Synthesis of mansonone F based on the regioselective hydrolysis of a hydroquinone diacetate

Article abstract of DOI:10.1021/np990277g

The synthesis of mansonone F (1), an antimicrobial sesquiterpenequinone, is described. Starting from 2,5-dimethyl- 1,4-naphthoquinone (5), the corresponding selectively protected hydroquinone 9 was prepared in four steps. Alkylation of 9 using chloroacetone, cyclization, and oxidation to the o-quinone completed the reaction sequence in 7.5% overall yield. The regioselectivity for the basic hydrolysis of hydroquinone diacetate 6 was discussed on the basis of MO calculations.

Full text of DOI:10.1021/np990277g

J . Nat. Prod. 1999, 62, 1643-1645
1643
Syn th esis of Ma n son on e F Ba sed on th e Regioselective Hyd r olysis of a
Hyd r oqu in on e Dia ceta te
Ruth L. Nunes, Lothar W. Bieber,* and Ricardo L. Longo
Departamento de Quı´mica Fundamental, CCEN, Universidade Federal de Pernambuco 50.740-540 Recife-PE, Brazil
Received J une 4, 1999
The synthesis of mansonone F (1), an antimicrobial sesquiterpenequinone, is described. Starting from
2,5-dimethyl-1,4-naphthoquinone (5), the corresponding selectively protected hydroquinone 9 was prepared
in four steps. Alkylation of 9 using chloroacetone, cyclization, and oxidation to the o-quinone completed
the reaction sequence in 7.5% overall yield. The regioselectivity for the basic hydrolysis of hydroquinone
diacetate 6 was discussed on the basis of MO calculations.
An intensely violet compound, later called mansonone
F (1),1 was isolated from the heartwood of a West African
tree, Mansonia altı´ssima Chev. (Sterculiaceae). The saw-
dust of this tree is responsible for heart problems and
irritation in workers involved in the regional furniture
industry,2 and its bark extracts are used by natives for
poisoning darts.3 Several related compounds, mansonones
A, B, C (2), D (3), and E (4),2 were also identified, but only
compound 1 has the rare 1-oxaphenalene-o-quinone struc-
ture found previously in the diterpene biflorine.4
oxaphenalenequinone chromophore of biflorine.17 Instead
of menadione, our starting material was 2,5-dimethyl-1,4-
naphthoquinone (5), obtained by direct oxidation of the
corresponding naphthalene18,19 or by BF3-catalyzed Diels-
Alder cycloaddition.20 Compound 5 was transformed into
the diacetate 6 by reductive acetylation (Scheme 1).21
The next step, hydrolysis of one of the acetate groups,
was not expected to be regioselective for steric reasons.
However, careful basic hydrolysis under very mild condi-
tions occurred with high selectivity, producing the monoac-
etate 7 and its 4-substituted isomer in a ratio of 78:22. The
substitution pattern of 7 was deduced by comparison of the
1H NMR spectrum with the analogous compound obtained
from menadione.21
The selectivity observed in the mild basic hydrolysis of
6 can be explained by steric effects in the tetrahedral
anionic intermediate22 resulting from attack of a hydroxyl
ion to one of the acetate groups. In fact, AM1 (Austin Model
1)23 calculations on these intermediates show that their
dissociation to the corresponding phenolate anion and
acetic acid should be the rate-determining step. Further-
more, when solvent effects are included via discrete model,
hydrolysis of the acetate in position 4 has an activation
energy about 3 kcal/mol lower than that in position 1. A
more detailed presentation of these theoretical calculations
is presented elsewhere.24
Compounds 1 and 4 can also be classified as phytoalexins
due to their formation in Ulmus hollandica5,6 and Ulmus
glabra,7 in response to infection caused by the fungus
Ceratocystis ulmi. Mansonone F was isolated also as
constituent from Ulmus laciniata,8,9 Thespesia populnea,10
Ulmus davidiana,11 and Hibiscus tibiaceus.12 Compound
1 showed greater antifungal activity than 4,5 except against
Coriolus versicolor and Chondrostereum purpureum.7
Detailed studies of the pharmacological properties and
possible therapeutic application of 1 have, to our knowl-
edge, not been performed due to its scarcity in nature.
Furthermore, synthesis of such an orthoquinone repre-
sented an exciting synthetic challenge.
Compound 7 was then protected by the benzyl group,
which is rather stable under strongly basic conditions and
easily cleaved by hydrogenolysis or strong acids, producing
compound 8. The next step was the basic hydrolysis of the
acetate group to produce compound 9. Due to its instability
in oxygen, crude 9 was immediately alkylated with chlo-
roacetone and anhydrous K2CO3, producing crystalline 10.
Cyclization of 10, following the polyphosphoric acid proce-
dure,17 produced only traces of the expected oxaphenalene
11, easily recognized by its bright blue fluorescence, and
several unidentified decomposition products. Use of con-
centrated H2SO4 produced exclusively 11, but only in 10%
yield. Clean cyclization of 10 was achieved in good yield
using tetrafluoroboric acid in ether. However, crude 11 is
easily oxidized to 1 and to other decomposition products
when standing in air. For this reason 11 was immediately
oxidized to 1 using SeO2, a well-known reagent for the
synthesis of 1,2-diketones that has been used successfully
in a similar oxidation in the synthesis of 3.15 This method
proved to be very clean and high yielding, much superior
to the oxidation by Fe3+ or Fremy’s salt reported in the
literature.16,17
Resu lts a n d Discu ssion
Syntheses of mansonones C (2),13,14 D (3),15 and E (4)16
have been reported. The last procedure could be applied
to the preparation of 1, but was not used because of its
complexity. Our synthetic approach followed the general
strategy outlined by Prelog for the elucidation of the
* To whom correspondence should be addressed. Tel.: (55)81-271-8441.
Fax: (55)81-271-8442. E-mail: lothar@dqfex.ufpe.br.
10.1021/np990277g CCC: $18.00
© 1999 American Chemical Society and American Society of Pharmacognosy
Published on Web 11/04/1999

1644 J ournal of Natural Products, 1999, Vol. 62, No. 12
Nunes et al.
Sch em e 1
(d, C-6), 126.9 (s), 126.5 (s), 122.9 (d, C-8), 120.2 (d, C-3), 24.0
(q, 5-CH3), 22.3 (q, 4-CH3), 21.3 (q, 1-CH3), 16.9 (q, 2-CH3) ppm;
MS (EI, 70 eV) m/z (%) 272 [M+] (12), 230 (33), 188 (100); anal.
C 70.24, H 5.98; calcd for C16H16O4, C 70.60, H 5.92.
1-Acetoxy-2,5-d im eth yl-4-h yd r oxyn a p h th a len e (7). Di-
acetate 6 (2 mmol; 0.54 g) was dissolved in 5 mL of MeOH
and, at 0 °C, a solution of 1 mmol (0.13 g) of K2CO3 and 1
mmol (0.174 g) of Na2S2O4 in 5 mL of H2O was added. The
flask was tightly closed and stirred at 29 °C. After 4 days, the
mixture was poured over 50 g of ice and acidified with HOAc
to pH 6. Extraction with EtOAc, drying over Na2SO4 and
evaporation of the solvent gave a crystalline mass whose 1H
NMR analysis indicated a ratio 1-Ac:4-Ac of 78:22. Crude
yield: 0.39 g (84%). Crystallization from CCl4-CH2Cl2 gave
colorless crystals of 7. Yield: 0.30 g (64%); mp 184-185 °C;
UV (MeOH) λmax (log ꢀ) 227 (2.61), 306 (2.36) nm; IR (KBr)
ν
max 3409, 1731, 1395, 1226 cm-1; 1H NMR (CD3COCD3) δ 2.16
(3H, s, 2-CH3), 2.40 (3H, s, 1-OAc), 2.89 (3H, s, 5-CH3), 6.75
(1H, s, H-3), 7.12 (1H, d, J ) 7.2 Hz, H-6), 7.28 (1H, dd, J )
8.4, 7.2 Hz, H-7), 7.56 (1H, d, J ) 8.4 Hz, H-8), 8.84 (1H, s,
OH) ppm; 13C NMR (CDCl3) δ 170.4 (s, 1-CdO), 154.6 (s, C-4),
139.0 (s, C-1), 137.1 (s, C-5), 131.1 (s, C-2), 130.5 (s, C-9), 128.7
(s, C-6), 127.8 (d, C-7), 124.8 (d, C-10), 120.4 (s, C-8), 112.8 (d,
C-3), 25.5 (q, 5-CH3), 21.2 (q, 1-CH3), 16.9 (q, 2-CH3) ppm;
EIMS (70 eV) m/z (%) 230 [M]+ (29), 188 (100), 173 (25), 145
(37); anal. C 72.89, H 6.21; calcd for C14H14O3, C 73.02, H 6.13.
1-Acetoxy-4-ben zyloxy-2,5-d im eth yln a p h th a len e (8).
To a solution of 2 mmol (0.46 g) of monoacetate 7 in 15 mL of
Me2CO, 5 mmol (0.7 g) of anhydrous K2CO3 and 2.2 mmol (0.25
mL) of benzyl bromide were added. The mixture was stirred
with exclusion of oxygen over 6 h at 29 °C, filtered, and the
solvent evaporated, yielding a crystalline mass: 0.54 g (85%).
The solid residue was crystallized from heptane. Yield: 0.45
g (70%) of colorless crystals; mp 134-135 °C; UV (MeOH) λmax
(log ꢀ) 224 (3.13), 301 (2.57), 331 (1.91) nm; IR (KBr) νmax 1759,
1
1256, 1198, 1148, 1076 cm-1; H NMR (CDCl3) δ 2.26 (3H, s,
2-CH3), 2.43 (3H, s, 1-CH3), 2.81 (3H, s, 5-CH3), 5.11 (2H, s,
CH2C6H5), 6.70 (1H, s, H-3), 7.14 (1H, d, J ) 7.3 Hz, H-6),
7.32 (1H, dd, J ) 7.0, 7.5 Hz, C6H5), 7.35 (1H, td, J ) 7.0, 1.8
Hz, C6H5), 7.4 (1H, dd, J ) 8.5, 7.3 Hz, H-7), 7.47 (1H, dd, J
) 7.5, 1.8 Hz, C6H5), 7.53 (1H, d, J ) 8.5 Hz, H-8) ppm; 13C
NMR (CDCl3) δ 170.1 (s, CdO), 155.5 (s, C-4), 139.7 (s), 138.8
(s, C-1), 137.5 (s, C-5), 136.4 (s, C-9), 129.8 (s, C-2), 129.2 (d),
128.9 (d), 128.6 (d), 128.5 (d), 127.3 (d, C-7), 126.5 (d, C-6),
125.2 (s, C-10), 119.3 (d, C-8), 109.2 (d, C-3), 71.7 (t, CH2), 26.2
(q, 5-CH3), 21.3 (q, 1-CH3), 17.3 (q, 2-CH3) ppm; EIMS (70 eV)
m/z (%) 320 [M]+ (39), 278 (100), 200 (35), 187 (48); anal. C
78.88, H 6.44; calcd for C21H20O3, C 78.72, H 6.29.
Starting from 2,5-dimethyl-1,4-naphthoquinone (5), the
described sequence of seven steps produced mansonone F
(1) in 7.5% overall yield; chromatographic purification was
necessary only in the last step. Physical and spectroscopic
properties (NMR and MS) of 1 were in agreement with data
published for the natural product.11
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Melting points were
determined on an Electrothermal 9100 instrument and are
1
uncorrected. H (300 MHz) and 13C (75.4 MHz) NMR spectra
1-Hyd r oxy-4-ben zyloxy-2,5-d im eth yln a p h th a len e (9).
To a solution of 2.5 mmol (0.1 g) of NaOH and 1 mmol (0.18 g)
of Na2S2O4 in 1 mL of H2O-MeOH, 0.5 mmol (0.16 g) of
product 8 was added. This mixture was stirred with exclusion
of oxygen. After 24 h, 3 mL of 1N HOAc were added, and the
mixture was extracted with ether. The extract was dried over
Na2SO4 and evaporated. Yield: 0.12 g (80%) of crude 9 as a
brownish solid. This product decomposed on standing in air
or during attempted crystallization and, for this reason, was
used immediately for the next step without purification.
1-(2-Oxop r op oxy)-4-b en zyloxy-2,5-d im et h yln a p h t h a -
len e (10). Crude 9 [0.35 mmol (0.1 g)] was dissolved in 10 mL
of Me2CO; 1.7 mmol (0.23 g) of anhydrous K2CO3 and 0.4 mmol
(0.03 mL) of chloroacetone were added. After stirring for 12 h
at 29 °C and under exclusion of oxygen, the solution was
diluted with H2O and extracted with ether. The extract was
dried over Na2SO4. Evaporation of solvent resulted in an oily
mass (0.08 g, 70%) that was crystallized from hexane contain-
ing some drops of diisopropyl ether. Yield: 0.09 g (60%) of
colorless crystals: mp 107-109 °C; UV (MeOH) λmax (log ꢀ)
216 (3.33), 304 (2.57) nm; IR (KBr) νmax 1727, 1254, 1235, 1176,
were obtained on a Varian Unity plus spectrometer. UV
spectra were recorded on a Perkin-Elmer Lambda 6 spec-
trometer. IR spectra were obtained on a Fourier transform
spectrometer Bruker IFS66. MS were performed on a Finnigan
Mat GCQ spectrometer, equipped with a 30-m DB5 capillary
column. Direct insertion was used for mass analysis of
compounds 1 and 10. HREIMS was performed on a VG
Autospec spectrometer.
1,4-Dia cetoxy-2,5-d im eth yln a p h th a len e (6). A mixture
of 10 mmol (1.8 g) of 2,5-dimethylnaphthoquinone (5), 12 mL
of Ac2O, 22 mmol (1.8 g) of anhydrous NaOAc, and 23 mmol
(1.5 g) of zinc dust was heated under reflux until complete
disappearance of the yellow color of the quinone (about 15
min). Then, 20 mL of HOAc were added, heating continued
for 2 min, and the mixture poured over 100 g of ice. After
standing for 12 h in the refrigerator, the crystalline product
was filtered, washed with water, and dried. Yield: 2.58 g
(95%). Crystallization from HOAc-H2O gave pure 6 as color-
less needles. Yield: 2.37 g (87%); mp 139-140 °C; UV (MeOH)
λ
max (log ꢀ) 226 (3.47), 290 (2.56) nm; IR (KBr) νmax 1749, 1213
cm-1 1H NMR (CDCl3) δ 2.29 (3H, s, 2-CH3), 2.38 (3H, s,
;
1073 cm-1; H NMR (CDCl3) δ 2.22 (3H, s, 2-CH3), 2.30 (3H,
1
1-OAc), 2.46 (3H, s, 4-OAc), 2.74 (3H, s, 5-CH3), 7.01 (1H, s,
H-3), 7.22 (1H, d, J ) 7.2 Hz, H-6), 7.35 (1H, dd, J ) 8.4 and
7.2 Hz, H-7), 7.62 (1H, d, J ) 8.4 Hz, H-8) ppm; 13C NMR
(CDCl3) δ 170.6 (s, 1-CdO), 169.5 (s, 4-CdO), 145.6 (s, C-4),
143.3 (s, C-1), 133.5 (s, C-5), 131.0 (s, C-2), 129.8 (s, C-7), 127.3
s, 1-CH3), 2.78 (3H, s, 5-CH3), 4.20 (2H, s, CH2), 4.97 (2H, s,
CH2- C6H5), 6.60 (1H, s, H-3), 7.20 (1H, d, J ) 7.2 Hz, H-6),
7.32 (1H, dd, J ) 7.0, 7.5 Hz, C6H5), 7.35 (1H, td, J ) 7.0, 1.8
Hz, C6H5), 7.5 (1H, dd, J ) 8.3, 7.2 Hz, H-7), 7.47 (1H, dd, J
) 7.5, 1.8 Hz, C6H5), 7.55 (1H, d, J ) 8.3 Hz, H-8) ppm; 13C

Synthesis of Mansonone F
J ournal of Natural Products, 1999, Vol. 62, No. 12 1645
F following the intramolecular Diels-Alder strategy16 in
13 steps and 2% yield: Best, W. M.; Wege, D. Aust. J .
Chem. 1986, 39, 647.
NMR (CDCl3) δ 170.5 (s, CdO), 153.6 (s, C-4), 139.8 (s), 138.8
(s, C-1), 136.4 (s, C-5), 135.7 (s, C-9), 129.8 (s, C-2), 129.2 (d),
128.9 (d), 128.6 (d), 128.5 (d), 127.5 (d, C-7), 126.5 (d, C-6),
125.2 (d, C-10), 119.3 (s, C-8), 110.1 (d, C-3), 71.1 (t, CH2), 69.8
(t, CH2), 26.2 (q, 5-CH3), 21.5 (q, 1-CH3), 17.8 (q, 2-CH3) ppm;
EIMS (70 eV) m/z (%) 334 [M]+ (40), 278 (100), 200 (18); anal.
C 79.09, H 6.71; calcd for C22H22O3, C 79.01, H 6.63.
Refer en ces a n d Notes
(1) Sandermann, W.; Dietrichs, H. H. Holz Roh Werkst. 1959, 3, 88.
(2) Betto`lo, G. B. M.; Casinovi, C. G.; Galeffi, C. Tetrahedron Lett. 1965,
52, 4857.
Ma n son on e F (1). A solution of 0.2 mmol (0.07 g) of
compound 10 in 1 mL of CH2Cl2 was added at once to 0.7 mL
of ice-cold HBF4-Et2O (48%). After stirring for 2 min, H2O
was added. The mixture was extracted with CHCl3, dried over
Na2SO4, filtered, and concentrated to a volume of approxi-
mately 3 mL. To this solution, 3 mmol (0.3 g) of SeO2 was
added and the mixture stirred for 12 h at room temperature.
The violet solution was filtered and evaporated. The dark
residue was purified on a Si gel column eluting with toluene-
10% EtOAc. Dark brown crystals of metallic glitter were
obtained from CHCl3-cyclohexane. Yield: 0.026 g (40%); mp
213-214 °C; UV (MeOH) λmax (log ꢀ) 227 (4.90), 554 (3.78) nm;
IR (KBr) νmax 3089.6, 1682.7, 1626.6, 1599.9, 1576.0 cm-1; 1H
NMR (CDCl3) δ 1.97 (3H, s, 9-CH3), 2.13 (3H, d, J ) 1.5 Hz,
3-CH3), 2.72 (3H, s, 6-CH3), 7.08 (1H, d, J ) 1.5 Hz, H-2), 7.41
(1H, d, J ) 8.1 Hz, H-5), 7.47 (1H, d, J ) 8.1 Hz, H-4) ppm;
13C NMR (CDCl3) δ 181.9 (s, C-7), 177.9 (s, C-8), 161.7 (s, C-9a),
146.6 (s, C-6), 140.4 (d, C-2), 136.4 (d, C-5), 129.5 (s, C-3a),
128.4 (d, C-4), 126.2 (s, C-6a), 123.9 (s, C-9b), 113.4 (s, C-9),
112.2 (s, C-3), 23.1 (q, 6-CH3), 12.9 (q, 3-CH3), 7.7 (q, 9-CH3)
ppm; EIMS (70 eV) m/z (%) 240 [M]+ (12), 212 (100), 211 (74),
195 (59), 169 (31); anal. C 74.78, H 5.19; calcd for C15H12O3, C
74.99, H 5.03; HRMS (EI) m/z 240.0768 (calcd for C15H12O3,
240.0786).
(3) Porte`res, R. Bull. Etudes Hist. et Scient. de l’A. O. F. 1935, 18, 133.
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Ack n ow led gm en t. The authors thank the Brazilian fund-
ing agencies: FINEP, FACEPE, CAPES, CNPq, and PADCT
for financial support. One of the authors (R.L.N.) wishes to
acknowledge the fellowship from CNPq.
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Note Ad d ed in P r oof: After conclusion of this work
we took knowledge of a previous synthesis of mansonone
NP990277G