Convenient syntheses of biogenic aldehydes, 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde

Article abstract of DOI:10.1016/S0045-2068(03)00019-1

The title compounds were prepared from a common precursor, a bis-THP-protected dihydroxyphenylacetic acid methyl ester. Key steps are the introduction of the α-hydroxyl group by Davis oxaziridine reagent and formation of the aldehydes by DIBALH ester reduction.

Full text of DOI:10.1016/S0045-2068(03)00019-1

BIOORGANIC
CHEMISTRY
Bioorganic Chemistry 31 (2003) 191–197
www.elsevier.com/locate/bioorg
Convenient syntheses of biogenic aldehydes,
3,4-dihydroxyphenylacetaldehyde and
3,4-dihydroxyphenylglycolaldehyde
Jayan Narayanan, Yoshio Hayakawa, Junfa Fan,
and Kenneth L. Kirk*
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, DHHS, Bethesda, MD 2089, USA
Received 19 November 2002
Abstract
The title compounds were prepared from a common precursor, a bis-THP-protected di-
hydroxyphenylacetic acid methyl ester. Key steps are the introduction of the a-hydroxyl group
by Davis oxaziridine reagent and formation of the aldehydes by DIBALH ester reduction.
Published by Elsevier Science (USA).
Keywords: Dopal; Dopegal; Davis reagent; Amine metabolites; Neurotoxicity
1. Introduction
As the primary mechanism of deactivation, monoamine neurotransmitters are me-
tabolized to the corresponding aldehydes by monoamine oxidase (MAO)-catalyzed
deamination within the nerve terminal. 3,4-Dihydroxyphenylacetaldehyde (dopal)
is produced by the action of MAO on dopamine and 2-(3,4-dihydroxyphenyl)-2-hy-
droxyacetaldehyde (dopegal) is formed by MAO deamination of norepinephrine. The
oxidative deactivation of the amines is key to maintenance of proper concentrations
of these neurotransmitters. The further degradation of the aldehydes, either through
* Corresponding author. Fax: 1-301-402-4182.
E-mail address: kennethk@bdg8.niddk.nih.gov (K.L. Kirk).
0045-2068/03/$ - see front matter. Published by Elsevier Science (USA).
doi:10.1016/S0045-2068(03)00019-1

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further oxidation to acid metabolites or reduction to the corresponding alcohols is an
important subsequent process. There is substantial evidence that high concentration
of reactive aldehydic metabolites may be detrimental, since these can undergo
non-enzymatic reactions with a number of compounds normally present in the
CNS. Examples include Pictet–Spengler reactions with biogenic amines to form tet-
rahydroisoquinolines or Schiff base formation with endogenous amines such as lysine
residues [1]. Recent reports provide evidence for the selective toxicity of both dopal
[2] and dopegal [3]. As part of our research to study these reactions and to examine
the appearance of the biogenic aldehydes under pathological conditions, we had need
for authentic samples of dopal and dopegal, synthetic routes to which have been pub-
lished [4,5]. We report herein alternative convenient procedures for the preparation of
these compounds. The convenience of the syntheses together with the importance of
these compounds prompt us to publish our alternative procedures.
2. Results and discussion
A recent report describes the preparation of dopal from piperanal using a Darzens
glycidic ester synthesis, as well as its complete characterization [4]. We have chosen a
different approach that involves reduction of carboxylic ester to carbanal in a sub-
strate possessing the requisite carbon framework, thus obviating the carbon–carbon
bond-forming step. DIBALH reduction of readily available bis-THP-protected 3,4-
dihydroxyphenylacetic acid methyl ester (5) proceeded in high yield to give bis-THP-
protected dopal. The THP groups were removed under mild condition (stirring with
Amberlite–Hþ) to give dopal (Scheme 1). The physical and spectral data agreed with
the literature values [4].
The simplicity of this approach prompted us to examine the intermediate ester 5
as a source of dopegal. In the previously reported synthesis [5], the lithium salt of
dithiane was added to bis-3,4-tetrahydropyranoxybenzaldehyde in order to intro-
duce an aldehyde equivalent. Subsequent hydrolysis of the dithiane using mercuric
salts elaborated the aldehyde. Our approach again adjusts functionality of the pre-
existing carbon framework. The benzylic OH group was introduced by oxygenation
of the ester enolate using Davis oxaziridine reagent. Additional OH protection by
THP and DIBALH reduction gave the tris-THP protected intermediate. Mild acid
treatment of the tris-THP-protected product afforded dopegal. Physical and spectral
data agreed with literature values [5] (Scheme 2).
3. Conclusion
We describe an efficient and convenient synthesis of the biologically important al-
dehydes, dopal, and dopegal. The chemical procedures are simple, and the yields are
satisfactory. In addition to the simplicity of this procedure, we avoid the use of en-
vironmentally unfriendly mercuric salts that were required in a previous synthesis of
dopegal.

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193
Scheme 1.
Scheme 2.

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4. Experimental
All the reagents were from Aldrich and used without further purification. NMR
spectra were run in CDCl3 or DMSO-d6 on a Varian Gemini 300 MHz spectrometer.
Mass spectra were determined in Jeol SX-102 instrument. Infra red spectra were re-
corded in BioRad Win FTIR instrument.
4.1. 3,4-Dihydroxyphenylacetic acid methyl ester (4)
A solution of 2.85 g (16.9 mmol) of 3,4-dihydroxyphenylacetic acid 3 in 100 mL of
MeOH containing 3 mL of con. H2SO4 was refluxed overnight. The MeOH was
evaporated and the residue was dissolved in 100 mL of EtOAc. The organic layer
was washed with dilute NaHCO3, water, brine, and then dried ðNa2SO4Þ. The sol-
vent was evaporated to give 2.99 g of the ester 4 (97%) that was used in the next step
without further purification.
IR (Film, cmꢀ1) : 3369, 1715, 1608, 1521, 1463, 1113, 1013, 964, 797, 720.
1H NMR (300 MHz, CDCl3) d: 6.77–6.49 (m, 3H, ArH), 3.71 (s, 3H, OCH3), 3.52
(s, 2H, ArCH2).
13C NMR d: 174.23, 143.97, 143.25, 126.05, 121.81, 116.56, 115.68, 52.59, 40.51.
MS (FAB): C9H10O4, 182.11 (Mþ).
4.2. 3,4-Bis-(tetrahydropyranyloxy)phenylacetic acid methyl ester (5)
A solution of 3.40 g (18.7 mmol) of 4 and 120 mg (0.48 mmol) of pyridinium p-
tosylate in 70 mL of CH2Cl2 was treated dropwise with 16 mL (175.0 mmol) of di-
hydropyran in 20 mL of CH2Cl2. The mixture became homogeneous after about
1 h and the reaction was essentially complete. When the TLC indicated the absence
of starting material the reaction mixture was washed twice with water, dried
(Na2SO4), and evaporated to give 6.5 g of 5 (98%) as a mixture of diastereoisomers,
used in the next step without further purification.
IR (Film, cmꢀ1): 3063, 1738, 1588, 1508, 1463, 1434, 1388, 1356, 1260, 1202, 1108,
730, 720.
1H NMR (300 MHz, CDCl3) d: 7.08–7.05 (m, 2H, ArH), 6.86–6.84 (m, 1H, ArH),
5.43–5.39 (m, 2H, THP), 4.01–3.97 (m, 2H, THP), 3.66 (s, 3H, OMe), 3.61–3.57 (m,
2H, THP), 3.53 (s, 2H, CH2), 2.01–1.85 (m, 6H, THP), 1.70–1.62 (m, 6H, THP).
13C NMR d: 172.17, 143.34, 140.57, 128.35, 128.21, 123.48, 123.33, 119.49, 118.70,
118.45, 97.73, 97.37, 97.32, 61.94, 61.78, 52.00, 40.68, 30.44, 30.39, 25.37, 18.72,
18.69, 18.61, 18.57.
MS (FAB): C19H26O6, 351.2 (MHþ).
4.3. 3,4-Bis-tetrahydropyranyloxyphenylacetaldehyde (6)
A solution of 700 mg (2.0 mmol) of 5 in 10 mL of toluene was stirred and cooled to
)78 °C (dry nitrogen atmosphere). To this was added dropwise (syringe) 3.5 mL of a

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1.5 M solution of DIBALH in toluene. After 30 min the reaction was quenched with
aqueous ammonium chloride. Water was added and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and brine, and then evapo-
rated. The residue was chromatographed (20% EtOAc/PE) to give 330 mg of alde-
hyde 6 (52%) as a mixture of diasteroisomers.
IR (Film, cmꢀ1): 3060, 1726, 1588, 1508, 1464, 1356, 1260, 1109, 963, 816.
1H NMR (300 MHz, CDCl3) d: 9.70 (s, 1H, CHO), 7.14–6.99 (m, 2H, ArH), 6.85–
6.78 (m, 1H, ArH), 5.43–5.41 (m, 2H, THP), 4.03–3.96 (m, 2H, THP), 3.67–3.54 (m,
4H, ArCH2 & THP), 2.05–1.87 (m, 6H, THP), 1.81–1.63 (m, 6H, THP).
13C NMR d: 199.83, 148.03, 146.81, 126.04, 126.02, 123.70, 120.15, 119.71, 100.41,
98.76, 98.37,97.78, 97.38, 96.52, 76.77, 76.72, 61.84, 52.06, 50.10, 30.42, 25.37, 24.93,
18.57.
4.4. 3,4-Dihydroxyphenylacetaldehyde Dopal, (1)
A 100 mg (0.31 mmol) of bis-THP aldehyde 6 was treated with 0.5 mL of water,
0.5 mL of THF, and 60 mg strongly acidic amberlite resin. After stirring for 25 min
an additional 0.5 mL of THFwas added (homogeneous). The reaction was nearly
complete after 4 h (TLC). It was filtered and the solution was concentrated to dry-
ness. The product was purified by silica gel column chromatography (5% MeOH/
CHCl3) to give 23 mg (50%) of 3,4-dihydroxyphenylacetaldehyde (1). NMR and
MS were in good agreement with the literature data [4].
4.5. 3,4-Bis-(tetrahydro-pyran-2-yloxy)-phenyl-2-hydroxy-acetic acid methyl ester
(7)
A 250 mL flask containing 100 mL of anhydrous of THFand 30 mL of KHMDS
(0.5 M in toluene) was kept in a )78 °C bath and a solution of 3.5 g (10.0 mmol) of
compound 5 in 20 mL of anhydrous THFwas slowly added. The solution was stirred
for an additional 30 min at the same temperature and a solution of 3.9 g (15.0 mmol)
of 2-sulfonyloxaziridine [6] in 10 mL of anhydrous THFwas added. After stirring the
mixture at )78 °C for 20 min, the reaction was quenched by addition of 15 mL of
saturated aqueous NH4Cl. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (2 ꢁ 50 mL). The organic fractions were combined
and washed with water (2 ꢁ 20 mL) and brine (2 ꢁ 20 mL). The solution was dried
( Na2SO4) and the solvent was evaporated. The residue was purified by chromatog-
raphy on silica gel (50% EtOAc/PE) to afford 3.12 g of compound 7 (85%) as a mix-
ture of diastereoisomers.
IR (Film, cmꢀ1): 3271, 3070, 1739, 1507, 1463, 1331, 1260, 1203, 1164, 1106, 1072,
1024, 963, 756, 721.
1H NMR (300 MHz, CDCl3) d: 7.60–7.49 (m, 1H, ArH), 7.21–6.97 (m, 2H, ArH),
5.45–5.41 (m, 2H, THP), 5.14–5.09 (m, 1H, ArCHOH), 4.02–3.98 (m, 2H, THP),
3.74 (s, 3H, OCH3), 3.62–3.57 (m, 2H, THP), 3.46 (s, 1H, OH), 2.07–1.81 (m, 6H,
THP), 1.75–1.64 (m, 6H, THP).

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13C NMR d: 172.89, 146.76, 143.39, 131.25, 128.22, 127.65, 126.85, 125.43, 120.40,
117.70, 96.88, 96.67, 72.10, 61.24, 59.64, 51.54, 29.72, 24.65, 18.06.
MS (FAB): C19H26O7, 367.20 (MHþ).
4.6. 3,4-Bis-(tetrahydro-pyran-2-yloxy)-phenyl-(tetrahydro-pyran-2-yloxy)-acetic
acid methyl ester (8)
To a solution of 1.87 g (5.0 mmol) of compound 7 in 20 mL of anhydrous dichlo-
romethane was added 630 mg (7.5 mmol) of 3,4-dihydropyran and 125 mg
(0.5 mmol) of pyridinium p-toluene sulfonate. The mixture was stirred at room tem-
perature overnight after which time TLC indicated that the reaction was essentially
completed. The reaction was quenched by addition of 10 mL of 30% aqueous
NaHCO3 and the organic layer was washed with brine and dried (Na2SO4). After
removal of the solvent and purification of the residue with chromatography on silica
gel (33% EtOAc/PE) there was obtained 2.05 g of compound 8 (91%) as a mixture of
diastereoisomers.
IR (Film, cmꢀ1): 3063, 1754, 1599, 1507, 1463, 1434, 1387, 1258, 1182, 1075, 967,
872, 755, 720.
1H NMR (300 MHz, CDCl3) d: 7.27–7.04 (m, 3H, ArH), 5.46–5.42 (m, 2H, Ar-
OTHP), 5.24 (s, 1H, ArCH), 4.86–4.84 (m, 1H, ArCHOTHP), 4.05–3.91 (m,
3H, THP), 3.70 (s, 3H, OCH3), 3.62–3.46 (m, 3H, THP), 2.04–1.49 (m, 18H,
THP).
13C NMR d: 172.04, 118.29, 118.00, 100.44, 97.66, 96.52, 65.02, 62.55, 61.90,
60.07, 52.28, 38.37, 30.47, 30.28, 25.44, 18.65.
MS (FAB): C24H34O8, 451.28 (MHþ).
4.7. 3,4-Bis-(tetrahydro-pyran-2-yloxy)-phenyl-(tetrahydro-pyran-2-yloxy)-acetalde-
hyde (9)
To a solution of 900 mg (2.0 mmol) of compound 8 in 15 mL of anhydrous toluene
at )78 °C was slowly added 2.2 mL of 1 M DIBALH in CH2Cl2. The mixture was
stirred for 2 h at the same temperature. Then 3.0 mL of cooled CH3OH was added
at )78 °C to quench the reaction. The mixture was stirred for an additional 30 min
and 100 mL of CH2Cl2 was added. The mixture was washed with 30 mL of water
and the organic layer was extracted with CH2Cl2 (2 ꢁ 50 mL). The combined organic
fractions were washed with brine and dried (Na2SO4). Removal of the solvent and
purification of the residue with chromatography on silica gel (20% EtOAc/PE) gave
780 mg of compound 9 (93%) as a mixture of diastereomers.
IR (Film, cmꢀ1): 3070, 1726, 1698, 1588, 1464, 1434, 1356, 1266, 1118, 1071, 908,
810, 725.
1H NMR (300 MHz, CDCl3) d: 9.56–9.54 (m, 1H, CHO), 7.26–6.85 (m, 3H, ArH),
5.42–5.41 (m, 2H, ArOTHP), 4.95 (s, 1H, ArCH), 4.86 (m, 1H, ArCHOTHP), 4.06–
3.80 (m, 3H, THP), 3.70–3.30 (m, 6H, THP), 2.04–1.51 (m, 15H, THP).
13C NMR d: 199.04, 148.01, 122.25, 121.95, 118.23, 116.52, 115.00, 100.01,
98.05, 97.81, 97.70, 97.26, 83.18, 81.49, 64.10, 63.80, 63.07, 62.40, 62.28, 62.14,

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61.94, 32.11, 30.91, 30.81, 30.49, 30.29, 25.62, 25.44, 20.42, 19.98, 19.69, 18.96,
18.90.
MS (FAB): C23H32O7, 421.40 (MHþ).
4.8. 3,4-Dihydroxyphenylglycolaldehyde (Dopegal, 2)
To a solution of 210 mg (0.5 mmol) of compound 9 in 10 mL of methyl alcohol
was added 10 mg (0.05 mmol) of pyrdinium p-tosylate. The mixture was stirred at
room temperature for 4 h at which time TLC indicated that the starting material
had almost disappeared completely. Ethyl acetate (40 mL) was added and the mix-
ture was washed with water (2 ꢁ 10 mL) and brine (2 ꢁ 10 mL). Removal of the sol-
vent gave brown oil. This was dissolved in 10 mL of THFand 5 mL of H 2O. To this
was added 0.1 mL of 3 M HCl and the solution was stirred at room temperature for
3 h. Ethyl acetate (20 mL) was added and the resulting mixture was washed with
water (2 ꢁ 5 mL) and brine (2 ꢁ 10 mL). The solution was dried (Na2SO4 ), the sol-
vent was removed, and the residue was purified by silica gel column chromatography
1
(10% MeOH/CH2Cl2) to afford 42 mg of dopegal (2) (50%) as a white solid. The H
NMR and MS were in complete agreement with the data reported in literature [5].
Acknowledgments
The authors thank Wesley L. White and Victor Livengood for providing NMR
and Mass Spectra, respectively.
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