Approaches Towards a Truncated Anthracycline (1)
In this study, we decided to make use of naphthazarin glucoside (7) as the chiral dienophile in the cycloaddition. Following previous work1 in the Stoodley group, Naphthazarin (5) was sonicated with the acetobromoglucose (8) and silver(I) oxide to afford the glucoside (7) after chromatographic work-up in 21% yield. However, the commercially cheaper copper(I) oxide failed to carry out this process.
Previously, the glucoside (7) reacted with the
diene (9) to afford the cycloadduct (10) in 87%
In this study we decided to investigate the reactions of the glucoside
with Danishefsky's Diene (12), in a similar fashion to the Juglone
(11)4 in formation of the trione (13) with high
The mixture of isomers (14) and (15) was hydrolysed by the action of 0.1M hydrochloric acid in THF; the hydroxytrione (17) was isolated in 44% yield after two crystallisations.
Another approach to the novel
was carried out using the more typical Diels-Alder reaction to afford a
(18) that was difficult to ethynylate yielding a mixture of
It is inherent that more effective practical ethynylation methods are
in anthracycline synthesis, or better still new ways of introducing the
This may be compared to a synthesis of (rac)-4- demethoxydaunomycinone devised by Krohn6 and co-workers. Naphthazarin (19) was heated with the diene (20) to afford, after hydrolysis, the (rac)-ketone (21) in 91% yield. Fuctionalisation of ring-A, followed by reaction of the less-stable tautomer (22a) with 1-methoxybuta-1,3-diene afforded a cycloadduct which was converted into (rac)-4-demethoxydaunomycinone (23) (an aglycone precursor to the chemotherapeutic agent Idarubicin) in an overall yield of 29% from naphthazarin (19). Alternatively3, the more stable tautomer (22) was hydrated and the derived (rac)-product (2) [also the aglycone precursor to the truncated anthracycline (1)] was reacted with 1- methoxycyclohexa-1,3-diene to afford the racemic daunomycinone (23) in an overall yield of 33% from naphthazarin (19).
1. A. D. Curtis and R. J. Stoodley, Ph.D. thesis, University of Manchester, 1990. Naphthazarin glucoside has also been used in an enantioselective synthesis of (+)-Hatomarubigin B using Diels-Alder chemistry, G. B. Caygill, D. S. Larsen and S. Brooker, J. Org. Chem., 2001, 66, 7427.
2. M. J. Broadhurst, C. H. Hassall and G. J. Thomas, J. Chem. Soc., Chem. Commun., 1982, 158; Y. Kita, H. Maeda, F. Tekahashi and S. Fukui, J. Chem. Soc., Perkin Trans 1, 1993, 2639.
3. K. Krohn and K. Tolkiehn, Chem. Berichte, 1979, 112, 3453.
4. B. Beagley, A. D. M. Curtis, R. G. Pritcard and R. J Stoodley, J. Chem. Soc., Perkin Trans. 1, 1992, 1981; see also a citation in a review, editor: G. R. Stephenson, Advanced Asymmetric Synthesis, Chapman & Hall, London, 1996, pages 126-145 [i.e. chapter 7, 'Asymmetric Diels-Alder reactions', A. Whiting (University of Manchester), author] and references within J. P. Miller, ChemInform, 2013, 44 (48) DOI: 10.1002/chin.201348243.
5. E. Ghera and Y. Ben-David, J. Org. Chem., 188, 52, 2972; T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima and Y. Kamiya, J. Am. Chem. Soc., 1989, 111, 4392.
6. K. Krohn and K. Tolkiehn, Tetrahedron Letters, 1978, 4023.
Relevant experiments from Experimental
[Labelling of the compounds here differs to the experimental!]
Preparation of Naphthazarin Glucoside
Reaction of Naphthazarin Glucoside with Danishefsky's Diene
Preparation of the Hydroxytrione
Attempted ethynylation of the Hydroxytrione
Attempted ethynylation of the Hydroxytrione using a cerium(III) reagent