An efficient and tunable route to AG7088, a rhinovirus protease inhibitor

Article abstract of DOI:10.1016/j.tetlet.2004.08.179

Aldol reaction of N,N-dibenzyl valinal with propiolic acid ethyl ester derived lithium reagent provides anti-aminoalcohol 8 and syn-aminoalcohol 9, which are converted into the lactone 6 via two different routes. Alkylation of 6 followed by lactone ring o

Full text of DOI:10.1016/j.tetlet.2004.08.179

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8103–8105
An efficient and tunable route to AG7088, a rhinovirus
protease inhibitor
Dawei Ma,a,* Weiqing Xie,a Bin Zou,a Qiong Leia and Duanqing Peib
aState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354Fenglin Lu, Shanghai 200032, China
bDepartment of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
Received 16 June 2004;revised 18 August 2004;accepted 24 August 2004
Available online 21 September 2004
Abstract—Aldol reaction of N,N-dibenzyl valinal with propiolic acid ethyl ester derived lithium reagent provides anti-aminoalcohol
8 and syn-aminoalcohol 9, which are converted into the lactone 6 via two different routes. Alkylation of 6 followed by lactone ring
opening afford the acid 2a, which is coupled with the amine 3 and 5-methylisoxazole-3-carboxylate acid 1, respectively, to deliver
AG7088.
Ó 2004 Elsevier Ltd. All rights reserved.
H
N
AG7088 is a potent 3C protease inhibitor with an EC90
of less than 0.1lM against 48 different serotypes of
human rhinovirus (HRV).1,2 This compound was dis-
covered by Agouron researchers and is currently in hu-
man clinical trials to treat the common cold.1,2 This
inhibitor was received more attention recently because
it was proposed as a promising inhibitor to viral main
proteinase (Mpro, also called 3Clpro), a key enzyme for
controlling the activities of the coronvirus replication
complex.3 Since the coronvirus is the causative agent
of severe acute respiratory syndrome (SARS), develop-
ment of potent inhibitors for this enzyme would be of
benefit for SARS therapy.
O
O
O
P2
OEt
N
H
N
H
N
O
O
O
F
AG7088
H
N
OH
O
O
O
P2
BocHN
OR
+
+
N
O
O
OEt
H N
2
By computer modeling, Hilgenfeld and co-workers indi-
cated that the p-fluorobenzyl side chain at the P2 posi-
tion of AG7088 might be too big for fitting into the
S2 pocket of coronvirus Mpro and those AG7088 ana-
logues with smaller groups at this site might have more
favored interaction with this enzyme thereby serving as
more potent inhibitors.3 In order to prove this hypothe-
sis, as well as to discover potent coronvirus Mpro inhibi-
tors based on this hypothesis, we initiated a program to
synthesize AG7088 analogues.
F
O
1
2
3
F
O
O
CO H
2
NHBoc
NH
2
4
Agouron route
O
O
O
As the retrosynthetic analysis outlined in Figure 1,
AG7088 was prepared initially by Agouron researchers
N
Me
NHBoc
alkylation
alkylation
5
6
*
Corresponding author. Tel.: +86 21 6416 3300;fax: +86 21 6416
6128;e-mail: madw@pub.sioc.ac.cn
Figure 1. Structure of AG7088 and its retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.179

8104
D. Ma et al. / Tetrahedron Letters 45 (2004) 8103–8105
by coupling the ketomethylene dipeptide isostere 2 with
5-methylisoxazole-3-carboxylate acid 1 at its left hand
and 3 at its right hand.1 The ketoester 2 was obtained
through a lactone 4 using diastereoselective alkylation
of (ꢀ)-pseudoephedrine-derived amide 5 with p-fluoro-
benzyl bromide and subsequent lactonization promoted
by NBS as the key steps.4 Obviously, this protocol is not
so efficient for quickly assembling AG7088 analogues
with different side chains at the P2 site because installa-
tion of this side chain was set up at the early stage. This
drawback, together with the requirement of (ꢀ)-pseudo-
ephedrine as the chiral auxiliary, promoted us to de-
velop a new route to the lactone 4 by direct alkylation
of lactone 6. This lactone could be prepared using L-
valine as the starting material.
After hydrogenation of the syn-aminoalcohol 9 cata-
lyzed by Pd(OH)2/C along with in situ protection with
di-tert-butyl dicarbonate, alcohol 12 was obtained.
Treatment of 12 with acetic acid in toluene delivered
the lactone 67 in 89% yield. In order to convert the
anti-aminoalcohol 8 to 6, its C4 stereochemistry should
be reversed. Accordingly, hydrogenolysis of 8 followed
by in situ protection produced alcohol 10, which was
transformed into its mesylate 11 with mesyl chloride.
It was expected to obtain the lactone 6 by simple lactoni-
zation of 11 through an intramolecular SN2 reaction.
However, we found that a mixture of 6 and its 5-epimer
13 were isolated under various conditions such as expo-
sure of 11 to NaOH in ethanol or DMF. The ratio of 6
and 13 was about 2:1–1:1, which implied that SN1 reac-
tion might also take place. Thus, we had to give up this
protocol for assembling 6 from the alcohol 10.
Our synthesis for the lactone 6 was illustrated in Scheme
1. After L-valine was treated with benzyl bromide under
the assistance of potassium carbonate, the resultant ester
was reduced with LAH to provide N,N-dibenzyl valinol
7. Swern oxidation of 7 followed by nucleophilic attack
by a lithium reagent derived from propiolic acid ethyl
ester provided anti-aminoalcohol 8 in 70% yield, to-
gether with syn-aminoalcohol 9 in 13.5% yield. The ster-
eochemistry of 8 was assigned by transformation of it to
known lactone 16 as described below. Since the diastereo-
selectivity (8:9 = 5.2) was not good at the aldol reaction
step, we attempted to improve it using suitable additives.
It was found low diastereoselectivity was still encoun-
Occasionally, we found that 11 was spontaneously
transformed into oxazolidone 14 by standing at room
temperature, which indicated that an intramolecular
SN2 reaction between mesylate unit and carbonyl moiety
of Boc group occurred. Based on this observation, we
developed a route from 11 to 6 as depicted in Scheme
2. Heating 11 in DMF at 65°C produced 14 quantita-
tively, which was treated with di-tert-butyl dicarbonate
to afford 15 in 89% yield. After hydrolysis to cleavage
the ester group and the oxazolidone ring, the resultant
c-hydroxy acid was converted into the lactone 6 medi-
ated with TsOH.
tered when TiCl4,5 Al(OPr-i)3,5 or MgCl2 was used.
6
However, the ratio of 8 to 9 jumped to 9:1 when 2equiv
of HMPA6 was added. Unfortunately, the yield was
only 58% in this case. Consequently we still employed
the initial condition to get aldol products when the reac-
tion was scaled up.
With the lactone 6 in hand, we finished the total synthe-
sis of AG7088 starting from its alkylation. As depicted
in Scheme 3, treatment of 6 with LiHMDS followed
by trapping the anion with 4-fluorobenzyl bromide pro-
vided lactone 16 in 63% yield, together with its 2-epimer
in 4.5% yield. Next, the lactone ring was opened with
aqueous LiOH in DME, the liberated hydroxy group
was oxidated with PCC to afford 2a in 61% yield.
Finally, coupling of 2a with the amine 38 mediated with
HATU produced 17 in 80% yield, which was exposed
to trifluoroacetic acid to remove the Boc protecting
group. The liberated amine was connected with 5-
methylisoxazole-3-carboxylic acid 1 assisted by HATU
to furnish AG70889 in 73% yield. Its analytical data
were all identical with those reported.
1. Swern oxidation
1. BnBr/K CO
2. LAH/THF, 0
83%
2
3
L-Valine
o
OH
2. Li
CO Et
C
2
NBn
2
7
OH
OH
+
NBn
CO Et
NBn
CO Et
2
2
2
2
8 (70% yield)
9 (13.5% yield)
As a conclusion, we have developed a novel protocol to
construct AG7088 using L-valine as the chiral starting
material. The key elements include a diastereoselective
Pd(OH) /C/H
2
Pd(OH) /C/H
2
2
2
(Boc) O, EtOAc
2
(Boc) O, EtOAc
2
90%
90%
OH
OH
CO Et
CO Et
2
2
CO2Et
DMF, 65 o
C
(Boc)2O/DMAP
NHBoc
10
NHBoc
12
HN
O
11
Et3N/THF
89%
O
MsCl/Et N
HOAc, toluene
3
14
95%
89%
O
O
O
O
OMs
O
O
NaOH
CO2Et
1. aq. LiOH/EtOH
2. TsOH, toluene
72%
+
BocN
CO Et
2
NHBoc
O
NHBoc
NHBoc
NHBoc
11
O
6
13
15
6
Scheme 1.
Scheme 2.

D. Ma et al. / Tetrahedron Letters 45 (2004) 8103–8105
8105
(Grant 20132030 and 20342002), and Science and Tech-
nology Commission of Shanghai Municipality (Grants
02JC14032 and 03XD14001) for their financial support.
F
O
O
LiHMDS, -78 oC, then
4-fluorobenzyl bromide
O
O
NHBoc
6
NHBoc
16
References and notes
O
3/HATU/i-PrNEt2
1. aq. LiOH/DME
2.
BocHN
OH
1. Dragovich, P. S.;Prins, T. J.;Zhou, R.;Webber, S. E.;
Marakovits, J. T.;Fuhrman, S. A.;Patick, A. K.;
Matthews, D. A.;Lee, C. A.;Ford, C. E.;Burke, B. J.;
Rejto, P. A.;Hendrickson, T. F.;Tuntland, T.;Brown, E.
L.;Meador, J. W., III.;Ferre, R. A.;Harr, J. E. V.;Kosa,
M. B.;Worland, S. T. J. Med. Chem. 1999, 42, 1213–
1224.
79%
O
F
2a
H
O
N
O
2. Zalman, L. S.;Brothers, M. A.;Dragovich, P. S.;Zhou, R.;
Antimicrob.
1. TFA/CH2Cl2
OEt
Prins, T. J.;Worland, S. T.;Patick, A. K.
Agents Chemother. 2000, 44, 1236–1241.
BocHN
O
N
H
2. 1/HATU/i-PrNEt2
O
3. Anand, K.;Ziebuhr, J.;Wadhwani, P.;Mesters, J. R.;
Hilgenfeld, R. Science 2003, 300, 1763–1767.
4. Dragovich, P. S.;Prins, T. J.;Zhou, R.;Fuhrman, S. A.;
Patick, A. K.;Matthews, D. A.;Ford, C. E.;Meador, J.
W., III;Ferre, R. A.;Worland, S. T. J. Med. Chem. 1999,
42, 1203–1212.
F
H
N
17
O
O
O
P2
OEt
N
H
N
5. DeCamp, A. E.;Kawaguchi, A. T.;Volante, R. P.;Shinkai,
I. Tetrahedron Lett. 1991, 32, 1867–1870.
H
N
O
O
O
6. Fujisawa, T.;Nagui, M.;Koike, Y.;Shimizu, M.
Chem. 1994, 59, 5865–5867.
J. Org.
F
AG7088
15
D
7. Selected data: ½aŠ ꢀ 48:3 (c 1.1, CHCl3); 1H NMR
(CDCl3, 300MHz): d 4.74 (t, J = 6.9Hz, 1H), 4.56 (d,
J = 9.9Hz, 1H), 3.45 (t, J = 9.6Hz, 1H), 2.53 (dd, J = 9.6,
5.7Hz, 2H), 2.29–2.04 (m, 2H), 1.90–1.79 (m, 1H), 1.45 (s,
9H), 1.02 (d, J = 6.6Hz, 3H), 0.98 (d, J = 6.6Hz, 3H);ESI-
MS m/z 275 (M + NH4)+.
Scheme 3.
aldol reaction of N-protected valinal, transformation of
the alcohol 8 into the lactone 6, and subsequent alkyla-
tion. This route is obviously efficient for tuning the sub-
stituents at the P2 position to obtain AG7088 analogues.
Further synthetic work, as well as the biological evalua-
tion of the resultant compounds, are underway and will
be reported in due course.
8. Tian, Q.;Nayyar, N. K.;Babu, S.;Chen, L.;Tao, J.;Lee,
S.;Tibbetts, A.;Moran, T.;Liou, J.;Guo, M.;Kennedy, T.
P. Tetrahedron Lett. 2001, 42, 6807–6809.
26
9. Selected data: ½aŠ þ 32:8 (c 0.5, CHCl3); 1H NMR
D
(CDCl3, 300MHz): d 7.30–7.11 (m, 4H), 7.00–6.94 (m,
2H), 6.63 (dd, J = 15.3, 4.8Hz, 1H), 6.40 (s, 1H), 5.92 (s,
1H), 5.50 (d, J = 15.6Hz, 1H), 4.71–4.61 (m, 1H), 4.51–4.41
(m, 1H), 4.18 (q, J = 7.2Hz, 2H), 3.42–3.30 (m, 2H), 3.24–
3.13 (m, 1H), 2.98–2.84 (m, 2H), 2.73–2.52 (m, 3H), 2.48 (s,
3H), 2.43–2.26 (m, 2H), 1.93–1.70 (m, 2H), 1.61–1.51 (m,
1H), 1.30 (t, J = 7.2Hz, 3H), 1.02 (d, J = 6.6Hz, 3H), 0.84
(d, J = 6.6Hz, 3H);ESI-MS m/z 599 (M + H)+.
Acknowledgements
The authors are grateful to the Chinese Academy of Sci-
ences, National Natural Science Foundation of China