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Approaches Towards 8-Hydroxyidarubicin (4)
Previously, Arcamone has synthesised C-8 (1)1 and C-10 (2)2 methoxy derivatives of daunomycin (3) via opening of oxirane intermediates with methanol in the presence of p-toluenesulfonic acid. The C-10R derivative still remained effective as an antileukaemic agent where as the C-10S epimer was ineffective. It is hoped that the C-8 hydroxy derivative (4) would lead to a more stable DNA-drug complex by providing an additional hydrogen bonding substituent. This effect may result in increased anticancer efficiacy. In addition, the additional 'bulk' at C-8 could hinder the approach of the enzyme responsible for metabolising the anthracyclines via a reductive deglycosidation pathway3, so changing it's pharmacological properties.
i.
Prepararion of
the
Trihydroxytrione
(5)
Previously4a,
a synthesis
directed at the
ring-A
anthracycline
(4) had
commenced; it had
culminated in the
predominant
formation of an
ethynylated
material of type
(6), whose
stereochemistry at
the C-8, 9 and 10a
positions had not
been rigorously
established. The
anticipated
synthesis of the
aglycone of the
anthracycline
(4)
parallels that for
(+)-4-demethoxydaunomycinone:
The
difference in the
synthesis of
8-hydroxyidarubicinone
is the new hydroxyl
functionality at
C-8 is introduced
after the
cycloaddition step.
Unfortunately
compound (6)
failed to undergo
effective oxidation
to the
anthracycline
(7) using
lead(IV)
acetate.
Following
literature
procedures5,
the epoxytetraone
(10) was
prepared from
quinizarin
(8) via the
tetraone (9)
in 36% yield after
crystallisation.
Allowing
the epoxytetraone
(10) to
react with the
D-glucose
based diene
(14) in
acetone6
afforded a 75% d.e.
of the cycloadduct
(11); it was
isolated in 65%
yield after
trituration with
diethyl ether (77%
recovery yield) and
crystallisation
from
dichloromethane and
hexanes. However,
using benzene as a
solvent, a lower
yield (60%) of the
cycloadduct
(11) (with a
d.e. of 60% prior
to trituration and
crystallisation).
Previously,
the cycloadduct
(11) was
shown to
react4a
with an aqueous
osmium tetroxide -
barium chlorate
solution in a
mixture of THF and
carbon
tetrachloride to
afford the
hydroxypentaone
(13) in 52%
yield. In this
study, the use of
dimethyldioxirane
(12)
(DMDO)4b, 7
in acetone proved
to be more
effective,
affording the
hydroxypentaone
(13) in 97%
yield after
crystallisation.
The C-8S
configuration would
suggest that the
DMD (12)
attacks from the
more sterically
favourable topside
of the cycloadduct
(11).
However, no
evidence for an
intermediate
epoxycycloadduct9,10
of type (15)
was detected,
indicating that the
conditions cause
hydrolysis of the
trimethylsilyloxy
group to the ketone
moiety.
Hückel
molecular orbital
theory could shed
some light on the
correct side of the
DMD oxygen atom to
attack the
silylenol ether
double bond.
Frontier orbital
calculations of
sizes of molecular
orbitals are used
to determine
regiochemistry in
reactions e.g.
Diels-Alder
reactions and
stereo-electronic
effects. The energy
difference (DE
= 5.43
eV8)
between the
Highest
Occupied Molecular
orbital
(HOMO)
of the compound
(12)
and
Lowest Unoccupied
Molecular Orbital
(LUMO)
of DMD (13)
is smaller than
LUMO
of compound
(12) and
HOMO
DMD
(13)(8.45
eV). This would
then give the
quickest reaction
rate with the
lowest Activation
Energy. A model of
the
HOMO
of (12) is
shown above the
LUMO
of (13).
Sadly, the
molecular orbitals
(lobes seen as blue and red
shapes) of the
double bond is not
shown here to the
right side of the
ring on the
right.
[Legend:
Carbon atom =
grey ball;
Hydrogen = light
blue, Oxygen
= red and
Silicon =
purple]:
An ab initio (wavefunction) Hartree-Fock (6-31G**) calculation found the values to be rather different using the known tert-butyldimethylsilyl analogue of 11: HOMO = -9.67 and LUMO = 1.27 eV; for DMDO 12 HOMO = -12.51 and LUMO = 6.20 eV (ELUMO - EHOMO = 13.78 eV). This time, an equilibrium geometry for DMDO 12 was used in the energy calculation.
The best
method for
effecting the
reduction of the
hydroxypentaone
(13) to the
trihydroxytrione
(5)4
was to use
activated zinc
(ca. mol
equiv.) in a 1:1
acetic
acid-dichloromethane
mixture. The pure
trihydroxytrione
(5) was
obtained in 29%
yield after
crystallisation4a. A
change in the
solvent from
dichloromethane to
ethyl acetate or
the use of sodium
dithionite in
aqueous methanol at
-20 oC
and room
temperature as the
reducing agent led
to reduced yields
of the
trihydroxytrione
(5).
ii.
Ethynylation of
the
Trihydroxytrione
(5)
The
trihydroxytrione
(5) was
treated in THF with
ethynylmagnesium
chloride (ca. 30
mol equiv.) to
afford, after
crystallisation, a
mixture (ca. 88%
yield) containing a
3:1 ratio of the
ethynylcarbinols
(6) and
(16). The
anticipated
C-10R epimer
(16) was not
the major epimer in
this
instance.
The
C-10aS
epimer (6)
is thought to arise
by way of extensive
C-10a base
catalysed
enolisation. The
axial
orientation of the
sugar substituent
played a major tole
in the approach of
the Grignard
reagent from the
sterically
less-hindered top
re-face of
the C-9 ketone
moiety. In
addition, to
overcome any
potential hindrance
of the C-8S
hydroxyl
substituent, it is
quite possible that
the C-8s hydroxyl
group forms an
intermediate
chelated bond with
the Grignard
reagent, as
typified by complex
(17),
thereby favouring
the
re-approach.
iii.
Protection of
the Ethynylcarbinol
(6)
as the
O-Isopropylidene
Derivative
(18)
In
order to
investigate whether
the ethynylcarbinol
(6) could be
converted into an
O-isopropylidene
derivative
(18), a
mixture containing
mainly compound (6)
was allowed to
react with an
excess of
2,2-dimethoxypropane
in the presence of
p-toluenesulfonic
acid. Work-up
afforded a 5:1
mixture of the
O-isopropylidene
(18)
derivative and an
unidentified
compound. Limited
NMR and mass
spectra data were
consistent for
compound
(18) with a
likely C-8S,
9S and
10aS
configuration as
depicted.
Shown
below are some 3D
models of compound
(18); notice the
chair-like
structure of the
D-glucose auxiliary
in the third
structure and in
all structures
C-10a anf C-6a
hydrogen antoms are
anti to each
other:
[Legend:
Hydrogen,
blue; oxygen
red and
carbon
grey].
iv.
Oxidation of the
Ethynylcarbinol
(6)
to the
Anthracycline
(7)
As lead(IV) acetate proved an unsuitable oxidant for the (6) to (7) conversion, activated manganese(IV) oxide (MnO2) (which is sometimes used in the presence of air11) was examined as an alternative oxidant12. Heating compound (6) with manganese(IV) oxide (90 mol. equiv.) in dry benzene gave a mixture which contained mainly the oxidised compound (19); crystallisation from ethanol gave the anthracycline (7) in only 10% yield. Refluxing toluene proved an alternative solvent for the oxidation, albeit with a slightly lower recovery of compound. Spectroscopic data with the help of a 2D COSY spectrum were consistent for compound (7). Unfortunately, crystals suitable for X-ray analysis could not be obtained by attempted slow crystallisation from ethanol or a mixture containing a 1:1 ratio of mainly anthracycline (7) and urea in ethanol or just using n-butanol13 as a solvent. The solvent diffusion technique14 using hexanes to diffuse into the aforementioned solvents containing mainly compound was largely rewarding.
In a 3D
model, the
half-chair
structure of the
ring-A is
just
noticable:
References
1.
S. Penco, F.
Angelucci, M.
Ballabio, A.
Vigevani and F.
Arcamone,
Tetrahedron
Lett., 1980,
21,
2253.
2. S.
Penco, F. Gozzi, A.
Vigevani, M.
Ballabio and F.
Arcamone,
Heterocycles,
1979, 13,
281.
3. F.
Arcamone,
"Doxorubicin
Anticancer-Antibiotics",
Academic Press, New
York, 1981. ISBN
0-12-059280-0.
4 (a)
F. T. Escribano and
R. J. Stoodley,
"Synthetic
Approaches to
8/10-Hydroxyidarubicins",
Report No.
2, 1991.
(b) More recently, Bourghli has synthesised (+)-8-hydroxy-8-methylidarubicinone using similar Diels-Alder reactions and DMDO to introduce the (+)-8-hydroxy substituent; L. M. S. Bourghli and R. J. Stoodley, Bioorganic & Medicinal Chemistry, 2004, 12, 2863.
5.
M. Chandler and R.
J. Stoodley, J.
Chem. Soc., Perkin
Trans. 1, 1980,
1007.
6. M. M.
L. Crilley and R.
J. Stoodley,
"Synthesis of
Anticancer
Anthracyclines",
Report No.
1, 1984.
7.
W. Adam, J. Bialas
and L.
Hadjiarapoglou,
Chem. Ber.,
1991, 124,
2377.
8.
Molecular Orbitals
energies and shapes
calculated from
Hückel
surfaces using
CambridgeSoft
Chem3D Pro
software.
9. R.
F. Lowe and R. J.
Stoodley, Ph.D.
thesis,
University of
Manchester,
1993.
10. W.
Adam, L.
Hadjiararapoglou,
V. Jager, J.
Klicic, B. Seidel
and X. Wang,
Chem. Ber.,
1991, 124,
2361.
11. B.
Beagley, A. D. M.
Curtis, R. G.
Prtichard and R. J.
Stoodley, J.
Chem. Soc., Perkin
Trans. 1, 1992,
page 1981.
12.
D. S. Larsen and R.
J. Stoodley,
Tetrahedron,
1990, 46,
4711.
13. C.
Courseille, B.
Busetta, S. Geoffre
and M. Hospital,
Acta
Crystallogr.,
1979, B35,
364.
14. P. G.
Jones, Chemistry
in Britain,
1981, 17,
222.
Unpublished data, output and figures have been deposited at doi:10.7910/DVN/26971.
Relevant
experiments from
Experimental:
[Labelling
of the compounds
here differs to the
experimental!]
Preparation
of the Epoxide
6
Preparation
of the cycloadduct
8
Reaction
of the cycloadduct
8 with DMDO
Formation
of the
Trihydroxytrione
Grignard
Ethynylation of the
Trihydroxytrione
Protection
of the
Ethynylcarbinols
with
Dimethoxypropane
Formation
of the
Anthracycline
