Asymmetric synthesis of unnatural amino acids and tamsulosin chiral intermediate

Article abstract of DOI:10.1080/00397911.2012.748075

An efficient and enantioselective hydrogenation of N-acetylamino phenyl acrylic acids was successfully developed by using ruthenium catalyst. This methodology is important in the field of pharmaceuticals and provides a new process for the preparation of unnatural amino acids and tamsulosin chiral intermediate.

Full text of DOI:10.1080/00397911.2012.748075

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Asymmetric Synthesis of Unnatural Amino Acids and
Tamsulosin Chiral Intermediate
Veera Reddy Arava a , Srinivasulu Reddy Amasa a , Bharath Kumar Goud Bhatthula a , Laxmi
Srinivas Kompella a , Venkata Prasad Matta a & M. C. S. Subha b
a R&D Center, Suven Life Sciences Ltd , Hyderabad , India
b Dept. of Chemistry , Sri Krishnadevaraya University , Ananthapur , A.P. , India
Accepted author version posted online: 31 May 2013.
To cite this article: Synthetic Communications (2013): Asymmetric Synthesis of Unnatural Amino Acids and Tamsulosin Chiral
Intermediate, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI: 10.1080/00397911.2012.748075
To link to this article: http://dx.doi.org/10.1080/00397911.2012.748075
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Asymmetric synthesis of unnatural amino acids and Tamsulosin chiral intermediate
Veera Reddy Arava1, Srinivasulu Reddy Amasa1, Bharath Kumar Goud Bhatthula1,
Laxmi Srinivas. Kompella1, Venkata Prasad Matta1, M. C. S. Subha2
1R&D Center, Suven Life Sciences Ltd, Hyderabad, India, 2Dept. of Chemistry, Sri
Krishnadevaraya University, Ananthapur, A.P., India
R&D Center, Suven Life Sciences Ltd, Plot No.#18, Phase-III, Jeedimetla, Hyderabad
500055, India Tel.: 0091 939 248 3004; Email: reddyvenis@rediffmail.com
Abstract
An efficient and enantioselective hydrogenation of N-acetylamino phenyl acrylic acids
was successfully developed by using ruthenium catalyst. This methodology is important
in the field of pharmaceuticals and provides a new process for the preparation of
unnatural amino acids and tamsulosin chiral intermediate.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: chiral metal catalyst, asymmetric hydrogenation, [(S)-BINAPRuCl
(benzene)]Cl, unnatural amino acids, Tamsulosin intermediate.
INTRODUCTION
Asymmetric synthesis plays an important role in the chemical production of
pharmaceutical agents since many of them were launched as chiral molecules. Since the
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Knowles[1] initial success of L-Dopa (1977) with Rh catalyzed asymmetric hydrogenation
of N-acylated α-dehydro amino acids or esters, has received a lot of attention from both
academic and industrial[2] scientific community. Later scientists at Dupont[3] and
Takasago[4] developed variety of ligands for asymmetric hydrogenation of prochiral
alkenes, imines and ketones.
Asymmetric hydrogenation uses a very small amount of chiral catalysts, providing the
most powerful way to produce enantio-enriched compounds in a large quantity with out
forming any waste. This is a smart and economic way to obtain chiral products. The
catalytic hydrogenation is a reaction of growing importance in modern chemistry.
Chiral α-amino acids are important biological molecules. In this paper we are presenting
an asymmetric synthesis of unnatural amino acids and tamsulosin key intermediate: 2-(4-
methoxyphenyl)-1-methyl-ethylamine using chiral catalyst [(S)-BINAPRuCl
(benzene)]Cl.
RESULTS AND DISCUSSION
Optically active natural and unnatural α-amino acids are important precursors for the
synthesis of pharmaceuticals, agrochemicals, and food ingredients[5]. They also have long
been used as chiral building blocks in organic synthesis[6,7]. Because of their widespread
use, intensive research efforts have been directed towards the development of new and
improved stereoselective synthesis of α-amino acids[7]. Of these, particular interests are
catalytic methods that possess high degree of enantioselective control.
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The selective reduction of intermediate acrylic acid 3 via an asymmetric hydrogenation
catalyst, using commercially available [(S)-BINAPRuCl(benzene)]Cl, provides a very
useful route.
Compound 11, the key intermediate of tamsulosin was prepared starting from
commercially available 4-methoxybenzaldehyde 1f with high enantiomeric excess
(>99%ee).
Optically active N-Cbz-2-(4-methoxyphenyl)-1-methyl-ethylamine 11, a useful chiral
building block in medicinal chemistry, was synthesized from 1f by using a chiral catalyst
via asymmetric reduction of intermediate 2-acetylamino-3-(3-methoxyphenyl)acrylic
acid 3 with [(S)-BINAPRuCl(benzene)]Cl. Other unnatural chiral amino acids 5a-i were
also prepared from commercially available benzaldehydes as shown in Scheme 1.
Azlactones 2a-i were synthesized via Erlenmeyer reaction of benzaldehyde and N-
acetylglycine. The intermediate azlactones were subsequently ring opened by reflux in
acetone[8] (Scheme 1 & Table 1).
Asymmetric hydrogenation of acrylic acids 3a-i with [(S)-BINAPRuCl (benzene)]Cl
catalyst at 50°C and 5 kg/cm2 hydrogen pressure gives chiral acids 4a-i as shown in
Scheme 1 & Table 2.
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The chiral amino acids 5a-i was prepared by deacetylation of 4a-i, using 10% aq. HCl
(Scheme 1 & Table 3).
In our interest to develop an asymmetric hydrogenation method to prepare the key chiral
intermediate of tamsulosin, an antihypertensive drug, the amino acid 5f was converted to
its ethyl ester with ethanol and thionyl chloride and protected using Cbz in ethyl acetate
to give Cbz-ester 7. Reduction of Cbz-ester 7 to alcohol 8 was achieved with sodium
borohydride, and tosylation of alcohol was done using similar protocol of Harumichi[9].
Preparation of methyl derivative 11 was carried via two methods: the first is a one pot
synthesis from tosyl 9 to 11 and the second one was performed from iodo 10, as shown in
Scheme 2[9].
The optical purity of N-Cbz derivative (R)-11 was determined to be >99% ee by chiral
HPLC. And the corresponding other enentiomer (S)-11 can be prepared by using [(R)-
BINAPRuCl (benzene)]Cl catalyst, using the same starting material and with similar
procedure.
In conclusion, an efficient and enantioselective hydrogenation of N-acetylamino phenyl
acrylic acids was successfully developed by using chiral ruthenium catalyst to produce
unnatural chiral amino acids and key chiral intermediate of Tamsulosin hydrochloride
drug.
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EXPERIMENTAL
General
All reagents were obtained from commercial sources and used without further
purification. Reverse phase HPLC analysis was carried out using YMC pack C18 (5µm),
250x4.6mm. Chiral HPLC analysis was carried out using Chiral PAK AD-H 250x4.6mm
(5µm). Chiral catalyst was purchased from Umicore. Optical rotations were measured in
a Perkin Elmer-341 polarimeter. 1H and 13C NMR spectra were recorded on Bruker AV
400MHz. Column chromatography was performed with silica gel 100-200 mesh size.
General Procedure For The Preparation Of N-Acetylamino Phenyl Acrylic Acids
(3a–3i):
Crude azlactone 2 (35.0g) in acetone (263mL) and water (105mL) mixture was stirred
under reflux for 6h, and then evaporated under reduced pressure at below 50°C. Water
(140mL) was added and pH adjusted to 10 with potassium carbonate and washed with
ethyl acetate (175mL) at room temperature. The layers were separated and then aqueous
layer was washed two times with EtOAc (175mL×2). The aqueous layer was acidified to
pH 3–4 with citric acid and filtered. The solid obtained was washed with water (35mL) to
give the residue. The residue was recrystallized from MTBE (40mL) to give pure N-
acetylamino phenyl acrylic acids 3.
3f
yellow solid, (62.8% yield over two steps); HPLC (210nm) tR 16.97min (98.69%); 1H
NMR (DMSO-d6): δ 1.97 (s, 3H), 3.77 (s, 3H), 6.96 (d, J=8.7 Hz, 2H), 7.21 (s,1H) 7.59
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(d, J=8.7 Hz, 2H), 9.35 (s, 1H), 12.52 (bs, 1H); 13C NMR (DMSO-d6): δ 23.03, 55.68,
114.50, 125.41, 126.63, 132.07, 132.18, 160.45, 167.08, 169.62.
Synthesis Of Chiral N-Acetylamino Acids (4a–4i)
Acrylic acid 3 (10.0g, 0.048 mol), [(S)-BINAPRuCl(benzene)]Cl (100mg, 1.1 mol%) and
anhydrous methanol (250mL) were charged in an autoclave vessel at room temperature.
The autoclave was flushed twice with nitrogen before finally evacuating and flooding
with hydrogen. Hydrogen was introduced into the autoclave until the pressure gauge
indicated over 5kg/cm2. The pressure was carefully released and the procedure was
repeated two times, and finally the inside of the autoclave pressurized with hydrogen to
5kg/cm2. The reaction was maintained for 12h at 50°C under 5 kg/cm2 hydrogen
pressure. Reaction completion was monitored and confirmed by 1H NMR. The reaction
mixture was filtered off through hyflo, and then the filtrate was evaporated under reduced
pressure at below 50°C. The residue was crystallized in MTBE to get (S)-4.
4f
yellow solid, (89.2% yield); HPLC (210nm), tR16.50 min (97.56%), HPLC chiral purity
(210nm) 91.07% ; 1H NMR (DMSO-d6): δ 1.77 (s, 3H), 2.76 (dd, J1=13.7, J2=9.5 Hz,
1H), 2.96 (dd, J1= 13.8, J2=4.8 Hz, 1H), 3.70 (s, 3H), 4.31-4.36 (m, 1H), 6.83 (d, J=8.5
Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 8.16 (d, J=8.0 Hz, 1H), 12.5 (bs, 1H); 13C NMR
(DMSO-d6): δ 22.79, 36.41, 54.25, 55.38, 114.03, 129.97, 130.52, 158.33, 169.71,
173.73.
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Synthesis Of Chiral Amino Acids (5a–5i)
The solution of compound (S)-4 (10g, 0.048 mol) in 10% aqueous HCl (100mL) was
stirred at 95-100°C for 6h, and then neutralized the pH with triethylamine. The solid was
collected by filtration, washed with water (40mL) to give deacetylated product (S)-5.
5f
brown solid, (85.3% yield); [α]D25 = -6.9 (C=2, 1N HCl) (lit.[10] [α]D = -6.7 (C=2, 1N
HCl)) , HPLC (230nm), tR3.24 min (98.17%), HPLC chiral purity (200nm) 89.39% ; 1H
NMR (D2O): δ 2.93 (dd, J1= 14.6, J2=7.8 Hz, 1H), 3.08 (dd, J1=14.6, J2=5.0 Hz, 1H),
3.68 (s, 3H), 3.80 (t, J=6.4, 1H), 6.86 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H); 13C
NMR (D2O): δ 35.38, 55.27, 55.99, 114.44, 127.43, 130.56, 158.18, 173.91.
The chiral amino acid 5f was further converted to 11 (tamsulosin intermediate) and
confirmed in all respects. The optical purity of (R)-11 was determined to be >99%ee in
chiral HPLC.
For further details please see
Supporting Information: Full experimental detail, 1H and 13C NMR spectra, HPLC traces.
This material can be found via the “Supplementary Content” section of this article’s Web
page.
ACKNOWLEDGMENTS
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The authors are grateful to Suven Life Sciences management for allowing them to
publish these results.
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[4] Noyori, R.; Kitamura, M.; Ohkuma. T. Proc. Natl. Acad. Sci. US 101,5356, 2004 and
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[5] Kleeman, A.; Leuchtenberger, W.; Hoppe, B.; Tanner, H. Ullmann’s Encyclopedia of
Industrial Chemistry; VCH: Weinheim, 1985; vol. A2, pp. 57-97.
[6] Koskinen, A. Asymmetric Synthesis of Natural Products; Wiley, Chichester, 1993.
[7] Williams, R. M. Synthesis of Optically Active α-Amino Acids; Pergmon Press: Oxford,
1989.
[8] Herbst, R. M.; Shemin, D. Org. Synth., 1943, Coll.vol. 2, 1.
[9] Harumichi, K.; Takeo, I.; Kochiro, Y. Synth. Commun., 1998, 28, 1935.
[10] John, P.; John, D.; Jean R. Int. J. Pept. Prot. Res., 1987, 30, 13-21.
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[11]Valeri, P. K.; Yuri, N. B.; Vadim, A. S.; Nataly Yu, S.; Alexander, B. R.; Nadezhda,
A. K. Synthesis 1993, 117-120
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[13] Dieter, S.; Edward, D.; Linda, B.; Sergio, C.; Robert, F. Liebigs. Ann. Chem., 1989,
1215-1232.
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[17] Robert F.P. US patent 3669837, 1972.
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Table1. Preparation of acrylic acids via Erlenmeyer azlactone synthesis.
Entry Substrate
R1
H
F
R2
R3
Product
3a
Yield (%)a
01
02
03
04
05
06
07
08
09
1a
1b
1c
1d
1e
1f
H
H
58.4
H
H
3b
49.2
H
H
Cl
H
H
H
H
H
Cl
3c
57.2
H
Br
3d
61.7
H
Cl
3e
51.5
H
OMe
H
3f
62.8
1g
1h
1i
OMe
OMe
OEt
3g
57.0
OMe
OMe
3h
53.8
3i
48.5
a Isolated yields for two stages (1 to 3)
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Table 2. Preparation of N-acetyl chiral amino acids 4a–i
Entry Substrate
R1
R2
R3
Product Conversion ee
Yield
(%)c
83.3
84.0
90.0
72.0
80.0
89.2
80.0
82.0
84.0
(%)a
>99
>99
>99
>99
>99
>99
>99
>99
>99
(%)b
01
02
03
04
05
06
07
08
09
3a
3b
3c
3d
3e
3f
H
F
H
H
4a
4b
4c
4d
4e
4f
79.3
92.9
64.1
62.3
86.0
82.1
75.8
77.5
63.4
H
H
H
H
Cl
H
H
H
H
H
Cl
H
Br
H
Cl
H
OMe
H
3g
3h
3i
OMe
OMe
OEt
4g
4h
4i
OMe
OMe
a Conversion was determined by 1H NMR spectra
b ee were determined by chiral HPLC
Chiral ratio of the products was 81:19 (for bromo 4d) to 96:4 (for fluoro 4b)
c Isolated yield
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Table 3. Preparation of chiral amino acids 5a-i
Entry Substrate
R1
R2
R3
Product Conversion ee
Yield
(%)c
66.6
63.5
73.2
68.4
62.0
85.3
62.6
75.3
88.0
(%)a
>99
>99
>99
>99
>99
>99
>99
>99
>99
(%)b
01
02
03
04
05
06
07
08
09
4a
4b
4c
4d
4e
4f
H
F
H
H
5a
5b
5c
5d
5e
5f
76.6
99.4
98.8
99.5
89.6
78.7
97.4
94.5
71.8
H
H
H
H
Cl
H
H
H
H
H
Cl
H
Br
H
Cl
H
OMe
H
4g
4h
4i
OMe
OMe
OEt
5g
5h
5i
OMe
OMe
a Conversion was determined by TLC
b ee were determined by chiral HPLC
Chiral ratio of the products was 85.9 : 14.1 (for 5i) to 99.7 : 0.23 (for bromo 5d)
c Isolated yield
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Scheme 1. Synthesis of unnatural chiral amino acids 5a-i.
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Scheme 2. Synthesis of N-Cbz-2-(4-Methoxyphenyl)-1-methyl-ethylamine 11
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