Effective syntheses of quinoline-7,8-diol, 5-amino-L-DOPA, and 3-(7,8-dihydroxyquinolin-5-yl)-L-alanine

Article abstract of DOI:10.1016/j.tet.2003.02.004

A modification of the Baeyer-Villiger reaction allows the conversion of aromatic 2-hydroxy-3-nitroketones and aldehydes into 3-nitrocatechols, which can be reduced to 3-aminocatechols. Reaction of the latter with acrolein yields quinoline-7,8-diols under exceptionally mild conditions. This new reaction sequence was successfully applied to the synthesis of the title compounds.

Full text of DOI:10.1016/j.tet.2003.02.004

Tetrahedron 59 (2003) 9231–9237
Effective syntheses of quinoline-7,8-diol, 5-amino-L-DOPA, and
3-(7,8-dihydroxyquinolin-5-yl)-L-alanine
*
Markus R. Heinrich and Wolfgang Steglich
¨ ¨ ¨
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, D-81377 Munchen, Germany
Received 8 January 2003; revised 28 February 2003; accepted 28 February 2003
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
Abstract—A modification of the Baeyer–Villiger reaction allows the conversion of aromatic 2-hydroxy-3-nitroketones and aldehydes into
3-nitrocatechols, which can be reduced to 3-aminocatechols. Reaction of the latter with acrolein yields quinoline-7,8-diols under
exceptionally mild conditions. This new reaction sequence was successfully applied to the synthesis of the title compounds.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
even after several days of exposure to the peracid. The
reluctance of aromatic 2-hydroxy-3-nitroaldehydes and
ketones to undergo the Baeyer–Villiger rearrangement is
well known,8 and in a comprehensive review9 no successful
example for this type of reaction is given. We were,
therefore, pleased to obtain O-acetylcatechol 6 in up to 89%
yield by treatment of ketone 5 with peracetic acid, followed
by chromatography of the crude reaction mixture on a silica
gel column (Scheme 2). Even more effective is the direct
conversion of ketone 5 into the free catechol 7 by addition of
a solution of ammonia in methanol to the mixture of 5 and
the peracid.
Like the corresponding 8-hydroxy derivative,1 (7,8-dihy-
droxyquinolin-5-yl)-L-alanine (1) can be expected to form
metal complexes. In addition, 1 can participate in electron
transfer reactions and may be regarded as a biosynthetic
precursor of the cytotoxic marine alkaloid halitulin.2–4 In
this publication we describe an efficient synthesis of this
interesting amino acid from L-tyrosine.
Our procedure is of general value for the synthesis of 3-
nitrocatechols.3 Thus far, compounds of this type have only
been accessible by more complicated10 or uneconomic11
routes. Mechanistically, the action of ammonia or silica gel
on the reaction mixture may assist the formation and
breakdown of the crucial epoxy intermediate 1012 from the
phenolic precursor 9 (Scheme 3).
2. Results and discussion
Our synthesis of 1 commences from 3-acetyl-L-tyrosine (2)
which can be easily prepared by Friedel–Crafts acetylation
of L-tyrosine5 (Scheme 1). Esterification of 2 with methanol
and treatment of the resulting ester 3 with trichloroethoxy-
carbonyl (Troc) chloride yielded the N-protected amino acid
ester 4. Nitration of 4 with 100% nitric acid in acetic acid6
afforded the 3-acetyl-5-nitro-L-tyrosine derivative 5 in good
yield.
Methylation of the dihydroxyphenylalanine (DOPA) deriva-
tive 7 with dimethyl sulfate yielded the dimethyl ether 8. In
the same manner, acetate 6 may be used to prepare mono
O-protected derivatives of 7.
Hydrogenation of the 5-nitro-DOPA derivatives 7 and 8
with Pd–C (10%) in 0.2 M methanolic HCl yielded the
5-amino derivatives 11 and 12, respectively, in form of their
hydrochlorides. Neutral conditions led to partial dechlor-
ination of the N-protecting group. The hydrobromide of free
5-amino-L-DOPA (13) was obtained by heating 11 in 48%
aqueous HBr. The amine 12, prepared from L-tyrosine
in 30% overall yield, is a valuable starting material for
the synthesis of 5-substituted DOPA derivatives. Thus,
diazotation under standard conditions yielded the crystalline
Attempts to convert 5 with peracetic acid or meta-
chloroperbenzoic acid into the desired DOPA derivative
were unsuccessful,7 and the starting material was recovered
Keywords: Baeyer–Villiger reaction; 3-aminocatechols; quinolines; L-
DOPA derivatives.
*
Corresponding author. Tel.: þ49-89-2180-77757; fax: þ49-89-2180-
77756; e-mail: wos@cup.uni-muenchen.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.02.004

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Scheme 1. Synthesis of the 3-acetyl-5-nitro-L-tyrosine derivative 5. Reagents and conditions: (a) AcCl, AlCl3, PhNO2, 1008C, 80%. (b) SOCl2, MeOH, reflux,
100%. (c) Cl3CCH2OCOCl, NaHCO3, NaCl, CHCl3, H2O, 08C, 92%. (d) HNO3, AcOH, 158C!rt, 45–63%. Troc¼2,2,2-trichloroethoxycarbonyl.
Scheme 2. Oxidation of nitroketone 5 with peracids.
Scheme 3. Proposed mechanism for the base-catalysed formation of nitrocatechol 6.
tetrafluoroborate 14, which afforded the 5-fluoro-L-DOPA
derivative 1513 on heating in xylenes. Experiments aimed at
exploiting this reaction in the preparation of the 18F-labelled
compound are under investigation.
Treatment of amine 11 with acrolein in 1.3 M methanolic
HCl for three days at rt yielded the quinoline derivative 16
(Scheme 4), which can be converted into dibenzyl ether 17
by treatment with benzyl bromide. Due to the orthogonal

M. R. Heinrich, W. Steglich / Tetrahedron 59 (2003) 9231–9237
9233
Scheme 4. Synthesis of (7,8-dihydroxyquinolin-5-yl)-L-alanine dihydrobromide (18).
protecting groups, 17 may be used directly for the
synthesis of peptides containing (7,8-dihydroxyquinolin-5-
yl)-L-alanine (1). Indeed, the dihydrobromide salt, 18, of the
amino acid can be obtained by heating 16 in 48% aqueous
HBr.
4. Experimental
4.1. General
All reactions requiring anhydrous conditions were con-
ducted in flame or oven-dried apparatus under an atmo-
sphere of argon. Reactions were monitored by TLC using
commercially available aluminium-backed plates, pre-
coated with a layer of silica gel containing a fluorescent
indicator (Merck). Column chromatography was carried out
on silica gel 60 (40–63 mm, 230–400 mesh, Merck).
Hexanes refers to the fraction of petroleum ether with bp
40–608C. Melting points were measured on a Reichert
Thermovar hot-stage microscope and are uncorrected. IR
spectra were measured on a Perkin–Elmer FT spectrometer
Spectrum-1000. 1H and 13C NMR spectra were recorded in
CDCl3, CD3OD, [D6]DMSO, or [D6]acetone using a Bruker
ARX 300, Varian VXR 400S or Bruker AMX 600
spectrometer. Chemical shifts are reported relative to
CDCl3 (dH 7.26, dC 77.0), CD3OD (dH 3.35, dC 49.3),
[D6]DMSO (dH 2.49, dC 39.5) or [D6]acetone (dH 2.06, dC
29.8). Mass spectra (EI, FAB, ESI) were recorded on a
Finnigan MAT 90 or MAT 95Q spectrometer.
In the same manner, 3-aminocatechol hydrochloride (20),
prepared from 5-bromo-3-nitrocatechol (19)3 by hydro-
genolysis with Pd/C, gave quinoline-7,8-diol (21)14 in good
yield (Scheme 5).
The formation of quinoline-7,8-diols from the correspond-
ing 3-aminocatechols is a mild variant of the Skraup
reaction, in which air acts as oxidant for the dihydroquino-
line intermediate. The dehydrogenation step is meditated
by the catechol unit which forms a redox system with
the corresponding ortho-quinone. Compared to the
classical Skraup synthesis, the reaction does not depend
on the presence of an added oxidizing agent. When the
reaction is applied to the dimethyl ether 12, the yield is far
lower.
The biological activities of 1 and peptides derived therefrom
are now under investigation.
4.1.1. 3-Acetyl-L-tyrosine methyl ester hydrochloride (3).
SOCl2 (4.38 mL, 7.14 g, 60.0 mmol) was added dropwise to
a solution of 3-acetyl-L-tyrosine hydrochloride (2)5a
(10.39 g, 40.0 mmol) in dry methanol maintained at 08C.
After heating the reaction mixture at reflux for 8 h, the
solvents were removed under reduced pressure to give 3 as a
colourless solid (10.94 g, 100%); Rf¼0.6 (CHCl3–MeOH,
10:1, v/v); IR (KBr) 3045br, 1752s, 1639s, 1490s, 1446m,
1372m, 1302s, 1253s, 1235s, 1130w, 1061w, 848m, 810m,
635m, 616m cm21; 1H NMR (300 MHz, CD3OD) d 2.70 (s,
3H), 3.23 (dd, J¼14.5, 6.9 Hz, 1H), 3.31 (m, 1H), 3.87 (s,
3H), 4.40 (dd, J¼6.9, 6.4 Hz, 1H), 6.99 (d, J¼8.6 Hz, 1H),
7.45 (dd, J¼8.6, 2.3 Hz, 1H), 7.86 (d, J¼2.3 Hz, 1H); 13C
NMR (75.5 MHz, CD3OD) d 27.5, 36.6, 54.0, 55.4, 120.0,
121.5, 126.1, 133.6, 138.7, 163.07, 170.7, 206.5; MS (EI,
70 eV) m/z (rel. int.): 237 (3, Mþ), 178 (18), 150 (37), 149
3. Conclusions
In summary, we have achieved a modification of the
Baeyer–Villiger reaction which allows the conversion of
aromatic 2-hydroxy-3-nitroketones and aldehydes into
3-nitrocatechols. Reduction of the latter yields 3-aminoca-
techols,10,11 which represent valuable starting materials for
the synthesis of quinoline-7,8-diols, hitherto only be
accessible from pre-existing quinoline derivatives using
rather severe reaction conditions.14 The new methodology
was applied to the first syntheses of 3-(7,8-dihydroxy-
quinolin-5-yl)-L-alanine (1), 5-amino-L-DOPA (13), and
the complex marine alkaloid halitulin.3
Scheme 5. Synthesis of quinoline-7,8-diol (21).

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M. R. Heinrich, W. Steglich / Tetrahedron 59 (2003) 9231–9237
(100), 131 (25), 107 (11), 88 (31), 36 (65); HRMS (EI) calcd
for C12H15NO4 237.1001, found 237.0998.
2.03 mmol) in CH2Cl2 (150 mL) was treated with meta-
chloroperbenzoic acid (70%, 1.25 g, 5.08 mmol). The
resulting mixture was stirred for 24 h at rt and then
concentrated under reduced pressure. The residue was
directly applied to the top of a silica gel column which was
eluted with EtOAc–hexanes (2:3, v/v) to yield 6 (0.67–
0.86 g, 70–89%) as well as recovered starting material (10–
30%). During the chromatography, the formation of bubbles
inside the column was observed.
4.1.2. 3-Acetyl-N-(2,2,2-trichloroethoxycarbonyl)-L-
tyrosine methyl ester (4). A chilled (08C) solution of 3
(4.00 g, 14.6 mmol) in H2O (100 mL) and CHCl3 (100 mL)
was treated with NaHCO3 (2.45 g, 29.2 mmol), NaCl
(4.00 g), and 2,2,2-trichloroethyl chloroformate (2.11 mL,
15.3 mmol). The reaction mixture was stirred for 2 h at 08C,
then the phases were separated and the aq. layer extracted
with CHCl3 (2£50 mL). The combined organic phases were
washed with H2O and dried (MgSO4). Concentration under
reduced pressure gave 4 as a colourless oil (5.53 g, 92%);
Rf¼0.85 (CHCl3–MeOH, 10:1, v/v); [a]2D0¼29.7 (c 0.8,
MeOH); IR (KBr) 3340m, 3009m, 2956m, 1738s, 1732s,
1644s, 1532m, 1488s, 1437m, 1370m, 1299s, 1253s, 1219s,
1094m, 1047m, 820m, 769m, 722m, 634m, 568m cm21; 1H
NMR (300 MHz, CDCl3) d 2.60 (s, 3H), 3.04 (dd, J¼14.2,
6.1 Hz, 1H), 3.15 (dd, J¼14.2, 5.6 Hz, 1H), 3.75 (s, 3H),
4.62 (d, J¼12.1 Hz, 1H), 4.67 (m, 1H), 4.81 (d, J¼12.1 Hz,
1H), 5.63 (d, J¼8.3 Hz, 1H), 6.90 (d, J¼8.5 Hz, 1H), 7.23
(dd, J¼8.5, 2.2 Hz, 1H), 7.48 (d, J¼2.2 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3) d 26.6, 37.4, 52.6, 54.9, 74.5, 95.3,
118.7, 119.5, 125.8, 131.2, 137.4, 153.8, 161.5, 171.3,
204.2; MS (EI, 70 eV) m/z (rel. int.): 413 (1) [Mþ,
C15H16NO367Cl35Cl2þ], 411 (1) [Mþ, C15H16NO635Cl3þ], 354
(1), 352 (1), 264 (4), 220 (14), 150 (10), 149 (100), 131 (13);
HRMS (EI) calcd for C15H16NO365Cl3 411.0043, found
411.0044.
Compound 6. Light yellow oil; Rf¼0.75 (EtOAc–hexanes,
1:1, v/v); [a]2D0¼27.4 (c 1.0, MeOH); 1H NMR (300 MHz,
CDCl3) d 2.36 (s, 3H), 3.08 (dd, J¼14.1, 6.1 Hz, 1H), 3.23
(dd, J¼14.1, 5.6 Hz, 1H), 3.79 (s, 3H), 4.64 (d, J¼12.1 Hz.
1H), 4.65 (m, 1H), 4.83 (d, J¼12.1 Hz, 1H), 5.62 (d,
J¼7.4 Hz, 1H), 7.21, 7.98 (each d, J¼2.0 Hz, 1H), 10.53 (s,
1H); 13C NMR (75.5 MHz, CDCl3) d 20.4, 37.0, 52.9, 54.7,
74.6, 95.2, 122.6, 127.0, 131.7, 134.3, 140.7, 147.1, 153.8,
168.2, 170.7; MS (EI) m/z (rel. int.): 474 (0.1) [Mþ,
C15H15N2O937Cl35Clþ2 ], 472 (0.1) [Mþ, C15H15N2O395Cl3þ],
414 (1), 412 (1), 325 (2), 297 (2), 282 (22), 252 (5), 239
(100), 223 (24), 193 (4), 168 (67), 149 (29), 138 (9), 122 (8);
HRMS (EI) calcd for C15H16N2O395Cl3þ 472.9922, found
472.9911.
4.1.5. N-(2,2,2-Trichloroethoxycarbonyl)-5-nitro-L-
DOPA methyl ester (7). A solution of 5 (1.00 g,
2.19 mmol) in CH2Cl2 (40 mL) was treated with peracetic
acid (39% in AcOH, 0.74 mL, 4.38 mmol) under an argon
atmosphere. The resulting mixture was stirred for 2 h at rt
and then treated with NH3 (2.8 M in MeOH, 4.1 mL,
11.5 mmol). The ensuing intense red solution was stirred
under argon for an additional hour at rt and then quenched
with 1N HCl (20 mL). The organic phase was separated and
concentrated under reduced pressure. The resulting red oil
was diluted with EtOAc (40 mL), washed with sat. aq.
Na2S2O3 (2£30 mL), H2O (20 mL), sat. aq. NaCl (20 mL),
and dried (Na2SO4). Evaporation and drying of the residue
under reduced pressure gave 7 (0.86 g, 91%) as an orange–
brown foam; Rf¼0.6 (EtOAc–hexanes, 1:1, v/v);
[a]2D0¼25.1 (c 0.8, MeOH); IR (KBr) 3433s, 3331m,
2957w, 1734s, 1720s, 1545s, 1440m, 1348s, 1286s, 1242s,
1162m, 1092m, 1043m, 820m, 799m, 764m, 726m,
4.1.3. 3-Acetyl-N-(2,2,2-trichloroethoxycarbonyl)-5-
nitro-L-tyrosine methyl ester (5). A solution of 4
(22.68 g, 55.0 mmol) in AcOH (100 mL) maintained at
128C was treated, dropwise over 15 min, with 100% HNO3
(3.42 mL, 82.5 mmol). The mixture was warmed up to rt
over 1 h, diluted with H2O (300 mL), and extracted with
CHCl3 (3£150 mL). The combined organic phases were
washed with H2O and sat. NaCl solution, dried (Na2SO4),
and concentrated under reduced pressure. The residue was
purified by silica gel flash chromatography (EtOAc–
hexanes, 1:1, v/v) to give 5 (11.33–15.86 g, 45–63%) as
well as 20–25% starting material.
1
Compound 5. Yellow solid, mp 728C; Rf¼0.65 (EtOAc–
hexanes, 1:1, v/v); [a]D20¼217.8 (c 0.6, MeOH); IR (KBr)
3335m, 3076w, 3010m, 2958m, 1740br, 1702s, 1657s,
1589m, 1535s, 1462m, 1439m, 1361s, 1346s, 1279s, 1225s,
1094s, 1047m, 978m, 820m, 774m, 731m, 569m cm21; 1H
NMR (300 MHz, CDCl3) d 2.69 (s, 3H), 3.09 (dd, J¼14.3,
6.6 Hz, 1H), 3.26 (dd, J¼14.3, 5.3 Hz, 1H), 3.80 (s, 3H),
4.60 (d, 1H, J¼12.0 Hz), 4.67 (m, 1H), 4.79 (d, 1H,
J¼12.0 Hz), 5.80 (d, J¼7.8 Hz, 1H), 7.68, 7.98 (each d,
J¼2.2 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 28.2, 36.9,
52.9, 54.7, 74.5, 95.1, 123.6, 126.3, 132.0, 137.3, 137.4,
153.8, 155.1, 170.8, 202.4; MS (EI) m/z (rel. int.):
456 (0.03) [Mþ, C15H15N2O385Clþ3 ], 440 (2) [Mþ2H2O,
570m cm21; H NMR (300 MHz, [D6]DMSO) d 2.81 (dd,
J¼13.9, 10.3 Hz, 1H), 3.00 (dd, J¼13.9, 4.9 Hz, 1H), 3.63
(s, 3H), 4.27 (ddd, J¼10.3, 8.3, 4.9 Hz, 1H), 4.72, 4.77
(each d, J¼12.0 Hz, 1H), 6.98, 7.23 (each d, J¼2.1 Hz, 1H),
8.22 (d, J¼8.3 Hz, 1H), 10.01, 10.06 (each s, 1H); 13C NMR
(75.5 MHz, [D6]DMSO) d 35.2, 52.1, 55.3, 73.4, 96.0,
115.0, 120.9, 128.0, 136.6, 140.6, 147.4, 154.4, 171.6; MS
(EI) m/z (rel. int.): 432 (0.5) [Mþ, C13H13N2O387Cl35Cl2þ],
430 (0.5) [Mþ, C13H13N2O835Clþ3 ], 414 (1), 412 (1), 397 (2),
395 (2), 373 (3), 371 (3), 337 (1), 335 (2), 283 (11), 264 (7),
262 (7), 240 (12), 239 (100), 168 (36), 151 (18), 133 (14),
131 (14); HRMS (EI) calcd for C13H13N2O385Cl3 429.9738,
found 429.9745.
C15H13N2O377Cl35Cl2þ],
438
(3)
[Mþ2H2O,
C15H13N2O375Clþ3 ], 309 (3), 308 (4), 265 (24), 250 (8), 195
(11), 194 (100), 176 (11), 148 (11), 105 (15); HRMS (EI)
calcd for C15H15N2O835Cl3 455.9894. found 455.9865.
4.1.6. N-(2,2,2-Trichloroethoxycarbonyl)-3-O,4-O-
dimethyl-5-nitro-L-DOPA methyl ester (8). A solution
of catechol 7 (0.10 g, 0.23 mmol) in dry acetone (10 mL)
maintained under argon was treated with dimethyl sulfate
(0.13 mL, 1.4 mmol) and anhydrous K2CO3 (0.19 g,
1.4 mmol). After heating at reflux for 6 h, the cooled
4.1.4. 3-O-Acetyl-N-(2,2,2-trichloroethoxycarbonyl)-5-
nitro-L-DOPA methyl ester (6). A solution of 5 (0.93 g,

M. R. Heinrich, W. Steglich / Tetrahedron 59 (2003) 9231–9237
9235
reaction mixture was concentrated under reduced pressure
and the residue treated with 1N HCl (20 mL) and EtOAc
(30 mL). The phases were separated, and the organic layer
was washed with H2O (20 mL), sat. aq. NaCl (20 mL), and
then dried (Na2SO4). Purification by silica gel flash
chromatography (EtOAc–hexanes, 1:2, v/v) yielded 8
(83 mg, 79%) as a light brown solid, mp 768C; Rf¼0.4
(EtOAc–hexanes, 1:2, v/v); [a]D¼216.9 (c 0.8, MeOH);
IR (KBr) 3338m, 3004w, 2950m, 1752s, 1708s, 1535s,
1450m, 1434m, 1348m, 1281s, 1225m, 1148m, 1090m,
1064m, 1042m, 996m, 825m, 730m, 571w cm21; 1H NMR
(300 MHz, CDCl3) d 3.07 (dd, J¼14.1, 6.3 Hz, 1H), 3.26
(dd, J¼14.1, 5.4 Hz, 1H), 3.78, 3.89, 3.94 (each s, 3H), 4.61
(d, J¼12.0 Hz, 1H), 4.68 (m, 1H), 4.83 (d, J¼12.0 Hz, 1H),
5.63 (d, J¼8.0 Hz, 1H), 6.89, 7.09 (each d, J¼2.0 Hz, 1H).
13C NMR (75.5 MHz, CDCl3) d 37.8, 52.8, 54.7, 56.5,
61.95, 74.6, 95.2, 116. 6, 117.0, 131.8, 142.0, 144.6, 153.8,
154.0, 170.9; MS (EI): m/z (rel. int.): 460 (3) [Mþ,
C15H17N2O837Cl35Cl2þ], 458 (3) [Mþ, C15H17N2O835Cl3þ],
311 (11), 268 (10), 267 (74), 196 (100), 180 (8), 135 (13), 90
(19); HRMS (EI) calcd for C15H17N2O385Cl3 458.0051,
found 458.0079.
0.7, MeOH); IR (KBr): 3435s, 2959w, 2926w, 2854w,
2526w, 2268w, 1736m, 1637m, 1513m, 1438m, 1337m,
1292m, 1226m, 1149m, 1084m, 1061m, 904w, 820w,
765w, 723w, 570w 523w cm21 1H NMR (300 MHz,
;
[D6]acetone) d 3.16 (dd, J¼14.2, 9.7 Hz, 1H), 3.36 (dd,
J¼14.2, 5.1 Hz, 1H), 3.70, 4.06, 4.36 (each s, 3H), 4.60 (dd,
J¼9.7, 5.1 Hz, 1H), 4.71, 4.75 (each d, J¼15.0 Hz, 1H),
7.95, 8.00 (each d, J¼1.8 Hz, 1H); 13C NMR (75.5 MHz,
[D6]acetone) d 36.3, 52.3, 54.9, 57.2, 63.5, 74.2, 96.1,
106.6, 122.2, 128.1, 135.8, 152.0, 152.0, 154.7, 171.0; MS
(FAB) m/z 442 [Mþ, C15H17N3O367Cl35Cl2], 440 [Mþ,
C15H17N3O365Cl3]; HRMS (ESI) m/z calcd for
C15H17N3O365Cl3 440.0183, found 440.0178.
4.1.9. N-(2,2,2-Trichloroethoxycarbonyl)-5-fluoro-3-O,4-
O-dimethyl-L-DOPA methyl ester (15). The diazonium
salt 14 (221 mg, 0.42 mmol) was heated in xylenes (5 mL)
at 1308C for 2 h and then cooled to rt. After concentration
under reduced pressure, the residue was purified by column
chromatography on silica gel (EtOAc–hexanes, 1:3, v/v) to
give 15 (58 mg, 31%) as a colourless oil; Rf¼0.35 (EtOAc–
1
hexanes, 1:3, v/v); [a]2D0¼213.1 (c 1.1, MeOH); H NMR
(300 MHz, CDCl3) d 3.02 (dd, J¼14.0, 6.1 Hz, 1H), 3.11
(dd, J¼14.0, 5.5 Hz, 1H), 3.76, 3.83 (each s, 3H), 3.89 (d,
5JHF¼1.0 Hz, 3H), 4.63 (d, J¼12.0 Hz, 1H), 4.65 (m, 1H),
4.82 (d, J¼12.0 Hz, 1H), 5.54 (d, J¼8.1 Hz, 1H), 6.45 (dd,
4.1.7. 5-Amino-N-(2,2,2-trichloroethoxycarbonyl)-3-O,4-
O-dimethyl-L-DOPA methyl ester (12). A solution of 8
(0.23 g, 0.50 mmol) in dry MeOH was treated with 10% Pd/
C (50 mg). After saturating the resulting mixture with
hydrogen, HCl (1.25 M in MeOH, 1.0 mL) was added and
the mixture stirred for 24 h under 50 atm of hydrogen. The
reaction mixture was filtered through a short pad of Celite
and concentrated under reduced pressure to give the
hydrochloride of 12, which was accompanied by less than
5% of the corresponding N-ethoxycarbonyl derivative.
Treatment of the aq. hydrochloride solution with Na2CO3,
extraction with CH2Cl2, and removal of the solvent yielded
the free amine 12 (0.22 g, .95%) as a light brown oil;
Rf¼0.6 (EtOAc–hexanes, 1:1, v/v); [a]2D0¼26.1 (c 0.8,
MeOH 12-hydrochloride); IR (KBr) 3368m, 2953m, 1736s,
1617m, 1596m, 1511s, 1438m, 1360m, 1232m, 1135m,
1093m, 1047w, 1004w, 818w, 761w, 568w cm21; 1H NMR
(300 MHz, CD3OD) d 2.83 (dd, J¼13.8, 9.3 Hz, 1H), 3.06
(dd, J¼13.8, 5.3 Hz, 1H), 3.75, 3.77, 3.82 (each s, 3H), 4.49
(dd, J¼9.3, 5.3 Hz, 1H), 4.72, 4.81 (each d, J¼12.3 Hz, 1H),
6.28, 6.33 (each d, J¼2.0 Hz, 1H); 13C NMR (75.5 MHz,
CD3OD) d 38.9, 53.1, 56.5, 57.4, 60.5, 75.7, 97.3, 104.7,
111.3, 134.4, 136.4, 142.3, 154.3, 156. 7, 173.9; MS (EI) m/z
(rel. int.): 430 (4) [Mþ, C15H19N2O367Cl35Cl2], 428 (4) [Mþ,
C15H19N2O365Cl3], 281 (6), 280 (26) [Mþ2C2H3OCl3], 222
(13), 196 (22), 167 (13), 166 (100) [C9H12NO2], 151 (9);
HRMS (EI) calcd for C15H19N2O365Cl3 428.0309, found
428.0297.
5
3
4J¼1.8 Hz, JHF¼1.6 Hz, 1H), 6.49 (dd, JHF¼10.8 Hz,
4J¼1.8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 37.9, 52.6,
4
54.8, 56.3, 61.4 (d, JCF¼3.5 Hz), 74.6, 95.3, 108.7 (d,
4JCF¼2.3 Hz), 109.9 (d, JCF¼20.2 Hz), 130.9 (d,
2
3JCF¼9.4 Hz), 135.9 (d, JCF¼12.9 Hz), 153.6 (d,
2
3JCF¼5.9 Hz), 153.8, 155.8 (d, JCF¼245.4 Hz), 171.2;
1
MS (EI) m/z (rel. int.) 433 (1) [Mþ, C15H17NO637Cl35Cl2F],
431 (1) [Mþ, C15H17NO635Cl3F], 284 (4), 283 (9)
[Mþ2C2H3OCl3], 240 (8), 169 (100) [C9H10O2F]; HRMS
(EI) calcd for C15H17NO635Cl3F 431.0106, found 431.0087.
4.1.10. 5-Amino-N-(2,2,2-trichloroethoxycarbonyl)-L-
DOPA methyl ester hydrochloride (11). To a solution of
7 (100 mg, 0.23 mmol) in HCl (0.2 M in MeOH, 5 mL) was
added 10% Pd/C (25 mg), and the resulting mixture was
stirred under 1 atm of hydrogen. After completion of the
reaction (TLC control), the catalyst was removed by
filtration over a Celite pad. Concentration under reduced
pressure gave 11 (96 mg, .95%) as a colourless solid, mp
958C; Rf¼0.4 (CHCl3–MeOH, 10:1, v/v); [a]2D0¼26.6 (c
0.7, MeOH); IR (KBr) 3369s, 2956w, 2580m, 1727s, 1520s,
1440s, 1311s, 1224s, 1096m, 1049m, 820m, 767w, 727m,
569m cm21 1H NMR (300 MHz, CD3OD) d 2.89 (dd,
;
J¼14.0, 9.1 Hz, 1H), 3.10 (dd, J¼14.0, 5.6 Hz, 1H), 3.75 (s,
3H), 4.46 (dd, J¼9.1, 5.6 Hz, 1H), 4.76 (m, 2H), 6.73, 6.81
(each d, J¼1.4 Hz, 1H); 13C NMR (75.5 MHz, CD3OD) d
38.0, 53.2, 57.3, 75.7, 97.2, 115.8, 117.9, 119.6, 130.1,
140.1, 147.6, 156.7, 173.5; MS (EI) (rel. int.): 402 (5) [Mþ,
C13H15N2O637Cl35Cl2þ], 400 (6) [Mþ, C13H15N2O635Cl3þ],
253 (8), 252 (31) [Mþ2C2H3OCl3], 226 (6), 209 (9), 193
(21), 192 (7), 176 (8), 175 (15), 138 (100) [C7H8NOþ2 ];
HRMS (EI) calcd for C13H15N2O365Cl3 399.9996, found
399.9986.
4.1.8. N-(2,2,2-Trichloroethoxycarbonyl)-5-diazonium-
3-O,4-O-dimethyl-L-DOPA methyl ester tetrafluorobo-
rate (14). A solution of amine 12 (0.32 g, 0.75 mmol) in
HCl (0.4N, 3 mL) maintained at 08C was treated with
NaNO2 (52 mg, 0.75 mmol). The resulting mixture was
stirred for 5 min, and after the addition of tetrafluoroboric
acid (32% aq. solution, 0.6 mL) stirring was continued for
30 min at 08C. The precipitated solid thus formed was
filtered off and re-precipitated from acetone/Et2O to give the
diazonium salt 14 (333 mg, 84%) as an orange–brown
foam; Rf¼0.2 (CHCl3–MeOH, 10:1, v/v); [a]2D0¼218.7 (c
4.1.11. 5-Amino-L-DOPA (13). The protected amino acid
11 (50 mg, 0.11 mmol) was dissolved in 48% aq. HBr
(5 mL) and heated at reflux for 6 h. After removal of the

9236
M. R. Heinrich, W. Steglich / Tetrahedron 59 (2003) 9231–9237
solvent under reduced pressure and drying of the residue in
vacuo, the hygroscopic dihydrobromide of 13 (39 mg, 91%)
was obtained as a brown foam.
(CH), 72.4 (CH2), 74.6 (CH2), 76.1 (CH2), 95.2 (Cq), 119.4
(CH), 119.8 (CH), 123.6 (Cq), 127.6 (2£CH), 127.8 (CH),
128.1 (2£CH), 128.2 (Cq), 128.6 (2£CH), 128.7 (2£CH),
132.7 (CH), 136.7 (Cq), 137.6 (Cq), 142.0 (Cq), 143.5 (Cq),
149.5 (CH), 150.5 (Cq), 153.8 (Cq), 171.2 (Cq) (only 25 of
the 26 signals were observed); MS (EI) m/z (rel. int.): 618
(0.1) [Mþ, C30H27N2O637Cl35Cl2], 616 (0.1) [Mþ,
C30H27N2O365Cl3], 583 (0.1), 581 (0.1), 561 (0.1), 559
(0.2), 527 (5), 525 (5), 379 (13), 378 (55), 354 (6), 264 (4),
248 (4), 174 (10), 92 (9), 91 (100); HRMS (FAB) calcd for
C30H27N2O365Cl3 616.0935, found 616.0938.
Compound 13-dihydrobromide. [a]D¼26.6 (c 0.3, MeOH);
1H NMR (300 MHz, CD3OD) d 3.13 (dd, J¼14.5, 7.3 Hz,
1H), 3.25 (dd, J¼14.5, 6.0 Hz, 1H), 4.28 (m, 1H), 6.86 (d,
J¼2.0 Hz, 1H), 6.92 (d, J¼2.0 Hz, 1H); 13C NMR
(75.5 MHz, CD3OD) d 36.8 (CH2), 55.4 (CH), 116.4
(CH), 118.1 (CH), 120.0 (Cq), 127.4 (Cq), 141.1 (Cq),
148.2 (Cq), 171.2 (Cq); MS (ESI) m/z 213.1 [MþþH];
HRMS (ESI) calcd for C9H13N2O4 213.0875, found,
213.0867.
4.1.14. (7,8-Dihydroxyquinolin-5-yl)-L-alanine (1). Com-
pound 16 (15 mg, 0.03 mmol) was dissolved in 48% aq. HBr
(3 mL) and the resulting solution heated at reflux for 6 h.
After removal of the solvent under reduced pressure and
drying in vacuo, 1-dihydrobromide (18) (10 mg, 81%) was
obtained in high purity as a hygroscopic brown foam. Due to
the intense colour and resulting concerns regarding
4.1.12. N-(2,2,2-Trichloroethoxycarbonyl)-3-(7,8-dihy-
droxyquinolin-5-yl)-L-alanine methyl ester hydrochlo-
ride (16). A solution of 11 (2.10 g, 4.81 mmol) in HCl
(1.25 M in MeOH, 30 mL) was treated, dropwise at 08C,
with acrolein (2.39 mL, 36 mmol). The ice-bath was
removed and the solution stirred for at least 4 days at rt
(1H NMR control). After careful concentration and drying in
vacuo, crude 16 was obtained as a reddish brown foam,
which was directly converted into the dibenzyl derivative
17. Purification of an analytical sample of 16 was carried out
by HPLC on a Prontosil 120-5-C18-SH column [5.0 mm,
250£20 mm; solvent gradient: 0–10 min: H2O/CH3CN 9:1
(þ0.5% TFA)!50 min: 100% CH3CN; flow rate 3 mL/min,
Rt¼32 min]. 16-trifluoroacetate was obtained as a yellow
oil, Rf¼0.4 (CHCl3–MeOH, 3:1, v/v); [a]2D0¼27.8 (c 0.2,
MeOH); 1H NMR (300 MHz, CD3OD) d 3.46 (dd, J¼14.6,
9.6 Hz, 1H), 3.78 (dd, J¼14.6, 5.4 Hz, 1H), 3.79 (s, 3H),
4.61 (d, J¼12.2 Hz, 1H), 4.66 (dd, J¼9.6, 5.4 Hz, 1H), 4.75
(d, J¼12.2 Hz, 1H), 7.51 (s, 1H), 7.86 (dd, J¼8.5, 5.5 Hz,
1H), 8.91 (dd, J¼5.5, 1.3 Hz, 1H), 9.24 (dd, J¼8.5, 1.3 Hz,
1H); 13C NMR (75.5 MHz, CD3OD) d 34.7 (CH2), 53.4
(CH/CH3), 56.9 (CH/CH3), 75.7 (CH2), 97.2 (Cq), 119.2
(CH), 124.9 (CH), 125.1 (Cq), 129.3 (Cq), 132.6 (Cq), 133.9
(Cq), 143.8 (CH), 144.7 (CH), 145.0 (Cq), 156.7 (Cq), 172.9
(Cq); MS (FAB) m/z 439 [Mþ, C16H15N2O637Cl35Cl2], 437
[Mþ, C16H15N2O365Cl3]; HRMS (FAB) calcd for
C16H15N2O365Cl3 437.0074, found 437.0085.
1
accuracy, the optical rotation of 1 was not determined. H
NMR (600 MHz, CD3OD) d 3.71 (dd, J¼15.1, 7.6 Hz, 1H),
3.86 (dd, J¼15.1, 7.1 Hz, 1H), 4.42 (dd, J¼7.6, 7.1 Hz, 1H),
7.64 (s, 1H), 7.93 (dd, J¼8.5, 5.6 Hz, 1H), 8.98 (dd, J¼5.6,
1.2 Hz, 1H), 9.26 (dd, J¼8.5, 1.2 Hz, 1H); 13C NMR
(151 MHz, CD3OD) d 33.3 (CH2), 55.1 (CH), 119.6 (C-3),
124.9 (C-4a), 125.5 (C-6), 126.5 (C-5), 132.8 (C-8a), 134.7
(C-8), 144.1 (C-2), 144.5 (C-4), 149.9 (C-7), 171.0 (CO2H);
MS (FAB) m/z 249 [MþþH]; HRMS (ESI) calcd for
C12H13N2O4 249.0875, found 249.0848.
4.1.15. 3-Aminocatechol hydrochloride (20). To a solution
of bromonitrocatechol 193 (0.96 g, 4.10 mmol) in dry
MeOH (5 mL) was added 10% Pd/C (150 mg). After
saturating the mixture with hydrogen, HCl (1.25 M in
MeOH, 5.0 mL) was added and the mixture stirred for 24 h
under 50 atm of hydrogen. The reaction mixture was filtered
through a short pad of Celite and concentrated under
reduced pressure to give 20 (0.63 g, .95%) as a light brown
foam. 1H NMR (300 MHz, CD3OD) d 6.78 (dd, 1H, J¼8.0,
8.0 Hz), 6.86 (dd, 1H, J¼8.0, 1.8 Hz), 6.93 (dd, 1H, J¼8.0,
1.8 Hz); 13C NMR (75.5 MHz, CD3OD) d 115.3 (CH),
117.1 (CH), 119.9 (Cq), 120.9 (CH), 141.3 (Cq), 147.8 (Cq);
MS (EI) m/z (rel. int.): 126 (10) [MþþH], 125 (100) [Mþ],
96 (12), 79 (55), 78 (5); HRMS (ESI) calcd for C6H7NO2
125.0477, found 125.0472.
4.1.13. 3-(7,8-Dibenzyloxyquinolin-5-yl)-N-(2,2,2-tri-
chloroethoxycarbonyl)-L-alanine methyl ester (17). The
crude hydrochloride 16 (2.5 g, ,2.75 mmol), obtained as
described before, was dissolved in dry DMF (25 mL) at 08C
and treated with benzyl bromide (3.14 mL, 26.4 mmol) and
anhydrous K2CO3 (4.39 g, 31.8 mmol). The ice-bath was
removed and the mixture stirred for 24 h at rt. After the
addition of sat. aq. NaHCO3 (50 mL) and extraction with
Et2O (3£100 mL), the combined organic phases were
washed with sat. aq. NaHCO3 and H2O and dried
(Na2SO4). The solvents were removed under reduced
pressure, and the residue was purified by silica gel flash
chromatography (CH2Cl2–acetone, 15:1, v/v) to give 17
(0.40 g, 24% from 11) as a light yellow oil; Rf¼0.45
(CH2Cl2–acetone, 15:1, v/v); [a]2D0¼210.0 (c 0.2, MeOH);
1H NMR (300 MHz, CDCl3) d 3.49 (m, 2H), 3.54 (s, 3H),
4.65 (d, J¼12.0 Hz, 1H), 4.70 (m, 1H), 4.76 (d, J¼12.0 Hz,
1H), 5.21 (s, 2H), 5.39 (m, 2H), 5.73 (d, J¼8.0 Hz, 1H),
7.17 (s, 1H), 7.25–7.44 (m, 9H), 7.51–7.57 (m, 2H), 8.36
(dd, J¼8.5, 1.4 Hz, 1H), 8.97 (dd, J¼4.2, 1.4 Hz, 1H); 13C
NMR (75.5 MHz, CDCl3) d 34.9 (CH2), 52.5 (CH3), 54.9
4.1.16. 7,8-Dihydroxyquinoline (21). A solution of 20
(0.63 g, 3.90 mmol) in HCl (1.25 M in MeOH, 20 mL) was
treated, dropwise at 08C, with acrolein (1.90 mL, 29 mmol).
The ice-bath was removed and the resulting solution stirred
for at least 4 days at rt (1H NMR control!). After careful
concentration and drying in vacuo, crude 21-hydrochloride
(0.54 g, .70% as judged by 1H NMR analysis) was
obtained as a reddish brown foam. Recrystallization from
acetonitrile/MeOH afforded the pure hydrochloride. The
free base 21 was obtained by precipitation of the lead salt
and treatment with H2S.14b
1
Compound 21£HCl. H NMR (300 MHz, CD3OD) d 7.39
(d, J¼9.1 Hz, 1H, 6-H), 7.54 (d, J¼9.1 Hz, 1H, 5-H), 7.59
(dd, J¼8.2, 5.2 Hz, 1H, 3-H), 8.72 (d, J¼5.2 Hz, 1H, 2-H),
8.80 (d, J¼8.2 Hz, 1H, 4-H); 13C NMR (75.5 MHz,
CD3OD) d 119.3 (C-3), 122.0 (C-5), 123.3 (C-6), 126.0

M. R. Heinrich, W. Steglich / Tetrahedron 59 (2003) 9231–9237
9237
5. (a) Boger, D. L.; Yohannes, D. J. Org. Chem. 1987, 52,
5283–5286. (b) Bretschneider, H.; Hohenlohe-Oehringen, K.;
¨
Kaiser, A.; Wolcke, U. Helv. Chim. Acta 1973, 56,
(C-4a), 131.6 (C-8a), 134.5 (C-8), 144.1 (C-2), 148.2 (C-4),
150.5 (C-7). The assignments given were established by
HMBC and HSQC experiments. MS-EI m/z (%): 161 (Mþ,
48), 153 (10), 150 (6), 149 (10), 147 (6), 136 (36), 133 (17),
132 (12), 128 (8), 127 (7), 126 (7), 125 (7), 124 (5), 115 (3),
112 (22), 111 (9), 110 (100), 109 (11), 108 (17), 107 (21),
106 (18), 105 (19), 104 (15), 103 (6); HRMS-ESI calcd for
C9H7NO2 161.0477, found 161.0471.
2857–2860.
6. Burdeska, K. Synthesis 1982, 940–942.
7. Compare, however, the successful Baeyer–Villiger oxidation of
a 3-acetyltyrosine derivative lacking the nitro group: Chen, C.;
Zhu, Y.-F.; Wilcoxen, K. J. Org. Chem. 2000, 65, 2574–2576.
8. See, for example, Dakin, H. D. Am. Chem. J. 1909, 42, 495.
9. Krow, G. R. Org. React. 1993, 43, 251–798.
10. Shopova, M.; Vassileva, E.; Fugier, C.; Henry-Basch, E.
Synth. Commun. 1997, 27, 1661–1667.
Acknowledgements
The authors are grateful to the Fonds der Chemischen
Industrie for financial support and to Mrs Sabine Voss and
Ms Kathrin Hohnholt for skilful technical assistance.
11. Horner, L.; Sturm, K. Liebigs Ann. Chem. 1957, 608,
128–139, and literature cited therein.
12. (a) Habich, A.; Barner, R.; von Philipsborn, W.; Schmid, H.
Helv. Chim. Acta 1965, 48, 1297–1316. (b) Spiroepoxides are
also formed from 2-hydroxybenzyl alcohols by oxidation with
NaIO4: Becker, H.-D.; Bremholt, T.; Adler, E. Tetrahedron
Lett. 1972, 13, 4205–4208.
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