Synthesis of ptaeroxylin (desoxykarenin): An unusual chromone from the sneezewood tree Ptaeroxylon obliquum

Article abstract of DOI:10.1055/s-2008-1078250

The first synthesis of the oxepinochromone ptaeroxylin (also known as desoxykarenin) isolated from the sneezewood tree is described, in which the key steps are a Claisen rearrangement and a ring-closing metathesis to form the seven-membered oxygen heterocyclic ring. Georg Thieme Verlag Stuttgart. (Table Presented).

Full text of DOI:10.1055/s-2008-1078250

LETTER
2101
Synthesis of Ptaeroxylin (Desoxykarenin): An Unusual Chromone from the
Sneezewood Tree Ptaeroxylon obliquum
S
ynthesis of Ptaeroxyl
a
in rina Muscarella,a,b Marc C. Kimber,a Christopher J. Moody*a
a
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax +44(115)9513564; E-mail: c.j.moody@nottingham.ac.uk
b
Dipartimento Farmacochimico Tossicologico e Biologico, Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy
Received 3 July 2008
Dedicated to Professor Sir Jack Baldwin on the occasion of his 70th birthday
from 2,4,6-trihydroxyacetophenone.5 Selective protection
Abstract: The first synthesis of the oxepinochromone ptaeroxylin
(also known as desoxykarenin) isolated from the sneezewood tree is
described, in which the key steps are a Claisen rearrangement and a
ring-closing metathesis to form the seven-membered oxygen het-
erocyclic ring.
of the nonhydrogen-bonded phenol as its methoxymethyl
(MOM) ether 6 was followed by formation of the allyl
aryl ether 7. At this stage it proved more effective to
deprotect the MOM-ether under acidic conditions before
conducting a Claisen rearrangement to transfer the allyl
group to C-6. The rearrangement was conveniently car-
ried out by heating ether 8 in N,N-dimethylaniline and
acetic anhydride in a microwave reactor, and gave a mix-
ture of the acetates 9 and 10, which, although they could
be separated and characterised, were more conveniently
hydrolyzed together to give the chromone 11.6 A further
selective alkylation of the C-7 hydroxy group gave the
Keywords: natural products, chromones, Claisen rearrangement,
ring-closing metathesis reaction
African trees of the Ptaeroxylon genus produce timber
that is valued for its extreme durability, although once
sawn, the dust apparently causes violent sneezing – hence
the tree is more commonly known as sneezewood. The
constituents of Ptaeroxylon obliquum were investigated
independently by two research groups in the 1960s, and
resulted in the isolation of a number of novel chromones
upon extraction of the heartwood.1–3 The first of these,
ptaeroxylin, was originally assigned the oxepino-
chromone structure 1,1 but upon reisolation by the second
research group was reassigned the linear oxepino[3,2-
g]chromone structure 2 and given the name desoxykare-
nin.2 Karenin (3) was isolated from the same source,2 and
the isomeric ptaeroxylinol 4 was subsequently isolated
from the tree (Figure 1).3 We now report the first synthe-
sis of a member of this group of natural products.
OH
O
OH
O
MOMCl, DIPEA
DMF
90%
HO
O
Me
MOMO
O
Me
5
6
H2C=CHCH2Br
NaH, DMF
49%
O
O
O
O
O
aq HCl, THF
92%
HO
O
Me
MOMO
Me
Our plan was to form the seven-membered oxygen hetero-
cycle by a ring-closing metathesis (RCM) reaction, and
therefore the problem reduced to a relatively simple
chromone derivative. The key starting material, 5,7-dihy-
droxy-2-methylchromen-4-one (5), is a natural product it-
self known as noreugenin,4 and was readily prepared in
modest yield using the Kostanecki–Robinson synthesis
8
7
PhNMe2, Ac2O
200 °C (MW)
92%
OR
O
OH
O
O
K2CO3, MeOH
87%
OH
O
OH
5
O
4
AcO
O
Me
HO
Me
6
11
7
9 R = H; 10 R = Ac
3
R2
8
H2C=CMeCH2Br,
K2CO3, DMF
73%
2
O
O
Me
O
R1
9
O
11
2 R1 = R2 = Me; ptaeroxylin
OH
O
O
OH
O
O
(desoxykarenin)
1
Me
Grubbs I
CH2Cl2
3 R1 = CH2OH, R2 = Me; karenin
4 R1 = Me, R2 = CH2OH; ptaeroxylinol
Me
64%
Me
O
Me
O
Figure 1
SYNLETT 2008, No. 14, pp 2101–2102
2
12
2
2
.0
8
.2
0
0
8
Me
Advanced online publication: 05.08.2008
DOI: 10.1055/s-2008-1078250; Art ID: D25208ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2102
M. Muscarella et al.
LETTER
(7) (a) Stefinovic, M.; Snieckus, V. J. Org. Chem. 1998, 63,
methallyl ether 12, the substrate for the RCM reaction.
The RCM reaction has rapidly gained acceptance as a key
tactic in the construction of a wide range of carbo- and
heterocyclic ring systems, and has found use in the syn-
thesis of fused medium ring ethers.7 In the present case,
treatment of the precursor 12 with bis(tricyclohexylphos-
phine)benzylidene ruthenium(IV) dichloride (Grubbs
first-generation catalyst) resulted in formation of the de-
sired seven-membered ring 2 (Scheme 1).8 Although one
has to exercise caution in comparing spectroscopic data
2808. (b) Chattopadhyay, S. K.; Dey, R.; Biswas, S.
Synthesis 2005, 403. (c) Rotzoll, S.; Görls, H.; Langer, P.
Synthesis 2008, 45.
(8) Synthesis of 5-Hydroxy-6,9-dihydro-2,8-dimethyl-4H-
oxepino[3,2-g]chromen-4-one (Ptaeroxylin, 2)
A solution of 6-allyl-5-hydroxy-2-methyl-7-[(2-methyl-
prop-2-en-1-yl)oxy]-4H-chromen-4-one (12, 0.035 g, 0.135
mmol) in CH2Cl2 (65 mL, 0.002M) was treated with a single
portion (0.021 g, 20 mol%) of
bis(tricyclohexylphosphine)benzylidene ruthenium(IV)
dichloride. The solution was heated under reflux for 18 h.
The solvent was removed in vacuo and the brown residue
filtered through a short pad of Celite using cyclohexane–
EtOAc (9:1) as eluent. The solvent was then removed and
the residue purified by chromatography (cyclohexane–
EtOAc, 9:1) to give the title compound 2 as a colourless
solid (0.020g, 64%); for analytical data, see ref. 9.
1
from over 40 years ago, the melting point, H NMR, IR,
and UV data quoted for the natural product1,2 very closely
match those of our synthetic sample, leading us to con-
clude that they are the same compound (Table 1).9 Hence
we have completed a short synthesis of one of the sneeze-
wood oxepinochromones, ptaeroxylin (2), thereby con-
firming its structure.
(9) Table 1 Comparison of Data for Natural and Synthetic Ptaerox-
ylin
Natural product
(ref. 1)
Natural product
(ref. 2)
Synthetic
sample
Acknowledgement
We thank the Università di Palermo, Italy, for funding (to M.M.).
Mp
135–138 °C
133–135 °C
CDCl3
126–128 °C
CDCl3
1H NMR CDCl3
References and Notes
OH
13.02 (1 H, s)
6.56 (1 H, s)
6.06 (1 H, s)
(1) Dean, F. M.; Taylor, D. A. H. J. Chem. Soc. C 1966, 114.
(2) McCabe, P. H.; McCrindle, R.; Murray, R. D. H. J. Chem.
Soc. C 1967, 145.
H-11
H-3
6.51 (1 H, s)
6.01 (1 H, s)
(3) Dean, F. M.; Parton, B.; Somvichien, N.; Taylor, D. A. H.
Tetrahedron Lett. 1967, 3459.
(4) Brown, R. T.; Blackstock, W. P.; Chapple, C. L. J. Chem.
Soc., Perkin Trans. 1 1975, 1776.
H-7
5.6 (1 H, t)
5.67 (1 H, t,
J = 6 Hz)
5.73-5.70 (1 H,
br t, J = 4.4 Hz)
(5) Rehder, K. S.; Kepler, J. A. Synth. Commun. 1996, 26, 4005.
(6) Synthesis of 6-Allyl-5,7-dihydroxy-2-methyl-4H-
chromen-4-one (11)
H-9
H-6
4.4 (2 H, s)
3.4 (2 H, m)
4.53 (2 H, s)
4.53 (2 H, s)
3.48 (2 H, d,
J = 6 Hz)
3.60 (2 H, d,
J = 4.4 Hz)
5-Allyloxy-7-hydroxy-2-methyl-4H-chromen-4-one (8,
0.15 g, 0.65 mmol) was heated in N,N-dimethylaniline (1.5
mL) and Ac2O (1.5 mL) at 200 °C for 1.5 h in a microwave
reactor (300 W). The mixture was poured into HCl (6 M, 40
mL) and then extracted with EtOAc (3 × 30 mL).
Chromatography (CH2Cl2–EtOAc, 95:5) gave a mixture of
6-allyl-5-hydroxy-2-methyl-4-oxo-4H-chromen-7-yl
acetate (9, 0.06 g, 34%) and 6-allyl-2-methyl-4-oxo-4H-
chromene-5,7-yl diacetate (10, 0.12 g, 58%).
2-Me
8-Me
IR
2.34 (3 H, s)
1.60 (3 H, s)
CHCl3 (cm–1)
ca. 2970
2.37 (3 H, s)
1.62 (3 H, s)
CHCl3 (cm–1)
3011
1.54 (3 H, s)
Nujol (cm–1)
1650
1656
1655
To the above mixture (0.13 g) was added a solution of
K2CO3 (0.15 g) in MeOH (2.5 mL). The solution was heated
under reflux for 30 min. The solvent was removed in vacuo
and H2O (10 mL) was added. The solution was then acidified
with HCl (6 M) and the resulting solid filtered to give the
title compound 11 as a colourless solid (0.09 g, 87%); mp
232–234 °C. HRMS: m/z calcd for C13H13O4: 233.0808;
found [MH+]: 233.0811. IR (CHCl3): nmax = 3007, 1657,
1634, 1587, 1456, 1152 cm–1. 1H NMR (400 MHz, CDCl3):
d = 13.08 (1 H, s, OH), 10.78 (1 H, s, OH), 6.40 (1 H, s, H-
8), 6.15 (1 H, s, H-3), 5.91–5.81 (1 H, m, =CH), 4.96–4.90
(2 H, m, =CH2), 3.25 (2 H, d, J = 6.0 Hz, CH2), 2.33 (3 H, s,
Me). 13C NMR (100 MHz; CDCl3): d = 183.3 (C), 167.9 (C),
162.3 (C), 159.1 (C), 156.2 (C), 136.1 (CH), 115.1 (CH2),
109.3 (C), 108.3 (CH), 103.6 (C), 93.4 (CH), 26.4 (CH2),
20.3 (Me).
1610
1627
1626
1590
1595
1592
UV
EtOH (nm)
206 (log e 4.20)
230 (log e 4.17)
EtOH (nm)
209 (log e 4.23)
232 (log e 4.27)
241 (log e 4.22)
255 (log e 4.24)
284 (log e 3.68)
321 (log e 3.59)
MeCN (nm)
232 (log e 4.2)
254 (log e 4.1)
322 (log e 3.5)
255 (log e 4.15)
320 (log e 2.60)
Synlett 2008, No. 14, 2101–2102 © Thieme Stuttgart · New York

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