An approach to amino ester subunits of tamiflu

Article abstract of DOI:10.1055/s-2007-983710

A two-step synthesis of amino cyclohexene carboxylic acid esters has been achieved in good overall yield from nitro phosphonate and unsaturated aldehydes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983710

SHORT PAPER
1765
An Approach to Amino Ester Subunits of Tamiflu
An
A
pproach to A
e
mino Ester
oSubunits of
Tamiflu ge A. Kraus,* Tinopiwa Goronga
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Fax +515(294)0105; E-mail: gakraus@iastate.edu
Received 30 March 2007
CO2Et
1. (CH2O)n, piperidine
CO2Et
O
Abstract: A two-step synthesis of amino cyclohexene carboxylic
acid esters has been achieved in good overall yield from nitro phos-
phonate and unsaturated aldehydes.
O
EtO
EtO
P
NO2
2. PTSA
3. MeNO2, MeONa
P
EtO
EtO
3
Key words: Tamiflu, Michael addition, ring closure
54% overall
Scheme 2
The emergence of virulent strains of avian influenza,
combined with the concern that one of these strains could
evolve and trigger a human health emergency, has
prompted considerable research into new antiviral
agents.1 Antiviral agents typically used to manage influ-
enza, such as the M2 ion channel blockers amantidine and
rimantadine, inhibit viral replication. Unfortunately,
drug-resistant variants have developed rapidly.2 Tamiflu
(1) is a neuraminidase inhibitor and prevents the release of
the virus from cells.3 Tamiflu treatment must be started
within two days of the onset of flu symptoms. Recently,
two routes to Tamiflu have been reported.4
and Michael addition of nitromethane, afforded nitro
phosphonate 3 in 54% overall yield.
Initially, we studied the reaction of the dianion of 3, gen-
erated using two equivalents of potassium tert-butoxide in
tetrahydrofuran, with crotonaldehyde. These conditions
led to destruction of the aldehyde. The use of one equiva-
lent of sodium methoxide produced a low yield of product
derived from Michael addition of the nitroalkane moiety
to the unsaturated aldehyde. Fortunately, with two equiv-
alents of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
dichloromethane from ambient temperature to reflux, ni-
tro ester 2 was produced in 74% isolated yield. Interest-
ingly, if the reaction was quenched before completion, the
hydroxyphosphonate ester 5 was co-produced with 2
(Scheme 3). Intermediates such as 5 are rarely isolated.7
CO2Et
CO2Et
O
R1
+
EtO
P
CHO
NO2
R2
NX2
EtO
3
4
R1
In order to understand the scope and limitations of this an-
nulation, we reacted nitro phosphonate 3 with a number of
unsaturated aldehydes and ketones. The results of this
study are summarized in Table 1.
1: R1 = NHAc, R2 = OCHEt2, X = H
2: R1 = Me, R2 = H, X = O
Scheme 1
Compounds 2, 6, 7, 8 and 9 were formed as predominantly
single diastereomers (80–85%). Proton NMR data sup-
ported a trans-diequatorial relationship between the nitro
group and R1. In the case of compound 2, the NMR mul-
tiplet (d = 4.41 ppm), corresponding to the methine proton
alpha to the nitro group, was a doublet of triplets with cou-
pling constants of J = 5.6 and 10 Hz. In the case of bicyclic
As part of a program to develop useful antiviral agents,5
we devised a [3+3] ring-forming strategy using the phos-
phonate 3 and an unsaturated aldehyde 4 (Scheme 1).
Phosphonate 3 was prepared in three steps as shown in
Scheme 2. Base-catalyzed hydroxymethylation followed
by p-toluenesulfonic acid (PTSA)-mediated dehydration6
CO2Et
O
CO2Et
O
OEt
OEt
OEt
HO
O
DBU
P
P
+
Me
OEt
3
2
CHO
NO2
NO2
Me
Me
5
Scheme 3
SYNTHESIS 2007, No. 12, pp 1765–1767
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.06.2007
DOI: 10.1055/s-2007-983710; Art ID: M02207SS
© Georg Thieme Verlag Stuttgart · New York

1766
G. A. Kraus, T. Goronga
SHORT PAPER
THF was distilled from sodium benzophenone ketyl. CH2Cl2, tolu-
ene and HMPA were distilled over CaH2. All experiments were
performed under argon atmosphere. Organic extracts were dried
over anhydrous Na2SO4. IR spectra were obtained on a Perkin-
Elmer model 1320 spectrophotometer. NMR experiments were
performed with either a Varian 300 MHz or a Bruker 400 MHz in-
strument. HRMS were recorded on a Kratos model MS-50 spec-
trometer and LRMS were performed with a Finnegan 4023 mass
spectrometer. Standard grade silica gel (60 Å) was used for flash
column chromatography.
Table 1 Reaction of 3 with Aldehydes and Ketones
CO2Et
R2
R3
R2
R1
DBU
3
+
O
R3
NO2
R1
R1
R2
R3
Temp
(°C)
Yielda Product
(%)
Me
Ph
Ph
H
H
H
H
H
H
40
74
59
26
60
64
45
36
2
6
Synthesis of Phosphonate 3
To a solution of MeONa (1.2 M, 17.6 mL, 21.2 mmol) at 0 °C under
argon, was added a solution of nitromethane (2.6 g, 42.6 mmol) in
MeOH (3 mL). The reaction mixture was stirred for 1 h and allowed
to warm to r.t. After cooling to 0 °C for 10 min, a solution of ethyl
diethylphosphonoacetate (5 g, 21.2 mmol) in MeOH (5 mL) was
added to the reaction flask dropwise. The reaction mixture was
slowly warmed to r.t. and stirred for 3–4 h. The reaction mixture
was filtered to remove the precipitate that formed during the course
of the reaction, neutralized to pH 7 with AcOH and evaporated. A
brown solid was obtained which was dissolved in EtOAc (25 mL).
The resulting mixture was filtered, and the filtrate was evaporated
to give a brown oil. Column chromatography on silica gel (EtOAc–
hexanes, 50%) gave pure 3.
H
40
Me
H
80b
25
7
2-furyl
C7H16
8
H
40
9
–CH2CH2CH2–
H
40
10
11
–CH2SCH2–
H
25
a Isolated yield.
b Reaction performed in MeCN.
Yield: 3.4 g (54%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.13–1.23 (9 H, m), 2.36–2.50
(2 H, m), 2.90–3.08 (1 H, m), 3.97–4.11 (6 H, m), 4.30–4.50 (2 H,
m).
13C NMR (100 MHz, CDCl3): d = 14.1, 16.4, 41.5, 42.8, 62.1, 63.2,
73.0, 167.9.
products 10 and 11, the nitro group appears to be on the
exo-face of the fused bicyclic ring system. In nitro ester 11
the ratio of exo- to endo-nitro group was 4:1.
We could not find any literature precedent for the selec-
tive reduction of an aliphatic nitro group in the presence
of an unsaturated ester. The most promising reducing
agents appeared to be Raney nickel or tin and hydrochlo-
ric acid.8 However, the latter reductive system also re-
duced a,b-unsaturated ketones to saturated ketones.9
Fortunately, when the reduction was carried out in etha-
nol, amino esters 12, 13 and 14 from nitro esters 2, 10 and
6 were cleanly provided in 67%, 86% and 72% yields, re-
spectively (Figure 1).
HRMS: m/z calcd for C10H20NO7P: 297.0977; found: 297.0982.
Synthesis of Nitro Esters; General Procedure
To a solution of unsaturated aldehyde (0.34 mmol) in CH2Cl2 (1
mL) was added DBU (0.64 mmol). The reaction mixture was cooled
to 0 °C and, after 10 min, a solution of 3 (0.34 mmol) in CH2Cl2 (1
mL) was added dropwise to the reaction mixture, which was then al-
lowed to warm to r.t. over 2 h. The reaction mixture was then heated
as indicated in Table 1. After cooling to r.t., HCl (2 M, 1 mL) was
added and the organic layer was taken and again washed with HCl
(2 M, 5 mL) and brine (2 × 10 mL), dried (Mg2SO4) and evaporated
to give an oil. Column chromatography on silica gel yielded pure
product. For the ketone example leading to product 7, the solvent
was MeCN.
CO2Et
CO2Et
CO2Et
H
NH2
NH2
NH2
2
H
1H NMR (300 MHz, CDCl3): d = 1.04 (3 H, d, J = 6.3 Hz), 1.27
(3 H, t, J = 6.9 Hz), 1.60–2.10 (1 H, m), 2.28–2.42 (1 H, m), 2.48–
2.60 (1 H, m), 2.85–2.92 (1 H, m), 2.94–3.24 (1 H, m), 4.17 (2 H, q,
J = 7.2 Hz), 4.35–4.45 (1 H, dt, J = 5.6, 10 Hz), 6.90 (1 H, br s).
H
Me
12
13
14
13C NMR (75 MHz, CDCl3): d = 15.3, 17.8, 29.1, 32.6, 61.1, 88.2,
127.1, 137.6, 166.0.
Figure 1
HRMS: m/z calcd for C10H15NO4: 213.1001; found: 213.1005.
The development of a two-step synthesis of amino esters
from nitro phosphonate 3 constitutes a flexible synthetic
6
pathway to these little-studied compounds. With suitably 1H NMR (300 MHz, CDCl3): d = 1.26 (3 H, t, J = 7.2 Hz), 2.47–
2.60 (1 H, m), 2.68–2.82 (1 H, m), 2.94–3.02 (1 H, m), 3.08–3.18
(1 H, m), 3.38–3.49 (1 H, m), 4.21 (2 H, q, J = 7.2 Hz), 4.90–5.00
(1 H, m), 7.05–7.09 (1 H, m), 7.21–7.33 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 14.5, 30.0, 33.2, 43.5, 61.2, 87.0,
127.3, 127.5, 128.2, 129.2, 137.8, 139.3, 165.8.
modified unsaturated aldehydes, this chemistry is expect-
ed to readily provide promising new candidates for viral
assays.
HRMS: m/z calcd for C15H17NO4: 275.1158; found: 275.1161.
Synthesis 2007, No. 12, 1765–1767 © Thieme Stuttgart · New York

SHORT PAPER
An Approach to Amino Ester Subunits of Tamiflu
1767
7
(1 H, m), 2.22–2.48 (2 H, m), 2.57–2.70 (2 H, m), 4.14 (2 H, q,
J = 7.2 Hz), 6.88 (1 H, br s).
13C NMR (100 MHz, CDCl3): d = 14.5, 18.2, 33.4, 33.5, 35.1, 52.3,
60.6, 129.0, 138.3, 167.3.
1H NMR (400 MHz, CDCl3): d = 1.29 (3 H, t, J = 7.2 Hz), 2.11
(3 H, s), 2.50–2.65 (2 H, m), 2.92–3.02 (1 H, m), 3.10–3.2 (1 H, m),
3.40–3.48 (1 H, m), 4.20 (2 H, q, J = 7.2 Hz), 4.88–4.96 (1 H, m),
7.20–7.33 (5 H, m).
HRMS: m/z calcd for C10H17NO2: 183.1259; found: 183.1262.
13C NMR (75 MHz, CDCl3): d = 14.5, 21.4, 32.1, 41.4, 44.0, 60.8,
87.0, 120.6, 127.4, 128.1, 129.2, 139.3, 146.3, 166.9.
13
HRMS: m/z calcd for C16H19NO4: 289.1314; found: 289.1317.
1H NMR (400 MHz, CDCl3): d = 1.27 (3 H, t, J = 6.9 Hz), 1.33–
1.38 (1 H, m), 1.38–1.44 (1 H, m), 1.50–1.62 (1 H, m), 1.73–1.83
(2 H, m), 1.88–2.02 (2 H, m), 2.03–2.17 (2 H, m), 2.80–2.84 (1 H,
br s), 2.84–2.89 (1 H, br s), 2.94–3.03 (1 H, m), 3.04–3.14 (1 H, m),
4.16 (2 H, q, J = 7.2 Hz), 7.05 (1 H, br s).
8
1H NMR (400 MHz, CDCl3): d = 1.30 (3 H, t, J = 6.9 Hz), 2.68–
2.74 (2 H, m), 2.98–3.20 (2 H, m), 3.62–3.70 (1 H, m), 4.21 (2 H, q,
J = 7.2 Hz), 4.90–4.98 (1 H, m), 6.15 (1 H, d, J = 3.2 Hz), 6.29–
6.35 (1 H, m), 7.02–7.06 (1 H, m), 7.35–7.36 (1 H, m).
13C NMR (100 MHz, CDCl3): d = 14.5, 22.5, 27.2, 28.3, 31.3, 45.4,
46.0, 52.4, 60.7, 130.1, 141.2, 167.3.
13C NMR (100 MHz, CDCl3): d = 14.5, 28.9, 29.4, 36.6, 61.2, 84.9,
107.6, 110.6, 126.9, 136.8, 142.7, 152.0, 165.7.
HRMS: m/z calcd for C12H19NO2: 209.1416; found: 209.1419.
HRMS: m/z calcd for C13H15NO5: 265.0956; found: 265.0961.
14
1H NMR (400 MHz, CDCl3): d = 1.27 (3 H, t, J = 7.2 Hz), 2.17–
2.28 (1 H, m), 2.32–2.48 (2 H, m), 2.52–2.62 (1 H, m), 2.63–2.72
(1 H, m), 2.82 (1 H, br s), 2.86 (1 H, br s), 3.18–3.26 (1 H, m), 4.17
(2 H, q, J = 7.2 Hz), 7.00 (1 H, br s), 7.21–7.27 (3 H, m), 7.29–7.35
(2 H, m).
9
1H NMR (400 MHz, CDCl3): d = 0.86 (3 H, t, J = 7.2 Hz), 1.27–
1.33 (14 H, m), 1.38–1.44 (1 H, m), 1.96–2.10 (1 H, m), 2.20–2.34
(1 H, m), 2.50–2.62 (1 H, m), 2.89–2.93 (2 H, m), 4.19 (2 H, q,
J = 7.2 Hz), 4.47–4.6 (1 H, m), 6.93–6.98 (1 H, m).
13C NMR (100 MHz, CDCl3): d = 14.5, 33.0, 34.3, 47.6, 51.4, 60.8,
127.3, 127.9, 128.1, 129.2, 138.5, 142.4, 167.0.
13C NMR (100 MHz, CDCl3): d = 14.3, 14.5, 22.8, 26.3, 28.7, 29.3,
29.6, 29.7, 32.0, 36.2, 61.1, 86.8, 126.9, 137.5, 166.0.
HRMS: m/z calcd for C15H19NO2: 245.1416; found: 245.1420.
HRMS: m/z calcd for C16H27NO4: 297.1940; found: 297.1944.
Acknowledgment
10
1H NMR (400 MHz, CDCl3): d = 1.28 (3 H, t, J = 6.9 Hz), 1.38–
1.48 (2 H, m), 1.80–1.90 (3 H, m), 1.98–2.10 (2 H, m), 2.16–2.28
(1 H, m), 2.88–2.94 (1 H, m), 3.08–3.16 (1 H, m), 4.18 (2 H, q,
J = 7.2 Hz), 4.60–4.68 (1 H, m), 7.07–7.09 (1 H, m).
We thank the Iowa State University Research Foundation and the
Department of Chemistry for partial support of this research.
13C NMR (100 MHz, CDCl3): d = 14.5, 22.2, 27.0, 28.4, 31.5, 44.6,
46.7, 61.1, 86.8, 128.5, 140.6, 166.1.
References
(1) De Clercq, E. Curr. Opin. Microbiol. 2005, 8, 552.
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Novelli, P.; Lambkin, R. Clin. Microbiol. Infect. 2003, 9, 1.
(3) (a) Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.;
Trussardi, R.; Wirz, B.; Zutter, U. Chimia 2004, 58, 621.
(b) Ward, P.; Small, I.; Smith, J.; Suter, P.; Dutkowski, R. J.
Antimicrob. Chemother. 2005, 55 (Suppl. 1), i5.
(4) (a) For the Corey route, see: Yeung, Y.-Y.; Hong, S.; Corey,
E. J. J. Am. Chem. Soc. 2006, 128, 6310. For the Shibasaki
route, see: (b) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312.
(c) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.;
Shibasaki, M. Tetrahedron Lett. 2007, 48, 1403. (d) Mita,
T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M.
Organic Lett. 2007, 9, 259.
(5) Krishnamoorthy, G.; Webb, S.; Nguyen, T.; Chowdhury, P.
K.; Halder, M.; Wills, N. J.; Carpenter, S.; Kraus, G. A.;
Gordon, M. S.; Petrich, J. W. Photochem. Photobiol., A
2005, 81, 924.
(6) Martyres, D. H.; Baldwin, J. E.; Adlington, R. M.; Lee, V.;
Probert, M. R.; Watkin, D. J. Tetrahedron 2001, 57, 4999.
(7) Kleschick, W.; Heathcock, C. H. J. Org. Chem. 1978, 43,
1256.
HRMS: m/z calcd for C12H17NO4: 239.1158; found: 239.1160.
11
1H NMR (300 MHz, CDCl3): d = 1.29 (3 H, t, J = 7.2 Hz), 2.36–
2.48 (1 H, m), 2.70–2.82 (2 H, m), 2.98–3.02 (2 H, m), 3.12–3.25
(3 H, m), 4.21 (2 H, q, J = 7.2 Hz), 4.66–4.78 (1 H, m), 7.00 (1 H,
br s).
13C NMR (100 MHz, CDCl3): d = 14.5, 31.4, 32.2, 33.3, 46.9, 48.1,
61.5, 86.1, 129.2, 137.4, 165.6.
HRMS: m/z calcd for C11H15NO4S: 257.0756; found: 257.0722.
Reduction of Nitro Esters; General Procedure
To a solution of the nitro ester (1 equiv) in EtOH (2 mL) was added
tin shot (5.3 equiv). The reaction was heated to 70 °C and HCl (12
M, 54 equiv) was added. The reaction was boiled for 20 min and
cooled to r.t. The solution was made weakly basic (pH 8) with
NaOH (2 M) and the aqueous layer was extracted with EtOAc (2 ×
25 mL). The combined organic layers were washed once with brine
(25 mL), dried (Mg2SO4) and evaporated to give a yellow oil. Flash
silica gel column chromatography yielded the pure product.
12
(8) Kahnberg, P.; Lager, E.; Rosenberg, C.; Schougaard, J.;
Camet, L.; Sterner, O.; Nielsen, E. O.; Nielsen, M.; Liljefors,
T. J. Med. Chem. 2002, 45, 4188.
1H NMR (300 MHz, CDCl3): d = 1.01 (3 H, d, J = 7 Hz), 1.26 (3 H,
t, J = 6.9 Hz), 1.46–1.57 (1 H, m), 1.82–1.98 (2 H, m), 1.99–2.08
(9) Schaefer, J. P. J. Org. Chem. 1960, 2027.
Synthesis 2007, No. 12, 1765–1767 © Thieme Stuttgart · New York