Synthesis of the reported structure of crassiflorone, a pentacyclic naphthoquinone isolated from the African ebony diospyros crassiflora

Article abstract of DOI:10.1055/s-0029-1218578

A short synthesis of the furocoumarin naphthoquinone structure reported for the natural product crassiflorone is described, in which the key steps are a Diels-Alder reaction to form 2-bromo-8-hydroxy-6-methylnaphthoquinone, followed by O-protection and co

Full text of DOI:10.1055/s-0029-1218578

514
LETTER
Synthesis of the Reported Structure of Crassiflorone, a Pentacyclic
Naphthoquinone Isolated from the African Ebony Diospyros crassiflora
Synthesis
a
of the
R
epo
l
rted St
i
ructure
n
of
C
rassiflo
d
rone ar Padwal, William Lewis, Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Fax +44(115)9513564; E-mail: c.j.moody@nottingham.ac.uk
Received 30 October 2009
Dedicated with respect and affection to Professor Gerry Pattenden on the occasion of his 70th birthday.
methyl 3,3-dimethylacrylate,4 with 2,6-dibromoquinone5
in benzene at room temperature. Aromatization of the ini-
tial adduct was achieved by stirring over silica gel and de-
livered the known naphthoquinone6 in 50% yield. The
Abstract: A short synthesis of the furocoumarin naphthoquinone
structure reported for the natural product crassiflorone is described,
in which the key steps are a Diels–Alder reaction to form 2-bromo-
8-hydroxy-6-methylnaphthoquinone, followed by O-protection and
copper(II)-mediated coupling to 4-hydroxy-5-methylcoumarin to phenolic hydroxy group was subsequently protected as its
establish the pentacyclic framework.
benzyl ether 4 in order to avoid potential problems in en-
suing coupling reactions.
Key words: quinones, natural products, fused ring systems, Diels–
Alder reaction, copper
OH
O
Br
Quinones occur widely in nature and exhibit wide-ranging
properties.1 Prominent amongst quinone natural products
are the naphthoquinones, some of which have important
functions in living systems. For example, phylloquinone
(vitamin K1) plays a key role in photosynthetic electron-
transport processes.1a,b Recently, a new antibacterial
naphthoquinone was isolated from the stem bark of the
African ebony Diospyros crassiflora.2,3 The compound,
named crassiflorone, was assigned the pentacyclic naph-
thoquinone structure 1 (Figure 1) on the basis of NMR
spectroscopic studies,2 and shares the furocoumarin ring
system with well-known natural products such as
coumestrol. We now report a short synthesis of structure
1, which appears to cast some doubt on the original struc-
tural assignment of the natural product.
OH
O
O
Me
O
Me
O
O
2
Me
OH Me
O
1
O
O
3
Scheme 1 Retrosynthetic analysis of crassiflorone
4-Hydroxy-5-methylcoumarin (3) was also readily acces-
sible and was prepared from ethyl 6-methylsalicylate (5)
by addition of the lithium enolate of tert-butyl acetate fol-
lowed by acid-mediated cyclization according to the liter-
ature procedure.7
OH
O
Me
O
The stage was now set for the pivotal union of bromo-
quinone 4 and hydroxycoumarin 3 fragments. The bro-
mine in bromo-, benzo-, and naphthoquinones is known to
be readily displaced under basic (K2CO3) conditions by
various nucleophiles, including phenols8 and enamines. In
the latter case, in the presence of copper(II) salts, the in-
termediate adducts can undergo oxidative cyclization
onto the quinone ring.9,10 Hence the coupling reaction of
4-hydroxy-5-methylcoumarin (3), and the bromonaphtho-
quinone 4 was conducted in the presence of potassium
carbonate and copper(II) acetate, and pleasingly gave di-
rectly the pentacyclic framework 6 in 56% yield.11 Final
removal of the benzyl ether protecting group by hydro-
genolysis over Pearlman’s catalyst gave the desired furo-
coumarin naphthoquinone 1 (Scheme 2),12 the structure of
which was unambiguously confirmed by X-ray crystal-
lography (Figure 2).13
Me
O
O
O
crassiflorone (1)
Figure 1 Reported structure of the naphthoquinone crassiflorone
isolated from Diospyros crassiflora
Our plan was to access the naphthofurocoumarin quinone
1 by coupling together a bromonaphthoquinone fragment
2 with 4-hydroxy-5-methylcoumarin (3) as outlined in
Scheme 1. 2-Bromo-8-hydroxy-6-methylnaphthoquinone
(2) was readily prepared by Diels–Alder reaction of 1-
methoxy-3-methyl-1-trimethyl-siloxy-1,3-butadiene, ob-
tained by silylation of the LDA-generated enolate of
SYNLETT 2010, No. 4, pp 0514–0516
0
1.
0
3.
2
0
1
0
Advanced online publication: 17.12.2009
DOI: 10.1055/s-0029-1218578; Art ID: D30609ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of the Reported Structure of Crassiflorone
515
OH
O
O
O
O
OMe
Br
Br
Br
C6H6, r.t.
OTMS
then silica gel
(50%)
Me
Me
2
BnBr, Ag2O
CH2Cl2
(68%)
Me
OH Me
OBn
O
EtO2C
HO
Br
ref. 7
Figure 2 X-ray crystal structure of the synthetic furocoumarin
naphthoquinone 113
O
O
Me
5
3
4
O
rial was insufficiently soluble in DMSO to obtain good
data. Differences in the IR and UV spectra were also not-
ed, but sadly it has proved impossible to obtain a sample
of the natural material for direct comparison. Therefore,
unfortunately, our short synthesis of the furocoumarin
naphthoquinone 1, rather than confirming the structure of
the unusual natural product crassiflorone has raised some
doubt about its structural assignment.
Cu(OAc)2, K2CO3
MeCN, reflux
(56%)
OBn
O
Me
O
H2, EtOAc
Pearlman's cat.
1
(93%)
Me
O
O
Acknowledgment
O
We thank Dr. Martyn Inman for helpful discussions, and the Uni-
versity of Nottingham for support of this work.
6
Scheme 2
Although the 1H NMR data for compound 1 are complete-
ly consistent with the structure,12 there are some signifi-
cant differences between the data and those reported for
the natural product (Table 1).2 Likewise the 13C NMR
data (in CDCl3) are at variance with those reported for the
natural material (in DMSO-d6),2 although accurate com-
parison was hampered by the fact that the synthetic mate-
References and Notes
(1) (a) Thomson, R. H. Naturally Occurring Quinones;
Butterworths: London, 1957. (b) Thomson, R. H. Naturally
Occurring Quinones, 2nd ed.; Academic Press: London,
1971. (c) Thomson, R. H. Naturally Occurring Quinones III.
Recent Advances, 3rd ed.; Chapman and Hall: London,
1987. (d) Thomson, R. H. Naturally Occurring Quinones IV.
Recent Advances, 4th ed.; Blackie: London, 1997.
Table 1 Comparison of 1H NMR Data Reported for Natural and Synthetic Material
14
Me
OH
11
O
2
O
10
3
15
Me
8
4
O
O
O
Proton
11-OH
H-8
Natural2 material (500 MHz, DMSO-d6) Synthetic material (400 MHz, DMSO-d6) Synthetic material (400 MHz, CDCl3)
11.91 (1 H, s)
11.60 (1 H, s)
11.84 (1 H, s)
7.47 (1 H, s)
7.55 (1 H, s)
7.66 (1 H, s)
H-3
7.45 (1 H, t, J = 8.0 Hz)
7.23 (1 H, s)
7.66 (1 H, t, J = 7.6 Hz)
7.23 (1 H, s)
7.58 (1 H, dd, J = 8.2, 7.6 Hz)
7.14 (1 H, s)
H-10
H-2
7.11 (1 H, br d, J = 8.0 Hz)
7.09 (1 H, br d, J = 8.0 Hz)
2.61 (3 H, s)
7.43 (1 H, d, J = 8.0 Hz)
7.37 (1 H, dd, J = 7.6, 0.8 Hz)
2.88 (3 H, s)
7.26 (1 H, d, J = 7.6 Hz)
7.38 (1 H, d, J = 8.2 Hz)
2.96 (3 H, s)
H-4
14-Me
15-Me
2.46 (3 H, s)
2.50 (3 H, s)
2.51 (3 H, s)
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J. Padwal et al.
LETTER
(2) Tangmouo, J. G.; Meli, A. L.; Komguem, J.; Kuete, V.;
Ngounou, F. N.; Lontsi, D.; Beng, V. P.; Choudhary, M. I.;
Sondengam, B. L. Tetrahedron Lett. 2006, 47, 3067.
(3) Kuete, V.; Tangmouo, J. G.; Meyer, J. J. M.; Lall, N. Int. J.
Antimicrob. Agents 2009, 34, 322.
(4) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455.
(5) Perumal, P. T.; Bhatt, M. V. Synthesis 1979, 205.
(6) Bringmann, G.; Gotz, R.; Keller, P. A.; Walter, R.; Boyd,
M. R.; Lang, F. R.; Garcia, A.; Walsh, J. J.; Tellitu, I.;
Bhaskar, K. V.; Kelly, T. R. J. Org. Chem. 1998, 63, 1090.
(7) Appendino, G.; Cravotto, G.; Giovenzana, G. B.; Palmisano,
G. J. Nat. Prod. 1999, 62, 1627.
(8) For some recent examples, see: Bolognesi, M. L.; Lizzi, F.;
Perozzo, R.; Brun, R.; Cavalli, A. Bioorg. Med. Chem. Lett.
2008, 18, 2272.
(9) Luly, J. R.; Rapoport, H. J. Am. Chem. Soc. 1983, 105, 2859.
(10) Murphy, W. S.; O’Sullivan, P. J. Tetrahedron Lett. 1992, 33,
531.
s, CH2), 2.94 (3 H, s, Me), 2.50 (3 H, s, Me). 13C NMR (100
MHz, CDCl3): d = 177.9 (C), 172.2 (C), 162.0 (C), 159.8
(C), 155.2 (C), 154.9 (C), 154.3 (C), 147.4 (C), 136.0 (C),
135.9 (C), 136.6 (C), 132.5 (CH), 128.7 (CH), 127.9 (CH),
127.1 (CH), 126.7 (CH), 124.2 (C), 121.9 (C), 120.1 (CH),
117.2 (C), 115.2 (CH), 110.7 (C), 107.3 (C), 70.8 (CH2),
22.5 (Me), 21.5 (Me).
(12) 11-Hydroxy-1,9-dimethyl-6H-naphtho[2¢,3¢:4,5]furo[3,2-c]-
chromene-6,7,12-trione (1, ‘crassiflorone’)
The benzyl ether 6 (0.10 g,) was dissolved in EtOAc (10
mL), and Pearlman’s catalyst (20 mg) was added. The
reaction mixture was flushed carefully with nitrogen
followed by hydrogen, then stirred for 16 h under a hydrogen
atmosphere. The reaction mixture was filtered through
Celite, washing with 5% MeOH in CH2Cl2 (100 mL). The
filtrate was concentrated under reduced pressure, and the
residue was subjected to silica gel chromatography to give
the title compound (0.09 g, 93%); mp 230 °C (decomp.).
HRMS: m/z calcd for C21H12O6 + H+: 361.0707; found:
361.0700 [M + H+]; m/z calcd for C21H12O6 + Na+: 383.0526;
found: 383.0537 [M + Na+]. IR (CHCl3): nmax = 3689, 3604,
3043, 1755, 1644, 1603, 1239 cm–1. UV/Vis (MeOH):
(11) 11-Benzyloxy-1,9-dimethyl-6H-naphtho[2¢,3¢:4,5]furo[3,2-c]-
chromene-6,7,12-trione (6)
To a mixture of 2-bromo-8-benzyloxy-6-methyl-1,4-
naphthoquinone (4, 0.20 g, 0.56 mmol), Cu(OAc)2 (0.30 g,
1.67 mmol), 4-hydroxy-5-methylcoumarin (3, 0.10 g, 1.67
mmol), and K2CO3 (0.20 g, 1.67 mmol) was added MeCN
(10 mL). The reaction mixture was heated to reflux for 8 h
with constant stirring. After 8 h, the mixture was diluted with
CH2Cl2 (100 mL), and filtered through Celite, washing with
CH2Cl2–MeOH (9:1; 100 mL). The filtrate was concentrated
under reduced pressure, and the residue was purified by flash
column chromatography to give the title compound (0.14 g,
56%); mp 236–238 °C. HRMS: m/z calcd for C28H18O6 +
Na+: 473.0996; found: 473.0985 [M + Na+]. IR (CHCl3):
l
max = 305 (log e 4.056), 440 (log e 3.54) nm. 1H NMR (400
MHz; CDCl3): d = 11.84 (1 H, s, 11-OH), 7.66 (1 H, s, H-8),
7.58 (1 H, dd, J = 8.2, 7.6 Hz, H-3), 7.38 (1 H, d, J = 8.2 Hz,
H-4), 7.26 (1 H, d, J = 7.6 Hz, H-2), 7.14 (1 H, s, H-10), 2.96
(3 H, s, Me-14), 2.51 (3 H, s, Me-15). 13C NMR (125 MHz;
CDCl3): d = 177.7 (C), 177.3 (C), 162.83 (C), 162.80 (C),
155.1 (C), 154.7 (C), 152.9 (C), 149.4 (C), 136.0 (C), 133.2
(C), 133.1 (CH), 127.3 (CH), 127.2 (C), 124.7 (CH), 122.5
(CH), 115.4 (CH), 112.4 (C), 110.5 (C), 107.9 (C), 22.4
(Me), 21.4 (Me).
n
max = 2985, 1731, 1446, 1374, 1249, 1045 cm–1. 1H NMR
(13) Crystallographic data (reference number CCDC 75266) can
be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB21EZ, UK;
fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk].
(400 MHz, CDCl3): d = 7.71 (1 H, s, ArH), 7.62 (2 H, d, J =
7.4 Hz, ArH), 7.52 (1 H, dd, J = 8.0, 7.8 Hz, ArH), 7.42 (2
H, dd, J = 7.4, 7.8 Hz, ArH), 7.33 (2 H, d, J = 7.6 Hz, ArH),
7.22 (1 H, d, J = 7.5 Hz, ArH), 7.18 (1 H, s, ArH), 5.28 (2 H,
Synlett 2010, No. 4, 514–516 © Thieme Stuttgart · New York