An efficient synthesis of a key intermediate for the preparation of the rhinovirus protease inhibitor AG7088 via asymmetric dianionic cyanomethylation of N-Boc-L-(+)-glutamic acid dimethyl ester

Article abstract of DOI:10.1016/S0040-4039(01)01416-2

An efficient synthetic route to a key intermediate for the preparation of the rhinovirus protease inhibitor AG7088 has been developed employing a key asymmetric dianionic cyanomethylation of N-Boc-L-(+)-glutamic acid dimethyl ester. This methodology enables the preparation of this compound in kilogram quantities with an overall yield of 30%.

Full text of DOI:10.1016/S0040-4039(01)01416-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6807–6809
An efficient synthesis of a key intermediate for the preparation
of the rhinovirus protease inhibitor AG7088 via asymmetric
dianionic cyanomethylation of N-Boc- -(+)-glutamic acid
L
dimethyl ester
Qingping Tian,* Naresh K. Nayyar,* Srinivasan Babu, Lijian Chen, Junhua Tao, Steven Lee,
Anthony Tibbetts, Terence Moran, Jason Liou, Ming Guo and Timothy P. Kennedy
Chemical Research & Development, La Jolla Laboratories, Pfizer Global Research & Development, 3565 General Atomics Ct.,
San Diego, CA 92121, USA
Received 14 June 2001; accepted 27 July 2001
Abstract—An efficient synthetic route to a key intermediate for the preparation of the rhinovirus protease inhibitor AG7088 has
been developed employing a key asymmetric dianionic cyanomethylation of N-Boc-L-(+)-glutamic acid dimethyl ester. This
methodology enables the preparation of this compound in kilogram quantities with an overall yield of 30%. © 2001 Elsevier
Science Ltd. All rights reserved.
As part of our ongoing efforts to develop rhinovirus
protease inhibitors for treatment of the common cold,
large quantities of the drug candidate AG7088 were
required. This necessitated the development of a new,
efficient and cost-effective synthetic approach to the
drug substance. One general synthetic strategy is based
on a convergent union of subunits 1 and 2 (Scheme 1).
The medicinal chemistry synthesis of 2 employed 13
steps and was prohibitively lengthy for scale-up.1
Therefore, our efforts have been focused on developing
a new and efficient synthetic route to 2 which is more
practical and viable for scale-up. In this communica-
tion, we report the realization of this goal.
A retrosynthetic analysis indicated that lactam ester 3
could be converted to 2 via a sequence of reduction,
oxidation and Wittig olefination reactions. A synthesis
of the tert-butyl ester analogue of 3 from lactam ester
4 has been reported in the literature,2 although the key
step (cyanomethylation of lactam ester 4) yielded the
desired product as a 2:1 mixture of diastereomers (Eq.
(1)). Obviously, a more stereoselective approach to 3 is
H
O
N
H
O
O
O
N
O
O
N
N
H
OH
+
N
O
N
H
N
H
O
O
O
BocHN
COOEt
F
COOEt
F
2
AG7088
1
Scheme 1.
Keywords: asymmetric synthesis; lactams; alkylation.
* Corresponding authors. Fax: 858-622-3299; e-mail: qingping.tian@agouron.com; naresh.nayyar@agouron.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01416-2

6808
Q. Tian et al. / Tetrahedron Letters 42 (2001) 6807–6809
highly desirable. Recently, Hanessian has studied the
1,3-asymmetric induction in dianionic alkylation of the
O
O
O
CN
CN
Ref. 2
Boc
Boc
Boc
commercially available N-Boc- -(+)-glutamic acid
L
N
N
N
+
dimethyl ester 5 and reported high stereoselectivities.3
For example, alkylation of the dianion of 5 with allyl
bromide afforded the desired anti isomer 6 in 92% yield
and >98% de (Eq. (2)). We reasoned that this type of
alkylation could be employed in an approach to lactam
ester 3.
COOt-Bu
COOt-Bu
COOt-Bu
4
2 : 1
(1)
almost exclusively with the desired stereochemistry in
high yield.4 This was an additional example of the novel
stereochemistry which was first developed by Hanes-
sian.3 According to the original report, the chemistry
was limited to allylic halides.3 Our results demonstrated
that this type of dianionic asymmetric alkylation could
be extended to other activated halides.
H
N
H
N
O
O
OCH3
BocHN
BocHN
O
COOEt
In the following step, 7 was subjected to hydrogenation
in the presence of PtO2 and chloroform.5 The reaction
went smoothly to furnish the corresponding amine HCl
salt 8. It is interesting to note that the widely used Boc
group is not affected by the hydrogenation in the
presence of chloroform, although it has been reported
that the reaction could tolerate some acid-labile func-
tional groups.5 The salt 8 was then treated with
2
3
Our synthesis commenced with dianionic alkylation of
5 using 2.16 equiv. of LiHMDS and 1.07 equiv. of
bromoacetonitrile (Scheme 2). As expected, this alkyla-
tion reaction was highly stereoselective and afforded 7
NHBoc
NHBoc
OCH3
Ref. 3
H3CO
OCH3
H3CO
syn-isomer
+
(2)
O
O
O
O
6
5
anti : syn > 99 : 1
NC
O
NHBoc
OCH3
LiHMDS, - 78 oC
H2, 50 psi, PtO2
NHBoc
OCH3
H3CO
H3CO
Br
CN
MeOH/CHCl3
O
O
O
5
7
H
N
O
O
OCH3
Na2CO3
NaBH4
MeOH/CHCl3
NH2
HCl
MeOH/ THF
89%
40% overall from 5
OCH3
OCH3
BocHN
O
BocHN
O
O
8
3
H
N
H
N
O
1. Py SO3, DMSO
EtN(i-Pr)2, CH2Cl2
2. Et3P, BrCH2CO2Et
CH2Cl2
85%
BocHN
BocHN
COOEt
OH
9
2
30% overall yield from 5
97% pure, 98% de, 100% E isomer
Scheme 2.

Q. Tian et al. / Tetrahedron Letters 42 (2001) 6807–6809
6809
Na2CO3 at 60°C for 4–5 h to produce the lactam ester
3 in an overall yield of 40% from 5. In an alternative
procedure, 7 was converted to 3 in a yield of 80% by
employing the combination of NaBH4 and CoCl2.6
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, III, J. W.; Ferre, R. A.; Harr, J. E. V.; Kosa,
M. B.; Worland, S. L. J. Med. Chem. 1999, 42, 1213–1224.
2. Murray, P. J.; Starkey, I. D.; Davies, J. E. Tetrahedron
Lett. 1998, 39, 6712–6714.
3. Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39,
5887–5890.
4. Representative procedure: To a solution of N-Boc-L-(+)-
The next step was to reduce the ester group selectively
to the corresponding alcohol 9 in the presence of the
lactam. We examined both NaBH4 and LiBH4 for this
transformation and both reagents proved equally effec-
tive.7 In the case of NaBH4, the reaction afforded 9 in
an 89% yield versus an 81% yield for LiBH4. Since
NaBH4 is easier to handle during scale-up, we chose
NaBH4 over LiBH4 as the reducing agent.
glutamic acid dimethyl ester (5, 600 g, 2.18 mol, 1 equiv.)
in THF (6.0 L) was added dropwise a solution of LiH-
MDS in THF (4.7 L, 1 M, 4.7 mol, 2.16 equiv.) at −78°C
under an argon atmosphere. The resulting dark mixture
was stirred at −78°C for 1 h. At the same time, bromoace-
tonitrile (400 g) was stirred with basic aluminum oxide (70
g) for 2 h and then filtered. The freshly filtered bromoace-
tonitrile (280 g, 2.33 mol, 1.07 equiv.) was added dropwise
to the dianion solution over a period of 1 h while main-
taining the temperature below −70°C. The reaction mix-
ture was stirred at −78°C for additional 1–2 h and the
disappearance of the starting material (5) was confirmed
by TLC analysis. The reaction was quenched with pre-
cooled methanol (300 ml) in one portion and stirred for 30
min. The resulting methoxide was then quenched with a
pre-cooled acetic acid in THF solution (270 ml HOAc/2 L
THF) in one portion. After stirring for 30 min, the cooling
bath was removed and replaced with water bath. The
reaction mixture was allowed to warm up to 0 5°C and
then poured into a brine solution (250 g of NaCl in 4 L of
water) in a 50 L extractor. The layers were separated, and
the organic layer was concentrated to afford a dark brown
oil (ꢀ850 g). Silica gel (800 g), activated carbon (200 g)
and methylene chloride (2 L) were added to the Rotovap
flask and spun on a Rotovap for 1 h without heat and
vacuum. The slurry was then filtered and washed with
another 2 L of methylene chloride. The light brown filtrate
was concentrated to afford a light brown oil (7, 620 g, 90%
crude yield). The crude product 7 was used in the next step
Completion of the synthesis required lactam alcohol 9
to be oxidized to the corresponding aldehyde followed
by Wittig olefination. Initial studies indicated that the
a-amino aldehyde intermediate resulting from the oxi-
dation of 9 was highly water soluble and prone to
epimerization. With this in mind, and also to make the
process efficient and simple, we combined these two
reactions (oxidation/olefination) in a single reaction
vessel.8 Thus, 9 was oxidized with pyridine·SO3 in
DMSO and then treated with the Wittig reagent (gener-
ated from triethylphosphine and ethyl bromoacetate) to
afford crude 2 which was further purified through a
trituration procedure. According to chiral HPLC analy-
sis, compound 2 from this new route had a purity of
97% and a de of 98%. More importantly, this product is
exclusively the E isomer as indicated by HPLC and
proton NMR spectral analyses. The yield of 2 from 9
was 85%.
In summary, a new synthetic route to the key interme-
diate 2 via asymmetric dianionic cyanomethylation has
been developed and could be scaled up to the multi-
kilogram level. This route is highly efficient (4 steps and
30% overall yield), highly stereoselective (98% de and
100% E isomer), utilizes inexpensive starting materials
and requires no chromatographic purification.
1
without further purification. H NMR (CDCl3): l 1.46 (s,
9H), 2.12–2.24 (m, 2H), 2.77–2.82 (m, 2H), 2.85–2.91 (m,
1H), 3.78 (s, 3H), 3.79 (s, 3H), 4.32–4.49 (m, 1H), 5.13 (d,
J=6.0 Hz, 1H); 13C NMR (CDCl3): l 19.4, 28.6, 34.3,
38.6, 49.8, 53.1, 80.9, 117.5, 155.9, 172.4, 172.8; HRMS:
m/z 314.1481 (calcd for C12H22N2O4: 314.1486).
5. Secrist, III, J. A.; Logue, M. W. J. Org. Chem. 1972, 37,
335–336.
6. Reddy, P. A.; Hsiang, B. C. H.; Latifi, T. N.; Hill, M. W.;
Woodward, K. E.; Rothman, S. M.; Ferrendelli, J. A.;
Covey, D. F. J. Med. Chem. 1996, 39, 1898–1906.
7. Huang, S.-B.; Nelson, J. S.; Weller, D. D. Synth. Commun.
1989, 3485–3496.
Acknowledgements
We are grateful for many helpful discussions through-
out the course of this work with Dr. Kim Albizati, Dr.
Ben Borer and Dr. David Kucera. We also thank Ms.
Laura Kuhn, Mr. Michael Mohajeri and Mr. Jason
Ewanicki for providing HPLC data.
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