Efficient three-step sequence for the deamination of α-aminoesters. Application to the synthesis of CysLT1 antagonists

Article abstract of DOI:10.1016/j.tetlet.2009.03.118

A practical and efficient three-step sequence for the deamination of α-aminoesters is reported. This method is based on the NaBH₄-mediated selective reduction of α-diazoesters to α-hydrazonoesters and has been successfully applied to the deamin

Full text of DOI:10.1016/j.tetlet.2009.03.118

Tetrahedron Letters 50 (2009) 2750–2753
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient three-step sequence for the deamination of
Application to the synthesis of CysLT1 antagonists
a-aminoesters.
Alfredo González a, Daniel Pérez a, Carles Puig a, Hamish Ryder b, , Jordi Sanahuja b, Laia Solé a, Jordi Bach a,
*
a Department of Medicinal Chemistry, Almirall S. A., Carrer del Treball 2-4, E-08960 Sant Just Desvern, Barcelona, Spain
b Almirall S. A. R&D Center, Laureà Miró 408, E-08980 Sant Feliu de Llobregat, Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and efficient three-step sequence for the deamination of
a
-aminoesters is reported. This
Received 29 January 2009
Revised 13 March 2009
Accepted 17 March 2009
Available online 21 March 2009
method is based on the NaBH4-mediated selective reduction of
and has been successfully applied to the deamination of several representative
some -cysteine ethyl ester derivatives, key intermediates in the synthesis of a series of CysLT1
antagonists.
a
-diazoesters to
a-hydrazonoesters
a
-aminoesters including
L
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Deamination
a
a
a
-Aminoesters
-Diazoesters
-Hydrazonoesters
Reduction
CysLT1 antagonists
Asthma is a complex, chronic inflammatory disease of the
airways which affects around 300 million people worldwide, and
is the most common chronic disease in children.1 Cysteinyl leuko-
trienes (LTC4, LTD4 and LTE4) are products of the 5-lipoxygenase
pathway of arachidonic acid metabolism which play a crucial role
in asthma pathophysiology by causing bronchoconstriction, mucus
production and increased vascular permeability.2 They exert their
biological actions by activating two G-protein-coupled receptors
called CysLT1 and CysLT2.3 CysLT1 receptor antagonists have been
shown to be effective in the treatment of asthma4 and several com-
pounds with this mechanism of action have reached the market in
recent years.5
tion failed, we were successful in separating them by crystallizat-
ing the corresponding mixtures of formamides 5a–c and 6a–c
(easily prepared from aminoesters by reaction with HCOOEt).
Deprotection of the formyl group by using EtOH/HCl/H2O gave
the desired isolated aminoesters 3a–c and 4a–c with de values
>97% in all cases (measured by 1H NMR analysis).
With the separation of diastereoisomers successfully accom-
plished in all three examples, our attention was then focused on
the removal of the
a-amino group. Deamination of aminoesters
3a–c and 4a–c, the key step in our synthetic approach towards
enantiomerically pure acids 1a–c, proved to be more difficult than
anticipated. At this point, aminoesters 3a–c and 4a–c were trans-
As part of an Almirall research programme for the design, synthe-
sis and pharmacological evaluation of novel CysLT1 antagonists, the
preparation of a series of tricyclic carboxylic acids (Fig. 1) has been
carried out.6 In order to prepare multigram quantities of these new
anti-asthmatic compounds for further testing, an efficient synthesis
of both enantiomers of compounds 1a–c was developed.
formed to the corresponding
a-acetamidoesters, a-aminoacids
and
a
-isonitriloesters7 and several methods for the reductive
The first step in our synthetic approach towards acids 1a–c in
an enantiomerically pure form was the reaction of L-cysteine ethyl
ester hydrochloride with racemic alcohols 2a–c6 to give the diaste-
reoisomeric aminoesters 3a–c and 4a–c in a 1:1 ratio (Scheme 1).
Although all attempts to separate diastereoisomers by crystalliza-
* Corresponding author. Tel.: +34 93 291 2847; fax: +34 93 312 8635.
E-mail address: jordi.bach@almirall.com (J. Bach).
Present address: Cancer Research Technology Ltd, Wolfson Institute for Biomed-
ical Research, Gower Street, London WC1E 6BT, UK.
Figure 1. Tricyclic carboxylic acids as CysLT1 receptor antagonists.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.118

A. González et al. / Tetrahedron Letters 50 (2009) 2750–2753
2751
Scheme 1. Reagents and conditions: (i) L-Cysteine ethyl ester hydrochloride, TFA, 60 °C (80–91%); (ii) ethyl formate, reflux; separation of diastereoisomers by crystallization
(42–74%); (iii) EtOH, HCl, H2O, reflux, 30 min (80–98%); (iv) isoamyl nitrite, AcOH (cat.), CHCl3, reflux (60–98%).
cleavage of such intermediates were explored without reward.8
Methods involving the reduction of both enantiomers of
a-diazo-
esters 7a–c (easily prepared by treatment of aminoesters 3a–c
and 4a–c with isoamyl nitrite)9 were also studied with little suc-
cess.10 Of these, only HI-mediated reduction of
a
-diazoesters10c,6
gave moderate yields of the desired deaminated products in just
one of the examples (7c) so a different approach for the cleavage
of the amino group was needed.
The key to the solution of our problems was found in a reaction
reported by Bestmann and Kolm who observed that elimination of
Scheme 2. N2 elimination of a-hydrazonoester 8 described by Bestmann and Kolm.
N2 from a-hydrazonoester 8 was achieved under very mild condi-
Although several examples of selective reduction of
a-diazoest-
tions by treating this compound with a tertiary amine through a
Wolff–Kishner type process (Scheme 2).11 With this result in mind,
an alternative strategy for the deamination of aminoesters 3a–c
and 4a–c was then investigated. This new approach was based
ers to -hydrazonoesters have been described in the literature,
a
reports on practical and general examples of such a process are
scarce.12 In this context, there was a need to devise a mild and
general method for the selective reduction of
a-diazoesters to
on the conversion of our
-hydrazonoesters 10a–c in order to perform N2 elimination by
treatment of such intermediates with a suitable base as described
by Bestmann and Kolm. -Hydrazonoesters could be prepared by
selective reduction of -diazoesters 7a–c, intermediates already
a-aminoesters into the corresponding
a-hydrazonoesters. To our delight and after examining a host of
a
reducing agents and conditions, we observed that NaBH4 in THF
was able to effect this reduction in excellent yields in all examples
under very mild reaction conditions (Scheme 3). At this juncture
a
a
and with both enantiomers of
a-hydrazonoesters 10a–c in hand,
prepared in an enantiomerically pure form from aminoesters 3a–
c and 4a–c.
we were prepared to test the base-promoted elimination of N2.
Of all the bases investigated, the best results were obtained with
Scheme 3. Reagents and conditions: (i) NaBH4, THF, rt (77–98%); (ii) DBU, CHCl3, rt (77–81%); (iii) LiOH, THF, H2O, rt (80–93%).

2752
A. González et al. / Tetrahedron Letters 50 (2009) 2750–2753
Table 1
Three-step deamination sequence of several representative
a
-aminoestersa
Entry
1
R1
R2
a
-Aminoester
Step 1 yield (%)
81
Step 2 yield (%)
92
Step 3 yield (%)
79
Me
12a
12b
12c
12d
12e
12f
O2N
Cl
Cl
2
3
4
5
6
7
Me
Me
Me
Me
Me
Me
71
81
50
62
41
75
72
80e
95
56
52
75
94
CONH
O
65e
46e
35e
49
N
O
O
N
N
H
H
N
H
N
O
N
12g
83e
O
S
O
8
9
Me
Et
12h
12i
12j
12k
12l
75
76
83
77
94
71
95e
97e
61
S
97
NC
10
11
12
Et
70e
59e
11f
SO2NH
Me
Bn
83
80
13
14
Bn
Bn
12m
12n
94
95
28f
19f
53
70
O
a
All isolated products were characterized by 1H NMR, MS and HPLC or GC.
b
c
d
e
f
General procedure: A solution of
General procedure: NaBH4 (1 mmol) was added to a solution of
General procedure: A solution of DBU (2 mmol) and
Reaction was carried out at rt for 24 h.
a
-aminoester (1 mmol), isoamyl nitrite (1.2 mmol) and AcOH (6
-diazoester (1 mmol) in THF (20 mL) and the resulting mixture was stirred for 2 h at rt.
-hydrazonoester (1 mmol) in CHCl3 (14 mL) was heated at reflux overnight.
lL) in CHCl3 (14 mL) was heated at reflux for 2.5 h.
a
a
Reaction was carried out with 4 mmol of NaBH4 at rt for 3 days.
DBU. When 2 equiv of DBU was added to an
solution in CHCl3, elimination of N2 proceeded efficiently at rt to
give esters 11a–c in excellent yields. Finally, hydrolysis of the ester
a
-hydrazonoester
group with LiOH in THF/H2O furnished both enantiomers of the
desired acids 1a–c, whose optical purity was analyzed by capillary
electrophoresis giving ee values >97% in all cases.13

A. González et al. / Tetrahedron Letters 50 (2009) 2750–2753
2753
Encouraged by these remarkable results and having established
the preferred reaction conditions for each step, deamination of sev-
eral representative -aminoesters bearing a variety of functional
Supplementary data
a
Supplementary data (experimental procedures and character-
ization data are provided for all new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.03.118.
groups was performed to demonstrate the versatility of this
three-step deamination sequence. As shown in Table 1, many func-
tional groups tolerated the mild reaction conditions of all three
steps, including amides (entry 2), carbamates (entry 3), ureas
(entry 4), nitriles (entry 9) and sulfonamides (entry 10). Phenylal-
anine derivatives (entries 1–4) proved to be excellent substrates
for the deamination process with good yields in almost all the
steps and examples. Successful deamination of aminoester 12d is
also a good example of the potential of the method: Although
yields in all three synthetic steps are only moderate, the allylic
urea functionality of aminoester 12d probably would be affected
by the reaction conditions of many of the deamination methods
described in the literature. On the other hand, yields obtained in
References and notes
1. Masoli, M.; Fabian, D.; Holt, S.; Beasley, R. Allergy 2004, 59, 469–478.
2. (a) Hay, D. W. P.; Torphy, T. J.; Undem, B. J. Trends Pharmacol. Sci. 1995, 16, 304–
309; (b) Lane, S. J. Respir. Med. 1998, 92, 795–809.
3. (a) Dahlen, S.-E. Am. J. Respir. Crit. Care Med. 2000, 161, S41–S45; (b) Nicosia, S.;
Capra, V.; Ravasi, S.; Rovati, G. E. Am. J. Respir. Crit. Care Med. 2000, 161, S46–S50.
4. (a) Barnes, N. C. Am. J. Respir. Crit. Care Med. 2000, 161, S73–S76; (b) Holgate, S.
T.; Sampson, A. P. Am. J. Respir. Crit. Care Med. 2000, 161, S147–S153.
5. Rodger, I. W. Am. J. Respir. Crit. Care Med. 2000, 161, S7–S10.
6. Puig, C.; Perez, D.; Bach, J.; Ryder, H. PCT Patent WO2004/043966, 2004.
7. Bergemann, M.; Neidlein, R. Synthesis 1996, 975–980.
diazo formation and reduction steps in other aromatic
ers (entries 5–6) were only moderate.
a-aminoest-
8. For the reductive deamination of
SmI2 see: (a) Honda, T.; Ishikawa, F. Chem. Commun. 1999, 1065–1066; For the
NH2OSO3H/NaOH mediated removal of the amino group in -aminoacids see:
(b) Doldouras, G. A.; Kollonitsch, J. J. Am. Chem. Soc. 1978, 100, 341–342; For the
Bu3SnH/AIBN radical-induced reductive cleavage of the isonitrile group in
a-aminoesters and a-acetamidoesters with
For the reduction step, steric factors seemed to play an
important role and contributed to the decreased reactivity of
b-substituted-a-diazoesters (entries 12–14) compared with the
a
a-
non-substituted ones. In these examples, not only a large excess
of NaBH4 and longer reaction times (up to three days) were needed
in order to obtain significant amounts of the desired b-substituted-
isonitrile esters see: (c) Barton, D. H. R.; Bringmann, G.; Motherwell, W. B.
Synthesis 1980, 68–70.
9. Takamura, N.; Mizoguchi, T.; Koga, K.; Yamada, S. Tetrahedron 1975, 31, 227–
230.
a
-hydrazonoesters but also higher reaction temperatures did not
have a beneficial effect on the reaction.
Finally, treatment of -hydrazonoesters with DBU led to the
10. For the reduction of
aÀdiazoesters by hydrogenation see: (a) Pelliciari, R.;
Natalini, B.; Cechetti, S.; Fringuelli, R. J. Chem. Soc., Perkin Trans. 1 1985, 493–
497; Grant Buchanan, J.; Edgar, A. R.; Hewitt, B. D. J. Chem. Soc., Perkin Trans 1
a
1987, 2371–2376; For the Bu3 SnH mediated diazo decomposition of a-diazo
desired deaminated esters with satisfactory results in all the exam-
ples studied. In order to force the reaction to completion, N2 elim-
ination was carried out under reflux in CHCl3 in many examples.
In summary, we have developed an efficient and practical three-
carbonyl compounds see: (b) Tan, Z.; Qu, Z.; Chen, B.; Wang, J. Tetrahedron
2000, 56, 7457–7461; Kim, S.; Cho, J. R. Bull. Korean Chem. Soc. 1993, 14, 664–
665; For the HI-mediated reduction of a-diazoketones see: (c) Wolfrom, M. L.;
Brown, R. L. J. Am. Chem. Soc. 1943, 65, 1516–1521; Haworth, R. D.; Pindred, H.
K.; Jefferies, P. R. J. Chem. Soc. 1954, 3617–3625.
11. Bestmann, H. J.; Kolm, H. Chem. Ber. 1963, 96, 1948–1958.
12. (a) Staudinger, H.; Lüscher, G. Helv. Chim. Acta 1922, 5, 75–86; (b) Pfleger, R.;
Reinhardt, F. Chem. Ber. 1957, 90, 2404–2411; (c) Takamura, N.; Yamada, S.
Chem. Pharm. Bull. 1976, 24, 800–803; (d) Hasegawa, K.; Arai, S.; Nishida, A.
Tetrahedron 2006, 62, 1390–1401.
13. Separated enantiomers of carboxylic acids 1a–c are identified based on the sign
of their optical rotation values. Studies to assign the absolute configuration of
these isolated enantiomers are underway.
step sequence for the reductive elimination of the amino group in
aminoesters based on the NaBH4-mediated selective reduction of
a
a
-
-
diazoesters to
a-hydrazonoesters. The scope and limitations of this
method have been examined with several representative
a-amino-
esters bearing different functionalities with excellentresults in most
of the examples. This methodology has also been successfully ap-
plied to the synthesis of a series of CysLT1 antagonists.