Unexpected transformation of quinones to spirolactones and to naturally occurring naphthalenic compounds

Article abstract of DOI:10.1016/j.tetlet.2009.01.058

In the last few years, natural quinones of the lapachol group have been used as starting points for the preparation of several bioactive heterocyclic compounds. Herein, we announce that lapachones, derivatives of lapachol, under certain conditions in the presence of inorganic reagents give unexpected products, spirolactones and naphthalenic derivatives, nordihydrolapachenone and tetrahydrotectol, both naturally occurring compounds. Nordihydrolapachenone was identified by X-ray analysis. Lapachol itself can also be converted to tetrahydrotectol.

Full text of DOI:10.1016/j.tetlet.2009.01.058

Tetrahedron Letters 50 (2009) 1550–1553
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Tetrahedron Letters
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Unexpected transformation of quinones to spirolactones and to naturally
occurring naphthalenic compounds
Eufrânio N. da Silva Júnior b, Carlos A. de Simone c, Adolfo C. B. de Souza b, Cleverson N. Pinto a,
Tiago T. Guimarães a, Maria do Carmo F. R. Pinto a, Antônio V. Pinto a,
*
a Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, PO Box 68035, 21941-971 Rio de Janeiro, RJ, Brazil
b Instituto de Química, Universidade de Brasília, 70910-970 Brasília, DF, Brazil
c Instituto Química e Biotecnologia, Universidade Federal de Alagoas, 57072-970 Maceió, AL, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In the last few years, natural quinones of the lapachol group have been used as starting points for the
preparation of several bioactive heterocyclic compounds. Herein, we announce that lapachones, deriva-
tives of lapachol, under certain conditions in the presence of inorganic reagents give unexpected prod-
ucts, spirolactones and naphthalenic derivatives, nordihydrolapachenone and tetrahydrotectol, both
naturally occurring compounds. Nordihydrolapachenone was identified by X-ray analysis. Lapachol itself
can also be converted to tetrahydrotectol.
Received 10 December 2008
Revised 10 January 2009
Accepted 12 January 2009
Available online 19 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Lately, interest for spiro acetals and spirolactones has been
stimulated by the discovery of several important pharmacological
compounds endowed with these subunits in their chemical struc-
tures.1,2 For instance, many marine toxins including the spiro-
lides,3–5 pinnatoxins,6,7 and pteriatoxins8 are naturally occurring
compounds with spirocyclic subunits in their molecular skeleton.
The presence of such subunits brings about pertinent challenges
in organic synthesis,2,3,9,10 as in Brimble’s11 recent article reporting
the construction of the aromatic spiroketal subunits of rubromyc-
ins, a family of antibiotics isolated from Streptomyces‘s cultures
which exhibits activity against Gram-positive bacteria.12 Another
challenging area in organic synthesis is the compounds belonging
to the binaphthyl group,13–15 which has led to the development
of new synthetic methodologies of substantial importance.16,17
The great interest for these conspicuous classes of important
compounds has motivated us to report herein unexpected reac-
tions that lead to two of these compound classes, outcomes that
proved to be of practical importance in organic synthesis and rep-
resent new chemical reactivities of the quinoidal structure not yet
cited in the pertinent organic chemistry literature.
O
O
O
O
Cu
O
O
AcOH
H2SO4
O
OH
4 (80%)
2
O
O
O
O
1
O
Cu
AcOH
O
O
3
5 (75%)
Scheme 1. Synthetic route21 to obtain the spirolactones 4 and 5.
by using Zn/HOAc,19 but the use of metallic copper revealed unan-
ticipated new reactions.
Another unexpected reaction in our studies emerged when we
tried to cyclize lapachol (1) to b-lapachone (2) using HI as acidic
agent. Usually, the cyclization of 1 to 2 is easily realized with sul-
furic acid or HCl, but in this report, the acidic condition used results
in the formation of colorless crystals, compound 6,20 Scheme 2,
identified as tetrahydrotectol, a natural product that occurs in Tab-
ebuia avellanedae (bignoniaceae).20 This reaction course reveled a
new anomalous type of reactivity of the naphthoquinonoid struc-
ture under acidic conditions. We also observed that b-lapachone
(2) in HI/HOAc solution formed compound 6 in good yield. It was
also possible to distinguish in the first crystallization step, the
In the course of our studies on the chemical reactivity of qui-
nones from the Brazilian flora (bignoniaceae), we hoped to carry
out the reduction of the quinoidal compounds 2 and 3 to the
respective quinols by using powdered copper in acetic acid, but
surprisingly we observed the formation of colorless spirocyclic
products 4 and 5,18 respectively (Scheme 1). Normally, the reaction
of naphthoquinones to the respective quinols is easily conducted
* Corresponding author. Tel.: +55 21 25626794.
E-mail address: avpinto@globo.com (A.V. Pinto).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.058

E. N. da Silva Júnior et al. / Tetrahedron Letters 50 (2009) 1550–1553
1551
O
OH
O
O
O
OH
O
OH
H2SO4
HI
+
OH
AcOH
O
O
O
7
1
2
6 (96%)
Scheme 2. Reaction of b-lapachone with HI. Obtaintion of tetrahydrotectol (6).
presence of distinct colorless crystals of a compound correspond-
ing to 7, as a trace by-product. After the usual workup, traces of
7 can be observed in the borders of the crystallization flask, and
by careful collection with the aid of a tong, 7 can be separated from
6. Further re-crystallization of the remaining mass gave pure 6. The
structure of 7 was determined by X-ray crystallographic analysis,
and compound 7 was identified as being nordihydrolapachenole,
a compound extracted from T. avellanedae (bignoniaceae).20
The assigned structure of 6 was promptly determinated by
comparison with the spectroscopic and physical data reported in
the literature for this compound.21a It is interesting to observe, in-
ter alia, that our formal chemical sequence starting with 1, and
going through 2, 6, and 7, may be considered a hypothetical chem-
ical mimicry of the biogenetic pathway for these compounds in the
bignoniaceous plants. Unfortunately, our attempts to obtain appro-
priate crystals of 4, 5, and 6 for X-ray analyses were fruitless.
Lapachol (1) was extracted from the heartwood of Tabebuia sp.
(Tecoma) and was purified by a series of recrystallizations. The syn-
thesis of 3 from lapachol (1) was made according to Hooker‘s
[M+] at m/e 264, but clearly did show the fragment [M+ꢀH2O], m/
e at 246, a coherent and expected dehydration for a hemicetal/ter-
tiary alcohol (Scheme 3). For the other equilibrium keto-ketal,
compounds 10/11, the results were similar.
Mechanistically, we propose that the formation of spirolactones
does first occur by oxidative cleavage of the ortho-quinone moie-
ties,23 followed by hydrolysis and decarboxylation in the workup
steps. The final products 4 and 5 were obtained after the lactoniza-
tion as demonstrated in Scheme 4. For the formation of the binaph-
thyl 6, it can be proposed that carbonyl quinoidal group after
protonation with iodidric acid does suffer nucleophilic attack fol-
lowed by lost of water and iodine. The formed radical intermediate
suffers coupling with itself leading to the formation of binaphthyl
product as described in Scheme 5.
To the best of our knowledge, the two reactivates reported here
for our naphthoquinones represent new reactions of the quinoidal
structure which are not yet cited in the literature. We hope that
these new reactions of quinones will be eventually useful for the
elaboration of synthetic routes toward spirolactones and binaph-
thols units.
21b,c
methodology.
The spectroscopic and mass spectrometric data of the new com-
pounds 4 and 5 and those of tetrahydrotectol (6) are in accordance
with the proposed chemical structures. In an exploratory reaction,
compounds 4 and 5 were treated with methanol/HCl(g) at room
temperature, resulting in high yields of colorless oils. Further, as
seen from analysis by 1H and 13C NMR spectroscopy, it was possi-
ble to conclude that these products are an equilibrium mixture of
tautomers 8/9 (1:1) in CDCl3 as a solvent22 (Scheme 3). These re-
sults are in some way coherent with the formation of alcohol,
which after ketalization generates the subsequent spirolactone as
proposed in Scheme 4.
2. X-ray analysis of compound 7
X-ray diffraction data collections were performed on an Enraf-
Nonius Kappa-CCD diffractometer (95 mm CCD camera on
goniostat) using graphite monochromated Mo radiation
j-
Ka
(0.71073 Å) at room temperature. Data collections were carried
out using the COLLECT software24 up to 50° in 2h. Final unit cell
parameters were based on 2938 reflections. Integration and scaling
of the reflections, correction for Lorentz and polarization effects
were performed with the HKL DENZO-SCALEPACK system of pro-
grams.25 The structure of the compound was solved by direct
methods with SHELXS-97.26 The models were refined by full-matrix
least squares on F2 using SHELXL-97.27 The program ORTEP-328 was
In the electron-impact mass spectrum (70 eV) for the equilib-
rium keto-ketal, compounds 8/9, the colorless ester product does
not show the presence of the inspected molecular ion fragment
O
O
O
O
OCH3
OH
O
OCH3
Cu
O
MeOH
O
AcOH
HCl (gas)
O
OH
O
O
(8)
(9)
(4)
(2)
O
O
O
O
O
OCH3
OH
O
OCH3
Cu
O
MeOH
OH
O
HCl (gas)
AcOH
O
O
(10)
(11)
(3)
(5)
Scheme 3. Equilibrium keto-ketal, compounds 8/9 and compounds 10/11.

1552
E. N. da Silva Júnior et al. / Tetrahedron Letters 50 (2009) 1550–1553
O
O
O
COOH
COOH
O
OH
O
H3O+
Cu, O2
AcOH
OH
O
O
H
O
O
O
OH
O
O
OH
O
Scheme 4. Mechanism proposed for the formation of spirolactones.
O
O
OH
O
+
O
O
I
:
O
H
OH
I
O
H
I
: -
HI
I
-(I2 and H2O)
+HI
O
OH
OH
O
OH
O
.
.
OH
O
Scheme 5. Mechanism proposed for the formation of tetrahydrotectol (6).
Table 1
Crystallographic parameters
Empirical formula
C15H16O2ꢁH2O
238.29
293(2)
Formula weight (g molꢀ1
Temperature (K)
)
Crystal dimensions (mm)
Crystal system
Space group
0.19 ꢂ 0.13 ꢂ 0.11
Tetragonal
P42
Unit cell dimensions
a (Å)
b (Å)
c (Å)
V (Å3)
Z
12.6820(1)
12.6820(8)
8.0840(3)
1300.17(1)
2
k (Mo K
Calcd density (mg mꢀ3
(Mo K
) (mmꢀ1
F000
a
) radiation (Å)
0.71073
1.22
0.081
)
l
a
)
512
h Range for data collection (°)
Index range
2.9–27.5
ꢀ16 6 h 6 12
ꢀ10 6 k 6 13
ꢀ10 6 l 6 8
5223
Figure 1. A projection ORTEP3 of 7, showing the atom-numbering and displace-
ment ellipsoids at the 50% probability level.
Reflections collected
Independent reflections [Rint
Reflections with I > 2 (I)
Number of parameters refined
]
2838 [0.033]
2030
160
0.06
1.12
r
used for graphic representation and the program WINGX29 was used
to prepare materials for publication. All H atoms were located by
geometric considerations placed (C–H = 0.93–0.98 Å) and were re-
fined as riding with Uiso(H) = 1.5Ueq(C-methyl) or 1.2Ueq(other). An
R [F2 > 2
r
(F2)]
Goodness-of-fit on F2
Residual electron density (e Åꢀ3
)
0.14

E. N. da Silva Júnior et al. / Tetrahedron Letters 50 (2009) 1550–1553
1553
confirmed by TLC, the mixture was added to H2O and extracted with CH2Cl2
(3 ꢂ 50 mL) and washed several times with H2O. After the organic phase was
dried with Na2SO4, the solvent was evaporated under reduced pressure. The
residue was chromatographed over silica gel and eluted with mixtures of
hexane/EtOAc of increasing polarity. With 3% EtOAc/hexane, the colorless oils
were isolated and characterized as being the corresponding spirolactone 4
Ortep-3 diagram of the molecule is shown in Figure 1, and Table 1
shows the main crystallographic parameters.
Bond lengths and angles are in good agreement with the ex-
pected values reported in the literature.30 The atoms of the naph-
thoquinonic ring are coplanar, and the largest deviation
[0.028(2) Å] from the least-square plane is exhibited by atom C4.
Atom O2 lies in the mean least-square plane of the naphthoqui-
nonic ring with deviations of 0.062(2), while atom O1 is
0.125(2) Å out of that plane. The pyrano ring has a half chair con-
formation, and the puckering parameters calculated for this con-
(80% yield) or 5 (75% yield). Spirolactone 4 kmax (EtOH) nm (loge): 221 (4.10).
MS [70 eV, m/z (%)]: 217(15), 204(10), 188(12), 174(9), 159(50), 149(100),
105(45), 84(90), 77(30), 56(80). IR (KBr) cmꢀ1: 2970, 2940, 1770, 1620, 1610,
1280, 1100, 770, 750, 700. 1H NMR (200 MHz, CDCl3) d: 7.8 (1H, dt, J = 0.8,
8.0 Hz), 7.7 (1H, ddd, J = 2.0, 8.0, 7.9 Hz), 7.6 (1H, m), 7.5 (1H, m), 2.4–1.6 (6H,
m), 1.5 (3H, s), 1.3 (3H, s). 13C NMR (50 MHz, CDCl3) d: 168.5 (C@O), 150.0 (C0),
134.0 (CH), 129.9 (CH), 126.4 (C0), 124.9 (CH), 121.9 (CH), 107.4 (C0), 75.7 (C0),
35.1 (CH2), 33.6 (CH3), 31.7 (CH2), 26.3 (CH3), 16.0 (CH2). Spirolactone 5 kmax
formation
were
q2 = 0.3500(3) Å,
q3 = 0.3157(2) Å,
Q =
(EtOH) nm (loge): 223 (4.07). MS [70 eV, m/z (%)]: 203(20), 185(15), 174(60),
0.4713(3) Å, h = 47.9(3)° and u = ꢀ149.9(5).31 The compound crys-
tallized with one solvent water molecule that forms OW–
H1Wꢁ ꢁ ꢁO1i and OW–H2Wꢁ ꢁ ꢁO1ii [i = x, y, z ꢀ 1; ii = ꢀx + 1, ꢀy,
z ꢀ 1] hydrogen-bonding interactions where H1Wꢁ ꢁ ꢁO1i =
2.260(2) Å; OW–H1Wꢁ ꢁ ꢁO1i = 110° and H2Wꢁ ꢁ ꢁO1ii = 1.906(2) Å;
OW–H2Wꢁ ꢁ ꢁO1ii = 165°. Crystallographic data for compound 7
have been deposited with the Cambridge Crystallographic Data
Center as Supplementary Publication No. CCDC 697642. Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CH21EZ, UK (fax: +44 1223 336 033
or e-mail: deposit@ccdc.cam.ac.uk).
160(50), 149(40), 105(100), 77(30). IR (KBr) cmꢀ1: 2964, 1754, 1615, 1284,
1123, 1087, 774, 756, 731. 1H NMR (200 MHz, CDCl3) d: 7.8 (1H, d), 7.7 (1H, t),
7.6 (1H, t), 7.5 (1H, d), 2.6–2.0 (4H, m), 1.5 (3H, s), 1.4 (3H, s). 13C NMR
(50 MHz, CDCl3) d: 168.0 (C@O), 146.7 (C0), 134.2 (CH), 130.2 (CH), 127.3 (C0),
124.9 (CH), 122.0 (CH), 114.3 (C0), 86.3 (C0), 37.9 (CH2), 36.9 (CH2), 29.1 (CH3),
28.1 (CH3).
19. Hooker, S. C. J. Am. Chem. Soc. 1936, 58, 1163.
20. Burnett, A. R.; Thomson, R. H. J. Chem. Soc. 1968, 850–853. Procedure for the
synthesis
of
2,2,20,20-tetramethyl-3,4,5,6,30,40-hexahydro-2H,20H-
[5,50]bi[benzo[h]chromenyl]-6,6’-diol (6): To
a
solution of b-lapachone
(1 mmol) in 10 mL of acetic acid was added 2.5 mL of HI under agitation.
Soon after the mixture was refluxed for 2 h it was added to a solution of
metabisulfite 2%. The precipitate that was formed was filtered and washed
with H2O distilled. The product was crystallized from benzene and was
obtained as a white solid in 96% yield, mp 125 °C. kmax (EtOH) nm (log
e): 340,
331, 252, 211. MS [70 eV, m/z (%)]: 454(100), 398(30), 227(17). IR (KBr) cmꢀ1
:
Acknowledgments
3483, 2970, 2929, 2579, 1592, 1388, 765. 1H NMR (200 MHz, CDCl3) d: 8.2–8.1
(4H, m), 7.6–7.4 (4H, m), 4.9 (2H, s), 2.5–2.2 (4H, m), 1.8 (4H, t, J = 7.0 Hz), 1.4
(12H, s). 13C NMR (50 MHz, CDCl3) d: 143.4 (C0), 142.6 (C0), 126.7 (C0), 126.1
(CH), 125.4 (CH), 123.5 (C0), 122.1 (CH), 121.5 (CH), 113.3 (C0), 112.1 (C0), 73.7
(C0), 32.7 (CH2), 26.7 (CH3), 26.4 (CH3), 21.0 (CH2). 3,4-dihydro-2,2-dimethyl-
2H-benzo[h]chromen-6-ol (7): 1H NMR (200 MHz, CDCl3) d: 8.1–8.0 (2H, m),
7.5–7.4 (2H, m), 6.5 (1H, s), 2.8 (2H, t), 1.8 (2H, t), 1.4 (6H, s).
This work was supported by CNPq (National Council of Research
of Brazil), CAPES, UFAL, UnB, and UFRJ.
References and notes
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200 (Varian, Palo Alto, CA, USA) in the solvents indicated, with TMS as internal
standard. Chemical shifts (d) are given in ppm and coupling constants (J) in
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22. General procedure for the synthesis of the compounds 8/9 and 10/11: 200 mg of
the spirolactone 4 or 5 was dissolved in 20 mL of CH3OH, then dry HCl(gas) was
bubbled for 20 min under constant agitation. After addition, the mixture was
maintained under agitation in room temperature for an additional 4 h. The end
of the reaction was monitored by TLC. After the solvent was evaporated under
reduced pressure, the obtained residue was chromatographed over silica gel
and eluted with mixtures of hexane/AcOEt of increasing polarity. With a
mixture of 4% EtOAc/hexane, colorless oil was isolated in 95% yield. Compound
8/9 MS [70 eV, m/z (%)]: 246(5), 214(10), 163(100), 146(25), 104(20). 1H NMR
(200 MHz, CDCl3) d: 8.0–7.2 (8H, m), 3.9 (3H, s), 3.0 (3H, s), 2.8 (2H, t), 2.3–1.6
(10H, m), 1.6 (6H, s), 1.5 (3H, s), 1.4 (3H, s). 13C NMR (50 MHz, CDCl3) d: 204.9
(C0), 167.9 (C0), 166.8 (C0), 146.3 (C0), 142.9 (C0), 134.4 (CH), 131.9 (CH), 130.5
(CH), 129.7 (CH), 129.6 (CH), 128.2 (C0), 127.8 (C0), 126.0 (CH), 125.4 (CH),
122.3 (CH), 110.3 (C0), 70.6 (C0), 70.3 (C0), 52.3 (CH3), 50.9 (CH3), 45.5 (CH2),
44.9 (CH2), 42.3 (CH2), 38.4 (CH2), 32.2 (CH3), 32.1 (CH3), 19.5 (CH2), 18.8 (CH2).
Compound 10/11 MS [70 eV, m/z (%)]: 232(3), 200(12), 87(100), 105(22). 1H
NMR (200 MHz, CDCl3) d: 8.0–7.3 (8H, m), 3.9 (3H, s), 3.1 (3H, s), 3.2 (2H, s),
2.5–1.6 (4H, m), 1.6 (6H, s), 1.5 (3H, s), 1.45 (3H, s). 13C NMR (50 MHz, CDCl3) d:
204.7 (C0), 167.8 (C0), 166.8 (C0), 146.1 (C0), 142.9 (C0), 134.5 (CH), 132.1 (CH),
130.6 (CH), 129.7 (CH), 129.6 (CH), 128.1 (C0), 127.6 (C0), 126.0 (CH), 125.4
(CH), 122.3 (CH), 110.1 (C0), 69.9 (C0), 69.6 (C0), 52.4 (CH3), 50.9 (CH3), 39.3
(CH2), 38.9 (CH2), 38.7 (CH2), 34.3 (CH2), 32.4 (CH3), 32.1 (CH3).
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a VG-autospec. The fragments were
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the relative abundance in percentage of the base peak intensity. General
procedure for the synthesis of the spirolactones 4 and 5: 3 g of finely divided
metallic copper, under strong agitation, was added to 1 mmol of the
corresponding quinone dissolved in 10 mL of acetic acid. The reaction
mixture was stirred at 60 °C for 20 h. After the end of the reaction was
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