The Claisen rearrangement followed by phenol oxidation: A simple route to naturally occurring benzoquinones including an ansa-bridged derivative related to the ansamycin antibiotics

Article abstract of DOI:10.1055/s-2002-34877

The naturally occurring benzoquinones primin 1 and pallasone B 2 were synthesised by a simple protocol involving microwave accelerated Claisen rearrangement of allyl ethers 4, followed by hydrogenation of the side chain alkene, and oxidation to the quinon

Full text of DOI:10.1055/s-2002-34877

1874
LETTER
The Claisen Rearrangement Followed by Phenol Oxidation: A Simple Route to
Naturally Occurring Benzoquinones Including an Ansa-Bridged Derivative
Related to the Ansamycin Antibiotics
ClaisenRearrang
h
ement Follow
r
edby
P
i
henol
O
s
xidationtopher J. Davis, Christopher J. Moody*
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Fax +44(1392)263434; E-mail: c.j.moody@exeter.ac.uk
Received 29 August 2002
Dedicated to the memory of Alex Larigo (1977–2002).
Simple retrosynthetic analysis (Scheme 1) of the quinones
Abstract: The naturally occurring benzoquinones primin 1 and pal-
lasone B 2 were synthesised by a simple protocol involving micro-
wave accelerated Claisen rearrangement of allyl ethers 4, followed
by hydrogenation of the side chain alkene, and oxidation to the
1 and 2 suggests that they could be obtained by oxidation
of the 2-methoxy-6-substituted phenols 3, themselves
available by Claisen rearrangement of the appropriately
quinone; by incorporating a ring-closing metathesis step, the meth- substituted allyl aryl ethers 4.
od was extended to the synthesis of the ansa-bridged benzoquinone
11, a structure related to the ansamycin antibiotics.
O
Key words: rearrangements, phenols, oxidations, quinones, natural
products
OMe
R
OMe
O
R1
R
OMe
OH
H
O
3
4
One group of natural products that exhibit wide-ranging
properties are the quinones.1 Not only do they constitute
the largest group of natural pigments (although surpris-
ingly their contribution to natural colouring is relatively
small), they participate in a range of biological redox pro-
cesses, and often exhibit potent biological activity. Exam-
ples include the ubiquinones which serve as essential
electron-transfer agents in the respiratory chain, and the
anticancer quinones adriamycin (doxorubicin) and mito-
mycin C. Although quinones such as these are structurally
quite complex, even relatively simple benzoquinones pos-
sess significant activity. In continuation of our interest in
the synthesis of quinonoid natural products,2,3 we now re-
port a simple and versatile route to benzoquinones based
on the Claisen rearrangement,4 and illustrate it by the syn-
thesis of the naturally occurring compounds primin 15–7
and pallasone B (dihydroirisquinone) 2,8,9 and the ansa-
bridged macrocyclic lactam 11 related to the benzo-
quinonoid ansamycin antibiotics.
Scheme 1
The requisite allyl ethers 4 were prepared as shown in
Scheme 2. Thus Mitsunobu reaction of 2-methoxyphenol
with commercially available 1-penten-3-ol or with 1-hep-
tadecen-3-ol, prepared by addition of vinylmagnesium
bromide to pentadecanal (65%), gave the allyl ethers 4a
and 4b in 49% and 74% yields respectively. Although the
Claisen rearrangement of the simple allyl ether 4 (R1 = H)
has been carried out by prolonged heating at 180 °C,10 we
investigated a range of different conditions using the ether
4a as substrate, including microwave heating, which is re-
ported to accelerate Claisen rearrangements.11–14 Heating
under reflux in 1,2-dichlorobenzene for 3 h resulted in iso-
lation of the required rearrangement product 5a in 50%
yield as a single (presumably E) isomer. However, under
controlled microwave irradiation (focused reactor, 300
W, 180 °C), the allyl ether 4a underwent Claisen rear-
rangement in DMF as solvent in 96% yield in 25 min. Ap-
plication of these conditions to allyl ether 4b resulted in
formation of the Claisen rearrangement product 5b in ex-
cellent yield as a single geometric isomer.15 The next step
was to hydrogenate the double bond to give the 2-meth-
oxy-6-alkylphenols (80% and 85%). Finally, phenol oxi-
dation using Fremy’s salt (potassium nitrosodisulfonate)
(for 1) or oxygen in the presence of salcomine (for 2) gave
the corresponding 2,6-disubstituted 1,4-benzoquinones
primin 1 and pallasone B (dihydroirisquinone) 2
(Scheme 2).16
O
R
OMe
O
1
R = C5H11 (primin)
2 R = C17H35 (pallasone B)
Figure 1
In order to extend the methodology to more complex de-
rivatives, we considered a new route to the benzoquinon-
oid ansamycins in which the substituents at the 2- and 6-
positions form part of the ansa-bridge in the form of a 19-
membered macrocyclic lactam. These antibiotics, exem-
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1874,1876,ftx,en;D15702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Claisen Rearrangement Followed by Phenol Oxidation
1875
DIAD, Ph3P
OH
O
Me
OMe
OMe
H2C=CHCH(OH)R1
N
O
OH
H
R1
O
H
6
Me
i. Ph3P, DIAD, ArOH (59%)
4a R1 = Et (49%)
4b R1 = C14H29 (74%)
ii. Sn, HCl, MeOH (75%)
iii. H2C=CH(CH2)2CO2H
DCC, CH2Cl2 (78%)
180 °C, DMF
MW, 25-30 min
7
O
Grubbs cat
CH2Cl2
(86%)
xylene, Na2CO3
heat (49%)
i. H2, Pd/C, EtOAc
R1
R
OMe
OMe
ii. Fremy's salt
[(KSO3)2NO]
Me2CO, aq. Na2HPO4
or
O
OH
O
O
5a R1 = Et (96%)
1 R = C5H11 (80/79%)
salcomine, O2
5b R1 = C14H29 (92%)
2 R = C17H35 (85/48%)
MeCN
N
H
N
H
OH
O
4
5
Scheme 2
Me
Me
plified by macbecin I17 and the herbimycins,18 possess a
range of biological activities, and are usually synthesised
by a route which involves formation of the amide bond to
close the macrocycle. In the present route the Claisen re-
arrangement is combined with a ring-closing metathesis
(RCM) reaction to form the 19-membered ring.19 Thus 2-
methyldodeca-1,11-dien-3-ol 6, prepared by addition of
isopropenylmagnesium bromide to 9-decenal (55%), un-
derwent Mitsunobu reaction with 2-nitrophenol (59%);
reduction of the nitro group (75%) followed by reaction
with 4-pentenoic acid in the presence of dicyclohexylcar-
bodiimide (DCC) (78%) gave the Claisen/RCM substrate
7 (Scheme 3). Initially the Claisen rearrangement was car-
ried out first by heating in xylene in the presence of sodi-
um carbonate, conditions which are reported to favour the
formation of the (E)-geometric isomer,20 and resulted in
the formation of the 2,6-disubstituted phenol 8 in modest
yield (49%) as a single alkene isomer; treatment of the
8
9
Grubbs cat
CH2Cl2
xylene, Na2CO3
heat (66%)
(76%)
O
O
O
Fremy's
salt
N
H
N
H
O
OH
4
Me
Me
Me2CO
aq. Na2HPO4
(69%)
5
10
11
Scheme 3
diene
8
with benzylidene bis(tricyclohexylphos-
phine)dichlororuthenium (Grubbs catalyst) resulted in
ring-closing metathesis reaction to give the 19-membered
macrocycle 10 as a ca. 1:1 mixture of E/Z-isomers at the
4-5 double bond in 76% yield. Alternatively RCM reac-
tion of 7 resulted in formation of the 17-membered mac-
rocycle 9 again as a mixture of E/Z-isomers at the 4-5
double bond in good yield,21 with reaction occurring, as
expected, at the two terminal CH=CH2 bonds. Claisen re-
arrangement then resulted in ring expansion to the 19-
membered ring 10.22 As far as we are aware this transfor-
mation of a n-membered 1,2-bridged macrocycle into an
ansa-bridged n+2-membered ring represents a new use for
the Claisen rearrangement. Finally, as above, oxidation of
the phenol with Fremy’s salt gave the ansa-bridged ben-
zoquinone 11 as an E/Z mixture of isomers.23
quinones primin and pallasone B; when combined with an
RCM reaction the method can be extended to ansa-
bridged derivatives related to the ansamycin antibiotics in
a new use of the Claisen rearrangement.
Acknowledgement
We thank the EPSRC for a Senior Research Fellowship (to C. J.
M.), and the EPSRC Mass Spectrometry Centre at Swansea for
mass spectra.
References
(1) Thomson, R. H. Naturally Occurring Quinones, 4th ed.;
Blackie: London, 1997.
(2) Martin, T.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1
1988, 241.
In summary, a simple protocol involving the formation
and Claisen rearrangement of allyl aryl ethers, followed
by phenol oxidation gives the naturally occurring benzo-
Synlett 2002, No. 11, 1874–1876 ISSN 0936-5214 © Thieme Stuttgart · New York

1876
C. J. Davis, C. J. Moody
LETTER
(15) General procedure. The allyl aryl ether 4 (0.200 g, 1.05
(3) Moody, C. J.; Swann, E. J. Chem. Soc., Perkin Trans. 1
1993, 2561.
mmol) was dissolved in DMF (3 mL) in a sealed tube. The
mixture was heated in a focused microwave reactor (300 W)
at 180 °C for 25–30 min. The mixture was diluted with ethyl
acetate (15 mL), washed with water (5 10 mL), brine (10
mL), dried (MgSO4), filtered and evaporated. The crude
product was purified by flash chromatography on silica,
eluting with ethyl acetate and light petroleum (1:4).
(16) Compound 1: mp 64.5–65.5 °C (lit.6 mp 66–67 °C);
compound 2: mp 97.5–98.5 °C (lit.8 90.5–91 °C.
(17) For a total synthesis, see: Panek, J. S.; Xu, F.; Rondon, A. C.
J. Am. Chem. Soc. 1998, 120, 4113.
(18) For a total synthesis, see: Nakata, M.; Osumi, T.; Ueno, A.;
Kimura, T.; Tamai, T.; Tatsuta, K. Bull. Chem. Soc. Jpn.
1992, 65, 2974.
(19) For another RCM-based route to the ansamycins, see: Bach,
T.; Lemarchand, A. Synlett 2002, 1302.
(4) For the use of a Claisen rearrangement in the synthesis of the
natural benzoquinone 4-methoxydalbergione, see: Barnes,
M. F.; Ollis, W. D.; Sutherland, I. O.; Gottlieb, O. R.;
Magalhaes, M. T. Tetrahedron 1965, 21, 2707.
(5) Isolation: Bloch, B.; Karrer, P. Vjschr. Naturforsch. Ges.,
Zürich 1927, 72, 1.
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O. G.; Coelho, S. D. Gazz. Chim. Ital. 1971, 101, 41.
(7) For a recent synthesis see: Mabic, S.; Vaysse, L.; Benezra,
C.; Lepoittevin, J. P. Synthesis 1999, 1127.
(8) Isolation: Seki, K.; Kaneko, R. Chem. Ind. (London) 1975,
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1991, 22, 57; Chem. Abstr., 1991, 115, 8400.
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Perkin Trans. 1 2000, 2681.
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J. Org. Chem. 1996, 61, 7355.
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(21) Compound 9 is formed as a 3:2 mixture of alkene isomers at
the 4,5-double bond; 1H NMR spectroscopic analysis does
not allow the assignment of the major isomer.
(12) An, J. Y.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor,
R. W. J. Org. Chem. 1997, 62, 2505.
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S. Synlett 2000, 1129.
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(22) The Claisen rearrangement of compounds similar to 9 has
also been successfully carried out under microwave
conditions (DMF, 150 °C).
(23) Macrocycle 11 is formed as a mixture of all four possible
geometric isomers at the two double bonds in the
approximate ratio 12:10:6:3. Hydrogenation of 11 (H2, Pd/C,
EtOAc), followed by reoxidation of the hydroquinone, gives
a single characterisable compound.
Synlett 2002, No. 11, 1874–1876 ISSN 0936-5214 © Thieme Stuttgart · New York