Efficient Stereoselective Synthesis of Proanthocyanidin Trimers with ­TMSOTf-Catalyzed Intermolecular Condensation

Akiko Saito; Akira Tanaka; Makoto Ubukata; Noriyuki Nakajima

doi:10.1055/s-2004-822905

LETTER

Efficient Stereoselective Synthesis of Proanthocyanidin Trimers with TMSOTf-Catalyzed Intermolecular Condensation [1]

Akiko Saito*^a, Akira Tanaka^b, Makoto Ubukata^c, Noriyuki Nakajima*^d
^a Biotechnology Center, Toyama Prefecture, Japan
^b Department of Bioresources Science, College of Technology, Toyama Prefectural University, Japan
^c Graduate School of Agriculture, Hokkaido University, Japan
^d Biotechnology Center, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
Fax: +81(766)562498; e-Mail: nori@pu-toyama.ac.jp;

Abstract

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Abstract

A stereoselective synthesis of seven benzylated proanthocyanidin trimers with TMSOTf-catalyzed condensation reaction is described. In particular, epicatechin-(4β-8)-epicatechin-(4β-8)-epicatechin trimer (procyanidin C1), catechin-(4α-8)-catechin-(4α-8)-catechin trimer (procyanidin C2), epicatechin-(4β-8)-epicatechin-(4β-8)-catechin trimer and epicatechin-(4β-8)-catechin-(4α-8)-epicatechin trimer derivatives were obtained in excellent yields. The structure of benzylated procyanidin C2 was confirmed by comparing the ¹H NMR spectra of protected procyanidin C2 that was synthesized by two different condensation approaches. Finally, deprotection of (+)-catechin and (-)-epicatechin trimers derivatives gave four natural procyanidin trimers in good yields.

Key words

polyphenol - condensed tannin - oligomeric flavonoid - catechin trimer - C-type procyanidin

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References

This report is Part 6 in the series ‘Synthetic studies of proanthocyanidins’.

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In this condensation reaction, excess amount (4.0-4.5 equiv) of a monomer nucleophile was used to avoid higher oligomer formation.

Data for 7c: [α]_D ²⁶ -82.2 (c 0.12, CHCl₃). ¹H NMR (400 MHz, CDCl₃, 0.83:0.17 mixture of rotational isomers) δ (major isomer) = 7.35-6.35 (57.27 H, m), 6.11 (0.83 H, s), 6.10 (0.83 H, d, J = 2.2 Hz), 6.02 (0.83 H, d, J = 2.2 Hz), 6.00 (0.83 H, s), 5.17-4.33 (21.58 H, m), 4.19 (0.83 H, d, J = 8.8 Hz), 3.97-3.86 (1.66 H, m), 3.73-3.68 (0.83 H, m), 3.53 (0.83 H, d, J = 9.0 Hz), 3.03 (0.83 H, dd, J = 6.1 and 16.1 Hz), 2.89 (0.83 H, d, J = 9.6 Hz), 2.78 (0.83 H, dd, J = 9.7 and 16.1 Hz), 1.31 (0.83 H, d, J = 2.6 Hz, OH), 1.78 (0.83 H, d, J = 3.9 Hz, OH), 1.07 (0.83 H, d, J = 3.7 Hz, OH); δ (minor isomer) = 7.35-6.35 (11.22 H, m), 6.28 (0.17 H, d, J = 1.7 Hz), 6.21 (0.17 H, d, J = 8.3 Hz), 6.18 (0.17 H, s), 6.15 (0.17 H, s), 6.05 (0.17 H, d, J = 2.2 Hz), 5.97 (0.17 H, d, J = 2.2 Hz), 5.80 (0.17 H, dd, J = 1.7 and 8.3 Hz), 5.17-4.33 (5.27 H, m), 4.06-3.86 (0.34 H, m), 3.73-3.68 (0.17 H, m), 3.58-3.57 (0.17 H, m), 2.93 (0.17 H, d, J = 10.0 Hz), 2.66 (0.17 H, m), 2.37-2.32 (0.17 H, m), 1.44-1.41 (0.17 H, m, OH), 1.36-1.34 (0.17 H, m, OH), 1.20-1.17 (0.17 H, m, OH). ¹³C NMR (100 MHz, CDCl₃): δ (major isomer) = 157.9, 157.8, 156.7, 155.5, 155.4, 155.1, 155.1, 154.9, 153.8, 149.2, 149.1, 149.0, 148.8 (× 2), 148.5, 137.6, 137.4, 137.4, 137.4, 137.3, 137.2, 137.2, 137.1, 137.1, 137.0, 136.0, 132.4, 132.3, 131.7, 128.8-126.9 (C × 37), 121.1, 120.6, 120.5, 115.0, 114.8, 114.7, 114.5, 114.1, 113.6, 112.2, 109.4, 108.6, 102.4, 101.1, 94.7, 93.8, 92.0, 91.8, 81.7, 81.0, 80.4, 73.0, 72.9, 71.9-69.8 (C × 11), 68.4, 65.2, 37.5, 37.4, 28.4; minor isomer was not identified. FAB-MS: m/z (%) = 1947 (0.26) [M + H]⁺. FAB-HRMS calcd for C₁₂₉H₁₁₀O₁₈ [M + H]⁺: 1947.7770; found: 1947.7694.

Data for 7a: [α]_D ²⁵ -233.7 (c 0.38, EtOH) {lit. [11a] [α]₅₇₈ -173 (c 1.03, EtOH)}; HPLC R_t 7a = 18.8 min. FAB-MS: m/z (%) = 890 (12.5), 889 (21.5) [M + Na]⁺, 888 (14.7), 887 (12.4), 868 (6.9), 867 (12.6) [M + H]⁺, 866 (10.9), 328 (100). FAB-HRMS calcd for C₄₅H₃₈O₁₈Na [M + Na]⁺: 889.1956; found: 889.2018.

HPLC analysis conditions: Mightysil^® RP-18 GP column (Kanto Chemical Co. Inc., Japan; 250 × 4.6 mm, 5µm); solvent (A) 0.1% CF₃CO₂H in MeCN, (B) 0.1% CF₃CO₂H in H₂O: Elution was done with a linear gradient 5% to 100% A in 40 min (flow rate: 0.5 mL/min.).

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Data for 1a: [α]_D ²⁵ +56.9 (c 0.30, EtOH) {lit. [11c] [α]_D +76.9}; HPLC R_t 1a = 20.5 min. ¹H NMR (400 MHz, CD₃COCD₃/D₂O, 15/1): δ = 7.13-6.69 (9 H, br), 6.10-5.83 (4 H, br), 5.30-5.05 (1 H, br), 5.04-5.03 (1 H, br), 4.89-4.54 (3 H, br), 4.16-3.95 (3 H, br), 2.75-2.60 (1 H, br), 2.58-2.51 (1 H, br). FAB-MS: m/z (%) = 889 (12.8) [M + Na]⁺, 888 (7.1), 887 (5.8), 867 (9.0) [M + H]⁺, 866 (6.7), 329 (100). FAB-HRMS calcd for C₄₅H₃₈O₁₈Na [M + Na]⁺: 889.1956; found: 889.1927.

Data for 4a: [α]_D ²⁴ -112.6 (c 0.40, MeOH) {lit. [11d] [a]_D ²⁷
-97.6 (c 1.0, MeOH)}; HPLC R_t 4a = 20.3 min. FAB-MS: m/z (%) = 890 (2.2), 889 (4.0) [M + Na]⁺, 888 (3.3), 887 (2.1), 868 (2.2), 867 (3.9) [M + H]⁺, 866 (3.1), 613 (4.2), 483 (11.7), 482 (25.2), 460 (48.2), 328 (100), 306 (100). FAB-HRMS calcd for C₄₅H₃₈O₁₈Na [M + Na]⁺: 889.1956; found: 889.1882.

Data for 2a: [α]_D ²⁷ +59.3 (c 0.30, MeOH) {lit. [α]_D +70.4 (c 2.2, MeOH)}; HPLC²⁰ R_t 2a = 22.0 min. FAB-MS: m/z (%) = 890 (1.9), 889 (3.3) [M + Na]⁺, 888 (2.2), 887 (1.7), 868 (1.6), 867 (3.3) [M + H]⁺, 866 (2.5), 613 (8.3), 482 (25.5), 459 (45.8), 328 (100), 306 (100). FAB-HRMS calcd for C₄₅H₃₈O₁₈Na [M + Na]⁺: 889.1956; found: 889.2031.

<A NAME="RU02904ST-22">22</A> Kozikowski AP. Tückmantel W. Hu Y. J. Org. Chem. 2003, 68: 1641

Efficient Stereoselective Synthesis of Proanthocyanidin Trimers with ­TMSOTf-Catalyzed Intermolecular Condensation [1]

Efficient Stereoselective Synthesis of Proanthocyanidin Trimers with TMSOTf-Catalyzed Intermolecular Condensation [1]