A convenient preparation of selectively protected L-Dopa derivatives from 3-iodo-L-tyrosine

Article abstract of DOI:10.1081/scc-100104476

Palladium-catalyzed hydroformylation of 3-iodo-L-tyrosine derivatives la,b followed by protection of the free phenol as its benzyl ether and Baeyer-Villiger oxidation of the 3-formyl group provided the desired L-Dopa derivatives 4b,c in 71 and 68% overall

Full text of DOI:10.1081/scc-100104476

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A CONVENIENT PREPARATION OF SELECTIVELY
PROTECTED L-DOPA DERIVATIVES FROM 3-IODO-L-
TYROSINE
Enrico Morera a & Giorgio Ortar b
a Dipartimento di Studi Farmaceutici e Centro di Studio per la Chimica del Farmaco del
C.N.R. , Università ‘La Sapienza’ , Roma, 00185, Italy
b Dipartimento di Studi Farmaceutici e Centro di Studio per la Chimica del Farmaco del
C.N.R. , Università ‘La Sapienza’ , Roma, 00185, Italy
Published online: 09 Nov 2006.
To cite this article: Enrico Morera & Giorgio Ortar (2001) A CONVENIENT PREPARATION OF SELECTIVELY PROTECTED
L-DOPA DERIVATIVES FROM 3-IODO-L-TYROSINE, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:14, 2115-2122, DOI: 10.1081/SCC-100104476
To link to this article: http://dx.doi.org/10.1081/SCC-100104476
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SYNTHETIC COMMUNICATIONS, 31(14), 2215–2222 (2001)
A CONVENIENT PREPARATION OF
SELECTIVELY PROTECTED L-DOPA
DERIVATIVES FROM 3-IODO-L-TYROSINE
Enrico Morera and Giorgio Ortar*
Dipartimento di Studi Farmaceutici e Centro di Studio per la
Chimica del Farmaco del C.N.R.,
Universita ‘La Sapienza’, 00185 Roma, Italy
ABSTRACT
Palladium-catalyzed hydroformylation of 3-iodo-L-tyrosine
derivatives la,b followed by protection of the free phenol as
its benzyl ether and Baeyer-Villiger oxidation of the 3-formyl
group provided the desired L-Dopa derivatives 4b,c in 71 and
68% overall yields, respectively.
L-Dopa derivatives in which the 4-OH group is selectively protected
are useful building blocks for the synthesis of a series of biologically active
natural products, in particular those containing the key structural unit iso-
dityrosine such as piperazinomycin,1 K-13,2 OF4949-I-IV,3 bouvardin and
deoxybouvardin,4 and RA-I-XVI.5
Past syntheses of selectively protected L-Dopa derivatives have
involved monoprotection of the unsymmetrical catechol moiety,6 diazotiza-
tion of 3-amino-L-tyrosine derivatives followed by copper(I)-promoted
phenol introduction6d,7 and Baeyer-Villiger oxidation of 3-acetyl-L-tyrosine8
* Corresponding author.
2215
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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MORERA AND ORTAR
and furnished the desired compounds in 30% yield or less. A benzylic
hydroperoxide rearrangement has been later utilized by Boger to obtain
4c from L-tyrosine in six steps and 34% overall yield.9 More recently, a
five-step synthesis of 4-O-benzyl-N-Boc-L-Dopa from L-tyrosine via
Reimer-Tiemann formylation followed by Dakin oxidation has been
described by Jung.10 The Reimer-Tiemann formylation step afforded how-
ever a low yield of the 3-formyl derivative (33%). Eventually, a method
based on a modified Baeyer-Villiger oxidation of N-Boc-3-acetyl-L-tyrosine
benzyl ester has been reported by Chen, Zhu, and Wilcoxen.11 Although
m-CPBA oxidation of the acetyl group was very clean (81% yield), it was
rather sluggish, requiring 7 days at room temperature.
Following our previous papers on the palladium-catalyzed elaboration
of a-amino acids,12 we report here an alternative and convenient procedure
for the preparation of 4b,c from the commercially available and rather
inexpensive 3-iodo-L-tyrosine which utilizes as the key step a palladium-
catalyzed hydroformylation reaction.
First attempts were made on a fully protected 3-iodo-L-tyrosine (1c),
adopting a procedure similar to that developed originally by Kotsuki13 for
aryl triflates and applied successfully by us to the preparation of 4-hydro-
xymethyl-L-phenylalanine.12b Reaction of 1c with carbon monoxide and
trioctylsilane in the presence of Pd(OAc)2/dppp14 as the catalyst in DMF
at 80ꢀC and atmospheric pressure resulted however in premature catalyst
decomposition and low conversion. The use of 2 mol of dppp per mole of
palladium prolonged the lifetime of the catalyst enough to allow a near
complete conversion after 24 h, but afforded the desired aldehyde 2c along
with the concomitant reduction product 3 in 34 and 50% yields, respect-
ively. Faster conversions were observed with dppe15 and, especially, dppf15
as the ligands, but again the main reaction product was 3, nor could the
selectivity be improved by slow addition of the organosilane.
The hydroformylation reaction using Pd(OAc)2/2dppf as the catalytic
system was then tried on the free phenol 1a. The reaction went to com-
pletion in 6 h and appeared uncontaminated from the reduction product,
even by fast introduction of silane reagent. Beside the aldehyde 2a (52%
yield), the trioctylsilyl ether 2b was produced (26% yield) as the result of the
silylation of the free phenol by Oct3SiI arising from hydroformylation reac-
tion. Subjecting the carbonylation reaction mixture to a fluoride ion-induced
desilylation before work-up, we were able to isolate 2a in 77% yield. Even
more gratifying was however the use of Et3SiH instead of Oct3SiH. The
reaction went to completion in 1.5 h and afforded 2a in 85% yield.
Thus, in contrast to Kotsuki’s findings, the use of dppf as the ligand
and of Et3SiH as the hydride donor did not ‘prove to be too reactive to
control the reaction selectivity’.13 Triethylsilane has been previously

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2217
employed as hydride donor in the carbonylation of arenediazonium salts16
and aryl iodides,17 but pressurized CO had to be used to obtain satisfactory
yields of aldehydes in the former case, while in the carbonylation of ary1
iodides a Pd-Co bimetallic system was investigated and the major products
were either benzyl silyl ethers or 1,2-diaryl-1,2-disiloxyethanes.
Benzylation of the free phenol was accomplished utilizing Boger’s con-
ditions (BnBr/K2CO3/n-Bu4NI/DMF, rt)9 to minimize possible racemiza-
tion and provided 2c in near quantitative yield. Baeyer-Villiger oxidation
of 2c with 1.5 equiv of m-chloroperbenzoic acid in CH2Cl2 at room tem-
perature was complete in 7 h to give the corresponding formate 4a in 88%
yield. The formate group was smoothly cleaved by treatment with metha-
nolic ammonia at room temperature for 0.5 h to afford 4b in 95% yield. The
two-step reaction sequence leading from 2c to 4b can be conveniently con-
ducted as a one-pot operation that omits the isolation of the formate. The
monoprotected L-Dopa derivative 4b was isolated in 84% yield from 2c.

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MORERA AND ORTAR
Thus, in a four-step procedure, 4b was obtained from 3-iodo-L-tyrosine
derivative 1a in 71% overall yield.
Repetition of the same four-step procedure on 1b led to N-Cbz-4-O-
benzyl-L-Dopa methyl ester (4c) in 68% overall yield. Physical data for 4c
were in good agreement with the values reported in the literature.9
EXPERIMENTAL SECTION
Melting points were determined on a Kofler hot-stage apparatus and
are uncorrected. Optical rotations were measured at 25ꢀC with a Schmidt-
Haensch Polartronic D polarimeter (1 dm-cell) in 1% CHCl3 solutions,
unless otherwise indicated. IR spectra were recorded on a Perkin-Elmer
983 spectrophotometer as CHCl3 solutions. 1H and 13C NMR spectra
were obtained on a Varian Mercury 300 spectrometer using CDCl3 as sol-
vent and TMS as internal standard. Microanalyses have been performed by
Dr. L. Petrilli of Servizio Microanalisi del C.N.R., Area della Ricerca di
Roma, 00016 Monterotondo Stazione, Roma, Italy.
N-[(1,1-Dimethylethoxy)carbonyl]-3-iodo-L-tyrosine Methyl Ester (1a).
Dry HCl was slowly bubbled through a stirred suspension of 3-iodo-L-tyr-
osine (2.00 g, 6.51 mmol) in dry MeOH (30 mL) for 2 h at 0ꢀC. The final
solution was evaporated under reduced pressure to leave a white solid
(2.31 g, 99%) which was used in the next step without further purification.
A suspension of the above methyl ester hydrochloride in dry CH2Cl2
(25 mL) was treated with Et3N (2.73 mL, 19.5 mmol) and di-tert-butyl dicar-
bonate (1.77 g, 8.12 mmol) at room temperature for 2 h. The reaction mix-
ture was concentrated under reduced pressure and the residue was diluted
with Et2O. The ethereal solution was washed with 10% aqueous NaHCO3
and brine, dried (Na2SO4), and evaporated. The residue (2.84 g) was purified
by chromatography on silica gel (57 g) using hexane/AcOEt ¼ 7/3 as eluent
to give 2.47 g (90%) of 1a: mp 111–112ꢀC (CH2Cl2/hexane); [a]D þ 46ꢀ,
þ14ꢀ (c 1.0, MeOH) {lit.18 mp 101–103ꢀC; [a]19–26 þ19ꢀ (c 1.0, MeOH)};
246
IR 3497, 3432, 2984, 1741, 1711, 1487, 1367, 1170cm À1; H NMR d 1.43
1
(9H, s, t-Bu), 2.93 (1H, dd, J ¼ 14.1, 6.0Hz, C HH), 3.03 (1H, dd, J ¼ 14.1,
6.0Hz, CH H), 3.73 (3H, s, CO2Me), 4.51 (1H, m, a-CH), 5.04 (1H, d, J ¼
7.5 Hz, NH), 5.88 (1H, m, OH), 6.86 (1H, d, J ¼ 8.1 Hz, ArH), 6.99 (1H, dd,
J ¼ 8.1, 2.1 Hz, ArH), 7.43 (1H, br s, ArH); 13C NMR d 28.32, 37.00, 52.34,
54.50, 80.21, 85.38, 115.05, 130.03, 130.97, 139.00, 154.19, 155.10, 172.20.
N-[(Phenylmethoxy)carbonyl]-3-iodo-L-tyrosine Methyl Ester (1b).
Crude 3-iodo-L-tyrosine methyl ester hydrochloride, obtained as above
from 3-iodo-L-tyrosine (2.00 g, 6.51 mmol), in a two-phase mixture of H2O
(32 mL) and Et2O (26 mL) was treated with Na2CO3 (2.07 g, 19.5 mmol) and

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L-DOPA DERIVATIVES
2219
benzyl chloroformate (0.92 mL, 6.51 mmol) and the resulting mixture was
stirred for 3 h at room temperature. The mixture was then diluted with Et2O,
the organic layer was separated, washed with brine, dried (Na2SO4), and
evaporated. The residue (2.90g) was chromatographed on silica gel (28 g)
with hexane/AcOEt ¼ 75/25 as eluent to give 2.64 g (89%) of 1b: mp 101–
102ꢀC (CH2Cl2/hexane); [a]Dþ49ꢀ, þ2ꢀ (c 1.0, MeOH) {lit.18 mp 99.5–
101ꢀC; [a]19–26246þ2ꢀ (c 1.0, MeOH)}; IR 3493, 3428, 2950, 1721, 1486,
1
1351 cmÀ1; H NMR d 2.96 (1H, dd, J ¼ 14.0, 6.0 Hz, CHH), 3.04 (1H,
dd, J ¼ 14.0, 6.0 Hz, CHH), 3.72 (3H, s, CO2Me), 4.59 (1H, m, a-CH), 5.08
(1H, d, J ¼ 12.1 Hz, PhCHHO), 5.12 (1H, d, J ¼ 12.1 Hz, PhCHHO), 5.28
(1H, d, J ¼ 7.8 Hz, NH), 5.59 (1H, br s, OH), 6.84 (1H, d, J ¼ 8.2 Hz, ArH),
6.95 (1H, dd, J ¼ 8.2, 2.1 Hz, ArH), 7.34–7.41 (6H, m, ArH); 13C NMR d
36.95, 52.42, 54.92, 67.13, 85.52, 115.11, 128.09, 128.25, 128.59, 128.84,
131.03, 136.18, 138.90, 154.20, 155.66, 171.79.
N-[(1,1-Dimethylethoxy)carbonyl]-3-formyl-L-tyrosineMethylEster(2a).
A mixture of N-Boc-3-iodo-L-tyrosine methyl ester (1a, 421 mg, 1 mmol),
Pd(OAc)2 (11 mg, 0.05 mmol), dppf (55 mg, 0.10 mmol), and Et3N
(0.35 mL, 2.5 mmol) in DMF (5 mL) was purged with carbon monoxide
for 5 min. Then, triethylsilane (0.32 mL, 2 mmol) was introduced in one
portion by a syringe and the mixture was stirred under a CO balloon
at 80ꢀC for 1.5 h. The mixture was then diluted with brine and extrac-
ted with AcOEt. The organic phase was washed two times with brine,
dried (Na2SO4), and evaporated. The residue (465 mg) was chromato-
graphed on silica gel (14 g) using CH2Cl2/AcOEt ¼ 95/5 as eluent to give
275 mg (85%) of 2a: mp 85–86ꢀC (CH2Cl2/hexane); [a]D þ57ꢀ; IR 3435,
2990, 1743, 1710, 1658, 1485, 1367, 1284, 1161 cmÀ1 1H NMR d 1.42
;
(9H, s, t-Bu), 3.01 (1H, dd, J ¼ 13.8, 6.3 Hz, CHH), 3.15 (1H, dd, J ¼ 13.8,
5.6 Hz, CHH), 3.73 (3H, s, CO2Me), 4.58 (1H, m, a-CH), 5.07 (1H, d,
J ¼ 8.1 Hz, NH), 6.93 (1H, d, J ¼ 8.4 Hz, ArH), 7.29–7.33 (2H, m, ArH),
9.86 (1H, s, CHO), 10.92 (1H, s, OH); 13C NMR d 28.29, 37.42, 52.39, 54.39,
80.19, 117.85, 120.49, 127.73, 134.10, 138.03, 155.03, 160.68, 172.08, 196.38.
Anal. Calcd for C16H21NO6 (323.4): C, 59.43; H, 6.55; N, 4.33. Found: C,
59.80; H, 6.81; N, 4.38.
N-[(Phenylmethoxy)carbonyl]-3-formyl-L-tyrosine methyl ester (2d)
could be prepared and isolated in a similar manner using N-Cbz-3-iodo-L-
tyrosine methyl ester (1b, 455 mg, 1 mmol) as starting material. The reaction
time was 3 h and the yield of 2d was 82%: mp 75–77ꢀC (Et2O/petroleum
ether); [a]Dþ47ꢀ; IR 3431, 2951, 2849, 1721, 1658, 1499, 1485, 1284 cmÀ1
;
1H NMR d 3.03 (1H, dd, J ¼ 14.1, 6.3 Hz, CHH), 3.16 (1H, dd, J ¼ 14.1,
5.7 Hz, CHH), 3.73 (3H, s, CO2Me), 4.65 (1H, m, a-CH), 5.06 (1H, d, J ¼
12.0Hz, PhC HHO), 5.12 (1H, d, J ¼ 12.0Hz, PhCH HO), 5.32 (1H, d, J ¼
7.2 Hz, NH), 6.89 (1H, d, J ¼ 7.8 Hz, ArH), 7.24–7.34 (7H, m, ArH), 9.76

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2220
MORERA AND ORTAR
(1H, s, CHO), 10.91 (1H, s, OH); 13C NMR d 37.24, 52.51, 54.79, 67.09,
117.93, 120.50, 127.37, 128.18, 128.35, 128.58, 134.09, 136.15, 137.94,
155.56, 160.72, 171.70, 196.38. Anal. Calcd for C19H19NO6 (357.4): C,
63.86; H, 5.36; N, 3.92. Found: C, 64.03; H, 5.40; N, 3.97.
N-[(1,1-Dimethylethoxy)carbonyl]-3-formyl-O-(phenylmethyl)-L-tyro-
sine Methyl Ester (2c). A solution of 2a (323 mg, 1 mmol), in dry DMF
(4 mL) was treated with K2CO3 (276 mg, 2 mmol), n-Bu4NI (37 mg,
0.1 mmol), and benzyl bromide (0.125 mL, 1.05 mmol). The resulting mix-
ture was stirred at room temperature for 1.5 h, then partitioned between
AcOEt and brine. The organic phase was washed twice with brine, dried
(Na2SO4), and evaporated. Flash chromatography of the residue (460mg)
on silica gel (10g) using hexane/AcOEt ¼ 65/35 as eluent gave 409 mg (99%)
of 2c: colorless oil; [a]Dþ58ꢀ; IR 3434, 2950, 1738, 1703, 1610, 1494, 1367,
1
1163 cmÀ1; H NMR d 1.41 (9H, s, t-Bu), 3.00 (1H, dd, J ¼ 14.0, 6.0 Hz,
CHH), 3.12 (1H, dd, J ¼ 14.0, 5.4 Hz, CHH), 3.73 (3H, s, CO2Me), 4.55
(1H, m, a-CH), 5.02 (1H, d, J ¼ 6.9 Hz, NH), 5.17 (2H, s, PhCH2O), 7.00
(1H, d, J ¼ 9.0Hz, ArH), 7.26–7.43 (6H, m, ArH), 7.60 (1H, br, s, ArH),
10.52 (1H, s, CHO); 13C NMR d 28.27, 37.40, 52.36, 54.42, 70.61, 80.07,
113.32, 125.00, 127.33, 128.33, 128.76, 128.86, 129.04, 136.04, 136.70,
155.02, 160.20, 172.09, 189.49. Anal. Calcd for C23H27NO6 (413.5): C,
66.81; H, 6.58; N, 3.39. Found: C, 67.10; H, 6.39; N, 3.20.
N-[(Phenylmethoxy)carbonyl]-3-formyl-O-(phenylmethyl)-L-tyrosine
methyl ester (2e) was prepared and isolated in a similar fashion from 2d in
98% yield: mp 118–119ꢀC (CH2Cl2/hexane); [a]Dþ59ꢀ; IR 3432, 2953, 2869,
1
1720, 1679, 1611, 1494, 1250 cmÀ1; H NMR d 3.03 (1H, dd, J ¼ 14.1,
6.1 Hz, CHH), 3.13 (1H, dd, J ¼ 14.1, 5.2 Hz, CHH), 3.73 (3H, s,
CO2Me), 4.63 (1H, m, a-CH), 5.08 (2H, s, PhCH2O2C), 5.15 (2H, s,
PhCH2O), 5.29 (1H, d, J ¼ 6.9 Hz, NH), 6.95 (1H, d, J ¼ 8.4 Hz, ArH),
7.25–7.42 (11H, m, ArH), 7.59 (1H, d, J ¼ 2.1 Hz, ArH), 10.50 (1H, s,
CHO); 13C NMR d 37.21, 52.41, 54.75, 66.96, 70.54, 113.28, 124.96,
127.26, 128.03, 128.13, 128.27, 128.47, 128.69, 128.90, 135.93, 136.15,
136.59, 155.51, 160.15, 171.66, 189.34. Anal. Calcd for C26H25NO6
(447.5): C, 69.79; H, 5.63; N, 3.13. Found: C, 70.08; H, 5.65; N, 3.17.
N-[(1,1-Dimethylethoxy)carbonyl]-3-hydroxy-O-(phenylmethyl)-L-tyro-
sine Methyl Ester (4b). A solution of 2c (413 mg, 1 mmol) and m-chloroper-
benzoic acid (381 mg, 68%, 1.5 mmol) in CH2Cl2 (10mL) was stirred at
room temperature for 7 h. A 2M solution of NH3 in MeOH (7.5 mL) was
added and the mixture was stirred at room temperature for another 0.5 h.
The solution was concentrated under reduced pressure and the residue was
diluted with AcOEt, washed with saturated aqueous Na2S2O3, saturated
aqueous NaHCO3 and brine, dried (Na2SO4), and evaporated. The residue
(415 mg) was chromatographed on silica gel (13 g) with hexane/AcOEt ¼ 73/

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L-DOPA DERIVATIVES
2221
27 as eluent to give 337 mg (84%) of 4b: colorless oil; [a]Dþ49ꢀ; IR 3539,
3438, 3003, 1709, 1594, 1499, 1368, 1274, 1164 cmÀ1 1H NMR d 1.42
;
(9H, s, t-Bu), 2.98 (2H, m, b-CH2), 3.71 (3H, s, CO2Me), 4.53 (1H, m, a-
CH), 5.01 (1H, d, J ¼ 8.1 Hz, NH), 5.07 (2H, s, PhCH2O), 5.84 (1H, br s,
OH), 6.57 (1H, dd, J ¼ 8.1, 2.1 Hz, ArH), 6.71 (1H, d, J ¼ 2.1 Hz, ArH),
6.83 (1H, d, J ¼ 8.1 Hz, ArH), 7.36–7.40(5H, m, ArH); 13C NMR d 28.31,
37.68, 52.17, 54.49, 71.20, 79.90, 112.36, 115.83, 120.76, 127.81, 128.38,
128.72, 129.58, 136.41, 145.01, 145.95, 155.16, 172.39. Anal. Calcd for
C22H27NO6 (401.5): C, 65.82; H, 6.78; N, 3.49. Found: C, 65.99; H, 6.87;
N, 3.39.
Repetition of the two-step procedure on 2e gave N-[(phenylmethoxy)-
carbonyl]-3-hydroxy-O-(phenylmethyl)-L-tyrosine methyl ester (4c) in 85%
overall yield: colorless oil; [a]Dþ44ꢀ, À14ꢀ (c 1.0, MeOH) {lit.9 colorless
oil; [a]22 À15.1ꢀ (c 1.0, MeOH)}; IR 3540, 3428, 2951, 1713, 1673, 1599,
D
1503, 1337, 1275 cmÀ1
;
1H NMR d 3.01 (2H, m, b-CH2), 3.71 (3H, s,
CO2Me), 4.61 (1H, m, a-CH), 5.05 (2H, s, PhCH2O or PhCH2O2C), 5.09
(2H, s, PhCH2O2C or PhCH2O), 5.26 (1H, d, J ¼ 8.1 Hz, NH), 5.74 (1H, br
s, OH), 6.54 (1H, dd, J ¼ 8.4, 2.1 Hz, ArH), 6.69 (1H, d, J ¼ 2.1 Hz, ArH),
6.80(1H, d, J ¼ 8.4 Hz, ArH), 7.25–7.40(10H, m, ArH); 13C NMR d 37.57,
52.29, 54.85, 66.96, 71.20, 112.36, 115.73, 120.77, 127.82, 128.08, 128.14,
128.40, 128.51, 128.73, 129.26, 136.35, 145.06, 145.99, 155.70, 172.01.
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Received in the UK July 17, 2000

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