Facile synthesis of L-Dopa tert-butyl ester by catalytic enantioselective phase-transfer alkylation

Article abstract of DOI:10.1016/S0040-4039(00)01443-X

Facile asymmetric synthesis of L-Dopa and related amino acid esters has been achieved by phase-transfer catalysis of the rationally designed C₂-symmetric chiral quaternary ammonium salts 1. The 'scale-up' experiment performed with 5.00 g of tert-butyl glycinate-benzophenone Schiff base (2) represents the practical aspect of our approach. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01443-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8339–8342
Facile synthesis of
L
-Dopa tert-butyl ester by catalytic
enantioselective phase-transfer alkylation
Takashi Ooi,a,b Minoru Kameda,a,b Hidenori Tannaib and Keiji Maruokaa,b,
*
aDepartment of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
bDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 3 July 2000; accepted 25 August 2000
Abstract
Facile asymmetric synthesis of
L
-Dopa and related amino acid esters has been achieved by phase-trans-
fer catalysis of the rationally designed C2-symmetric chiral quaternary ammonium salts 1. The ‘scale-up’
experiment performed with 5.00 g of tert-butyl glycinate-benzophenone Schiff base (2) represents the
practical aspect of our approach. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkylation; chiral phase-transfer catalysis; L-Dopa esters; glycine derivatives.
Recently, we reported the rational molecular design of C2-symmetric chiral quaternary
ammonium salt (S)-1a as a new chiral phase-transfer catalyst and demonstrated its remarkable
efficiency in the catalytic enantioselective alkylation of tert-butyl glycinate-benzophenone Schiff
base (2) under mild phase-transfer conditions (Scheme 1).1 Since both enantiomers of the
Scheme 1.
* Corresponding author. Tel/fax: +00 81 75 753 4041; e-mail: maruoka@kuchem.kyoto-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01443-X

8340
catalyst of type 1 can be readily assembled in exactly the same manner starting from either (R)-
or (S)-binaphthol, a wide variety of natural and unnatural a-amino acids can be synthesized in
an enantiomerically pure form by the phase-transfer catalytic alkylation of substrate 2. In this
letter, we wish to describe the successful utilization of this advantage for the facile synthesis of
L
-Dopa (
L
-3,4-dihydroxyphenylalanine) esters, which have usually been prepared in an enzy-
matic way and tested as potential drugs for the treatment of Parkinson’s disease.2
The simple synthetic route to -Dopa esters is illustrated in Scheme 2. Catalytic phase-transfer
L
alkylation of 2 with benzyl bromide 3 (R1=OBn) (1.2 equiv.)3 in toluene–50% KOH aqueous
solution (volume ratio=3:1) proceeded smoothly at 0°C in the presence of (R)-1a (1 mol%) to
furnish fully protected -Dopa tert-butyl ester, which was subsequently treated with a 1 M citric
L
acid in THF at room temperature for 10 h to afford the corresponding amino ester 4 (R1=OBn)
in 80% isolated yield. Although the enantiomeric excess was determined to be 90% ee by chiral
HPLC analysis, it did not seem fully satisfactory because further purification such as recrystal-
lization would be required to increase the enantiomeric purity. Therefore, we employed (R)-1b
as a catalyst4 and found that the alkylation of 2 with (R)-1b (1 mol%) and 3 (R1=OBn; 1.2
equiv.) under otherwise identical conditions gave rise to the amino ester 4 (R1=OBn) with
excellent enantioselectivity (98% ee). Debenzylation of 4 (R1=OBn) under catalytic hydrogena-
tion conditions produced the desired
-Dopa tert-butyl ester (5; R1=OH) in 93% yield. Being
L
exemplified by the feasibility of asymmetric synthesis of natural tyrosine tert-butyl ester (5;
R1=H), as also shown in Scheme 2, the present concise and practical procedures should enable
highly enantioselective synthesis of various -Dopa analogues and related a-amino acids.
L
Scheme 2.

8341
With this information at hand, we performed a ‘scale-up’ experiment with 5.00 g of 2 and 7.77
g of 3 (R1=OBn), providing 3.37 g of the desired
L
-Dopa tert-butyl ester (5; R1=OH) as
illustrated in Scheme 3. The attractive feature of this method is that, in addition to its
operational simplicity, the catalyst (R)-1b can be recovered and reused in the present enantio-
selective phase-transfer alkylation.5
Scheme 3.
The following typical procedures provide supporting experimental detail in a large-scale
preparation of -Dopa tert-butyl ester: a 300 mL round-bottom flask containing a magnetic
L
stirring bar and a solution of glycine tert-butyl ester benzophenone Schiff base (2; 5.00 g, 16.9
mmol), 3,4-dibenzyloxybenzyl bromide (7.77 g, 20.3 mmol) and (R)-1b (155 mg, 0.169 mmol) in
toluene (100 mL) was immersed in an ice-water bath. After 10 min of gentle stirring, cold 50%
KOH aqueous solution (33.3 mL) was added by a pipette and the reaction mixture was stirred
vigorously (1365 rpm) for 3 h.6 The resulting mixture was then poured into water (100 mL) and
extracted with CH2Cl2 (2×60 mL). The organic layer was dried over Na2SO4 and concentrated.
The residue was dissolved in THF (60 mL) and a 1.0 M citric acid aqueous solution (150 mL)
was added. This solution was stirred at room temperature for 15 h. After removal of THF in
vacuo, the aqueous solution was neutralized with NaHCO3 and extracted with CH2Cl2 (3×60
mL). The organic extracts were dried over Na2SO4 and concentrated. Purification of the residual
oil by column chromatography on silica gel (ethyl acetate/hexane=3:2, then ethyl acetate only
as eluants) gave the amino ester 4 (R1=OBn) (6.20 g, 14.2 mmol; 84% yield, 98% ee) as a
colorless oil. The enantiomeric excess was determined by chiral HPLC analysis (DAICEL
CHIRALCEL OD, hexane/2-propanol=4:1, flow rate=0.5 mL/min, retention time; 24.3 min
1
(S) and 28.4 min (R)). 400 MHz H NMR (CDCl3) l 7.44 (4H, d, J=7.6 Hz, Ph), 7.26–7.37
(6H, m, Ph), 6.87 (1H, d, J=8.0 Hz, ArꢀH), 6.82 (1H, s, ArꢀH), 6.72 (1H, d, J=8.0 Hz, ArꢀH),
5.13 (4H, s, 2(OCH2Ph)), 3.52 (1H, dd, J=5.6, 7.6 Hz, CHCꢁO), 2.93 (1H, dd, J=5.6, 13.6 Hz,
CHAr), 2.72 (1H, dd, J=7.6, 13.6 Hz, CHAr), 1.48 (2H, br s, NH2), 1.42 (9H, s, t-Bu).
To a THF (45 mL) solution of the amino ester 4 (R1=OBn) (6.20 g, 14.2 mmol) in a 100 mL
round-bottom flask was added 10% palladium on activated carbon (350 mg) at 0°C under argon.
Then, argon was replaced by H2 and the reaction mixture was stirred for 5 h at room
temperature. The mixture was filtered to remove the catalyst and the filtrate was concentrated.

8342
Purification of the residual oil by column chromatography on silica gel (ethyl acetate as eluant)
gave
L
-Dopa tert-butyl ester (5; R1=OH) [3.37 g, 13.3 mmol, 94% yield, [h]2D9 +19.7° (c 1.06,
1
MeOH)] as a white solid. 400 MHz H NMR (CDCl3) l 6.74 (1H, d, J=8.4 Hz, ArꢀH), 6.57
(1H, s, ArꢀH), 6.56 (1H, d, J=8.4 Hz, ArꢀH), 4.04 (4H, br, 2OH and NH2), 3.63 (1H, dd,
J=4.8, 8.4 Hz, CHCꢁO), 3.02 (1H, dd, J=4.8, 13.6 Hz, CHAr), 2.68 (1H, dd, J=8.4, 13.6 Hz,
CHAr), 1.42 (9H, s, t-Bu); IR (KBr) 3462, 3337, 3288, 2977, 2939, 2625, 1734, 1609, 1533, 1472,
1367, 1308, 1283, 1159, 1111, 1043, 854, 799 cm−1. MS: m/z 254 ([M+H]+), 238, 198 (100%), 181,
152, 123, 57. HRMS calcd for C13H20O4N: 254.1393 ([M+H]+). Found: 254.1384 ([M+H]+).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports and Culture, Japan.
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4. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.
5. After neutralization with 1N HBr, the catalyst (R)-1b can be recovered by short silica gel column chromatography
with dichloromethane/methanol=30:1 to 10:1 as eluant (72% recovery yield) before the acidic hydrolysis. The
recovered catalyst (R)-1b was reused several times without losing activity and enantioselectivity (second cycle:
80%, 98% ee; third cycle: 79%, 98% ee).
6. Use of a mechanical stirrer or a homogenizer would be required for further scale-up.
.
.