2017 Volume 65 Issue 1 Pages 25-32
A short-step total synthesis of the natural glycosides pterocarinin C and tellimagrandin II (eugeniin) has been performed by sequential and site-selective functionalization of free hydroxy groups of unprotected D-glucose. The key reactions are β-selective glycosidation of a gallic acid derivative using unprotected D-glucose as a glycosyl donor and catalyst-controlled site-selective introduction of a galloyl group into the inherently less reactive hydroxy group of the glucoside.
Carbohydrates are ubiquitous and play key roles in intercellular processes including infection, differentiation, and metastasis.1) In order to elucidate the biological processes and develop carbohydrate-based therapeutics,2) the chemical synthesis of carbohydrates is indispensable and has been extensively developed.3–5) However, the chemical synthesis of carbohydrates is often associated with difficulties in the selective manipulation of multiple hydroxy groups of the carbohydrates.3–5) Accordingly, carbohydrate synthesis has been developed in parallel with the development of protective groups since Emil Fisher’s discovery of isopropylidene protective groups.6) Recently, approaches toward direct site-selective manipulation of carbohydrates have been emerging,7) however, current organic synthesis of natural glycosides still relies largely on the protective-group strategy.8) Suitably protected carbohydrates are generally employed as the intermediate for the synthesis, which are prepared from the parent carbohydrates via step-wise introduction of protective groups. The protective groups should be removed afterwards. As a consequence, the protection/deprotection procedure results in the multistep processes and overall inefficiency. Here, we propose an approach toward a possible clue to solve this long-standing problem of carbohydrate synthesis. If the functional groups can be directly introduced at the desired sites in a site-selective manner into the unprotected parent carbohydrate, the overall steps for the carbohydrate synthesis would be largely diminished. We report here a streamlined total synthesis of natural glycosides of an ellagitannin family, pterocarinin C and tellimagrandin II (eugeniin), from unprotected D-glucose without using protective groups for D-glucose itself.
Ellagitannin is one of the large classes of polyphenolic hydrolysable tannins with a wide range of biological properties including anticancer, antiviral, and antioxidant activities.4,9) Due to their pharmaceutical potentials, extensive efforts have been devoted to their synthesis.4,9) The structure is basically composed of a central sugar core, typically D-glucose, to which are esterified gallic acid (3,4,5-trihydroxybenzoic acid) and hexahydroxy diphenoic acid (HHDP). Among ellagitannins, we chose tellimagrandin II (1) (eugeniin),10) and its regioisomeric natural product, pterocarinin C (2)11) (Fig. 1) as target molecules due to their significant biological activity including anti-herpes simplex virus (HSV)12) and neuroprotective activities.13) In 2015, we reported the total synthesis of strictinin and tellimagrandin II via chemo- and site-selective functionalization of D-glucose.14) Here, we describe the total synthesis of pterocarinin C (2). Although the total synthesis of tellimagrandin (1) has previously been reported,14) we describe its synthetic scheme here again in order to compare it with the biosynthetic pathway of 1.
An outline of the retrosynthesis of pterocarinin C (2) is shown in Chart 1. A pioneering work for the total synthesis of 2 has been reported by Khanbabaee and Lötzerich.15) A logical retrosynthetic analysis of 2 should lead to properly protected D-glucose derivative 3 (Chart 1a). On the other hand, we envisaged that unprotected D-glucose can be a precursor for the total synthesis if galloyl(oxy) groups could be introduced site-selectively in the order of G1, G2, G3, and G4 into unprotected D-glucose (Chart 1b). When this strategy is realized, several steps required for the introduction and removal of the protective groups can be eliminated. Thus, the proposed synthetic strategy is expected to provide an unconventional retrosynthetic route. A detailed synthetic plan is shown in Chart 2. Step 1: Direct β-glycosylation of protected gallic acid G1 (shown in blue) using unprotected D-glucose as a glycosyl donor. Step 2: Catalyst-controlled site-selective introduction of galloyl group G2 (shown in brown) into the inherently less reactive C(4)-OH of glycoside 7. Step 3: Introduction of galloyl group G3 (shown in green) into the C(6)-OH of glycoside 6 based on the inherent high reactivity of the primary hydroxy group. Step 4: Introduction of galloyl groups G4 (shown in yellow) into the remaining free C(2)-OH and C(3)-OH of 5. Steps 5–7: Deprotection of the OR2 groups, intramolecular oxidative phenol coupling of the resulting phenols to construct an HHDP moiety, and deprotection of the OR1 groups. If steps 2 and 3 can be combined by a one-pot operation (see Chart 6), it saves one step, and finally 6-step total synthesis would be realized. Similarly, total synthesis of tellimagrandin (1) was accomplished by modification of the protecting groups (R1 and R2) of the galloyl moiety for the oxidative coupling between the C(4)- and C(6)-galloyl groups.
The first key step for the total synthesis of these natural glycosides is stereoselective glycosylation using unprotected D-glucose (Chart 2, step 1). Suitably protected and activated D-glucose derivatives have generally been employed for stereoselective glycosylation.16) On the other hand, the pioneering example for direct glycosylation of acidic nucleophiles using unprotected carbohydrates as glycosyl donors under Mitsunobu conditions was first reported by Grynkiewicz.17) Shoda, Besset, and Aime also reported the glycosylation reactions using unprotected D-glucose as a glycosyl donor under similar conditions.18–20) However, the stereoselectivity of these direct glycosylation reactions (α/β=41 : 59–11 : 89) still has room for improvement. We applied their protocol for glycosylation using unprotected D-glucose as a glycosyl donor to the glycosylation reaction of gallic acid derivative 8. By modification of the reported conditions, we found highly stereoselective glycosylation of 8. Treatment of a suspension of D-glucose (0.03 M) and 8 with diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3) in 1,4-dioxane at room temperature (r.t.) for 30 min gave glycoside 7a in high stereoselectivity (α/β=99 : 1) and 78% yield14) (Chart 3). The key to the success for achieving high β-selectivity was the choice of the solvent, 1,4-dioxane, rather than a polar solvent such as N,N-dimethylformamide (DMF), which gave a α/β=51 : 49 mixture. Another key to the smooth progression of the glycosylation was the use of finely ground D-glucose powder and ultrasound sonication of the powder suspension in 1,4-dioxane prior to the addition of Mitsunobu reagents. Although D-glucose seems not to dissolve initially in 1,4-dioxane, the reaction gradually progressed within 30 min to give 7a in 78% yield in a β-selective manner.
The next transformation was site-selective 4-O acylation of glucoside 7a (Step 2 in Chart 2). As the background for the site-selective acylation, we developed organocatalyst 9 that enables direct and site-selective introduction of acyl groups on the C(4)-OH of glucoside derivatives in up to 99% site-selectivity21) (Chart 4). Thus, catalyst 9 is able to discriminate one out of four hydroxy groups in different microenvironments and promote acylation exclusively on the intrinsically less reactive secondary hydroxy group at C(4). The site-selective acylation promoted by catalyst 9 was especially effective when applied for β-glucosides.21–24) Accordingly, application of this method to site-selective introduction of a galloyl group into β-glucoside 7a seemed reasonable and promising, and was examined with catalyst 9 and the analogies.
Summary of optimization of the conditions for site-selective galloylation of glucoside 7a toward total synthesis of previously reported tellimagrandin II (1)14) is shown in Chart 5. As an initial attempt, the reported conditions21–23) for site-selective acylation of D-glucose derivatives were applied to site-selective galloylation of 7a with anhydride 10 in the presence of 10 mol% of catalyst 9 and 1.5 eq of 2,4,6-collidine at –45°C in CHCl3 to give desired 1,4-digallate 6a in only 18% yield even after 72 h (Chart 5b). After thorough screening of the conditions including solvents, catalysts, substrate concentration, and temperature, we found the conditions for highly site-selective galloylation of 7a14) (Chart 5a). Treatment of 7a with 1.05 eq of anhydride 10 in the presence of 10 mol% of catalyst 9 at 0.04 M substrate concentration in CHCl3–2,4,6-collidine (9 : 1) at −40°C for 72 h gave desired 6a in 91% yield and undesired 3-O-gallate 12 in 6% yield without the formation of 6-O-gallate 11. While the glycoside with OBn- and O-methoxymethyl (OMOM)-protected galloyl groups at C(4) and C(6), 5a (Chart 8), was required for the oxidative phenol coupling between the C(4)- and C(6)-gallates toward total synthesis of 1,14) the glycoside with OMOM-protected galloyl groups at C(4) and C(6), and OBn- and OMOM-protected galloyl groups at C(2) and C(3), respectively, seemed suitable for the oxidative phenol coupling between the C(2)- and C(3)-gallates toward total synthesis of pterocarinin C (2) (Charts 6, 7). Accordingly, the optimized conditions in Chart 5a was applied to C(4)-O-galloylation of glycoside 7a with OMOM-protected gallic anhydride 13 toward the total synthesis of pterocarinin C (2) (Chart 6).
According to the results in Chart 5, galloylation of 7a with anhydride 13 was expected to give C(4)-O-gallate 6b as the major product in a site-selective manner (Chart 6). Based on this assumption and the expectation that carboxylic acid 8 would be generated in situ from anhydride 13 and catalyst 9, a one-pot procedure for the sequential introduction of two OMOM-protected galloyl groups at C(4)-OH and C(6)-OH into 7a was examined. Glycoside 7a was treated with 13 in the presence of catalyst 9 under the optimized conditions shown in Chart 5a, then with chloro-1,3-dimethylimidazolinium chloride (DMC) and N,N-dimethyl-4-aminopyridine (DMAP) to give C(4)- and C(6)-gallate 5b in one-pot and in 53% isolated yield. This transformation was assumed to proceed through catalyst-controlled C(4)-O-galloylation of 7a with 13 followed by substrate-controlled C(6)-O-galloylation with in situ-generated 8 in a sequential and site-selective manner. Thus, synthetic intermediate 5b for the total synthesis of pterocarinin C (2) was prepared only by three steps from unprotected D-glucose in 41% overall yield.
The final steps for the total synthesis of pterocarinin C (2) are shown in Chart 7. Additional two OBn- and OMOM-protected galloyl groups were introduced at C(2)- and C(3)-OH of 5b by its treatment with acid 14 in the presence of a condensing agent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl) and DMAP, to give the corresponding 1,2,3,4,6-pentagallate. Removal of the benzyl groups in the C(2)- and (3)-gallic ester moieties of the resulting pentagallate by hydrogenolysis gave 15 in 83% yield from 5b. The intramolecular oxidative phenol coupling of the resulting phenol derivative was accomplished stereoselectively according to the excellent method developed by Yamada and colleagues.25) In the presence of CuCl2/n-BuNH2, the oxidative phenol coupling between the 2- and the 3-gallates proceeded to give hexahydroxydiphenoyl (HHDP) derivative 16 with the complete stereo-control of the newly formed chiral axis (S) in the HHDP moiety. Deprotection of the MOM groups under acidic conditions accomplished the total synthesis of pterocarinin C (2) in 6 overall steps from D-glucose and 10% overall yield. The number of synthetic steps from D-glucose is less than that of previous total synthesis of pterocarinin C (2)15) (9 steps without including the steps for the construction of the HHDP moiety). In this synthesis, five galloyl(oxy) groups were sequentially introduced in the order C(1) (blue in Chart 2), C(4)-OH (brown in Chart 2), C(6)-OH (green in Chart 2) followed by C(2)- and C(3)-OH (yellow in Chart 2) into the unprotected D-glucose.
We previously reported the total synthesis of tellimagrandin II (1).14) Here, we summarize a synthetic scheme of 1 (Chart 8) in order to compare it with the biosynthetic pathway of 1 as well as synthetic scheme of 2. Catalyst-controlled site-selective C(4)-O-galloylation of 7a with anhydride 10 in the presence of 9 followed by substrate-controlled C(6)-O-galloylation with in situ-generated 14 in the presence of DMC and DMAP gave 5a in one-pot and in 51% isolated yield. Additional two OMOM-protected galloyl groups were introduced at C(2)- and C(3)-OH of 5a to give the corresponding 1,2,3,4,6-pentagallate. Removal of the benzyl groups in the pentagallate gave 17 in 78% yield from 5a. The intramolecular oxidative phenol coupling between the 4- and the 6-gallates in 17 gave 18 with an (S)-HHDP moiety. Deprotection of the MOM groups of 18 afforded tellimagrandin II (1) in 6 overall steps from D-glucose and 18% overall yield. The number of synthetic steps from D-glucose is much less than that of previous total synthesis of tellimagrandin II26) (14 steps). Thus, regio-isomeric natural glycosides 1 and 2 could be readily prepared from common intermediate 7a by the proper choice of the protective groups for the galloyl groups.
Nature produces tellimagrandin II without using protective groups by combined enzymatic processes.27) A biosynthetic pathway for tellimagrandin II is shown in Chart 9a. In the first step, uridine 5′-diphosphate (UDP)-glucose is employed as a glycosyl donor in enzymatic stereoselective glycosylation of gallic acid to yield β-glucogallin (19). Four galloy groups are sequentially introduced to 19 in order at C(6)-OH, C(2)-OH, C(3)-OH and C(4)-OH to give β-pentagalloylglucose (β-PGG, 20), which is promoted by several galloyltransferases. Site-selective intramolecular oxidative phenol coupling between the 4- and 6-gallates among the five gallates of β-PGG is performed by a phenol oxidase (EC 1.10.3.2) to furnish tellimagrandin II (1). Interestingly, the first step in our synthetic scheme for tellimagrandin II is similar to that of the biosynthetic pathway (Chart 3). Our chemical synthesis initiates with the chemo- and stereoselective introduction of a galloyloxy group at C(1) of unprotected D-glucose to give 7a. Sequential and site-selective introduction of four galloyl groups into 7a gave β-PGG derivative 17, which gave tellimagrandin II (1) via oxidative phenol coupling between the 4- and 6-gallates. Our synthetic route is similar to the biosynthetic pathway because they both employ a common starting material (unprotected D-glucose) and similar intermediates such as 19/7a and 20/17. Synthetic linearity of our chemical synthesis of tellimagrandin II seems comparable with that of the biosynthetic pathway. On the other hand, the order of introducing the galloyl groups is quite different from each other. In the biosynthetic pathway, the galloyl groups appear to be introduced in the order to the higher intrinsic reactivities of hydroxy groups. Contrary to that, the order of introducing the galloy groups in our chemical synthesis is controlled by catalyst 9, resulting in being independent from the intrinsic reactivities of hydroxy groups.
The overall steps for the chemical total syntheses are much shorter than those reported based on the conventional synthetic strategy.15,26) It is worthy to note that the key player in our chemical synthesis, organocatalyst 9 with molecular weight of only 833, can effectively perform the site-selective introduction of the requisite galloyl group at the desired site, resulting in overall synthetic efficiency comparable with the biosynthetic pathway promoted by several enzymes with huge molecular weights. The advantages of chemical synthesis of naturally occurring bioactive compounds involve easier derivatization, definite structure-determination, and large-scale synthesis.
Extremely short-step total synthesis of tellimagrandin II and pterocarinin C has been accomplished based on the unconventional retrosynthetic routes without using protective groups for starting D-glucose. The key reactions are the β-selective glycosidation of a gallic acid derivative using unprotected D-glucose as a glycosyl donor, and catalyst-controlled site-selective introduction of a galloyl group into the inherently less reactive hydroxy group in the resulting glucoside. The present strategy represents an unconventional approach to natural glycosides. The concept of the catalyst-controlled site-selective functionalization may be applicable to other organic transformations and site-selective construction of complex natural products.
Reactions were magnetically stirred and monitored by TLC using Silica gel 60 F254 precoated plates (0.25 mm, Merck). Visualization was accomplished with UV light and p-anisaldehyde stain followed by heating. Purification of the reaction products was carried out by flash column chromatography using Ultra Pure Silica Gel (230–400 mesh) purchased from SILYCYCLE, unless otherwise noted. IR spectra were recorded using a JASCO FT-IR 4200 spectrometer and are reported in reciprocal centimetres (cm−1). 1H-NMR spectra were recorded on JEOL ECX-400 (400 MHz), JEOL ECA-600 (600 MHz), Bruker Avance 800 (800 MHz), and are reported in ppm using solvent resonance as the internal standard (acetone-d6 at 2.05 ppm, CDCl3 at 7.26 ppm, CD3CN at 1.94 ppm). 1H-NMR data are reported as follows: chemical shift; multiplicity; coupling constants (Hz); number of hydrogen. Multiplicity is abbreviated as follows: s=singlet, d=doublet, t=triplet, dd=double doublet, m=multiplet, br=broad. Proton-decoupled 13C-NMR spectra were recorded on an ECX-400 (100 MHz), ECA-600 (150 MHz), and Bruker Avance 800 (200 MHz), and are reported in ppm using solvent resonance as the internal standard (acetone-d6 at 29.84 ppm, CDCl3 at 77.16 ppm, CD3CN at 118.26 ppm). High-resolution (HR)-MS were obtained using a JEOL-DX 700 mass spectrometer for FAB and an Impact HD (Bruker Daltonics) for electrospray ionization (ESI). Melting points were measured with a Micro Melting Point Apparatus PM-500 (Yanagimoto) and are reported in degree Celsius (°C). Specific rotations were measured with a JASCO P-2200 digital polarimeter using the sodium D line and are reported as follows: [α]D20 (c=10 mg/mL, solvent).
Methods SummaryA procedure for the key reaction shown in Chart 6 is described: A screw-top test tube equipped with a stir bar was charged with 7a (640 mg, 1.38 mmol), catalyst 9 (115 mg, 0.138 mmol), and 2,4,6-collidine–CHCl3 (1 : 9, v/v, 34.5 mL). The reaction mixture was cooled to −40°C and acid anhydride 13 (865 mg, 1.48 mmol) was added. The resulting mixture was stirred at −40°C for 3.5 d. The reaction mixture was then allowed to warm to 5°C, and pyridine (34.5 mL), DMAP (168 mg, 1.38 mmol), and DMC (466 mg, 2.76 mmol) were added. After being stirred for 3 h at the same temperature, additional DMC (466 mg, 2.76 mmol) was added and the resulting mixture was stirred for an additional 5 h. The reaction mixture was quenched with MeOH. The resulting solution was concentrated under reduced pressure to give a residue. The residue was dissolved in AcOEt and the solution was washed with 1 M HCl. The organic layer was dried over a mixture of NaHCO3–Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, CHCl3–MeOH 100 : 0 to 30 : 1, v/v) to provide the pure 1,4,6-trigallate 5b (751 mg, 53%) as a single regioisomer as a white amorphous.
Chemicals and ReagentsAll reactions were carried out in an argon atmosphere under anhydrous conditions, and were stirred with Teflon-coated magnetic stir bars. Anhydrous acetonitrile (CH3CN), 1,4-dioxane, tetrahydrofuran (THF), DMF, methanol (MeOH), chloroform (CHCl3), dichloromethane (CH2Cl2), and isopropylalcohol (i-PrOH) were purchased from commercial suppliers and stored over activated molecular sieves. n-Butylamine was distilled from calcium hydride prior to use.
Synthetic procedures and physical properties of the intermediates in total synthesis of tellimagrandin II (1) have been already reported in ref. 14.
1,4,6-Tris-O-(3,4,5-trimethoxymethoxybenzoyl)-β-D-glucopyranoside (5b)A 100 mL round-bottom flask was charged with 7a (640 mg, 1.38 mmol), catalyst 9 (115 mg, 0.138 mmol), 2,4,6-collidine (3.45 mL) and CHCl3 (31.1 mL). The resulting solution was cooled to −40°C and acid anhydride 13 (865 mg, 1.48 mmol) was added. The reaction mixture was stirred at −40°C for 3.5 d until complete consumption of the starting material. The reaction mixture was allowed to warm to 5°C, and pyridine (34.5 mL), DMAP (168 mg, 1.38 mmol) and DMC (466 mg, 2.76 mmol) were added. Since TLC analysis indicated a small amount of the remaining 4-O acylate even after 3 h, additional DMC (466 mg, 2.76 mmol) was added. After stirring the mixture for 5 h at the same temperature, the reaction was quenched with MeOH (1 mL). The mixture was concentrated in vacuo to give a residue. The residue was dissolved in AcOEt and washed with 1 M HCl. The organic layer was dried over the mixture of NaHCO3–Na2SO4 and concentrated in vacuo. The resulting crude oil was purified by flash column chromatography (SiO2, CHCl3–MeOH 100 : 0 to 30 : 1, v/v) to afford the title compound 5b (751 mg, 53%) as a single regioisomer as a white amorphous substance. [α]D20 +33 (c=1.0, CHCl3); TLC (CHCl3–MeOH 20 : 1, v/v): Rf=0.14; 1H-NMR (600 MHz, acetone-d6+D2O) δ: 7.59 (s, 2H), 7.58 (s, 2H), 7.51 (s, 2H), 5.91 (d, J=8.4 Hz, 1H), 5.32–5.28 (m, 13H), 5.19–5.17 (m, 6H), 4.60 (d, J=9.6 Hz, 1H), 4.29–4.24 (m, 2H), 4.04 (t, J=9.0 Hz, 1H), 3.77 (t, J=9.0 Hz, 1H), 3.57–3.57 (m, 9H), 3.49–3.47 (m, 18H); 13C-NMR (150 MHz, acetone-d6) δ: 165.8, 165.6, 165.0, 151.9 (for two carbons), 151.8 (for two carbons), 151.7 (for two carbons), 142.5, 142.3, 142.1, 126.19, 126.17, 125.6, 112.54 (for two carbons), 112.49 (for two carbons), 112.40 (for two carbons), 99.1 (for three carbons), 96.0 (for six carbons), 95.9, 75.3, 73.9, 73.7, 72.6, 64.1, 57.21 (for two carbons), 57.18, 56.53 (for four carbons), 56.48 (for two carbons); IR (KBr, cm−1): 3482, 2958, 1725, 1593, 1498, 1436, 1395, 1189, 1080, 924; HR-MS-FAB+ (m/z): Calcd for C45H60O27Na [M+Na]+ 1055.3220. Found, 1055.3249.
1,4,6-Tris-O-(3,4,5-trimethoxymethoxybenzoyl)-2,3-bis-O-(3,5-dihydroxy-4-methoxymethoxybenzoyl)-β-D-glucopyranoside (15)A 10 mL round-bottom flask was charged with diol 5b (400 mg, 0.387 mmol), 14 (381 mg, 0.968 mmol), DMAP (141 mg, 1.16 mmol), and CH2Cl2 (3.9 mL). The resulting solution was cooled to 0°C and EDCI·HCl (222 mg, 1.16 mmol) was added. The reaction mixture was allowed to stir at r.t. for 20 h until full conversion to product was indicated by TLC analysis. The resulting solution was quenched by saturated aqueous citric acid solution and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (SiO2, AcOEt–hexane 1 : 1 to 2 : 1, v/v) to give the pentagallate (663 mg, 96%) as a pale yellow gum. A 10 mL round-bottom flask was charged with the pentagallate (200 mg, 0.112 mmol) and Pd(OH)2/C (10 wt%, 20 mg). THF (2.2 mL) was added and the atmosphere was replaced by H2 (balloon). The reaction mixture was stirred at r.t. for 1 h. The resulting suspension was filtered and washed with AcOEt. The filtrate was concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (SiO2, AcOEt–hexane 1 : 1 to 5 : 1, v/v) to give 15 (138 mg, 86%) as a white amorphous substance. [α]D20 +18 (c=0.8, CHCl3); TLC (CHCl3–MeOH 10 : 1, v/v): Rf=0.45; 1H-NMR (600 MHz, acetone-d6+D2O) δ: 7.57 (s, 2H), 7.51 (s, 2H), 7.46 (s, 2H), 7.04 (s, 2H), 7.01 (s, 2H), 6.41 (d, J=7.8 Hz, 1H), 6.18 (t, J=9.6 Hz, 1H), 5.75–5.70 (m, 2H), 5.30–5.13 (m, 22H), 4.73 (dd, J1=12.6, J2=2.4 Hz, 1H), 4.68–4.65 (m, 1H), 4.42 (dd, J1=12.6, J2=5.4 Hz, 1H), 3.58–3.47 (m, 33H); 13C-NMR (150 MHz, acetone-d6) δ: 165.73, 165.69, 165.5, 165.4, 164.4, 151.9 (for two carbons), 151.8 (for four carbons), {151.13, 151.11} (for four carbons), 142.7, 142.5, 142.2, 138.25, 138.17, 126.1, 125.6, 125.5, 125.3, 124.6, 112.50 (for two carbons), 112.46 (for four carbons), 110.24 (for two carbons), 110.19 (for two carbons), 99.10, 99.08 (for two carbons), 99.0, 98.9, 96.1 (for two carbons), 95.99 (for two carbons), 95.92 (for two carbons), 93.7, 73.8, 73.2, 71.8, 70.9, 63.7, 57.44, 57.43, 57.2 (for three carbons), {56.55, 56.53, 56.51} (for six carbons); IR (neat, cm−1): 3367, 2959, 1735, 1593, 1329, 1157, 1049; HR-MS-FAB+ (m/z): Calcd for C63H76O37Na [M+Na]+ 1447.3963. Found, 1447.3982.
1,4,6-Tris-O-(3,4,5-trimethoxymethoxybenzoyl)-2,3-O-(S)-(4,4′,6,6′-tetrahydroxy-5,5′-dimethoxymethoxydiphenoyl)-β-D-glucopyranoside (16)A solution of CuCl2 (12.7 mg, 0.095 mmol) and n-BuNH2 (93.6 µL, 0.95 mmol) in MeOH (1.6 mL) was stirred for 30 min at rt to prepare a blue solution of CuCl2–n-BuNH2 complex under argon atmosphere. A 10 mL round-bottom flask was charged with 15 (45 mg, 0.032 mmol) and CHCl3 (1.6 mL). Then a blue solution of CuCl2–n-BuNH2 complex was added in one portion. The reaction mixture was stirred at r.t. for 90 min. The resulting mixture was quenched with saturated aqueous NH4Cl solution. The layers were separated and the aqueous layer was extracted with CHCl3. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (SiO2, AcOEt–hexane 1 : 1 to 4 : 1, v/v) to give a mixture of the title compound 16 and a small amount of starting material. It was further purified with recycle HPLC (AcOEt–hexane 7 : 3, v/v) to give 16 as a pale brown amorphous substance (23.5 mg, 52%). [α]D20 +24 (c=0.4, CHCl3); TLC (CHCl3–MeOH 10 : 1, v/v): Rf=0.45; 1H-NMR (600 MHz, acetone-d6+D2O) δ: 7.58 (s, 2H), 7.56–7.55 (m, 4H), 6.47 (s, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 5.71–5.66 (m, 2H), 5.34–5.16 (m, 23H), 4.72 (dd, J1=12.3, J2=1.8 Hz, 1H), 4.61 (m, 1H), 4.44 (dd, J1=12.3, J2=4.8 Hz, 1H), 3.58–3.46 (m, 33H); 13C-NMR (150 MHz, acetone-d6) δ: 168.7, 168.1, 165.7, 165.3, 164.5, 152.1 (for two carbons), 152.0 (for two carbons), 151.8 (for two carbons), {150.2, 150.1} (for four carbons), 142.9, 142.7, 142.3, 135.7, 135.6, 131.0, 130.9, 126.1, 125.4, 124.9, 114.1, 113.9, {112.64, 112.59, 112.56} (for six carbons), 106.66, 106.58, 99.6 (for two carbons), 99.1 (for three carbons), {96.14, 96.08} (for six carbons), 92.4, 77.2, 75.1, 74.2, 69.2, 63.6, 57.8 (for two carbons), 57.24, 57.22, 57.20, {56.6, 56.51, 56.47} (for six carbons); IR (KBr, cm−1): 3432, 2958, 1758, 1731, 1590, 1496, 1438, 1331, 1157, 1048, 925; HR-MS-FAB+ (m/z): Calcd for C63H74O37Na [M+Na]+ 1445.3807. Found, 1445.3794.
Pterocarinin C (2)A 5 mL vial was charged with 16 (9.3 mg, 0.0065 mmol) and THF–i-PrOH–conc. HCl (50 : 50 : 1, v/v/v, 1.3 mL). The reaction was stirred at r.t. for 11 h until TLC analysis indicated complete consumption of the MOM ethers. (Note: An extension of reaction time led to the decomposition of the desired product.) The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by gel permeation chromatography (Sephadex LH-20, EtOH) to give pterocarinin C (2) (3.5 mg, 57%) as a pale brown amorphous. [α]D20 +3.9 (c=0.2, acetone); 1H-NMR (800 MHz, acetone-d6) δ: 7.17 (s, 4H), 7.15 (s, 2H), 6.46 (s, 1H), 6.44 (s, 1H), 6.35 (d, J=8.0 Hz, 1H), 5.64-5.58 (m, 2H), 5.21 (t, J=8.0 Hz, 1H), 4.56 (dd, J1=12.4, J2=1.6 Hz, 1H), 4.53–4.51 (m, 1H), 4.40 (dd, J1=12.4, J2=4 Hz, 1H); 13C-NMR (200 MHz, acetone-d6) δ: 169.0, 168.6, 166.4, 165.6, 165.0, 146.2 (for two carbons), 146.1 (for two carbons), 146.0 (for two carbons), 145.3, 145.2, 144.53, 144.52, 139.7, 139.3, 138.9, 136.3, 136.2, 126.5, 126.2, 121.4, 120.7, 120.1, 114.7, 114.3, 110.3 (for two carbons), 110.2 (for two carbons), 110.1 (for two carbons), 107.5, 107.4, 92.1, 77.4, 75.5, 74.2, 68.0, 62.8; IR (KBr, cm−1): 3390, 1739, 1711, 1619, 1543, 1451, 1208, 1038; HR-MS-FAB+ (m/z): Calcd for C41H30O26 Na [M+Na]+ 961.0923. Found, 961.0925.
This research was financially supported by Grants-in-Aid for Scientific Research (S) (JP26221301), “Advanced Molecular Transformations by Organocatalysts” (JP23105008), Young Scientists (B) (JP15K18827), and Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” (JP23105008) and “Middle Molecular Strategy” (JP16H01148).
The authors declare no conflict of interest.
The online version of this article contains supplementary materials.
