A regiodivergent synthesis of ring A C-prenylflavones

Organic Letters

Volumn 10, Issue 11, 2008, Pages 2267-2270

  Minassi, Alberto ^a   Giana, Anna ^a   Ech Chahad, Abdellah ^a   Appendino, Giovanni ^a  

^a UNIVERSITY OF EASTERN PIEDMONT   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CANNABIS; FLAVONE DERIVATIVE; PROSTAGLANDIN SYNTHASE; PROSTAGLANDIN SYNTHASE INHIBITOR;

ARTICLE; CHEMISTRY; STEREOISOMERISM; SYNTHESIS;

CANNABIS; CYCLOOXYGENASE INHIBITORS; FLAVONES; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; STEREOISOMERISM;

EID: 52649150410     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol800665w     Document Type: Article

References (38)

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10. There is considerable confusion in the literature regarding the paternity of the preparation of 4H-chromones from o-hydroxyacetophenones by reaction with an activated carboxylic acid, a transformation referred to as Robinson, Allan-Robinson, Baker-Venkataraman, or Kostanecki-Robinson synthesis. The original Robinson reaction involved a thermal, sodium benzoate catalyzed process, involving o-hydroxyacetophenone and aroyl anhydrides: Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192-2195.
11. A more general two-step protocol based on the base-catalyzed isomerization of o-acyloxyacetophenones to o-hydroxybenzoylacetophenones followed by cyclization under acidic conditions was later developed and became known as the Baker-Venkataraman synthesis: Baker, W. J. Chem. Soc. 1933, 1381-1389.
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14. For sake of clarity, we refer to the transformation of o-hydroxyacetophenones to flavones simply as the "Robinson reaction". For a discussion, see: Finar, I. L. Organic Chemistry; Longman: London, 1977; Vol. 2, pp 782-784.
15. Alternative strategies are the dehydrogenation of prenylflavanones to prenylflavones by treatment with iodine in pyridine (Dong, X.; Fan, Y.; Yu, L.; Hu, Y. Arch. Pharm. Chem. Life Sci. 2007, 340, 372-376. ) or the use of robust acid-sensitive, but difficult to remove, protecting groups.
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17. Flavone numbering.
18. MOM-Cl has been reported to selectively diprotect phloracetophenone (Bu, X. Y.; Zhao, L. Y.; Li, Y. L. Synthesis 1997, 1246-1248), but, in our hand, this procedure gave a chromatographically difficult to separate 2.5:1 mixture of di- and triprotected derivatives, in analogy with what observed with ester and carbamate protecting groups.
19. An improved procedure has been recently reported: Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2007, 70, 1507-1509.
20. While the thermal instability of the MOM group, especially in the presence of Lewis acids, has been observed previously (Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2007, 70, 1507-1509), that of the pivaloyl group was unexpected and might be related to traces of triphenylphosphine oxide from the Mitsunobu O-prenylation step.
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26. Alkoxy-substituted aroyl chlorides are poor acylating agents in flavone synthesis (Patonay, T.; Molnar, D.; Muranyi, Z. Bull. Soc. Chim. Fr. 1995, 32, 233-242), and the pivaloyl group was chosen to increase the electrophilicity of the acyl carbon. No reaction took place when pivaloylvanillic acid was reacted with 9 under Steglich conditions (DCC, DMAP).
27. The reaction takes place with a Baker-Venkataraman oxygen-to-carbon acyl shift, and its course could be followed by TLC (see Supporting Information). The best conditions for the reaction required the treatment with 1 equiv of NaH to produce an O-acyl ester, next converted in situ into the C-acylated product by treatment with 2 further equiv of NaH. The direct addition of a large excess of NaH gave a lower yield, while LDA and NaHMDS led to desilylated products.
28. Due to a decreased basicity, aryl tert-butyldimethylsilyl ethers are more stable to Lewis acids than their alkyl analogues: Collington, E. W.; Finch, H.; Smith, I. J. Tetrahedron Lett. 1985, 26, 681-684.
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32. 2 has been reported to dehydrate o-hydroxy-1,3- diaroylmethanes to flavones under microwave irradiation: Kabalka, G. W.; Mereddy, A. R. Tetrahedron Lett. 2005, 46, 6315-6317.
33. Nagarathnam, D. Cushman, M. Tetrahedron 1991, 47, 5071-5076. In general, enolization of 1,3-diaroylmethanes is fast in the presence of a ortho-phenolic hydroxyl (see ref 16).
34. o-Hydroxy-1,3-diaroylmethanes exist as an equilibrating mixture of the dicarbonyl form, two enol forms, and one 2-hydroxyflavanone structure, whose composition depends on the aryl substitution pattern: Borbély, J.; Szabó, V.; Sohár, P. Tetrahedron 1981, 37, 2307-2312.
35. Dehydration of the 2-hydroxyflavanone cyclic tautomer affords flavones: Cunnigham, B. D. M.; Lowe, P. R.; Threadgill, M. D. J. Chem Soc., Perkin Trans. 2 1989, 1275-1283.
36. TBDMS-chloride and TES-chloride were less effective, while TMS-triflate gave 4′-pivaloylcyclocannflavin B (i) as the major reaction product. Heterogeneous dehydrating agents (activated molecular sieves) were ineffective, as was trimethylorthoformate or azeotropic removal of water with Dean-Stark distillation. The mechanism by which TMS-chloride postpones desilylation of the ortho-hydroxyl to the flavone level might be more complex than a simple water trapping and might involve amplification of the oxyphilicity of the metal catalyst, activation of the "distal" carbonyl of the diaroylmethanes 12 and 14, or a combination of both. (Chemical Equation Presented)
37. For the spectroscopic characterization of cannflavins, see: Choi, Y. H.; Hazekamp, A.; Peltenburg-Looman, A. M. G.; Frédérich, M.; Erkelens, C.; Lefeber, A. W. M.; Verpoorte, R. Phytochem. Anal. 2004, 15, 345-354.
38. For a discussion, see: Kocieński, P. J. Protecting Group, 3rd ed.; Thieme: Stuttgard, 2003; pp 26-36.