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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:

R. C. Gupta, P. A. Harland and R. J. Stoodley, Tetrahedron, 1984, 40, 4657.

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).

Be careful not to confuse compound labels here with Experimental!


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]:

HOMO of silylenol ether (12)
LUMO of Dimethyldioxirane

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.

<I>Re</I>-face attack of ethynyl group


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].

PNG file
PNG file
PNG image file

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:

Looking towards ring-A, horizontally


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.

jonathan@jonathanpmiller.com

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

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