ArticleTETRAHEDRON LETTERS. 48(33): 5891-5894 (2007)journal articl

Hattori,  Y

Hirota,  M

Kamo,  T

Makabe,  H

Mohri,  Y

Morimura,  K

Sagehashi,  M

Yamada,  T

Mohri

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An Efficient Synthesis of Procyanidins. Rare Earth Metal Lewis Acid Catalyzed Equimolar Condensation of Catechin and Epicatechin.

Shinshu University Institutional Repository

An efficient synthesis of procyanidins. Rare earth metal Lewis acid catalyzed equimolar condensation of catechin and epicatechin Yoshihiro Mohri, Masayoshi Sagehashi, Taiji Yamada, Yasunao Hattori, Keiji Morimura, Tsunashi Kamo, Mitsuru Hirota, and Hidefumi Makabe* OBnOOBnOHOBnOBnOBnOOBn OMeOAcOBnOBnOBnOOBnOAcOBnOBnBnOOBnOOHOBnOBnOHOOHOHOHOHHOOHOOHOHOHprocyanidin B3 (3)1 eq.1 eq.+ 64%Yb(OTf)3                  1An efficient synthesis of procyanidins. Rare earth metal Lewis acid catalyzed equimolar condensation of catechin and epicatechin  2Yoshihiro Mohri,a Masayoshi Sagehashi,a Taiji Yamada,a Yasunao Hattori,b, c Keiji Morimura,b, d  Tsunashi Kamo,e Mitsuru Hirota,e and Hidefumi  Makabea* aSciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304, Minami-minowa, Kami-ina, Nagano 399-4598, Japan bInterdisciplinary Graduate School of Science and Technology, Shinshu University, 8304, Minami-minowa, Kami-ina, Nagano 399-4598, Japan  cSatellite Venture Business Laboratory, Shinshu University, 3-15-1, Tokida, Ueda, Nagano386-8567, Japan dGeol Cosmetics. Co., LTD, 111-1, Shinmura, Katsuragi, Nara 639-2121, Japan eDepartment of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304, Minami-minowa, Kami-ina, Nagano 399-4598, Japan  *Corresponding author. Tel. +81 265 77 1630; fax +81 265 77 1700, e-mail: makabeh@shinshu-u.ac.jp  Abstract: Stereoselective synthesis of catechin and epicatechin dimers under intermolecular condensasion is achieved by an equimolar amount of coupling catalyzed by Yb(OTf)3.  The coupled products were successfully converted to procyanidin B1, B2, B3, and B4. Proanthocyanidins are known as condensed or noncondensed hydrolysable tannins.1 These condensed tannins can be found in the vegetables kingdom.2 In particular, they exist in grape seeds and skins and red wines. Many biological activities, mainly a powerful free-radical scavenging activity, have been reported for flavonoids, and their investigation is increasingly important. Tannin extracts from plants give various types of polyphenols. Because their identification as well as purification is extremely difficult, further studies of proanthocyanidins remains. Recently, to obtain procyanidin oligomers in pure state, synthetic efforts were devoted. 3 However, efficient syntheses are very limited because the formation of the intermolecular C-4-C-8 bond has some problems. The typical synthetic methods are as follows. The first example is nucleophilic addition of C-8 lithiated nucleophile onto a C-4 protected ketocatechin as a substrate.4 This reaction generally proceeds with the regioselective and oligomerization control demands of the coupling reaction, however, it does not satisfy the stereochemical requirement of the newly formed C-4 asymmetric center. The next is the nucleophilic substitution method which needs to use nucleophilic partner in large excess (3.0-4.5 eq.) to prevent further oligomerization. Thus the efficient synthetic method to prepare procyanidin dimers has some restrictions, although recent advance was made in the regio and stereoselective reaction.3 Until now, only a few attempts to prepare procyanidin dimers under stoichiometric conditions have been reported in the literature. The first example is an intramolecular coupling of monomeric units bound by a temporary diester link.5 This method is suitable for synthesizing procyanidin B1 (1) and B3 (3), however, it suffers from low yield of condensation for synthesizing B2 (2) and B4 (4). The second is reported by E. Fouquet and co-workers. 6 They synthesized procyanidin dimers based on the intermolecular nucleophilic substitution of C-4 activated and C-8 halogenated monomer to prevent further oligomerization using TiCl4 as a Lewis acid. This reaction needs large excess of TiCl4. In the course of our research, we have developed a very simple and efficient intermolecular synthesis of procyanidin dimers. The key step is a coupling reaction between equimolar amounts of tetra-benzylated monomer 5a (nucleophile) and a C-4 activated monomer 6a (electrophile) using 1 eq. of rare earth metal Lewis acid such as Yb(OTf)3 (Fig. 1). OHOOHOHOHOHHOOHOOHOHOHOHOOHOHOHOHHOOHOOHOHOHprocyanidin B1 (1)procyanidin B3 (3)OHOOHOHOHOHHOOHOOHOHOHprocyanidin B2 (2)OHOOHOHOHOHHOOHOOHOHOHprocyanidin B4 (4)  Figure 1. The structures of procyanidin B1 (1)-B4 (4). We chose tetrabenzylated catechin 5a, a nucleophilic unit, prepared by the Kawamoto’s procedure 7 and electrophile unit 6a prepared by the Saito’s method.8 Equimolar condensation of 5a and 6a at room temperature was examined using various Lewis acids including rare earth metal at room temperature in CH2Cl2 (Scheme 1, Table 1). The first attempt at the coupling reaction was conducted with equimolar amounts of the protected catechin 5a and the acetylated substrate 6a to obtain α-7, which is the precursor of procyanidin B3 (3). Typical Lewis acids, such as TiCl4 and BF3•Et2O gave sluggish results. These reactions required a large excess of the nucleophile at low temperature in order to limit the reaction of the activated monomer with itself or with the dimeric product leading in both cases to oligomeric side products.7, 8 The next attempt at the coupling reaction was conducted with late transition metals as Lewis acids. Among Ag, Cu, and In, especially AgBF4 gave a good selectivity with moderate chemical yield. We further paid attention to rare metal Lewis acids such as Sc and La. While Sc gave poor stereoselectivity, La afforded high selectivity although the chemical yield was 34%. This result encouraged us to replace La to Yb. The reaction furnished good selectivity with 64% yield.9 The catalytic amount of Yb(OTf)3  (10 mol%) also afforded coupled product in 42% yield at 91 : 9 ratio of the desired product.  3This result indicates that this reaction could be carried out using catalytic amount of Yb(OTf)3. Further optimization of the catalytic reaction system is now underway.  OBnOOBnOHOBnOBnOBnOOBn OMeOAcOBnOBnOBnOOBnOAcOBnOBnBnOOBnOOHOBnOBnOBnOOBnOAcOBnOBnBnOOBnOOHOBnOBn6aα-75a+Lewis acidsβ-7+ Scheme 1. Lewis acids mediated coupling reaction between 5a and 6a. TimeTable 1. Equimolar coupling reaction of 5a and 6a by Lewis acidsaLewis acidsbBF3 Et2O.In(OTf)3Sc(OTf)3La(OTf)3Yb(OTf)3NDTiCl4AgBF4B(C6H5)3Cu(OTf)30.537.520.510 mol% of Yb(OTf)30.50.572212Yield (%)363850434550346442Selectivity (α : β)c75 : 25−89 : 1198 : 291 : 991 : 967 : 3398 : 298 : 291 : 9aThe reaction was carried out at room temperature in CH2Cl2.b1 equivalent of Lewis acid was used otherwise noted.cThe selectivity was determined by 1H NMR analysis of C-3 position of diacetate derivative of α-7 (5.80 and 5.83 ppm) and β-7 (5.53 and 5.58 ppm) according to the reported procedure.3b  As shown in Table 2, the reported condensation reaction between catechin nucleophile 5a or 8 and catechin electrophile 6a, 9, and 10 required large amount excess of catechin nucleophile 5a or 8 to obtain desired dimer in high yield. As shown in entry 1, the first report of condensation by Kawamoto and co-workers used 5 eqiv. of nucleophile 5a. They obtained coupled product in high yield, however, the stereoselectivity of α-11 and β-11 was only 60 : 40 ratio.7 Saito and co-workers used nucleophile 5a and electrophile 6a which combination was same of ours. This condensation afforded a coupled product in high yield with good stereoselectivity, however, it required 4.5 equiv. of nucleophile.3b, 8 Suzuki and co-workers reported the condensation reaction using 8 and 10 to obtain 12.10 Although the amount of nucleophile was smaller than Kawamoto and Saito, they still used 3 equiv. of nucleophile with 90 : 10 selectivity of the desired product. When they used 1.2 equivalent of nucleophile 8, the yield was 59% with same selectivity. Our result of equimolar condensation between 5a and 6a was shown in entry 4. Although the yield was lower than other groups, the stereoselectivity was superior to  4others. Using large excess amount of nucleophile is a big problem because composition of desired coupled product is only a small part in the reaction system and it is necessary to get rid of large amount of starting material by chromatography. Optimized equimolar condensation is extremely important for an efficient synthesis of catechin dimers (Scheme 2, Table 2). OBnOOBnOROBnOBnOBnOOBn XOR'OBnOBnOBnOOBnOR'OBnOBnBnOOBnOOROBnOBnOBnOOBnOR'OBnOBnBnOOBnOOROBnOBn6a: X = OMe, R' = Ac  9: X = OH, R' = H10: X = OAc, R' = Bn α-7: R = H, R' = Acα-11: R = R' = Hα-12: R = Bn, R' = Bn5a: R = H  8: R = Bn+Lewis acids +β-7: R = H, R' = Acβ-11: R = R'= Hβ-12: R = Bn, R' = Bn  Scheme 2. Examples of Lewis acids mediated coupling reaction between catechin nucleophile and catechin electrophile. Nucleophile / ElectrophileTable 2. Examples of condensation of the catechin nucleophile and electrophile by Lewis acidsLewis acidsTiCl4BF3 Et2O.BF3 Et2O.83TiCl4TMSOTfYb(OTf)354.54.531.2Yield (%)92quant.9459Selectivity (α : β)60 : 4097 : 390 : 1090 : 10Nucleophile Electrophile96 : 45a 95a 6a5a 6a8 108 10T (oC)0−20−78−30−30Entry12356Product117712124 5a 6a 1.0 7 64 98 : 2artaThe selectivity was determined by 1H NMR analysis of C-3 position of diacetate derivative of α-7 (5.80 and 5.83 ppm) and β-7  (5.53 and 5.58 ppm) according to the reported procedure.3b          Next, we examined the condensation of the combination of catechin nucleophile 5a and epicatechin nucleophile 5b with catechin electrophile 6a and/or epicatechin electrophile 6b using Yb(OTf)3 as a Lewis acid. In each case, the reaction worked well. As to the stereoselectivty, however, the epicatechin electrophile 5b gave a little bit poor results compared to catechin necleophile 5a. In case of tri-benzylated phloroglucinol, the stereoselectivity of 16 showed 75 : 25 ratio.11 Some stereochemical requirement of the nucleophile seems to be necessary to get high selectivity (Scheme 3).  Finally, condensed compounds α-7, β-13, β-14, and α-15 were subjected to the hydrolysis of the acetate with K2CO3 in MeOH followed by debenzylidation by Pd(OH)2 in THF-MeOH-H2O catalyzed hydrogenolysis to give procyanidin B1 (1)-B4 (4). All the spectral data for 1-4 were similar to those of the reported value.3a, 3d, 5a  5OBnOOBnOHOBnOBnOBnOOBnOHOBnOBnOBnOOBnOHOBnOBnOBnOOBnOHOBnOBnOBnOOBn OMeOAcOBnOBnOBnOOBn OMeOAcOBnOBnOBnOOBn OMeOAcOBnOBnOBnOOBn OMeOAcOBnOBnYb(OTf)3Yb(OTf)3Yb(OTf)3Yb(OTf)3OBnOBnBnOOBnOOBn OMeOAcOBnOBnYb(OTf)3OBnOOBnOAcOBnOBnBnOOBnOBnOBnOOBnOAcOBnOBnBnOOBnOOHOBnOBnOBnOBnOOBnOBnBnOOBnOBnOOHOBnOAcOBnOOBnOAcOBnOBnBnOOBnOOHOBnOBnOBnOOBnOAcOBnOBnBnOOBnOOHOBnOBn6b5b6b5a16+β-1362%β : α = 91 : 95b+ 76%β : α = 88 : 12β-146a+ 59%α : β = 98 : 2α-156a+α-1776%α : β = 75 : 251246aα-75a+ 64%α : β = 98 : 23aaaa Scheme 3. Equimolar coupling of epicatechin-catechin, epicatechin-epicatechin, catechin-catechin, and catechin-epicatechin using Yb(OTf)3 as a Lewis acid toward the synthesis of procyanidin B1(1)-B4 (4). Reagents and conditions: (a) (i) K2CO3, MeOH; (ii) H2, 20 wt% Pd(OH)2, THF-MeOH-H2O (47-67%).   6 7Acknowledgement We thank Geol Cosmetics. Co., LTD for financial support. References and notes 1. Ferreira, D.; Li. X. –C. Nat. Prod. Rep. 2000, 17, 193-212. 2. Ferreira, D.; Li. X. –C. Nat. Prod. Rep. 2002, 19, 517-541. 3. (a) Tückmantel, W.; Kozikowski, A. P.; Romanczyk, Jr., L. J. J. Am. Chem. Soc. 1999, 121, 12073-12081. (b) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M. Tetrahedron 2002, 58, 7829-7837. (c) Kozikowski, A. P.; Tückmantel, W.; Böttcher, G.; Romanczyk, Jr., L. J. J. Org. Chem. 2003, 68, 1641-1658. (d) Saito, A.; Nakajima, N.; Matsuura, N.; Tanaka, A.; Ubukata, M. Heterocycles 2004, 62, 479-489. 4. Kozikowski, A. P.; Tückmantel, W.; Hu, Y. J. Org. Chem. 2001, 66, 1287-1296. 5. (a) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M. Heterocycles 2003, 61, 287-298. (b) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M. Tetrahedron Lett. 2003, 44, 5449-5452. 6. Tarascou, I.; Barathieu, K.; Andé, Y.; Pianet, I.; Dufourc, E. J.; Fouquet, E. Eur. J Org. Chem. 2006, 5367-5377. 7. Kawamoto, H.; Nakatsubo, F.; Murakami, K. Mokuzai Gakkaishi 1991, 37, 488-493. 8. Saito, A.; Nakajima, N,; Tanaka, A.; Ubukata, M. Biosci. Biotechnol. Biochem. 2002, 66, 1764-1767. 9. General Procedure for the equimolar coupling reaction using Yb(OTf)3 (Table 1): To a solution of nucleophile 5a (190 mg, 0.263 mmol) and electrophile 6a (171 mg, 0.263 mmol) in CH2Cl2 (10 mL) under an argon atmosphere was added Yb(OTf)3 (163 mg, 0.263 mmol). After the resulting mixture had been stirred for 2 h, the reaction was quenched with water. The mixture was extracted with diethyl ether, and the combined organic layer were washed with brine, dried over MgSO4, and concentrated. The crude product was purified with silica gel chromatography (hexane:EtOAc:CH2Cl2 = 4:1:2) to give diasteremeric mixture α-7 and β-7 (226 mg, 64%) as a colorless oil. 1H NMR analysis of diacetate derivative showed more than 98 : 2 ratio of α-7 and β-7.3b, 7 The selectivity was determined by 1H NMR analysis of C-3 position of diacetate derivative of α-7 (5.80 and 5.83 ppm) and β-7 (5.53 and 5.58 ppm) according to the reported procedure.3b10. Ohomori, K.; Ushimaru, N.; Suzuki, K. Proc. Nat. Acad. Sci. USA  2004, 101, 12002-12007. 11. Hayes, C. J.; Whittaker, B. P.; Watson, S. A.; Grabowska, A. M. J. Org. Chem. 2006, 71, 9701-9712.   8     

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An efficient synthesis of procyanidins. Rare earth metal Lewis acid catalyzed equimolar condensation of catechin and epicatechin

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An Efficient Synthesis of Procyanidins. Rare Earth Metal Lewis Acid Catalyzed Equimolar Condensation of Catechin and Epicatechin.

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