Synthesis of xyloketal A, B, C, D, and G analogues

Journal of Organic Chemistry

Volumn 71, Issue 4, 2006, Pages 1620-1625

  Pettigrew, Jeremy D ^a   Wilson, Peter D ^a  

^a SIMON FRASER UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

3-HYDROXYMETHYL-2- METHYL-4,5-DIHYDROFURAN; BIOGENIC; DEMETHYL ANALOGUES; ELECTROPHILIC AROMATIC SUBSTITUTION REACTION;

AROMATIC COMPOUNDS; PHASE TRANSITIONS; SUBSTITUTION REACTIONS; SYNTHESIS (CHEMICAL);

PHENOLS;

3 HYDROXYMETHYL 2 METHYL 4,5 DIHYDROFURAN; ACETAL DERIVATIVE; BORON TRIFLUORIDE; FURAN DERIVATIVE; NATURAL PRODUCTS AND THEIR SYNTHETIC DERIVATIVES; PHENOL DERIVATIVE; UNCLASSIFIED DRUG; XYLOKETAL A; XYLOKETAL B; XYLOKETAL C; XYLOKETAL D; XYLOKETAL G;

ARTICLE; CHEMICAL REACTION; CYCLOADDITION; DRUG ISOLATION; DRUG STRUCTURE; DRUG SYNTHESIS; SUBSTITUTION REACTION;

BIOLOGICAL PRODUCTS; CATALYSIS; FURANS; PHENOLS; PYRANS;

EID: 33644519294     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo052371+     Document Type: Article

References (27)

1. Lin, Y.; Wu, X.; Feng, S.; Jiang, G.; Luo, J.; Zhou, S.; Vrijmoed, L. L. P.; Jones, E. B. G.; Krohn, K.; Steingröver, K.; Zsila, F. J. Org. Chem. 2001, 66, 6252.
2. Wu, X. Y.; Liu, X. H.; Lin, Y. C.; Luo, J. H.; She, Z. G.; Houjin, L.; Chan, W. L.; Antus, S.; Kurtan, T.; Elsässer, B.; Krohn, K. Eur. J. Org. Chem. 2005, 4061.
3. Wu, X.; Liu, X.; Jiang, G.; Lin, Y.; Chan, W.; Vrijmoed, L. L. P. Chem. Nat. Compd. 2005, 41, 27.
4. Herein, the numbering scheme is based on that described by Lin and co-workers (see refs 1 and 3).
5. Xyloketal B (2) is presumably more stable than the regioisomeric natural product, xyloketal C (3), because destabilizing dipole-dipole interactions are minimized. In addition, xyloketal B (2) in principle can also form a hydrogen bonded dimer in solution [cf. xyloketal F (6), see ref 2].
6. The stereochemistry of the quaternary benzylic center of xyloketal E (5), if this natural product is formed by an electrophilic aromatic substitution reaction of xyloketal B (2) and (4R)-4,5-dihydro-2,4-dimethylfuran, is opposite to what would be predicted on the basis of simple steric arguments. However, the level of diastereoselectivity of this proposed reaction is not predictable and it is possible that an epimer of xyloketal E (5) is also produced metabolically.
7. Pettigrew, J. D.; Bexrud, J. A.; Freeman, R. P.; Wilson, P. D. Heterocycles 2004, 62, 445.
8. Pettigrew, J. D.; Freeman, R. P.; Wilson, P. D. Can. J. Chem. 2004, 82, 1640.
9. We have also outlined an alternative approach for the synthesis of the xyloketal natural products based on a novel phenylboronic acid-mediated condensation reaction of α,β-unsaturated aldehydes with aromatic phenols, see: Pettigrew, J. D.; Cadieux, J. A.; So, S. S. S.; Wilson, P. D. Org. Lett. 2005, 7, 467.
10. (a) Krohn, K.; Riaz, M. Tetrahedron Lett. 2004, 45, 293.
11. (b) Krohn, K.; Riaz, M.; Flörke, U. Eur. J. Org. Chem. 2004, 1261.
12. This alternative high-yielding synthesis was also diastereoselective (8.5:1.5). However, the reported racemic synthesis of xyloketal D (4) and its diastereoisomer (80% combined yield) was also complicated by the formation of a diastereomeric mixture of the regioisomeric bicylic acetals (9%, combined yield). One of these latter diastereoisomers corresponds to xyloketal G (7) (see refs 10b and 3).
13. These researchers have also described the synthesis of demethyl analogues of xyloketal D (4) and G (7) from a model α,β-unsaturated ketone and 2,4-dihydroxyacetophenone (see ref 10b).
14. Krohn and co-workers have also attempted the synthesis of xyloketal A (1) from racemic 5-hydroxy-4-methyl-3-methylenepentan-2-one and phloroglucinol. In this instance, the desired tris-adducts were isolated in 6% yield as a mixture of eight diastereoisomers (the corresponding mono- and bis-adducts were also isolated) (see ref 10b).
15. The isolation of xyloketal F (6) suggests, as commented on by Lin and co-workers (and demonstrated by semisynthesis), that a formaldehyde equivalent is involved in the biosynthesis of this particular natural product (see ref 2). It can also be inferred that a formaldehyde equivalent could also be involved in additional steps in the biosynthesis of the xyloketals in view of this new synthetic proposal.
16. After the reports of our original syntheses of xyloketal D (4) (see: ref 7 and 8), Lin and co-workers have also commented that the biosynthesis of the xyloketals involves o-quinone methide intermediates (see ref 3). In view of the findings reported in this paper, in addition to our earlier observations, we believe that this conclusion is incorrect. Of note, the α,β- unsaturated ketone reported by Krohn and co-workers is a synthetic equivalent of the alcohol 16 (see ref 10). We believe that the former compound is not directly involved in the biosynthesis of the xyloketal natural products because relatively forcing conditions are required for this compound to react (nor was the reactivity of this compound influenced by the addition of acids, vide infra) and in view of the isolation of xyloketal E (5). However, the potentially biogenic route described by Krohn and co-workers cannot be discounted at this time.
17. (a) Korte, F.; Machleidt, H. Chem. Ber. 1957, 90, 2137.
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19. The preparation of the alcohol 20 by direct reaction of commercially available 2-methyl-4,5-dihydrofuran 13 with formaldehyde or related synthetic equivalents, under various reaction conditions, was unsuccessful.
20. Razdan, R. K.; Dalzell, H. C.; Handrick, G. R. J. Am. Chem. Soc. 1974, 96, 5860. Of note, the cosolvent, dichloromethane, was not used in these studies because of the poor solubility of phloroglucinol 15 in chlorinated solvents.
21. Boron trifluoride diethyl etherate has also been employed as a Lewis acid in the electrophilic aromatic substitution reaction of phloroglucinol 15 and 2-methylbut-3-en-2-ol, see: (a) Collins, E.; John, G. D.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1975, 96.
22. In addition, a key step in a total synthesis of the natural product, alboatrin, has involved a boron trifluoride diethyl etherate-promoted electrophilic aromatic substitution reaction of orcinol with 2,4-dimethyl-3-hydroxymethylfuran, see: (b) Ichiara, A.; Nonaka, M.; Sakamura, S.; Sato, R.; Tajimi, A. Chem. Lett. 1988, 27.
23. None of the desired products were formed on performing the reactions at room temperature in the absence of an acid promoter or in the presence of acetic acid.
24. For recent references regarding the facile decarboxylative saponification reactions of ortho-phenolic esters, see: (a) Hu, H.; Harrison, T. J.; Wilson, P. D. J. Org. Chem. 2004, 69, 3782.
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27. Methyl 2,4,6-trihydroxybenzoate 22 was prepared from the carboxylic acid 21, on reaction with dimethyl sulfate and sodium bicarbonate, according to a literature procedure, see: Carvalho, C. F.; Russo, A. V.; Sargent, M. V. Aust. J. Chem. 1985, 38, 777.