The First Synthesis of Uralenol, 5′-Prenylated Quercetin, via Palladium-Catalyzed­ O-Dimethylallylation Reaction with Concurrent Acetyl Migration

Abstract

The first synthesis of uralenol, 5′-prenylated quercetin, is described. The key step is a palladium-catalyzed O-1,1-dimethylallylation reaction, with concurrent acetyl migration to afford the desired intermediate as a major isomer, which was purified by recrystallization. Finally, Claisen rearrangement, followed by deprotection of all phenolic protecting groups, afforded uralenol in excellent yield.

Key words

palladium - prenylation - quercetin - flavonoids - rearrangement

• References

• 1a Yazaki K, Sasaki K, Tsurumaru Y. Phytochemistry 2009; 70: 1739
• 1b Nomura T. Yakugaku Zasshi 2001; 121: 535 ; Chem. Abstr. 2001, 135, 119570
• 1c Ren Y, Kardono LB. S, Riswan S, Chai H, Farnsworth NR, Soejarto DD, Carcache-Blanco EJ, Kinghorn AD. J. Nat. Prod. 2010; 73: 949
• 1d Huang Y.-C, Hwang T.-L, Chang C.-S, Yang Y.-L, Shen C.-N, Liao W.-Y, Chen S.-C, Liaw C.-C. J. Nat. Prod. 2009; 72: 1273
• 1e Tabopda TK, Ngoupayo J, Awoussong PK, Mitaine-Offer A.-C, Ali MS, Ngadjui BT, Lacaille-Dubois M.-A. J. Nat. Prod. 2008; 71: 2068
• 1f Meragelman KM, MaKee TC, Boyd MR. J. Nat. Prod. 2001; 64: 546
• 1g Conseil G, Decottignies A, Jault J-M, Comte G, Barron D, Goffeau A, Pietro AD. Biochemistry 2000; 39: 6910
• 1h Jia SS, Ma CM, Wang JM. Acta. Pharm. Sin. 1990; 25: 758
• 1i Fukai T, Wang Q.-H, Takayama M, Nomura T. Heterocycles 1990; 31: 373
• 2a Zheng Z.-P, Cheng K.-W, Chao J, Wu J, Wang M. Food Chem. 2008; 106: 529
• 2b Chen RM, Hu LH, An TY, Li J, Shen Q. Bioorg. Med. Chem. 2002; 12: 3387
• 3 Kawamura T, Hayashi M, Mukai R, Terao J, Nemoto H. Synthesis 2012; 44: 1308
• 4a Kaiho T, Miyamoto M, Nobori T, Katakami T. Yuki Gosei Kagaku Kyokaishi 2004; 62: 27
• 4b Kaiho T, Yokoyama T, Mori H, Fujiwara J, Nobori T, Odaka H, Kamiya J, Maruyama M, Sugawara T. Japanese Patent JP 06-128238, 1994 ; Chem. Abstr. 1995, 123, 55900.
• 5 When acetic anhydride was used as the solvent, the chemical yield and chemoselectivity of Claisen rearrangement were dramatically improved; see ref. 3.
• 6 Differentiation of C-4′ from C-3′ with migratory group such as acetyl group has not been reported prior to our result reported herein. In contrast, selective O-methylation of C-4′ of quercetin via six steps was reported: Li N.-G, Shi Z.-H, Tang Y.-P, Yang J.-P, Duan J.-A. Beilstein J. Org. Chem. 2009; 5: No. 60
• 7a Picq M, Prigent AF, Nemoz G, Andre AC, Pacheco H. J. Med. Chem. 1982; 25: 1192
• 7b Li M, Han X, Yu B. J. Org. Chem. 2003; 68: 6842
• 8 Peng W, Li Y, Zhu C, Han X, Yu B. Carbohydr. Res. 2005; 340: 1682
• 9 In fact, pure 8a was isolated from a mixture of 8a and 8b by recrystallization. Unfortunately, however, the purified 8a reverted to a mixture of 8a and 8b after a short time. Furthermore, even when Pd-catalyzed O-dimethylallylation was carried out immediately after isolation of pure 8a, a mixture of 10a and 10b was obtained. Incidentally, isomerization from 8b to 8a was also observed during recrystallization, because recrystallization of a mixture of 8a and 8b (76:24) afforded pure 8a in 84% (which is greater than 76%) yield. Accordingly, the best purification point in the synthesis of uralenol was after obtaining a mixture of 10a and 10b because 10 has no phenolic proton.
• 10 Pd-catalyzed O-dimethylallylation at the 7-position of tetraacetylated quercetin was reported in our recent paper (see, ref. 3). During the reaction, no acetyl migration was detected probably because the phenolic hydroxide was not located at the ortho-position of any of the acetoxy groups in the starting materials.
• 11 Shinozuka T, Yamamoto Y, Hasegawa T, Saito K, Naito S. Tetrahedron Lett. 2008; 49: 1619