,
CHCl3); mp 198–199.1 °C. 1H NMR (500 MHz, CDCl3, data
of a mixture of rotamers): d = 9.56 (s, 0.15 H), 9.54 (s, 0.85
H), 7.86–7.72 (m, 4 H), 6.68 (s, 0.15 H), 6.67 (s, 0.85 H),
5.58 (d, J = 7.6 Hz, 0.85 H), 5.26 (d, J = 7.6 Hz, 0.15 H),
4.95–4.87 (m, 0.85 H), 4.75–4.71 (m, 0.85 H), 4.50–4.32 (m,
1.15 H), 4.15–4.10 (m, 0.15 H), 3.46–3.33 (m, 1 H), 3.10–
2.97 (m, 1 H), 2.76–2.65 (m, 1 H), 2.05 (s, 0.45 H), 1.78 (s,
2.55 H), 1.60–1.50 (m, 4 H), 1.00–0.85 (m, 6 H). 13C NMR
(125 MHz, CDCl3, data of a mixture of rotamers): d = 192.2,
170.3, 168.1, 147.5, 138.8, 134.2, 131.6, 123.4, 82.4, 74.6,
54.3, 47.8, 26.3, 25.7, 25.5, 23.3, 9.6, 9.3. Anal. Calcd for
C22H26N2O5: C, 66.32, H, 6.58, N, 7.03. Found: C, 66.06; H,
6.72; N, 6.98.
(13) Daicel CHIRALCEL OD-RH; eluent: MeCN–H2O (10:1);
l = 254 nm; flow rate: 0.3 mL/min; tR(7a) = 7.8 min; tR (ent-
7a) = 9.9 min.
(14) A mixture of 7b (1.55 g, ca. 3.22 mmol), NaHCO3 (2.70 g,
32.2 mmol), a-pinene (10 mL), and decalins (10 mL) was
placed into a 100 mL round-bottomed flask fitted with a
reflux condenser. The reaction mixture was deoxygenated
by alternate evacuation–argon flush cycles (five iterations)
and heated with vigorous stirring at 150–155 °C for 6 h
under argon atmosphere. After being cooled to r.t., the
reaction mixture was partitioned between H2O (30 mL) and
EtOAc (30 mL). The organic layer separated was washed
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