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Daunosamine

Coupling of the Aminosugar to Anthracyclinones


Before daunosamine (1) can be coupled to the aglycone (anthracyclinone), it is necessary to protect the C-3 and C-4 substituents and convert the C-1 hydroxyl group into a better leaving group (e.g. a halide).  The coupling reaction may then be employed with Koenigs-Knorr or Lewis acid1-3 conditions.   Stereospecific formation of the alpha-glycosides are required for the anthracyclines to have the correct configuration, the aglycones being devoid of anticancer activity and the b-glycosides being less affective4 than their alpha-glycoside counterparts.
Several derivatives of daunosamine (1) have been prepared that are suitable for coupling to the aglycone.  These include the fairly stable N-acetyl-O-p-nitrobenzoyl daunosaminyl bromide (2)5 and chloride(3)6 as well as N-acetyl-1,4-bis(O-p-nitrobenzoyl)daunosamine (4).5,6
 
The bromide (2) was obtained by neutralising the daunosamine hydrochloride salt (6) with sodium methoxide in methanol at 0 oC and then converting the amino function into trifluoroacetamide (5) by adding S-ethyl trifluorothioacetate at room temperature.  The N-trifluoroacetamide (5), obtained in 68% yield, was converted into N-acetyl-1,4-bis(O-p-nitrobenzoyl) derivative (4) in 93% yield by addition of ca. 3 molar equivalents of p-nitrobenzoyl chloride in pyridine at 0 oC.   The bromide (2) was obtained by bubbling anhydrous hydrogen bromide into a suspension of the ester (4) in dichloromethane; it was not isolated but used directly for the coupling reaction.  The chloride (3) was obtained in a similar fashion using anhydrous hydrogen chloride; again it was not isolated.

The first report of the coupling of a daunosamine derivative to daunomycinone (7) was given by Henry5 in which the bromide (2) was refluxed with daunomycinone (7) in the presence of mercury(II) cyanide, mercury(II) bromide and 3 A molecular sieves in anhydrous THF to afford solely the alpha-glucoside (8) in 53% yield.   Deprotection was accomplished with 0.1M aqueous sodium hydroxide in THF at 0 oC to afford daunomycin (9) in 94% yield; upon acidification of a solution of daunomycin (9) in chloroform with one equivalent of hydrogen chloride in ethanol, daunomycin hydrochloride (10) was obtained in 61% yield after precipitation with ether.   Henry6 later reported the stereospecific glycosidation of daunomycinone (7) with the chloride (3); the alpha-glycoside (8) being obtained in 77% yield after chromatography.   The chloro derivative (3) is therefore the preferred coupling reagent.

Adriamycinone (11) [readily obtained in two steps by subjecting daunomycinone (7) to bromination and then alkaline hydrolysis6] has to be protected at the C-14 position in order for a selective alpha-glycosidation at the C-7 position to occur.  14-O-p-Anisyldiphenylmethyladriamycinone (12) was prepared in 84% yield by allowing adriamycinone (11) and p-anisylchlorophenylmethane to react together in the presence of pyridine.  The C-14 derivative was coupled to the chloride (3) using the aforementioned conditions to afford the alpha-glycoside (13); deacylation with 0.1M sodium hydroxide in aqueous THF at 0 oC gave the amine (14).  Treatment of compound (14) with 80% acetic acid and conversion of adriamycin (15) into the hydrochloride salt was achieved with hydrogen chloride in methanol.  Overall, a 40% yield of adriamycin (15) was obtained from adriamycinone (11).
 
In a similar fashion, idarubicin hydrochloride (19) has been prepared7 by the silver(I) triflate catalysed stereospecific alpha-glycosidation of (+)-4-demethoxydaunomycinone (16) [idarubicinone (16) was previously prepared by Stoodley within this website].

A third method of stereospecific glycosidation1, 8, 9 is to use trimethylsilyl triflate as the Lewis acid catalyst.  The Japanese team who discovered this procedure1 found that subjecting 4-demethoxydaunomycinone (16) to glycosidation using the p-nitrobenzoate (2) and 2-2.5 molar equivalents of trimethylsilyl triflate at low temperature in a dichloromethane-diethyl ether solvent mixture gave the alpha-glucoside (17) in 99.5% yield.  Selective deprotection of the p-nitrobenzoate group (1 molar equivalent of 0.1M aqueous sodium hydroxide in a CH2Cl2-MeOH mixture at 0 oC), gave the amide (18) in 83% yield which was further deprotected (12 molar equivalents of 0.1M NaOH) to afford idarubicin hydrochloride (19) in 77% yield after converting the free base into the hydrochloride salt (19).

This procedure has also been applied to beta-rhodomycin syntheses1, 9 such as oxaunomycin (20)1; protection of the C-10 hydroxyl group as an ester was required prior to the alpha-glycosidation to control the regiochemistry of the reaction.

 

References

1.  Y. Kita, H. Maeda, M. Kirahara and Y. Fujii, Tetrahedron Letters, 1990, 31, 7173.
2.  K. Krohn and W. Prigono, Tetrahedron, 1984, 40, 4609.
3.  P. N. Preston, T. Winwick and J. O. Morely, J. Chem. Soc., Perkin Trans 1, 1983, 1439.
4.  F. Arcamone, "Doxorubicin Anticancer-Antibiotics", Academic Press, New York, 1981.
5.  E. M. Acton, A. N. Fujiwara and D. W. Henry, J. Med. Chem., 1974, 17, 659.
6.  T. H. Smith, A. N. Fujiwara, W. W. Lee, H. Y. Wu and D. W. Henry, J. Org. Chem., 1977, 42, 3653.
7.  M. J. Broadhurst, C. H. Hassall and G. J. Thomas, J. Chem. Soc., Chem. Commun., 1982, 158.
8.  Y. Kimura, M. Suzuki, M. Matsumoto, R. Abe and S. Terashima, Bull. Chem. Soc., Jpn, 1986, 59, 423.
9.  Y. Kita, H. Maeda, F. Tekahashi and S, Fukui, J. Chem. Soc., Perkin Trans 1, 1993, 2639.

Author: J. P. Miller. This content was originally available on www.jonathanpmiller.com/daunosamine/, "Coupling of the Aminosugar to Anthracyclinones", Web [accessed 08/06/2017].
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Jonathan Miller,
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Jonathan Miller,
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Jonathan Miller,
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Jonathan Miller,
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Jonathan Miller,
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Jonathan Miller,
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