Derivatization of the C12-C13 functional groups of epothilones A, B and C

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 21, 1998, Pages 3031-3036

  Sefkow, Michael ^a,b   Kiffe, Michael ^a,c   Höfle, Gerhard ^a  

^a HELMHOLTZ CENTRE FOR INFECTION RESEARCH   (Germany)

^b UNIVERSITY OF POTSDAM   (Germany)

^c NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

EPOTHILONE A; EPOTHILONE B; EPOTHILONE C; NATURAL PRODUCT; UNCLASSIFIED DRUG;

ARTICLE; DERIVATIZATION; DRUG STRUCTURE; DRUG SYNTHESIS; MASS SPECTROMETRY; REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; STRUCTURE ACTIVITY RELATION;

ANTINEOPLASTIC AGENTS; EPOTHILONES; EPOXY COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 0032213635     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00546-0     Document Type: Article

References (17)

1. 1. a) Höfle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H.; Angew. Chem. Int. Ed. Engl. 1996, 35, 1567-1569;
2. b) Gerth, K.; Bedorf, N.; Höfle, G.; Irschik, H.; Reichenbach, H.; J. Antibiot. 1996, 49, 560-563.
3. 3 in 45 and 25% yield, respectively, and with similar regioselectivity (ratio: ∼75:25 in favour of C12-Br(I)andC13-OH).
4. 3 in 45 and 25% yield, respectively, and with similar regioselectivity (ratio: ∼75:25 in favour of C12-Br(I)andC13-OH).
5. 2O 3:7) and identified through the COSY spectra of their triformyl esters which allowed to distinguish between the C12 and C13 formiate.
6. 2O completely excluded the formation of diol congeners.
7. 5. The tertiary center at C12 of epothilone B clearly favours heterolytic ring opening of the epoxide at this position under acidic conditions, following by an attack of the nucleophile on the opposite side of the hydroxy group, In epothilone A only the steric and electronic differences between C12 and C13 are weaker.
8. 1H NMR shift of the C3-OH (5.9 ppm in 6a and 3.0 ppm in 6b), 2) the nOe between C21-H (methyl group at the thiazole moiety) and C22-H (methyl group at C5), and 3) a decreased polarity (less than that of epothilone A (1) and 6b). This hydrogen bond gives the molecule a scorpion-like shape (shown below) and allows the specification of the unkown asymmetric center at C15 (R for 6a and S for 6b). Hydrogens omitted, except at C21, C22 and C3-O (matrix presented)
9. 8. The ratio of diols 9/10 vs. rearranged diols 7a/7b is also dependent of organic co-solvents and of the temperature. Higher concentrations of organic solvent and higher temperature lead to more rearranged products 7a,b.
10. 9. Acetonides 11 and 12 were more conveniently prepared in a two step sequence: 1) hydrolysis of 1 in aqueous sulfuric acid to the diols 9 and 10 as described above, and 2) acetalization (acetone, cat. p-TsOH, r. t., 90 min) in good overall yield (>80%).
11. 2 r. t., 3 weeks) produced the rearranged and C7 oxidized analog 23 in 75% yield, see D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277-7287 (matrix presented)
12. 11. For example, bromine in presence of powdered sodium bicarbonate as buffer produced the C19-bromo analog of epothilone 1 in 40% yield.
13. 12. For a recent review, see: Pasto, D. J.; Taylor, R. T.; Organic Reactions 1991, 40, 91-155.
14. 13. VanRheenen, V.; Kelly, R. C.; Cha, D. Y.; Tetrahedron Lett. 1976, 1973-1976.
15. 14. For a discussion about the stereoselectivity on epoxidation of epothilone C, see: a) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D.-S.: Sorensen, E. J.; Danishefsky, S. J.; Angew. Chem. Int. Ed. Engl. 1996, 55, 2801-2803;
16. b) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C.; Angew. Chem. Int. Ed Engl. 1997, 36, 166-168;
17. c) Höfle, G.; et al., Angew. Chem. Int. Ed. Engl., in preparation.