Total synthesis of neuroprotective dictyoquinazol A, B, and C

Article abstract of DOI:10.1080/00397910701489537

A new protective compound, dictyoquinazol A, was synthesized starting from 5-methoxy-2-nitrobenzoic acid in six-steps in 36% overall yield. Two derivatives B and C, isolated from the mushroom Dictyophora indusiata, were also synthesized from Dictyoquinazo

Full text of DOI:10.1080/00397910701489537

Synthetic Communicationsw, 37: 3311–3317, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701489537
Total Synthesis of Neuroprotective
Dictyoquinazol A, B, and C
Chang Ho Oh and Chung Hyun Song
Department of Chemistry, Hanyang University, Seoul, Korea
Abstract: A new protective compound, dictyoquinazol A, was synthesized starting
from 5-methoxy-2-nitrobenzoic acid in six-steps in 36% overall yield. Two derivatives
B and C, isolated from the mushroom Dictyophora indusiata, were also synthesized
from Dictyoquinazole A.
Keywords: dictyoquinazol, natural products, neuroprotection, synthesis
Neurodegenerative diseases are one of the main leading causes of social
problems and death resulting from ischemic stroke, brain injury, and
epilepsy throughout the world.[1] Despite extensive research to slow down
the speed of degradation of neuron cells or alleviate the symptoms caused
by neurodegenerative diseases, an effective chemotherapeutic treatment is
still needed. NMDA (N-methyl-D-asparate) and AMPA (a-amino-3-
hydroxy-5-methyl-4-isoxazoleprop-ionic acid) receptors have been proposed
as two of the most important contributors to neuronal death in the brain.[2]
Methaqualone derivatives with a C-2 enol side chain have been reported as
potent noncompetative AMPA receptor antagonists.[3] Recently, three new
quinazoline compounds, named dictyoquinazoles A–C, were isolated from
the mushroom Dictyophora indusiata, which is an edible mushroom used in
Chinese food and medicine.[4]
Compounds A–C have an unique quinazoline moiety rarely found in
natural products that protects neurons from glutamate-induced neurotoxicity
to a significant degree at concentrations ranging from 5 to 10 mM, protects
Received September 17, 2006
Address correspondence to Chang Ho Oh, Department of Chemistry, Hanyang
University, Sungdong-Gu, Seoul 133-791, Korea. E-mail: changho@hanyang.ac.kr
3311

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C. H. Oh and C. H. Song
from toxicity induced by NMDA in a dose-dependent manner at concentrations
ranging from 10 to 30 mM, and has moderate MAO (monoamine oxidase)
inhibitory activity in the range 60–100 mM. In an effort to evaluate the mode
of action of these compounds for neuroprotection and to develop potent neuro-
protective compounds, we initiated research on an efficient syntheses for these
compounds. Here we report the first total synthesis of compounds A–C. A
synthetic scheme of dictyoquinazole A is given in Scheme 1.
A standard EDC coupling of 3-methoxy-5-nitrobenzoic acid (1) with
4-methoxy-2-methylaniline (2) in DMF solvent afforded the amide 3 in 77%
yield in 10–20 g. Nitro group reduction of 3 was quantitatively carried out
in methanol using an atmosphere of hydrogen over Pd-C catalyst to give the
amino amide 4. The amino amide 4 was refluxed in HCOOH for an hour to
give quinazoline-4-one 5 in 75% yield based on 1. Bromination of 5 was
problemic at the beginning of this research. When a mixture of N-bromosucci-
nimide and 5 was irradiated under a 200-W sun lamp at 108C in the presence of
a catalytic amount of benzoyl peroxide (BPO), the corresponding bromide 6
was obtained as an inseparable mixture with tetracyclic compound 6a in
90% yield (3:1 ratio). The benzylic radical 5-rad, produced under the
reaction conditions, showed two pathways: one for coupling with NBS to
form 6 and the other for radical cyclization to form 6a as shown in Eq. (1).
The mixture containing bromide 6 was directly subjected to potassium
acetate suspended in DMF and then treated with sodium methoxide in
Scheme 1. Conditions: (a) EDC, HOBt, Et3 N, DMF, rt, 5 h, 77%; (b) Pd/C, H2
(1 atm), MeOH, rt, 1 h, 100%; (c) HCOOH, reflux, 1 h, 100%; (d) NBS, (PhCOO)2,
200 W sun lamp, CCl4, 108C, 24 h, 68%; (e) KOAc, DMF, rt, 24 h, 62%;
(f) NaOMe, MeOH, rt, 3 h, 98%.

Dictyoquinazol A, B, and C
3313
methanol for methanolysis to give the corresponding alcohol, dictyoquinazole
A, in 98% yield. Consequently, dictyoquinazole A was synthesized in overall
32% yield based on 1. Because of the close structural similarity of dictyoqui-
nazol A, B, and C, the dictyoquinazol B and C could be synthesized from A
via two more simple chemical reactions (Scheme 2).
Thus, several reducing agents were treated for reduction of A. Of AlH3,
LiAlH4, BH3-SMe2, Cl3SiH-NaOH, and LiBH(t-Bu)3-Et3SiH, only AlH3
gave the fully reduced compounds 7 in good yield (63%). The reduced
compound 7 was formylated with acetic formic anhydride at room temperature
to give dictyoquinazol B in 67% yield. Selective imine reduction of A was
carried out through activation of A by oxalyl chloride followed by mild
reduction with sodium cyanoborohydride to give 8 in 57% yield. Formylation
of 8 was carried out as before to afford dictyoquinazol C in 78% yield. 1H NMR
spectra of dictyoquinazole A, B and C are identical to those reported in Ref. 4.
In conclusion, we have accomplished the first total syntheses of quinazol
A–C, novel neuroprotective compounds against excitatory neurotoxins
including glutamate, NMDA, and AMPA. Considering the fact that methaqua-
lone derivatives did not block NMDA, and glutamate receptor antagonist, dic-
tyoquinazols with the C-2 enol side chain might have important implications
for design of NMDA, glutamate, and AMPA receptor antagonists.
EXPERIMENTAL
Synthesis of Dictyoquinazol A
Preparation of 3
In a 100-mL, one-necked, round-bottomed flask, 1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride (2.92 g, 15.22 mmol) and 5-methoxy-2-
Scheme 2. Conditions: (a) AlH3 (2 eq), THF, rt, 0.5 h, 63%; (b) HCOOAc, THF, rt,
3 h, 67%; (c) (COCl)2, CHCl3, reflux, then NaBH3CN, rt, 6 h, 57%; (d) HCOOAc,
THF, rt, 3 h, 78%.

3314
C. H. Oh and C. H. Song
nitrobenzoic acid (1, 2.50 g, 12.68 mmol) were dissolved in DMF (20 mL). To
this solution, 1-hydroxybenzotriazole (2, 2.06 g, 15.22 mmol) and sub-
sequently 4-methoxy-2-methylaniline (1.91 g, 13.95 mmol) in DMF
(10 mL) and triethylamine (2.7 mL, 19.02 mmol) were added. After 5 h, a
20-mL portion of water was added to the reaction mixture at 08C, and 2 N
HCl solution was added until pH 4. The precipitate was collected by filtration.
The crude product was washed with EtOAc (30 mL). The solvent was
1
removed in vacuo to give 3.09 g (77%) of 3 as a dark ivory solid: H NMR
(400 MHz, CDCl3) d 8.17 (d, J ¼ 9.2 Hz, 1H), 7.62 (d, J ¼ 8.4 Hz, 1H),
7.13 (br, 1H), 7.06 (d, J ¼ 2.4 Hz, 1H), 7.01 (dd, J ¼ 9.2, 2.4 Hz, 1H),
6.80 (dd, J ¼ 9.2, 2.4 Hz, 1H), 6.78 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.30
(s, 3H); 13C NMR (100 MHz, CDCl3) d 164.89, 163.68, 157.73, 138.62,
135.50, 133.25, 127.38, 127.26, 126.24, 115.95, 114.79, 114.02, 111.72,
56.31, 55.48, 18.24.
Reduction of the Nitro Group to 4
A mixture of 3 (3.00 g, 9.48 mmol) and 5% Pd on charcoal (379 mg) in MeOH
(60 mL) was stirred with hydrogen for 1 h. The catalyst was filtered off, and
the filtrate was concentrated. Subsequent drying in vacuo yielded 4 (2.72 g,
1
100%) as an ivory solid: H NMR (400 MHz, CDCl3) d 7.71 (br, 1H), 7.54
(d, J ¼ 9.2 Hz, 1H), 7.07 (d, J ¼ 2.8 Hz, 1H), 6.91 (dd, J ¼ 8.8, 2.8 Hz,
1H), 6.79 (dd, J ¼ 8.8, 2.8 Hz, 1H), 6.78 (s, 1H), 6.71 (d, J ¼ 8.8 Hz,
1H), 4.93 (br, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 2.29 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 167.13, 157.20, 151.26, 142.06, 132.87, 128.33,
125.77, 119.28, 119.09, 117.67, 115.91, 112.14, 111.52, 55.05, 55.44, 18.41.
Preparation of qunazoline-4-one 5
A mixture of 4 (2.70 g, 9.43 mmol) and formic acid (5 mL) was refluxed for
1 h and treated with 5 N NaOH solution (30 mL). The precipitate was
collected by filtration. The crude product was dissolved in CHCl3. The
organic layer was dried over MgSO4. The solvent was evaporated in vacuo
1
to give the product 5 as an ivory solid (2.79 g, quantitatively): H NMR
(400 MHz, CDCl3) d 7.89 (s, 1H), 7.72 (d, J ¼ 3.2 Hz, 1H), 7.70
(d, J ¼ 9.2 Hz, 1H), 7.39 (dd, J ¼ 8.8, 2.8 Hz, 1H), 7.16 (d, J ¼ 8.8 Hz,
1H), 6.90 (d, J ¼ 2.4 Hz, 1H), 6.87 (dd, J ¼ 8.8, 2.4 Hz, 1H), 3.93
(s, 3H), 3.85 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) d 160.43,
159.93, 158.68, 144.49, 142.47, 136.94, 129.42, 128.97, 128.64, 124.48,
123.12, 116.29, 112.30, 106.43, 55.89, 55.51, 18.12.
Bromination of the Tolyl Compound 5 to 6 and 6a
To 5 (2.70 g, 9.11 mmol) in CCl4 (20 mL), N-bromosuccinimide (1.78 g,
10.02 mmol) were a catalytic amount of benzoyl peroxide (221 mg,

Dictyoquinazol A, B, and C
3315
0.91 mmol) were added. The reaction mixture was stirred at 108C for 1 day in
the presence of a 200-W sun lamp. The succinimide was filtered off, and the
filtrate was concentrated under reduced pressure. The crude oil was purified by
using flash column chromatography (EtOAc–n-Hex ¼ 1:1) to give the
1
mixture (6:6a ¼ 8:2) as a clear foam. H NMR (400 MHz, CDCl3) 6: d
7.98 (s, 1H), 7.72 (d, J ¼ 12.8 Hz, 1H), 7.72 (s, 1H), 7.42 (dd, J ¼ 8.8,
3.2 Hz, 1H), 7.20 (d, J ¼ 8.8 Hz, 1H), 7.09 (d, J ¼ 2.8 Hz, 1H), 7.01 (dd,
J ¼ 8.8, 2.8 Hz, 1H), 4.33 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 6a: d 7.85
(s, 1H), 7.70 (s, 1H), 7.69 (d, J ¼ 6.0 Hz, 1H), 7.61 (d, J ¼ 2.4 Hz, 1H),
7.39 (dd, J ¼ 8.8, 2.8 Hz, 1H), 7.07 (d, J ¼ 8.8 Hz, 1H), 6.98 (dd, J ¼ 8.8,
2.8 Hz, 1H), 6.43 (s, 1H), 3.92 (s, 6H).
Preparation of Benzyl Acetate 7
To a suspension of potassium acetate (933 mg, 9.51 mmol) in DMF (7 mL), 6
(2.38 g, 6.34 mmol) in DMF (5 mL) was added dropwise. After being stirred
at rt for 1 day, the reaction mixture was cooled to 08C, diluted with EtOAc
(5 mL), quenched with water (10 mL), and extracted with EtOAc (twice).
The combined organic layer was washed with water (twice), then dried over
MgSO4, and filtered. The residue was purified by flash-column chromato-
graphy (EtOAc–n-Hex ¼ 1:1) to obtain the product 7 as a clear foam
(1.39 g, 62%): 1H NMR (400 MHz, CDCl3) d 7.93 (s, 1H), 7.70
(d, J ¼ 6.4 Hz, 1H), 7.67 (s, 1H), 7.39 (dd, J ¼ 8.8, 3.2 Hz, 1H), 7.22
(d, J ¼ 8.4 Hz, 1H), 7.10 (d, J ¼ 3.2 Hz, 1H), 7.01 (dd, J ¼ 8.8, 2.8 Hz,
1H), 4.95 (q, J ¼ 12.8, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 1.97 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 169.98, 160.58, 160.09, 158.72, 144.42, 142.33,
135.00, 129.27, 129.03, 129.00, 124.55, 122.84, 115.59, 114.53, 106.40,
62.63, 55.86, 55.64, 20.74.
Preparation of Dictyoquinazole A
In a 25-mL, one-necked, round-bottomed flask, 7 (1.30 g, 3.67 mmol) and
sodium methoxide (20 mg, 0.37 mmol) were dissolved in methanol (5 mL).
The reaction mixture was stirred at rt for 3 h. The precipitate was collected
1
by filtration to give dictyoquinazole A as a white solid (1.15 g, 96%): H
NMR (400 MHz, CDCl3) d 7.94 (s, 1H), 7.71 (d, J ¼ 11.2 Hz, 1H), 7.70
(s, 1H), 7.42 (dd, J ¼ 8.8, 2.8 Hz, 1H), 7.19 (d, J ¼ 2.8 Hz, 1H), 7.17 (d, J
¼ 8.4 Hz, 1H), 7.00 (dd, J ¼ 8.8, 2.8 Hz, 1H), 4.46 (dd, J ¼ 12.4, 3.6 Hz,
1H), 4.40 (dd, J ¼ 12.0, 8.8 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.03 (dd,
J ¼ 8.8, 3.6 Hz, 1H).
Synthesis of Dictyoquinazol B
To A (100 mg, 0.3202 mmol) in THF (4 mL), a 1 M AlH3 solution in THF
(640 mL, 0.6404 mmol) was added at 08C. The reaction mixture was stirred
at rt for 30 min. The reaction mixture was cooled to 08C, diluted with

3316
C. H. Oh and C. H. Song
EtOAc (3 mL), and quenched with water (5 mL). The aqueous layer was
extracted with EtOAc, and the organic layer was collected, then dried over
MgSO4. The residue was purified by flash-column chromatography
(EtOAc–n-Hex ¼ 1:1) to allow the product 8 as a clear oil (11.5 mg, 12%).
To a solution of acetic formic anhydride (12.8 mg, 0.0952 mmol) in THF
(2 mL), 6 (11.0 mg, 0.0366 mmol) in THF (1 mL) was added via cannula.
The reaction mixture was stiired at rt for 3 h. The reaction mixture was
cooled to 08C, diluted with EtOAc (2 mL), and quenched with water
(2 mL). The aqueous layer was extracted with EtOAc, and the organic layer
was collected, then dried over MgSO4. The residue was purified by flash-
column chromatography (EtOAc–n-Hex ¼ 1:1) to allow the product B as a
mixture of rotamers Ba and Bb (8.1 mg, 67%): 1H NMR (400 MHz,
CD3OD) Ba: d 8.66 (s, 1H), 7.28 (d, J ¼ 9.0 Hz, 1H), 7.07 (d, J ¼ 3.0 Hz,
1H), 6.88 (dd, J ¼ 9.0, 3.0 Hz, 1H), 6.82 (d, J ¼ 8.7 Hz, 1H), 6.81
(d, J ¼ 3.0 Hz, 1H), 6.67 (dd, J ¼ 8.7, 3.0 Hz, 1H), 4.84 (s, 2H), 4.76
(s, 2H), 4.39 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H); Bb: d 7.92 (s, 1H), 7.98
(d, J ¼ 9.0 Hz, 1H), 7.06 (d, J ¼ 3.0 Hz, 1H), 6.86 (dd, J ¼ 9.0, 3.0 Hz,
1H), 6.81 (d, J ¼ 3.0 Hz, 1H), 6.78 (d, J ¼ 8.6 Hz, 1H), 6.69 (dd, J ¼ 8.6,
3.0 Hz, 1H), 4.80 (s, 2H), 4.74 (s, 2H), 4.47 (s, 2H), 3.81 (s, 3H), 3.76
(s, 3H); 13C NMR (100 MHz, CD3OD) Ba: d 162.4, 158.9, 158.6, 141.2,
139.4, 130.9, 129.0, 123.6, 119.2, 114.8, 114.6, 113.7, 112.6, 61.5, 61.2,
56.0, 55.8, 54.3; Bb: d 162.9, 158.7, 158.5, 141.2, 139.3, 130.5, 129.8,
124.9, 124.8, 115.8, 114.0, 113.5, 111.7, 68.0, 61.5, 56.0, 55.9, 54.7.
Synthesis of Dictyoquinazol C
To a suspension of A (500 mg, 1.60 mmol) in CHCl3 (4 mL), oxalyl chloride
(349 mL, 4.80 mmol) was added dropwise at 08C. After refluxing for 1 h, the
solvent was evaporated at 508C. The imidazolyl chloride compound was
dissolved in THF (5 mL), and sodium cyanoborohydride (503 mg,
8.00 mmol) was added at 08C. The reaction mixture was stirred at rt for 6 h,
then cooled to 08C, and treated with 5 N NaOH solution (10 mL). The
aqueous layer was extracted with EtOAc, and the organic layer was
collected, washed with 5 N NaOH solution, and then dried over MgSO4.
The residue was purified by flash-column chromatography (EtOAc–n-
1
Hex ¼ 1:1) to obtain the product 9 as a white solid (503 mg, 100%): H
NMR (400 MHz, CD3OD) d 7.41 (d, J ¼ 2.8 Hz, 1H), 7.10 (d, J ¼ 8.8 Hz,
1H), 6.99 (d, J ¼ 2.8 Hz, 1H), 6.98 (dd, J ¼ 8.8, 3.2 Hz, 1H), 6.85 (dd,
J ¼ 8.8, 3.2 Hz, 1H), 6.75 (d, J ¼ 8.8 Hz, 1H), 4.85 (d, J ¼ 10.0 Hz, 1H),
4.59 (d, J ¼ 10.0 Hz, 1H), 4.48 (d, J ¼ 12.0 Hz, 1H), 4.42 (br, 1H), 4.34
(d, J ¼ 12.0 Hz, 1H), 3.77 (s, 3H), 3.76 (s, 3H). 13C NMR (100 MHz,
CDCl3) d 164.53, 159.08, 153.87, 141.47, 138.83, 131.60, 127.59, 122.15,
118.89, 118.05, 115.21, 114.81, 111.17, 63.30, 61.84, 55.80, 55.51. To a
solution of acetic formic anhydride (94.9 mg, 0.7046 mmol) in THF (3 mL),

Dictyoquinazol A, B, and C
3317
9 (85.2 mg, 0.2710 mmol) in THF (2 mL) was added via cannula. The reaction
mixture was stirred at rt for 3 h. The reaction mixture was cooled to 08C, and
diluted with EtOAc (2 mL), and quenched with water (3 mL). The aqueous
layer was extracted with EtOAc, and the organic layer was collected, then
dried over MgSO4. The residue was purified by flash column chromatography
(EtOAc–n-Hex ¼ 1:1) to give the product C as a mixture of rotamers Ca and
1
Cb (16.1 mg, 17%). H NMR (400 MHz, CD3OD) Ca: d 8.69 (s, 1H), 7.59
(d, J ¼ 3.0 Hz, 1H), 7.48 (d, J ¼ 8.8 Hz, 1H), 7.25 (dd, J ¼ 8.8, 3.0 Hz,
1H), 7.22 (d, J ¼ 8.7 Hz, 1H), 7.16 (d, J ¼ 2.8 Hz, 1H), 6.94 (dd, J ¼ 8.7,
2.8 Hz, 1H), 5.41 (d, J ¼ 11.5 Hz, 1H), 5.36 (d, J ¼ 11.5 Hz, 1H), 4.53
(d, J ¼ 13.7 Hz, 1H), 4.49 (d, J ¼ 13.7 Hz, 1H), 3.87 (s, 3H), 3.85
(s, 3H); Cb: d 8.48 (s, 1H), 7.95 (d, J ¼ 8.8 Hz, 1H), 7.57 (d, J ¼ 3.0 Hz,
1H), 7.26 (d, J ¼ 8.6 Hz, 1H), 7.24 (dd, J ¼ 8.8, 3.0 Hz, 1H), 7.13
(d, J ¼ 2.9 Hz, 1H), 6.97 (dd, J ¼ 8.6, 2.9 Hz, 1H), 5.35 (d, J ¼ 11.5 Hz,
1H), 5.27 (d, J ¼ 11.5 Hz, 1H), 4.51 (d, J ¼ 13.7 Hz, 1H), 4.47 (d, J ¼
13.7 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H).
ACKNOWLEDGMENTS
This work was supported by the research fund of Korea Health Industry
Development Institute (KHIDI) (A010126), Korea.
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