Ring-DCB Dienophile Synthon Strategy1
The reaction of ring-DCB dienophile synthon of type (1) would appear to be the most
direct route to anthracyclines. However, two major problems exist in this approach.
Firstly, internal cycloadducts of type (3) may be formed 2-5 as well as or instead of the
desired cycloadducts of type (5) (Schemes 1 and 2). Secondly, regiochemical
outcome for unsymmetrical diquinones is not easy to control.
O
O
O
R
R1
1
O
+
R
R
2
O
(1)
O
OR
O
(2)
(3)
2
RO
O
Scheme 1
Table 1 Internal cycloadducts of type (3) formed with suitable dienes
Diene
R1
2a
CH2C(OCH2CH2O)H
2b
H
2c
OSiMe3(OTMS)
2d
H
O
O
O
R
R2
Me
Me
Me
Ac
O
H
1
1
R
+
R
R
O
(1)
O
R
2
H
O
(4)
O
2
R
(5)
Scheme 2
Table 2 Terminal cycloadducts of type (5) formed with suitable dienes
Diene
R1
R2
4a
H
H
4b
H
OAc
4c
CH2C(OCH2CH2O)H
Cl
4d
OAc
SiMe3
Generally, dienes that add to the internal double bond are electron-rich in character
(2a – 2d). Conversely, dienes of type (4) that add2-5 to the external (terminal) double
bond are either electron-deficient in character (4a –4d) or are unsubstituted (4a). The
major cycloadducts are shown in Scheme 2. Note these are racemic mixtures.
Hückel perturbation molecular orbital calculations6 suggest that internal addition will
be favoured by electron-rich dienes. This is due to the cumulative effect of the four
carbonyl groups adjacent to the C-5a,9a double bond, thus making it more electron
deficient and thereby decreasing it’s lowest unoccupied molecular orbital (LUMO)
energy. The LUMO is more reactive towards electron-rich dienes of type (2a-d)
which possess a high energy highest occupied molecular orbital (HOMO)7.
In my experimental work, oxidation of the bicyclic quinol [for compound (7) - see my
website, http://www.jonathanpmiller.com] with lead(IV) acetate in acetic acid at room
temperature afforded the tetraone (8) as green needles in 62% yield after
crystallisation from chloroform-hexanes. Spectroscopic and microanalytical data
were consistent for compound (8). The air-sensitive tetraone (8) was oxidized to the
epoxytetraone (9) using m-chloroperoxybenzoic acid in dichloromethane at 0 oC to
afford the compound (9) in 61% yield, after crystallisation from chloroform-hexanes.
O
OH
O
O
O
O
O
O
(7)
OH
O
(8)
O
O
O
(9)
Reaction of the epoxytetraone (9) with the D-glucose-based diene (10) is shown in
Scheme 3. The epoxytetraone (9) reacted with the diene (10) in acetone at 0-5 oC to
afford mainly the cycloadduct (11) on the basis of limited 300 MHz 1H NMR
spectroscopic and mass spectra data.
Unfortunately, attempted purification of compound (11) led to complications. The
sample was first subjected to low-temperature silica-gel chromatography [with
retention of regiostructure (11)]. Subsequent crystallisation from dichloromethanediethyl ether-hexanes caused rearrangement of the cycloadduct (11) to it’s
regioisomer (12), together with some hydolysis to the epoxypentaone (13) (islated in
only 2% yield). The regioisomer (12) [11% based on the epoxytetraone (9) was the
only identifiable component in the mother liquor. Spectroscopic data for these
compounds were analogous to compounds listed in the website.
This synthesis resulted in compatively lower yields than using dienohile (7), but is
analogous in steps to previously published work8-9 in the Dick Stoodley group.
O
O
O
O
H
OSiMe2But
OSiMe2But
O
O
+
Acetone,
H
o
O
0-5 C
O
O
(9)
O
O
O
OAc
OAc
(11)
O
O
OAc
OAc
OAc
OAc
OAc
OAc
(10)
O
Crystallisation
11% from (9)
O
O
H
O
H
O
O
O
H
O
OSiMe2But
O
H
O
O
O
O
OAc
OAc
O
O
OAc
OAc
(13)
OAc
OAc
OAc
Scheme 3
OAc
(12)
References:
1. Adapted from the J. P. Miller, “Asymmetric Synthesis of Anticancer
Anthracyclines”, Ph.D. Thesis, University of Manchester Institute of Science
and Technology, pages 27-28, 1994.
2. T. R. Kelly, R. N. Goerner, J. W. Gillard and B. K. Prozak, Tetrahedron
Letters, 1976, 3869.
3. T. R. Kelly and W. –G. Tsang, Tetrahedron Letters, 1978, 4457.
4. W. W. Lee, A. P. Martinez, T. H. Smith and D. W. Henry, J. Org. Chem.,
1976, 41, 2296.
5. R. B. Garland, J. R. Palmer, J. A. Schultz, P. B. Sollman and R. Pappo,
Tetrahedron Letters, 1978, 3669.
6. R. Sustmann, Tetrahedron Letters, 1971, 277.
7. I. Fleming, “Frontier Orbitals and Organic Chemical Reactions”, John Wiley
and Sons, Cambridge, 1986, pages 86-181.
8. M. Chandler and R. J. Stoodley, J. Chem. Soc., Chem. Commun., 1978, 997.
9. R. C. Gupta P. A. Harland and R. J. Stoodley, Tetrahedron, 1984, 40, 4657.