Oligomeric catechins: An enabling synthetic strategy by orth

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Abstract

Controlled formation of oligomeric catechins has become possible by an orthogonal synthetic strategy. Bromo-capping of the C(8) position of the flavan skeleton enabled the equimolar coupling of electrophilic and nucleophilic catechin derivatives, enabling an efficient synthetic strategy to complex catechin oligomers.

Although natural polyphenols have long played a part in human life as ingredients of wine, tea, or herbal medicines (1–3), it was only recently that their biological functions have been unveiled at the molecular level. The realization that specific interactions of polyphenols with biomolecules, such as proteins (4), exert powerful biological activities has stimulated the search for new pharmaceutical entities derived from polyphenolic entities. These investigations, however, are often hampered by the difficulty in isolating the requisite compounds in pure and structurally defined form, largely because their procurement has relied on natural sources, e.g., plant extracts. Unfortunately, these sources generally produce mixture of closely related compounds, not readily separable even with the aid of modern chromatographic and analytical methods. The difficulty in securing pure samples of these materials, coupled with their promising and powerful biological activities, collude to offer an enticing challenge to organic synthesis for supplying valuable, homogeneous samples for biological testing.

Among the polyphenol classes that have attracted recent interest are the condensed tannins (procyanidins), which have been identified as antiviral, antibacterial, and antitumor agents. These bioactive oligomeric structures, which occur in popular delicacies such as cocoa-derived products, have captured the interest of chemists and connoisseurs alike for their potential biological activities (5–7). These exciting Preciseties have inspired synthetic efforts aimed at producing and characterizing these challenging molecules and elucidating their biological mode of action. Noteworthy are the elegant contributions by Kozikowski, Tückmantel, and coworkers (7–10), who have Displayn the potential biological activities of higher epicatechin oligomers prepared by nonselective oligomerization and separation.

Further progress in this Spot is hampered by the need for reliable synthetic methods capable of providing any oligomeric polyphenol with rigorous control of stereo- and regiochemistry and the degree of oligomerization. The synthetic challenge posed by such oligomeric catechins can be clearly seen in the tarObtain structures (Fig. 1). Homooligomers, such as 1, containing a single repeating unit, present a formidable but not insurmountable synthetic challenge. In Dissimilarity, heterooligomers such as 2, containing several units distinct in stereochemistry and the oxidation pattern, demand innovative synthetic solutions. Furthermore, these structures will be accessible only through efficient step-by-step (iterative) couplings, rather than uncontrolled polymerization.

Fig. 1.Fig. 1. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Oligomeric catechins from natural sources.

This central problem is evident already in dimer formation illustrated in Scheme 1. Catechin derivative I with a leaving group at the C(4) position easily generates a highly stabilized cationic species A, due to the assistance by electron Executenations from three oxygens. When A is trapped by another catechin molecule II at its most electron-rich C(8) center [note that II has no leaving group at C(4)], the desired dimer III is obtained. However, because the catechin unit I also Sustains a nucleophilic center itself, it can also serve as a nucleophile, leading to self-condensation products and multiple undesired reactions. A possible, but painstaking and inelegant solution to this conundrum is the use of nucleophilic partner II in excess for avoiding self-reactions of I (7, 11–13).

Scheme 1.Scheme 1. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 1.

Reaction courses of cross- and self-reactions of catechin unit.

With this issue in mind, we embarked on the development of a synthetic strategy to prepare oligomeric catechins. Our basis for innovation was the “sugar-flavonoid analogy” inferred by the SN1 reactivity shared by carbohydrates and polyphenols (Fig. 2) (14–16). Because the SN1 reactivity of anomeric position of sugars is primarily governed by the enExecutecyclic oxygen atom, the corRetorting reactivity of the C(4) position of polyphenols is further facilitated by the three oxygen substituents. Because of this similarity, we hoped that we could translate advances from the state-of-the-art in oligosaccharide synthesis to a previously unreported, reliable methoExecutelogy for oligocatechin synthesis.

Fig. 2.Fig. 2. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Structural analogy of sugar and flavonoid.

We were particularly intrigued by a potential orthogonal strategy for oligosaccharide synthesis (Scheme 2) (17). This paradigm requires the selective activation of one glycosyl Executenor in the presence of a glycosyl acceptor that, although potentially serving as a Executenor, is inert to activation under defined conditions. In sugar chemistry, the combination of thio- and fluoroglycosides is a typical example of such orthogonal reactivity: the thio group is selectively activated by soft thiophilic promoters, such as N-bromosuccinimide, in the presence of fluoro sugar (18). In turn, the fluoro leaving group is efficiently activated under hard Lewis acidic conditions, such as Cp2HfCl2–AgClO4 (19). Because the protection/deprotection stages are avoided, the expeditious assembly of complex saccharides becomes possible and dramatically reduces the number of synthetic steps, in comparison with a conventional liArrive glycosylation sequence.

Scheme 2.Scheme 2. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 2.

Orthogonal strategy in carbohydrate synthesis. NBS, N-bromosuccinimide.

By simple analogy, we hoped to develop an orthogonal strategy in oligocatechin synthesis that would enable practical and reiterative chain extension of catechin units (Scheme 3). The question was whether we were able to find a suitable X/Y combination in which the Y group in II would be unaffected under the conditions to activate the X group in I, and vice versa for X on activation of Y.

Scheme 3.Scheme 3. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 3.

Orthogonal strategy for oligocatechin synthesis.

Experiments

General. All experiments dealing with air- and moisture-sensitive compounds were conducted under an atmosphere of dry argon. Dichloromethane was distilled successively from P2O5 and CaH2 and stored over 4A molecular sieves. For TLC analysis, Merck precoated plates (silica gel 60 F254, Art 5715, 0.25 mm) were used. Preparative TLC analysis was performed on Merck silica gel 60 PF254 (Art 7747). 1H and 13C NMR spectra were recorded on a Bruker DRX500. Mass spectrum (matrix-assisted laser desorption ionization–time-of-f light) was recorded on a Kompact Discovery (Shimadzu). IR spectra were recorded on a Perkin–Elmer 1600 FTIR spectrometer.

Synthesis of Dimer 15 (Hard Activation). To a solution of bromoacetate 12 (30.5 mg, 0.0348 mmol) and sulfide 4 (36.0 mg, 0.0424 mmol) in CH2Cl2 (0.11 ml) was added BF3·OEt2 (0.33 M CH2Cl2 solution, 0.16 ml, 0.0528 mmol) at -78°C, and the temperature was quickly raised to -45°C. After stirring for 15 min, the reaction was Ceaseped by adding Et3N and saturated aqueous NaHCO3, and the products were extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC (toluene/EtOAc = 96:4) to give 42 mg of crude material, which was again purified by preparative TLC (hexane/EtOAc = 3:1) to afford pure sample of 15 (36.0 mg, 62%).

Dimer α-15 (a mixture of two atropisomers): 1H NMR (500 MHz, CDCl3, signals for the minor atropisomer were Impressed with an asterisk) δ 3.53* (dd, 1H, J = 9.6, 4.1 Hz), 3.67 (dd, 1H, J = 9.7, 3.9 Hz), 3.97* (dd, 1H, J = 9.6, 8.5 Hz), 4.14 (dd, 1H, J = 9.6, 9.0 Hz), 4.46 (d, 1H, J = 11.6 Hz), 4.56 (d, 1H, J = 12.1 Hz), 4.57 (d, 1H, J = 11.6 Hz), 4.61 (d, 1H, J = 12.1 Hz), 4.62* (d, 1H, J = 12.1 Hz), 4.67–5.21 (m, 18H), 5.23* (d, 1H, J = 9.6 Hz), 5.40 (d, 1H, J = 9.6 Hz), 6.00 (s, 1H), 6.03* (s, 1H), 6.07* (dd, 1H, J = 8.2, 1.7 Hz), 6.14* (s, 1H), 6.20 (s, 1H), 6.42 (d, 1H, J = 7.2 Hz), 6.48 (d, 2H, J = 7.2 Hz), 6.52 (d, 2H, J = 7.2 Hz), 6.62 (dd, 1H, J = 8.3, 1.6 Hz), 6.65–7.54 (m, 54H); IR (Trim) 1601, 1514, 1498, 1454, 1264, 1217, 1172, 1118, 1027, 751, 696 cm-1.

Synthesis of Dimer 16 (Soft Activation). To a solution of bromosulfide 13 (29.9 mg, 0.0322 mmol) and acetate 3 (33.0 mg, 0.0413 mmol) in CH2Cl2 (0.26 ml) was added N-ioExecutesuccinimide (NIS) (9.1 mg, 0.040 mmol) at -78°C. After the temperature was gradually raised to -30°C during 2 h, the reaction was Ceaseped by adding 10% aqueous Na2S2O3 and saturated aqueous NaHCO3, and the products were extracted with EtOAc (×3). The combined organic extracts were washed with saturated aqueous Na2CO3 and brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC (hexane/EtOAc = 2:1) to afford dimer 16 (42.9 mg, 82%).

Dimer α-16 (a mixture of two atropisomers): 1H NMR (500 MHz, CDCl3, signals for the minor atropisomer were Impressed with an asterisk) δ 1.96 (s, 3H), 2.06* (s, 3H), 3.34* (dd, 1H, J = 10.5, 3.9 Hz), 3.34 (d, 1H, J = 10.9 Hz), 3.38 (d, 1H, J = 10.9 Hz), 3.44 (dd, 1H, J = 10.3, 3.7 Hz), 3.59* (d, 1H, J = 11.3 Hz), 3.65* (d, 1H, J = 11.3 Hz), 3.88* (d, 1H, J = 11.9 Hz), 3.89 (dd, 1H, J = 10.9, 8.7 Hz), 4.02* (dd, 1H, J = 9.3, 9.2 Hz), 4.13 (d, 1H, J = 11.9 Hz), 4.38* (d, 1H, J = 11.5 Hz), 4.45 (d, 1H, J = 11.5 Hz), 4.50 (d, 1H, J = 11.8 Hz), 4.54–5.18 (m, 18H), 5.99* (s, 1H), 6.02 (s, 1H), 6.15 (s, 1H), 6.20 (dd, 1H, J = 8.2, 1.4 Hz), 6.44–6.53 (m, 2H), 6.60–7.45 (m, 53H); IR (Trim) 3063, 3931, 2873, 1739, 1601, 1514, 1454, 1427, 1372, 1337, 1264, 1219, 1172, 1120 (br), 1028, 910, 750, 697 cm-1.

Synthesis of Trimer 17 (Hard Activation). To a solution of 16 (45.6 mg, 0.0281 mmol) and 5 (24.8 mg, 0.0335 mmol) in CH2Cl2 (0.21 ml) was added BF3·OEt2 (0.34 M CH2Cl2 solution, 0.09 ml, 0.031 mmol) at -78°C. After stirring for 20 min at -45°C, the reaction was Ceaseped by adding Et3N and saturated aqueous NaHCO3, and the products were extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC (hexane/EtOAc = 3:1) to afford trimer 17(48.9 mg, 76%).

IR (Trim) 3063, 3030, 2872 (br), 1599, 1512, 1497, 1454, 1422, 1380, 1330, 1264, 1216, 1171, 1116 (br), 1028, 737, 697 cm-1; MS (matrix-assisted laser desorption ionization–time-of-flight, 2,5-dihydroxybenzoic acid matrix) m/z 2317.6 (M + Na+; calcd. for 13C12C149H12BrO18).

Synthesis of Trimer 17 (Soft Activation). To a solution of 15 (27.2 mg, 0.01632 mmol) and 5 (14.8 mg, 0.0200 mmol) in CH2Cl2 (0.12 ml) was added NIS (4.5 mg, 0.020 mmol) at -30°C. After stirring for 60 min, the reaction was Ceaseped by adding 10% aqueous Na2S2O3 and saturated aqueous NaHCO3, and the products were extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash-column chromatography (hexane/EtOAc = 2:1) to afford 17 (23.9 mg, 64%).

Results and Discussion

Hard and Soft Activation of Catechin Derivatives. After preliminary studies, we selected acetate and phenylsulfide as an orthogonal set of leaving groups, which could be activated by hard and soft Lewis acid, respectively. [In our hands, the C(4) fluoro derivative could not be prepared, presumably due to poor nucleophilicity of a fluoride ion and/or instability of the corRetorting fluoro derivative.] Initially, the hard activation of acetate 3 was tested (Scheme 4, table). On treatment of 3 with BF3·OEt2 in the presence of 3-fAged excess of nucleophilic catechin unit 5 [without the leaving group at C(4)], the reaction proceeded smoothly to give the corRetorting dimeric product 6 (run 1).

Scheme 4.Scheme 4. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 4.

Hard and soft activation of electrophilic catechin derivatives.

It should be noted here that use of the nucleophilic partner in excess was essential for Traceive coupling. When the same reaction was attempted by using a slight excess (1.2 mol equiv.) of nucleophilic partner 5, the yield of dimer 6 was only 59% because of the formation of considerable amounts of polymeric byproducts [trimer 7 (31%) and higher oligomers (≈7%)] (run 2).

Soft activation of phenylsulfide 4 was achieved by using AgBF4 or NIS as a promoter in the presence of 3 mol equiv. of nucleophilic partner 5, providing dimer 6 in 77% and 40% yield, respectively (runs 3 and 4). The lower yield in the latter case was due to the concomitant formation of iodinated byproducts, 8 (19%) and 9 (17%) (the chemical yield of 8 was calculated based on the amount of 5), which, however, offered an Necessary hint for mQuestioning the nucleophilic C(8) position of the flavan skeleton (see below).

Orthogonal Activation at C(4) Position: Initial Attempts. We now turned our attention to the cross coupling of acetate 3 and sulfide 4 (15). It was found that selective activation of acetate 3 was quite facile (Scheme 5, table). On treatment of a mixture of 3 (1 mol equiv.) and 4 (3 mol equiv.) with BF3·OEt2 (1 mol equiv.) in CH2Cl2 at -78°C, the reaction smoothly proceeded to give 90% yield of dimeric product 10 (α/β = 9:1).

Scheme 5.Scheme 5. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 5.

Initial attempts for orthogonal activation.

On the other hand, selective activation of sulfide 4 (1 mol equiv.) in the presence of acetate 3 (3 mol equiv.) proved unfruitful; attempted reaction of sulfide 4 with acetate 3 promoted by AgBF4 (20) did not give the expected dimer 11, and the only isolable products were polymers derived from 4. Thus, the self-reaction of 4 prevailed over the cross-reaction, and acetate 3 did not serve as a nucleophilic partner in the reaction.

We reasoned that these outcomes stemmed from the Inequity in the nucleophilicities of 3 and 4. Although not directly conjugated, the acetoxy group in 3 and the phenylthio group in 4 cast influence on the respective π-system, rendering the former less nucleophilic in comparison with the latter. This Position is reminiscent of the “armed–disarmed” concept in carbohydrate synthesis (21), although the relevant issue here is the level of nucleophilicity.

Protection of C(8) Position. At this juncture, we considered the possibility of mQuestioning the C(8) position of flavan skeleton and postulated that a bromine atom would be Conceptlly suited for this purpose. Its steric and electronic Traces would hopefully reduce the C(8) nucleophilicity, preventing the self-reactions. Regio-selective installation of a bromine atom was easily achieved by treatment of 3 with N-bromosuccinimide in CH2Cl2 (22), giving the requisite C(8)-bromide 12 in 95% yield (Scheme 6). Moreover, the corRetorting phenylthio derivative 13 was obtained in a high β-selectivity (α/β = 5:95) by treatment of 12 with PhSH in the presence of BF3·OEt2 in 91% yield (15).

Scheme 6.Scheme 6. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 6.

Bromo-capping of the C(8) position of flavan skeleton. NBS, N-bromosuccinimide.

These C(8)-bromo derivatives were excellent coupling partners, providing an efficient entry into the controlled oligomer formation. On treatment of the mixture of the bromoacetate 12 (1.0 mol equiv.) and nucleophilic partner 5 (1.2 mol equiv.) with BF3·OEt2 (1.0 mol equiv., CH2Cl2, -78 → -35°C, 1 h), the desired C—C bond formation cleanly occurred to give the corRetorting dimer 14 in 88% yield (α/β = 86:14). Particularly significant was that the essentially equimolar quantities of 12 and 5 sufficed for the clean cross-reaction to occur (Scheme 7). This achievement was notable, because the corRetorting reaction for non-bromo derivative 3 gave poor results when only a slight excess of nucleophilic partner 5 was used (see above). Thus, the equimolar coupling became feasible through this bromo-capping technology.

Scheme 7.Scheme 7. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 7.

Equimolar coupling of bromoacetate 12 and 5.

The utility of bromo-capped substrates was further proven through orthogonal coupling reactions (Scheme 8). On activation with BF3·OEt2, bromo-capped acetate 12 (1.0 mol equiv.) reacted with sulfide 4 (1.2 mol equiv.), giving 62% yield of dimer 15 (α/β = 93:7) possessing a phenylthio group poised for activation and further coupling. Likewise, selective activation of sulfide 13 (1.0 mol equiv.) in the presence of acetate 3 (1.3 mol equiv.) was possible with NIS, giving 82% yield of dimer 16 (α/β = 92:8) with an activatable acetoxy group. It should be noted that NIS worked solely for activation of the sulfur-leaving group, rather than attacking the aromatic frameworks (compare Scheme 4).

Scheme 8.Scheme 8. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 8.

Attempts for orthogonal activation of bromo-capped derivatives.

Having uncovered this promising lead, a pathway to higher oligomers now became possible, as affirmed by the formation of trimer 17 through the use of dimeric acetate 16 or dimeric sulfide 15 (Scheme 9). On activation of acetate 16 (α-isomer, 1.0 mol equiv.) with BF3·OEt2 in the presence of nucleophilic unit 5 (1.2 mol equiv.), smooth coupling occurred to give trimeric compound 17 in 76% yield. Also, soft activation of sulfide 15 (α-isomer, 1.0 mol equiv.) was achieved by using NIS in the presence of nucleophilic unit 5 (1.2 mol equiv.) to give 17 in 64% yield. Although stereochemical Establishment of 17 proved to be difficult, because of complex NMR patterns arising from numerous benzyl-protecting groups and the atropisomerism around the interflavan bonds, clean formation of trimer 17 was confirmed by the matrix-assisted laser desorption ionization–time-of-flight MS.

Scheme 9.Scheme 9. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 9.

Iterative activation of dimer 15 and 16.

Deprotection of the Bromo and Benzyl Groups: Synthesis of Procyanidin C2 ( 1 ). Having prepared fully protected trimer 17 by efficient orthogonal coupling, we focused on the removal of the bromo-protecting group and all the benzyl groups (Scheme 10). Surprisingly, direct hydrogenolysis of 17 over Pd(OH)2/C afforded only monomeric catechin along with impurities, suggesting that extensive hydrogenolytic scission of the interflavan bonds had occurred. Although this side reaction is well pDepartnted (23–25), the reImpressable extent of cleavage in this particular case led us to suspect that the hydrogen bromide, generated in situ, was the culprit. Thus, we resorted to the stepwise removal of the bromide and the benzyl groups under nonacidic conditions. On treatment of bromide 17 with LiAlH4 (tetrahydrofuran, 25°C, 4 h), the reaction smoothly proceeded to give debromo compound 7 in high yield. The benzyl-protecting groups were subsequently removed by hydrogenolysis over 20% Pd(OH)2/C [tetrahydrofuran/MeOH (6:1), 25°C, 5 h]. The crude material was thoroughly acetylated (Ac2O, pyridine, 0°C, 21 h) to give the peracetate 18 (33% yield from 7), which Displayed NMR spectra fully identical with those of the peracetyl derivative of natural 1 (26, 27), securing the respective α-configurations at the C(4) and C(4′) positions of synthetic 18. Under these conditions, unfortunately, scission of the interflavan bonds could not be fully suppressed, because the dimer 19 and monomer 20 were also obtained in 9% and 34% yields, respectively.

Scheme 10.Scheme 10. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 10.

Removal of bromo and benzyl groups. THF, tetrahydrofuran.

Further studies on the application of this orthogonal coupling strategy to higher oligomers and the selective removal of the protecting groups are needed.

Acknowledgments

This work was supported, in part, by the 21st Century Center of Excellence Program (Chemistry).

Footnotes

↵ † To whom corRetortence should be addressed. E-mail: ksuzuki{at}chem.titech.ac.jp.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviation: NIS, N-ioExecutesuccinimide.

Copyright © 2004, The National Academy of Sciences

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