HETEROCYCLES

Communication | Special issue | Vol. 84, No. 1, 2012, pp. 349-354
Received, 29th June, 2011, Accepted, 8th August, 2011, Published online, 16th August, 2011.
DOI: 10.3987/COM-11-S(P)58

■ Condensation of Catechin and Epicatechin Incorporating a TBS-Protecting Group

Noriyuki Nakajima,* Keiko Horikawa, Norimasa Takekawa, Masahiro Hamada, and Takao Kishimoto

Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Kosugi, Toyama 939-0398, Japan

Abstract

Stereoselective synthesis of catechin and epicatechin dimers incorporating a tert-butyldimethylsilyl (TBS)-protecting group under intermolecular condensation is achieved using SnCl4 as the Lewis acid. Four TBS-protected dimers were successfully converted to the deca-acetates of procyanidin B1, B2, B3, and B4 easily via the TBS-deprotection process. This procedure offers an advantage for dimmer synthesis in large-scale over existing benzyl-protecting methods.

Proanthocyanidins are condensed or noncondensed hydrolysable tannins.1,2 Condensed tannins may be found in the foods such as fruits, beans, cocoa, and tea.3-6 Many biological properties of these compounds have been reported, including anti-inflammatory,7 hypotensive,8 and antibacterial properties,9 cancer-cell growth inhibition,10 antimutagenic properties,11 and the inhibition of HIV-1 replication in vitro,12 suppression of ulcer formation,13 neuroprotective properties,14 and reduction of risk of heart disease.15 Tannin extracts from plants are a source of various types of polyphenols. Because the identification and purification of these compounds is extremely difficult, further studies focusing on the procyanidins are required. Recently, considerable efforts have been devoted to synthesize procyanidin oligomers in pure state.16-22 The results of these initial studies have addressed some of the complex, challenges of synthesis posed by the procyanidins, relating to the difficulty of controlling the interflavan regio- and stereoselectivity, as well as the sensitivity of the unprotected compounds to acid, alkali, and oxidizing environments. A benzyl group is the group most commonly used to protect the phenolic functionalities of procyanidins. However, the large-scale synthesis of benzyl (+)-catechin and (-)-epicatechin is very limited because of the by-products formation at benzyl-protection.21a,23 We successfully synthesized procyanidin dimmers24 using a silyl-protecting group (tert-butyldimethylsilyl: TBS) instead of the benzyl-protecting group.
TBS protection of catechin 1 and epi-catechin 5 proceeded with TBS-Cl and imidazole in THF/CH2Cl2 to afford tetra-TBS products 2 and 6 in 95% and 46% yields, respectively. TBS-protection was carried out at hundred-gram scale within three hours to obtain TBS-ethers 2 and 6 after SiO2 short column chromatography purification. Dichloro-dicyano-benzoquinone (DDQ) oxidation at the C4 position of 2 and 6 with ethoxyethanol (EE) in CH2Cl2 afforded electrophiles 3 and 7 in 65% and 64% yields, respectively. The electrophiles obtained were acetylated to give acetates 4 and 8 in 100% and 78% yields, respectively (Scheme 1).

Condensation between tetra-O-TBS catechin electrophile 3 and nucleophile 2 proceeded in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf: 1 eq.) at −78 ˚C to afford a mixture of the 3,4-trans compound (4α)-9 and the 3,4-cis compound (4β)-9 in 61% coupling yield with a 1 : 2 ratio.25 Diastereoselectivity determination was performed after transformation into the deca-acetates (4α)-11 and (4β)-11. Each dimer was acetylated with acetic acid (AcOH), and N, N'-dicyclohexylcarbodiimide (DCC) in the presence of 4-dimethylaminopyridine (DMAP) to give 3,3’-O-diacetyl-octa-O-TBS procyanidin-B3 (4α)-10 and (4β)-10 in 66% and 92% yields, respectively. Eight TBS protecting groups were submitted to deprotection with 4 eq. of tetra-butyl ammonium fluoride (TBAF) and AcOH in tetrahydrofuran (THF). Deprotection of the TBS-group at the phenolic position proceeded without any trouble. Full acetylation of eight hydroxy groups with Ac2O and DMAP in pyridine afforded the deca-acetyl derivative (4α)-1124a in 77% yield and also (4β)-1124a in 95% yield (Scheme 2).

The intermolecular coupling of catechin and catechin units was examined with acetate 4 and 2 in the presence of a Lewis acid. In comparison with the benzyl-protected catechin and catechin coupling (97%, α:β = >48:1),24a the TMSOTf-mediated coupling reaction of a TBS-protecting catechin group was low isolation yield but only gave 3,4-trans procyanidin dimmer (4α-12). Coupling yields at −78 °C, −63 °C and −41 °C were 67, 63 and 62% yields, respectively; however, coupling yields have decreased to 29% and 21% yields as the reaction temperature increased up to −22 °C and 0 °C, respectively. When BF3•Et2O was used as a Lewis acid, the desired compound was obtained in 58% yield at 0 °C and trace at −78 °C. The best yield was obtained using SnCl4 at 0 °C (ice bath) to give 4α-12 in 84% yield (Table 1, entry 8).26
This finding encouraged us to investigate alternative combinations of nucleophile and electrophile. We next examined intermolecular epicatechin-catechin, epicatechin-epicatechin, and catechin-epicatechin condensations using SnCl4 as a Lewis acid at 0 °C. In all cases, the coupling reaction worked well to only give the corresponding 3,4-trans products, 13, 17, and 22 in 98, 98, and 100% yields, respectively (Scheme 3).
After acetylation of C-3” hydroxy group, the eight-TBS protecting groups of 14, 18, 10 and 23 were removed with TBAF in the presence of AcOH in THF to give 15, 19, 21, and 24 in 68, 100, 100%, and 100% yields, respectively. All the spectral data [NMR, IR, MS] of the corresponding deca-acetyl-procyanidins 16,24c 20,24e 11,24a and 2524c were identical to those of authenticated samples.

In conclusion, we prepared TBS-protected catechin derivatives as a procyanidin unit. TBS-protected catechin derivatives showed high efficiency in condensation with SnCl4 at 0 °C (ice bath). This procedure offers a real advantage for dimmer synthesis over existing methods in this area. The longer procyanidin oligomers synthesis using TBS-protected catechin and epicatechin units are in progress.

ACKNOWLEDGEMENTS
We gratefully acknowledge financial support by Grants-in-Aid for Scientific Research (20590106) from the Ministry of Education, Science, and Culture of Japan.

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25. The ratio of (4α)-9 and (4β)-9 was determined by the isolation yields of each compound from silica gel preparative TLC separation (Merck 1.0 mm, hexane/EtOAc= 10/1, 3 times development).
26. General Procedure for the coupling reaction using SnCl4 (Table 1, entry 8): To a solution of nucleophile 2 (600 mg, 0.80 mmol) and electrophile 4 (157 mg, 0.18 mmol) in CH2Cl2 (36 mL) under an argon atmosphere was added SnCl4 (46.5 mg, 0.18 mmol). After the resulting mixture had been stirred for 30 min, the reaction was quenched with water. The mixture was extracted with EtOAc, and the combined organic layer were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified with silica gel chromatography (hexane/EtOAc = 25/1) to give only 4α-12 (231 mg, 0.15 mmol, 84%) as an oil.