Facile Synthesis of Neokotalanol, a Potent α-glycosidase Inhibitor

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Article Cite This: ACS Omega 2019, 4, 7533−7542

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Facile Synthesis of Neokotalanol, a Potent α‑glycosidase Inhibitor Isolated from the Ayurvedic Traditional Medicine “Salacia” Genzoh Tanabe,*,†,‡ Satoshi Ueda,† Kazuho Kurimoto,† Naoki Sonoda,† Shinsuke Marumoto,§ Fumihiro Ishikawa,† Weijia Xie,¶ and Osamu Muraoka‡ †

Faculty of Pharmacy, ‡Pharmaceutical Research and Technology Institute, and §Joint Research Centre, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan ¶ State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China

ACS Omega 2019.4:7533-7542. Downloaded from pubs.acs.org by 109.236.53.179 on 04/25/19. For personal use only.

S Supporting Information *

ABSTRACT: Neokotalanol (5) is a sulfonium-type α-glucosidase inhibitor isolated from the traditional Ayurvedic medicine “ Salacia.” Its potency against maltase-glucoamylase was 2000-fold stronger than acarbose. Despite 5 having been recognized as the most active among this series of sulfonium salts, a facile and effective synthetic protocol leading to 5 has not been established to date because of the difficulty in selecting and designing a protected key intermediate. In this study, an appropriately protected epoxide (β-20) was successfully designed and diastereoselectively synthesized from the easily accessible D-galactose (18). By use of β-20, S-alkylation of sulfides (7b) was successfully proceeded in a highly diastereoselective manner to afford 5 in a good total yield (11%, via 14 steps), which was superior to the three previously reported sequences (∼1% via 15 steps, ∼0.5% via 18 steps, ∼2% via 14 steps).

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INTRODUCTION Diabetes mellitus, which is one of the largest global health emergencies of the 21st century, presently affects approximately 425 million people worldwide, including more than 200 million undiagnosed people according to the International Diabetes Federation.1 Over the past three decades, the global number of people living with diabetes has been dramatically increasing and is expected to reach approximately 693 million by 2045 if appropriate measures are not taken.1 α-Glucosidase inhibitors are drugs used to treat patients with type 2 diabetes or people with impaired glucose tolerance. In India, Sri Lanka, China, and South East Asian countries, the roots and stems of the plants of the Salacia genus (e.g., Salacia reticulata, Salacia oblonga, and Salacia chinensis) have been used for the prevention and specific remedy of diabetes. Toward the end of the 1990s, a highly potent α-glucosidase inhibitor, salacinol (1), was first isolated from S. reticulata. The α-glucosidase inhibitory activity of 1 was revealed to be as potent as that of clinically used antidiabetic drugs voglibose and acarbose.2 Xray analysis revealed that 1 has a unique structurethe thiosugar sulfonium cation is stabilized by the sulfate anion in the erythritol side chain by forming a spirobicyclic-like structure as shown in Figure 1.2 Because of the isolation of 1, related sulfonium sulfonates, kotalanol (2),3 and ponkoranol (3),4 as well as their de-O-sulfonated analogs neosalacinol (4),5 neokotalanol (5),6 and neoponkoranol (6)7 were © 2019 American Chemical Society

Figure 1. New class of natural α-glucosidase inhibitors.

subsequently isolated from plants of the same genus as other sulfonium components exhibiting potent antidiabetic activities. Among this series of sulfonium salts, neokotalanol (5) was proven to be the most active compound against rat intestinal Received: March 8, 2019 Accepted: April 16, 2019 Published: April 24, 2019 7533

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α-glucosidase by Ozaki et al.6a Shortly thereafter, its activity intensity was revealed to be 2000-fold stronger against maltaseglucoamylase than acarbose by Sim et al.8 Clinical trials revealed that the extract of S. reticulata was effective for the treatment of patients with type 2 diabetes and exhibited minimal side effects.9 Based on these findings, “Salacia” has recently gained considerable attention as a possible functional food for diabetic patients as well as people with impaired glucose tolerance. In this context, the quantitative analysis of sulfonium salts (1−6) based on liquid chromatography−mass spectrometry was performed. Among the six sulfonium salts, salacinol (1) and neokotalanol (5) were found to be the most abundant constituents in the extracts, although the content of sulfonium salts varies based on slight differences in the picking place and/or harvest period.10 Therefore, the development of effective supplying methods of sulfonium salts as reference standards is strongly recommended for evaluating the quality of Salacia extracts because of low supplies from “Salacia” raw materials. In addition, the limited amount of these naturally occurring α-glucosidase inhibitors can impede other broad biological evaluation, because efficient access to natural products that show pharmacologically important activity is essential for the development of pharmaceuticals. Intensive synthetic studies of 1,11 2,12 3,13 4,14 5,12,15 and 7,14b,16 6 and semisynthesis of 411d and 54 via de-Osulfonylation of 1 and 2, respectively, have been accomplished by other researchers and us. However, most of the studies did not report effective protocols in terms of synthetic strategies for the key building blocks, such as A, B, and C, and the diastereoselectivity of the key S-alkylation of thiosugars (7) with A, B, and C (Scheme 1). Four protocols aiming to

designed a building block (12), from which 5 was synthesized.15a Nonetheless, both synthetic protocols proved to be quite troublesome for the following reasons: (1) total yield of key building blocks 9 and 12 was too poor (9: around 3% via 13 steps, 12: around 4% via 15 steps); (2) S-alkylation of thiosugars (7a and 7b) requires a long reaction period (7 days). In addition, the yield of S-alkylation products was also not good (10: 61%, 13: 24%); and (3) the fuming toxic reagent BCl3 was required to remove the methylene acetal moiety of 10 and 13. However, a small amount of the target (5) could only be produced from the easily accessible starting materials [around 1% overall yield12 over 15 steps from Dmannitol (8); around 0.5% overall yield15a over 18 steps from D-mannose (11)]. On the other hand, we recently reported the synthesis of neokotalanol (5) via an alternative strategy, in which the sulfonium structure of 5 was constructed by the coupling reaction of thiol (15) with diiodide (16).15b However, the total yield of the key building block (15) was not good [around 5% via 11 steps from D-arabinose (14)]. The efficiency of the sulfonium formation reaction between 16 and 15 was better (16 h) than that with the conventional route (7 days), but the yield of the key intermediate (17) was unsatisfactory (59%). Although the compound (17) was subsequently converted to the target (5) via 2 steps, the overall yield of this sequence via 14 steps was around 2% (Scheme 2). Therefore, development of an efficient alternative route is highly desirable. In this study, we describe the complete details of our new protocol for synthesizing 5 in a good total yield starting from commercially available Dgalactose (18).

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RESULTS AND DISCUSSION In synthetic methodology, especially for sugar-related molecules, selection of protecting groups is the most important step. Thus, the synthetic intermediate (19) of neokotalanol (5) can be retrosynthetically simplified to a chiral thiosugar (7b) and an epoxide (20). The former (7b) can be easily synthesized from D-xylose (21).17 We previously proved that 7b can function as an appropriate sulfur donor for diastereoselective Salkylation of 7b in neoponkoranol (6) synthesis.16b In contrast, the latter (20) as an acceptor of sulfur of 7b has to be stereoselectively synthesized to avoid contamination by unnecessary diastereomeric isomers of 19. This is because these types of diastereomeric isomers may be obtained either as a poorly separable or an inseparable mixture on the Salkylation stage of thiosugars.13,18 Therefore, the oxirane moiety of 20 could be stereoselectively introduced by epoxidation of a chiral diol (22), which is derived from the corresponding olefin (23) via diastereoselective dihydroxylation. The requisite 23 could be synthesized by oxidation of alcohol (25) and the subsequent Wittig reaction of the resulting aldehyde (24). The alcohol (25) would be stereoselectively assembled through the Koenigs−Knorr reaction of the D-galactose derivative (26), which could be accessed from commercially available D-galactose (18) (Scheme 3). The first task of this total synthesis is to achieve and scale up the diastereoselective synthesis of epoxide (β-20). As shown in Scheme 4, based on the Koenigs−Knorr synthesis, the first stereogenic center was selectively constructed by treatment of α-D-galactopyranosyl bromide (26), which was prepared by the usual procedure starting from 15 g of D-galactose (18), with pmethoxybenzyl alcohol in the presence of silver carbonate to exclusively afford the p-methoxybenzyl β-D-galactopyranoside

Scheme 1. Key S-Alkylation in Conventional Routes to Sulfonium Salts

synthesize 1,11c 4,11d,14b and 6,14b,16b which possess an alditol side chain with a C4 or C6 chain length, seemed to be amenable to scale-up synthesis. Nevertheless, it is difficult to suitably design protected key building blocks for the persitoltype side chain of 2 and 5, because the building blocks were revealed to be predisposed to easy decomposition or intramolecularly cyclized at the S-alkylation stage.12,15a To avoid the difficulty resulting from the undesirable property of the building blocks of 2 and 5, Jayakanthan et al.12 successfully designed a cyclic sulfate (9) with methylene acetal protection in the course of kotalanol (2) synthesis. The subsequent deportation of the resultant sulfonium salt (10) with BCl3 caused de-O-sulfonylation besides de-O-benzylation, resulting in the formation of neokotalanol (5). We also alternatively 7534

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Scheme 2. Previous Synthesis of Neokotalanol (5)

Scheme 3. Retrosynthetic Analysis of Neolotalanol (5)

Scheme 4. Diastereoselective Synthesis of β-20

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Table 1. 13C NMR Data of Sulfonium Salts α-19 and β-19 (C1−C5 and C1′−C7′) and Those of 7b (C1−C5) and β-20 (C7− C1)a α-19 β-19 7b

C1

C2

C3

C4

C5

C1′

C2′

C3′

C4′

C5′

C6′

C7′

48.4 45.3 33.1

82.3 82.8 85.0

82.2 84.6 85.1

66.2 60.6 49.0

66.8 65.3 72.3

51.7 43.0

67.1 65.4

76.6 76.6

73.7 74.6

82.0 81.8

79.0 78.8

103.5 102.9

C7 46.9

C6 50.5

C5 75.1

C4 74.5

C3 81.7

C2 79.3

C1 102.5

β-20

a All spectra were measured in CDCl3 (200 MHz). Chemical shift values of β-19 are extracted from the spectrum of a mixture of α- and β-isomers. Other signals are provided in the Experimental Section.

Scheme 5. Conversion of β-20 to Neokotalanol (5)

purification because of their extremely similar chromatographic polarity. Mitsunobu epoxidation of the ca. 12/1 mixture of diols (β-22 and α-22) by treatment with diethyl azodicarboxylate (DEAD) and Ph3P in refluxing toluene afforded the desired key building block (β-20) and its diastereomeric isomer (α-20) in 79 and 6.5% yields, respectively. The overall yield of this sequence via 11 steps from D-galactose (18) was around 20%; thus, an efficient and practical route to the key building block (β-20) was successfully developed (Scheme 4). From 9.7 g of epoxide (β-20) in hand, we performed highly diastereoselective S-alkylation16b of thiosugar (7b) with 2.2 g of β-20 for constructing the stereogenic sulfonium center of the synthetic intermediate (19). The S-alkylation smoothly proceeded in a diastereoselective manner in refluxing 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). After 8 h, by the usual work-up using in situ treatment with methanolic hydrogen chloride, the corresponding chloride (19) was obtained in good yields with excellent dr (85%, α/β = ∼ca. 30/1). The ratio was determined based on 800 MHz 1H NMR spectroscopic measurement. The major isomer (α-19) was successfully separated from the β-isomer (β-19) by silica gel column chromatography. The FAB-MS spectrum run in the positive mode showed peaks at m/z 1003, which corresponded to the sulfonium cation structure [M − Cl]+. The compound (β-19) exhibited a positive reaction in the Beilstein test, indicating the presence of the Cl atom in the compound. As shown in Table 1, the 13C NMR spectrum of β-19 showed 12 resonances corresponding to 12 carbons (C1−C5 and C1′− C7′) of the sulfonium moiety of α-19. In particular, a downfield shift resulting from sulfonium ion formation with respect to signals caused by C-1 (δC 48.4) and C-4 (δC 66.2) carbons compared with those [C-1 (δC 33.1) and C-4 (δC 49.0)] of thiosugar (7b), and a signal that appeared at δC 51.7 because of C1′ carbon α to the sulfur atom in the side chain well supported the sulfonium ion formation. The relative stereochemistry of the side chain of α-19 was confirmed to be

derivative (27) in a good yield [23.4 g (60%)]. Deacetylation of 27 by NaOCH3 followed by tert-butyldimethylsimethylsilyl (TBDMS) protection of the primary hydroxyl in the resultant alcohol (28) afforded the corresponding TBDMS ether (29) with 84% yield. Complete benzylation of the remaining three hydroxyl groups of 29 was carried out with BnBr in the presence of tetrabutylammonium iodide (TBAI), and the TBDMS moiety of the resultant tri-O-benzyl ether (30) was selectively deprotected by tetrabutylammonium fluoride (TBAF) to afford alcohol (25) in a good yield. The compound (25) was then subjected to Dess−Martin oxidation to provide the corresponding aldehyde (24), which was then converted by the Wittig reaction with a phosphorous ylide, CH2PPh3, to provide 23 in 72% yield from 25. Next, diastereoselectivity of dihydroxylation of 23 is crucial to the establishment of side chain stereochemistry at the C2′ position of neokotalanol (5). Thus, asymmetric dihydroxylation of 23 using AD-mix-α was first carried out with the aim of stereoselectively synthesizing β-22, expectedly providing β-22 as a predominant isomer along with small amounts of α-22 with a good diastereomeric ratio (dr, β/α = ca. 12/1). In contrast, the dr ratio was decreased up to β/α = ca. 8/1 by asymmetric dihydroxylation of 23 using AD-mix-β. Notably, a similar dr ratio (β/α = ca. 9/ 1) was obtained by OsO4-catalyzed dihydroxylation in the presence of N-methylmorpholine N-oxide (NMO) as a reoxidant, indicating that hydroxylation of 23 afforded the desired β-22 in good yield with a moderate dr ratio, without the use of the expensive asymmetric inducing agent AD-mix-α. The newly constructed stereochemistry at C-6 of the major product (β-22) was confirmed to be in the R configuration after leading to the known heptitol, persitol (β-31), via acidic hydrogenolysis of the crude mixture of β-22 and α-22 and subsequent NaBH4 reduction of the resultant heptoses. The 13 C NMR data of the major heptitol (β-31) agreed well with those reported previously.19 The mixture of diols (β-22 and α22) was continuously used to the next stage without further 7536

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spectra. Low-resolution and high-resolution mass spectra were recorded on an orbitrap mass spectrometer (ESI). Optical rotations were determined with a digital polarimeter. Column chromatography was performed over silica gel (45−106 μM). All the organic extracts were dried over anhydrous Na2SO4 prior to evaporation. p-Methoxybenzyl 2,3,4,6-Tetra-O-acetyl-β-D-galactopyranoside (27). To a mixture of D-galactose (18, 15.0 g, 83.3 mmol), acetic anhydride, (55 mL, 582 mmol) was carefully added with three drops of concentrated sulfuric acid at 0 °C, and the mixture was stirred at room temperature for 2 h (when the exothermic reaction occurs, the mixture was cooled by the ice-water bath). After the reaction mixture was poured into cold water (500 mL), the resulting mixture was neutralized with NaHCO3 and extracted with EtOAc (3 × 100 mL). The extract was washed with brine and condensed in vacuo to give α- and β-D-galactose pentaacetate as a colorless oil (34.2 g, dr, α/β = ca. 3/1), which was immediately used for the subsequent reaction without further purification. To a solution of the crude pentaacetate (34.2 g) in dry CH2Cl2 (30 mL) was added dropwise 5.1 M solution of hydrogen bromide in acetic acid (25 mL) at room temperature. After being stirred at room temperature for 3 h, the reaction mixture was poured into cold water (500 mL) and extracted with CH2Cl2 (1 × 200 mL, 2 × 100 mL). The extract was washed with brine and condensed in vacuo to give practically pure 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (26) as a pale yellow oil (33.8 g), which was immediately used for the subsequent reaction without further purification. A solution of the crude bromide 26 (33.8 g) in dry CH2Cl2 (200 mL) was added dropwise to a mixture of pmethoxybenzylalcohol (15.5 mL, 125 mmol), silver carbonate (34.5 g, 125 mmol), molecular sieves 3A (60 g), iodine (0.5 g, 2.0 mmol), and dry CH2Cl2 (100 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. CH2Cl2-insoluble materials were filtered off through celite, and the filter cake was fully washed with CH2Cl2. The combined filtrate and washings were condensed in vacuo to give a pale yellow oil (43.6 g), from which excess p-methoxybenzylalcohol was removed at the reduced pressure. The residue was purified by means of column chromatography (CHCl3 → CHCl3−MeOH → 100:1 → 50:1 → 20:1) to give the title compound 27 (23.4 g, 60%) as a colorless viscous oil. [α]23 D −47.3 (c = 0.50, CHCl3). IR (neat): 1748, 1612 cm−1. 1H NMR (500 MHz, CDCl3): δ 1.97/2.00/2.07/2.16 (each 3H, s, COCH3), 3.81 (3H, s, OCH3), 3.88 (1H, ddd, J = 6.9, 6.7, 1.1, H-5), 4.15 (1H, dd, J = 11.5, 6.9, H-6a), 4.22 (1H, dd, J = 11.5, 6.7, H-6b), 4.48 (1H, d, J = 8.0, H-1), 4.58/4.83 (each 1H, d, J = 12.0, CH2PMP), 4.97 (1H, dd, J = 10.5, 3.4, H-3), 5.25 (1H, dd, J = 10.5, 8.0, H-2), 5.38 (1H, dd, J = 3.4, 1.0, H-4), 6.88/7.22 (each 2H, d-like, J = 8.6, arom.). 13C NMR (125 MHz, CDCl3): δ 20.55/20.64/20.66/20.72 (s, COCH3), 55.2 (OCH 3 ), 61.3 (C-6), 67.1 (C-4), 68.8 (C-2), 70.4 (CH2PMP), 70.7 (C-5), 70.9 (C-3), 99.4 (C-1), 113.8/129.5 (d, arom.), 128.6/159.5 (s, arom.), 169.3/170.1/170.3/170.4 (COCH3). HRMS (ESI) m/z: [M + Na]+ calcd for C22H28O11Na, 491.1524; found, 491.1512. p-Methoxybenzyl β-D-Galactopyranoside (28). A mixture of 27 (23.4 g, 50.0 mmol), sodium methoxide, (1.0 g, 18.5 mmol), and absolute MeOH (50 mL) was stirred at room temperature for 1 h. After the reaction mixture was neutralized with the ion exchange resin [IRA-120 (H+-form)], the resin

anti to the benzyloxymethyl moiety (BnOCH2) at C-4 by rotating frame Overhauser effect spectroscopy experiments in 1 H NMR spectroscopy as shown in Scheme 5. In contrast, the 13 C NMR spectra of minor isomers (β-19) showed a characteristic upfield-shift20 induced by the cis-oriented βsubstituent effect,21 with respect to three α-carbons C-1 (δC: 45.3), C-4 (δC: 60.6), and C-1′ (δC: 43.0) to the sulfur atom, compared with the corresponding carbons of the α-isomer (α19), thus supporting the β-orientation of the side chain. Finally, protection of both benzyl (Bn) and p-methoxybenzyl (PMB) of α-19 was removed by hydrogenolysis on Pd−C at 60 °C in a mixture of aqueous trifluoroacetic acid (TFA) and 1,4-dioxane, and the subsequent reduction of the resulting crude hemiacetal with NaBH4 afforded neokotalanol (5) in 64% yield (Scheme 5). 1H and 13C NMR spectroscopic properties of the product (5) agreed well with those of an authentic specimen reported4,12 (Table 1). In conclusion, total synthesis of neokotalanol (5), the most potent α-glucosidase inhibitor isolated from the traditional Ayurvedic medicine “Salacia”, was achieved in 14 steps via the longest linear sequence from commercially available Dgalactose (18). To avoid the disadvantages in S-alkylation of thiosugar (7b) with the key building block, an appropriately protected epoxide (β-20) was diastereoselectively synthesized in around 20% yield via 11 steps. Upscaling of the sequence was readily carried out to provide large amounts of β-20 (9.7 g), albeit on a modest laboratory scale. Application of highly diastereoselective S-alkylation of 7b with β-20 successfully enabled gram-scale synthesis of an intermediate (α-19) with a neokotalanol core, which was converted to the target via 2 steps. The total yield (11%) of 5 in the present study far exceeded the yields previously reported (∼1% via 15 steps,12∼0.5% via 18 steps,15a ∼2% via 14 steps15b). In addition, our new protocol can be considered a valid alternative to previously reported methods, because it avoids the use of the fuming toxic BCl3. Taken together, our protocol can provide adequate amounts of 5 as reference standards to evaluate the quality of Salacia extracts as well as for an investigation tool for further biological evaluation on diseases involving disorders of carbohydrate metabolism. Finally, as reducing the number of steps is an important consideration for large-scale industrial production, additional studies with a short and more concise sequence to 5 using an alternative key building block to β-20 are currently underway in our laboratory.

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EXPERIMENTAL SECTION General Experimental Details. mps were determined on a hot-stage melting point apparatus and are uncorrected. IR spectra were measured on a FT-IR spectrophotometer. NMR spectra were recorded on a FT-NMR spectrometer (1H, 500 or 800 MHz; 13C, 125 or 200 MHz). Chemical shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively. Tetramethylsilane was used as an internal standard for 1H NMR measurements in CDCl3, whereas 13C NMR measurements utilized the solvent signal (77.0 ppm) of CDCl3 for this purpose. For the measurement of 1H and 13C NMR spectra in CD3OD, the solvent signals 33.1 and 49.0 ppm were used, respectively, as internal standards. Sodium 2,2-dimethyl-2silapentane-5-sulfonate was used as an external standard in the measurement of 1H and 13C NMR spectra in D2O. 1D NMR peak assignments were confirmed by COSY and HSQC 7537

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was filtered off, and the resin was fully washed with MeOH. The combined filtrate and washings were condensed in vacuo to give the title compound 28 (16.2 g) as a pale orange viscous oil, which was used for the subsequent reaction without further purification. For analytical purpose a small portion was purified by means of column chromatography (CHCl3/MeOH = 10/1) to give a colorless glass-like solid, which on trituration with CHCl3 gave 28 as a white amorphous powder. Mp 107−108 °C. [α]23 D −39.8 (c = 1.06, CH3OH). IR (KBr): 3399, 1612, 1071, 1040 cm−1. 1H NMR (500 MHz, CD3OD): δ 3.44 (1H, dd, J = 9.6, 3.3, H-3), 3.49 (1H, ddd, J = 6.8, 5.3, 1.0, H-5), 3.56 (1H, dd, J = 9.6, 7.7, H-2), 3.74 (1H, dd, J = 11.3, 5.3, H6b), 3.78 (3H, s, OCH3), 3.80 (1H, dd, J = 11.3, 6.8, H-6a), 3.83 (1H, dd, J = 3.3 1.0, H-4), 4.28 (1H, d, J = 7.7, H-1), 4.59/4.85 (each 1H, d, J = 11.5, CH2PMP) 6.88/7.33 (each 2H, d-like, J = 8.7, arom.). 13C NMR (125 MHz, CD3OD): δ 55.7 (OCH3), 62.6 (C-6), 70.4 (C-4), 71.4 (CH2PMP), 72.6 (C-2), 75.0 (C-3) 76.7 (C-5), 103.6 (C-1), 114.6/130.9 (d, arom.), 131.1/160.8 (s, arom.). HRMS (ESI) m/z: [M + Na]+ calcd for C14H20O7Na, 323.1101; found, 323.1094. p-Methoxybenzyl 6-O-(tert-Butyldimethylsilyl)-β-Dgalactopyranoside (29). A mixture of the crude 28 (16.2 g), tert-butyldimethylsilyl chloride (8.6 g, 57.1 mmol), imidazole (7.9 g, 115 mmol), and dry dimethylformamide (DMF) (50 mL) was stirred at room temperature for 12 h. The reaction mixture was poured into cold water (250 mL) and extracted with EtOAc (1 × 200 mL, 2 × 100 mL). The extract was washed with brine and condensed in vacuo to give a colorless oil (23.5 g), which on column chromatography (nhexane−acetone, 3:2 → 1:1 → 2:3) gave the title compound 29 (17.4 g, 84% from 27) as a colorless viscous oil. [α]24 D −43.7 (c = 1.12, CHCl3). IR (neat): 3391, 1612, 1096, 1072 cm−1. 1 H NMR (500 MHz, CDCl3): δ 0.108/0.110 [each 3H, s, Si(CH3)2], 0.91 [9H, s, SiC(CH3)3], 2.71 (1H, br s, OH), 2.92 (2H, br s, OH), 3.46 (1H, ddd, J = 5.9, 5.3, 0.9, H-5), 3.53 (1H, dd, J = 9.4, 3.0, H-3), 3.68 (1H, dd, J = 9.4 7.7, H-2), 3.80 (3H, s, OCH3), 3.88 (1H, dd, J = 10.5, 5.3, H-6a), 3.94 (1H, dd, J = 10.5, 5.9, H-6b), 4.00 (1H, br d, J = ca. 3.0, H-4), 4.28 (1H, d, J = 7.7, H-1), 4.54/4.85 (each 1H, d, J = 11.2, CH2PMP), 6.88/7.28 (each 2H, d-like, J = 8.7, arom.). 13C NMR (125 MHz, CDCl3): δ −5.42/−5.39 [Si(CH3)2], 18.3 [SiC(CH3)3], 25.8 [SiC(CH3)3], 55.2 (OCH3), 62.6 (C-6), 68.9 (C-4), 70.5 (CH2PMP) 72.1 (C-2), 73.6 (C-3), 74.5 (C5), 101.4 (C-1), 113.9/130.0 (d, arom.), 129.0/159.5 (s, arom.). HRMS (ESI) m/z: [M + Na] + calcd for C20H34O7SiNa, 437.1966; found, 437.1957. p-Methoxybenzyl 2,3,4-Tri-O-benzyl-6-O-(tert-butyldimethylsilyl)-β-D-galactopyranoside (30). A solution of 29 (17.4 g, 42.0 mmol) in dry DMF (50 mL) was added dropwise to a mixture of benzyl bromide (20.0 mL, 168 mmol), NaH (7.6 g, 190 mmol, 60% in liquid paraffin), TBAI (7.8 g, 21.1 mmol), and dry DMF (150 mL) at 0 °C, the mixture was stirred at room temperature for 2 h, and then stirred at 50 °C for another 1 h. The reaction mixture was poured into cold water (850 mL) and extracted with EtOAc (1 × 300 mL, 2 × 200 mL). The extract was successively washed with aqueous Na2S2O3−NaHCO3 and brine, and condensed in vacuo to give a pale yellow oil (46.9 g), which on column chromatography (n-hexane−EtOAc, 50:1 → 10:1) gave the title compound 30 (24.1 g, 84%) as a colorless viscous oil. [α]24 D −20.1 (c = 1.25, CHCl3). IR (neat): 1612, 1103, 1072 cm−1. 1H NMR (800 MHz, CDCl3): δ 0.05/0.06 [each 3H, s, Si(CH3)2], 0.89 [9H, s, SiC(CH3)3], 3.36 (1H, ddd, J = 7.0,

6.0, 0.5, H-5), 3.49 (1H, dd, J = 9.7, 2.9, H-3), 3.67 (1H, dd, J = 10.0, 7.0, H-6a), 3.74 (1H, dd, J = 10.0, 6.0, H-6b), 3.80 (3H, s, OCH3), 3.84 (1H, dd-like, J = ca. 2.9, 0.5, H-4), 3.86 (1H, dd, J = 9.7, 7.7, H-2), 4.42 (1H, d, J = 7.7, H-1), 4.57/ 4.87 (each 1H, d, J = 11.7, CH2PMP), 4.64/4.96 (each 1H, d, J = 11.5, CH2Ph), 4.69/4.77 (each 1H, d, J = 12.0, CH2Ph), 4.75/4.91 (each 1H, d, J = 10.8, CH2Ph), 6.84 (2H, d-like, J = 8.6, arom.), 7.24−7.35 (17H, m, arom.). 13C NMR (200 MHz, CDCl3): δ −5.39/−5.33 [Si(CH3)2], 18.2 [SiC(CH3)3], 25.9 [SiC(CH3)3], 55.2 (OCH3), 61.9 (C-6), 70.4 (CH2PMP) 73.1/74.6/75.1 (CH2Ph) 73.7 (C-4), 75.1 (C-5), 79.6 (C-2), 82.3 (C-3), 102.4 (C-1), 113.7/127.40/127.44/127.53/ 127.54/128.09/128.13/128.15/128.19/128.3/129.6 (d, arom). 129.7/138.6/138.8/159.2 (s, arom). HRMS (ESI) m/ z: [M + Na]+ calcd for C41H52O7SiNa, 707.3375; found, 707.3364. p-Methoxybenzyl 2,3,4-Tri-O-benzyl-β-D-galactopyranoside (25). To a solution of 30 (24.1 g, 35.2 mmol) in tetrahydrofuran (30 mL) was added 1 M solution of TBAF in THF (38.7 mL, 38.7 mmol) at room temperature, and the mixture was stirred for 3 h. The reaction mixture was poured into cold water (1 L) and extracted with EtOAc (1 × 200 mL, 2 × 100 mL). The extract was washed with brine, and concentrated in vacuo to give a colorless solid (23.7 g), which on recrystallization from a mixture of n-hexane and EtOAc gave the title compound 25 (16.1 g, 80%) as colorless needles. Column chromatography (n-hexane−acetone, 2:1) of the mother liquid gave 25 (578 mg, 3%) as a colorless microcrystalline solid. mp 113−114 °C. [α]23 D −46.0 (c = 0.80, CHCl3). IR (KBr): 3337, 1612, 1095, 1057 cm−1. 1H NMR (500 MHz, CDCl3): δ 1.49 (1H, dd, J = 8.6, 4.0, OH), 3.35 (1H, ddd-like, J = ca. 7.0, 5.4, 0.5, H-5), 3.48 (1H, ddd, J = 11.1, 8.6, 5.4, H-6a), 3.51 (1H, dd, J = 9.7, 2.9, H-3), 3.768 (1H, dd-like, J = ca. 2.9, 0.5, H-4), 3.772 (1H, ddd-like, J = ca. 11.1, 7.4, 4.0, H-6b), 3.79 (3H, s, OCH3), 3.89 (1H, dd, J = 9.7, 7.7, H-2), 4.45 (1H, d, J = 7.7, H-1), 4.59/4.87 (each 1H, d, J = 11.7, CH2PMP), 4.67/4.96 (each 1H, d, J = 12.0, CH2Ph), 4.73/4.80 (each 1H, d, J = 11.7, CH2Ph), 4.76/4.93 (each 1H, d, 10.8, CH2Ph), 6.84 (2H, d-like, J = 8.6, arom.), 7.26−7.39 (17H, m, arom.). 13C NMR (125 MHz, CDCl3): δ 55.2 (OCH3), 61.9 (C-6), 70.8 (CH2PMP), 72.6 (C-4), 73.4/ 74.0/75.2 (CH2Ph), 74.4 (C-5), 79.6 (C-2), 82.3 (C-3), 102.7 (C-1), 113.7/127.5/127.6/127.7/128.0/128.1/128.2/128.41/ 128.43/128.7/129.6 (d, arom.), 129.5/138.1/138.3/138.6/ 159.2 (s, arom.). HRMS (ESI) m/z: [M + Na]+ calcd for C35H38O7SiNa, 593.2510; found, 593.2497. p-Methoxybenzyl 2,3,4-Tri-O-benzyl-β-D-galacto-hexodialdo-1,5-pyranoside (24). A mixture of 25 (16.7 g, 29.3 mmol), Dess−Martin periodinane (DMP, 18.6 g, 43.9 mmol), and dry CH2Cl2 (50 mL) was stirred at room temperature for 3 h. After the reaction was quenched by addition of aqueous Na2S2O3−NaHCO3 (300 mL), the resulting mixture was extracted with CH2Cl2 (1 × 200 mL, 2 × 100 mL). The extract was washed with brine and condensed in vacuo to give a colorless solid (17.7 g), which was used for the subsequent reaction without further purification. For analytical purposes, a small portion was purified by recrystallization from n-hexane to give the title compound 24 as colorless needles. mp 110−112 °C. [α]26 D −18.7 (c = 1.07, CHCl3). IR (KBr): 1740, 1613, 1092 cm−1. 1H NMR (500 MHz, CDCl3): δ 3.52 (1H, dd, J = 9.7, 2.9, H-3), 3.73 (1H, d, J = ca. 1.1, H-5), 3.80 (3H, s, OCH3), 3.94 (1H, dd, J = 9.7, 7.7, H-2), 4.20 (1H, dd, J = 2.9, 1.1, H-4), 4.52 (1H, d, J = 7.7, H-1), 4.57/4.89 (each 1H, d, J 7538

DOI: 10.1021/acsomega.9b00610 ACS Omega 2019, 4, 7533−7542

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= 11.3, CH2Ph), 4.64/4.96 (each 1H, d, J = 11.5, CH2PMP), 4.71/4.75 (each 1H, d, J = 11.9, CH2Ph), 4.77/4.92 (each 1H, d, J = 10.7, CH2Ph), 6.85 (2H, d-like, J = 8.6, arom.), 7.24− 7.34 (17H, m, arom.), 9.64 (1H, s, CHO). 13C NMR (125 MHz, CDCl3): δ 55.2 (OCH3), 70.9 (CH2PMP), 73.1/74.7/ 75.2 (CH2Ph), 74.9 (C-4), 78.7 (C-5), 78.9 (C-2), 81.1 (C-3), 102.2 (C-1), 113.8/127.6/127.7/127.8/128.1/128.2/128.3/ 128.4/129.7 (d, arom.), 129.2/137.8/138.0/138.4/159.3 (s, arom.), 200.8 (CHO). HRMS (ESI) m/z: [M + Na]+ calcd for C35H36O7SiNa, 591.2353; found, 591.2341. p-Methoxybenzyl 6,7-Dideoxy-2,3,4-tri-O-benzyl-β-Dgalacto-hept-6-enopyranoside (23). To a suspension of methyltriphenylphosphonium bromide (20.9 g, 58.5 mmol) in dry THF (80 mL) was added potassium tert-butoxide (6.6 g, 58.9 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h. A solution of the crude 24 (17.7 g) in dry THF (50 mL) was added to the mixture at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into cold water (500 mL) and extracted with EtOAc (1 × 200 mL, 2 × 100 mL). The extract was washed with brine and condensed in vacuo to give a pale yellow viscous oil (36.9 g), which on column chromatography (n-hexane−ethyl acetate, 10:1 → 5:1 → 2:1) gave the title compound 23 (11.9 g, 72% from 25) as a pale yellow microcrystalline solid. For analytical purposes, a small portion was purified by recrystallization from a mixture of n-hexane and EtOAc to give 23 as colorless needles. mp 108−109 °C. [α]22 D −27.4 (c = 0.94, CHCl3). IR (KBr): 1647, 1612, 1126, 1095, 1061 cm−1. 1H NMR (500 MHz, CDCl3): δ 3.52 (1H, dd, J = 9.7, 2.9, H-3), 3.72 (1H, dd, J = ca. 2.9, 0.7, H-4), 3.79 (3H, s, OCH3), 3.81 (1H, dddd, J = 5.6, 1.4, 1.4, 0.7, H-5), 3.90 (1H, dd, J = 9.7, 7.6, H-2), 4.46 (1H, d, J = 7.6, H-1), 4.59/4.92 (each 1H, d, J = 11.6, CH2PMP), 4.67/4.74 (each 1H, d, J = 11.9, CH2Ph), 4.71/4.90 (each 1H, d, J = 11.9, CH2Ph), 4.76/4.92 (each 1H, d, J = 11.0, CH2Ph), 5.20 (1H, ddd, J = 10.6, 1.4, 1.4, H-7a), 5.35 (1H, ddd, J = 17.3, 1.4, 1.4, H-7b), 5.89 (1H, ddd, J = 17.3, 10.6, 5.6, H-6), 6.84 (2H, d-like, J = 8.7, arom.), 7.23−7.37 (17H, m, arom.). 13C NMR (125 MHz, CDCl3): δ 55.2 (OCH3), 70.5 (CH2PMP), 73.0/ 74.4/75.1 (CH2Ph), 75.5 (C-5), 76.4 (C-4), 79.4 (C-2), 82.1 (C-3), 102.4 (C-1), 116.7 (C-7), 113.7/127.46/127.49/127.5/ 128.0/128.15/128.20/128.3/128.4/129.6 (d, arom.), 134.9 (C-6), 129.8/138.4/138.5/138.8/159.2 (s, arom.). HRMS (ESI) m/z: [M + Na]+ calcd for C36H38O6SiNa, 589.2561; found, 589.2548. Dihydroxylation of Compound 23. Method A (Asymmetric Dihydroxylation Using ADmix-α). To a solution of 23 (100 mg, 0.177 mmol) in a mixture of tert-butanol/THF/H2O (3/2/1, v/v, 3 mL) were added ADmix-α (177 mg), methanesufonamide (17 mg, 0.179 mmol), K2CO3 (73 mg, 0.53 mmol), K2OsO4·2H2O (19.5 mg, 0.053 mmol), and K3Fe(CN)6 (175 mg, 0.53 mmol) at 0 °C. The temperature was allowed to gradually rise to room temperature while the mixture was stirring. After 12 h, the reaction mixture was quenched by addition of aqueous NaHSO3, and the resulting mixture was extracted with EtOAc (1 × 30 mL, 2 × 15 mL). The extract was washed with brine and condensed in vacuo to give the crude diols, p-methoxybenzyl 2,3,4-tri-O-benzyl-Dglycero-β-D-galacto-heptopyranoside (β-22) and p-methoxybenzyl 2,3,4-tri-O-benzyl-L-glycero-β-D-galacto-heptopyranoside (α22) as a colorless solid (111 mg, dr, β/α = ca. 12/1). The product ratio was determined by 800 MHz NMR spectroscopic analysis of the crude mixture.

Similarly, in the presence of ADmix-α, 23 (11.9 g, 21.0 mmol) was dihydroxylated to give a ca. 12/1 mixture of β-22 and α-22 (13.4 g) as a colorless solid, which was used for the subsequent reaction without further purification. Major Isomer β-22 (NMR Data Extracted from the Spectrum of a ca. 12:1 Mixture). 1H NMR (500 MHz, CDCl3): δ 1.68/1.90 (each 1H, br s, OH), 3.18 (1H, br d, J = 8.6, H-5), 3.52 (1H, dd, J = 9.7, 2.9, H-3), 3.61 (1H, dd, J = 11.1, 5.2, H-7a), 3.78 (1H, dd-like, J = ca. 11.1, 3.2, H-7b), 3.79 (3H, s, OCH3), 3.82 (1H, br m, H-6), 3.88 (1H, dd, J = 9.7, 7.7, H-2), 3.98 (1H, br d, J = ca. 2.9, H-4), 4.39 (1H, d, J = 7.7, H-1), 4.56/4.82 (each 1H, d, J = 11.7, CH2PMP), 4.73/ 5.01 (each 1H, d, J = 11.8 CH2Ph), 4.75/4.80 (each 1H, d, J = 11.7, CH2Ph), 4.76/4.92 (each 1H, d, J = 10.9, CH2Ph), 6.84 (2H, d-like, J = 8.6, arom.), 7.24−7.41 (17H, m, arom.). 13C NMR (125 MHz, CDCl3): δ 55.2 (OCH3), 63.8 (C-7), 69.1 (C-6), 70.6 (CH2PMP), 71.6 (C-4), 73.3 (CH2Ph), 74.0 (CH2Ph and C5), 75.2 (CH2Ph), 79.5 (C-2), 82.3 (C-3), 102.4 (C-1), 113.7/127.5/127.6/127.7/128.1/128.2/128.4/ 128.6/128.76/128.84 (d, arom.), 129.3/138.3/138.4/138.5/ 159.2 (s, arom.). HRMS (ESI) m/z: [M + Na]+ calcd for C36H40O8Na, 623.2615; found, 623.2620. Method B (Asymmetric Dihydroxylation Using ADmix-β). Following the method A, a ca. 8/1 mixture of diols β-22 and α22 (113 mg) was obtained by using ADmix-β from 23 (100 mg, 0.177 mmol). The product ratio was determined by 800 MHz NMR spectroscopic analysis of the crude mixture. Method C (OsO4-Catalyzed Dihydroxylation). To a mixture of 23 (100 mg, 0.177 mmol), NMO (41 mg, 0.35 mmol), and acetone (4 mL) was added an aqueous solution of OsO4 (2 g/100 mL, 200 μL) at 0 °C. The temperature was allowed to gradually rise to room temperature while the mixture was stirring. After 12 h, the reaction mixture was quenched by addition of aqueous Na2S2O3−NaHCO3, and the resulting mixture was extracted with EtOAc (1 × 30 mL, 2 × 15 mL). The extract was washed with brine and condensed in vacuo to give the crude diols β-22 and α-22 (115 mg, dr, β/α = ca. 9/1). The product ratio was determined by 800 MHz NMR spectroscopic analysis of the crude mixture. Mitsunobu Epoxidation of Diols (β-22 and α-22). To a mixture of the crude diol (β-22 and α-22, 13.4 g), triphenylphosphine (16.5 g, 63.0 mmol), and toluene (100 mL) was added dropwise 40% solution of DEAD in toluene (28.6 mL, 63.1 mmol) at 0 °C. After being stirred at room temperature for 30 min, the mixture was heated under reflux for 9 h, cooled, and then the solvent was evaporated. The residue (29.0 g) was triturated with diethyl ether. The deposited solid was filtered off. The filtrate was evaporated to give an orange oil (22.6 g), which on column chromatography (n-hexane−AcOEt, 5:1 → 3:1 → 2:1) gave p-methoxybenzyl 6,7-anhydro-2,3,4-tri-O-benzyl-D-glycero-β-Dgalacto-heptopyranoside (β-20, 9.7 g, 79% from 23) as a colorless solid along with its epimer, p-methoxybenzyl 6,7anhydro-2,3,4-tri-O-benzyl-L-glycero-β-D-galacto-heptopyranoside (α-20) including impurities. Removal of the impurities in α-20 at the reduced pressure left α-20 as a colorless solid. (α20, 794 mg, 6.5% from 23). Major Isomer β-20. Colorless needles (from n-hexane− AcOEt). mp 87−89 °C. [α]25 D −17.6 (c = 0.94, CHCl3). IR (KBr): 1616, 1092, 1065 cm−1. 1H NMR (800 MHz, CDCl3): δ 2.77 (1H, dd, J = 5.1, 2.5, H-7a), 2.87 (1H, dd, J = 5.1, 4.0, H-7b), 3.01 (1H, dd, J = 5.8, 1.0, H-5), 3.17 (1H, ddd, J = 5.8, 4.0, 2.5, H-6), 3.48 (1H, dd, J = 9.7, 3.0, H-3), 3.79 (3H, s, 7539

DOI: 10.1021/acsomega.9b00610 ACS Omega 2019, 4, 7533−7542

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arom.), 7.11−7.35 (32H, m, arom.). 13C NMR (200 MHz, CDCl3): δ 48.4 (C-1), 51.7 (C-1′), 55.2 (OCH3), 66.2 (C-4), 66.8 (C-5), 67.1 (C-2′), 71.8 (CH2PMP), 71.9/72.3/73.1/ 73.66/75.0/75.1 (s, CH2Ph), 73.72 (C4′), 76.6 (C-3′), 79.0 (C-6′), 82.0 (C-5′), 82.2 (C-3), 82.3 (C-2), 103.4 (C-7′), 113.8/127.43/127.46/127.49/127.9/128.00/128.03/128.15/ 128.16/128.28/128.29/128.30/128.4/128.5/128.60/128.63/ 128.7/128.8/129.5 (d, arom.), 129.6/135.8/135.9/136.5/ 138.4/138.58/138.64/159.2 (s, arom). HRMS (ESI) m/z: [M − Cl]+ calcd for C36H38O7SiNa, 1003.4450; found, 1003.4441. Minor Isomer β-19 (NMR Data Extracted from the Spectrum of a ca. 1:1 Mixture). 1H NMR (800 MHz, CDCl3): δ 3.54−3.60 (2H, m, H-5a and H-5′), 3.75 (3H, s, OCH3), 3.64−3.68 (2H, m, H-1a and H-3′), 3.70−3.73 (1H, m, H-5b), 3.76−3.79 (1H, m, H-6′), 4.00−4.05 (1H, m, H-4 and H-1′b), 4.08−4.10 (1H, m, H-4′), 4.14 (1H, m, H-3), 4.31−4.33 (1H, m, H-2), 4.46−4.48 (1H, m, H-7′), 4.55−4.57 (1H, m, H-2′), 4.66−4.71 (1H, m, H-1′b), 4.31−4.49 (14H, m, CH2Ph), 6.72 (2H, d-like, J = 8.7, arom.), 7.14−7.43 (32H, m, arom). 13C NMR (200 MHz, CDCl3): δ 43.0 (C-1), 45.3 (C-1′), 55.2 (OCH3), 60.6 (C-4), 65.3 (C-5), 65.4 (C-2′), 71.0/72.1/72.3/73.0/73.3/75.0/75.1 (s, CH 2 PMP and CH2Ph), 74.6 (C4′), 76.6 (C-3′), 78.8 (C-6′), 81.8 (C-5′), 84.6 (C-3), 82.8 (C-2), 103.4 (C-7′), 113.8/127.57/127.60/ 127.6/128.07/128.14/128.2/128.5/128.7/128.8/129.2 (d, arom.), 129.3/135.86/135.89/136.4/138.2/138.3/138.5/ 159.2 (s, arom) other signals due to aromatic carbons overlapped with those of α-19. 1,4-Dideoxy-1,4-[(R)-(7-deoxy-D-glycero-D-galacto-heptitol-7-yl)episulfoniumylidene]-D-arabinitol Chloride [Neokotalanol (5)]. A suspension of 10% Pd−C (600 mg) in 20% aqueous TFA (25 mL) was pre-equilibrated with hydrogen. To the suspension a mixture of a solution of α-19 (500 mg, 0.48 mmol) in 1,4-dioxane (5 mL) was added. The resultant mixture was hydrogenated at 60 °C under atmospheric pressure until the uptake of hydrogen ceased. The catalyst was filtered off and fully washed with a 1:1 mixture of methanol and water. The combined filtrate and the washings were condensed in vacuo. The residue was purified by column chromatography (CHCl3/CH3OH, 10/1 → 5/1 → CHCl3/ CH3OH/H2O, 6/4/1) to give a ca. 1:1 anomeric mixture of 1,4-dideoxy-1,4-[(R)-(7-deoxy-D-glycero-D-galactoheptopyranos-7-yl)episulfoniumylidene]-D-arabinitol chloride as colorless amorphous (151 mg, 83%), which was then treated with NaBH4 (46 mg, 1.22 mmol) in H2O (5 mL). After being stirred at 0 °C for 1.5 h, the reaction mixture was acidified with 3% HCl to ca. pH 4 at 0 °C. After the resulting mixture was condensed in vacuo, the residue was purified by column chromatography (AcOEtCH3OHH2O, 20:4:1→6:3:1) to give the titled compound 5 (117 mg, 64%). 1H and 13C NMR data of 5 agreed well with those of reported neokotalanol4 with a methyl sulfate anion (see, Supporting Information p. S28− S29).

OCH3), 3.88 (1H, dd, J = 9.7, 7.7, H-2), 3.94 (1H, dd, J = 3.0, 1.0, H-4), 4.39 (1H, d, J = 7.7, H-1), 4.56/4.87 (each 1H, d, J = 11.6, CH2PMP), 4.69/4.73 (each 1H, d, J = 11.9, CH2Ph), 4.75/4.90 (each 1H, d, J = 10.8, CH2Ph), 4.76/5.01 (each 1H, d, J = 10.6, CH2Ph), 6.84 (2H, d-like, J = 8.6, arom.), 7.25− 7.38 (17H, m, arom.). 13C NMR (200 MHz, CDCl3): δ 46.9 (C-7), 50.5 (C-6), 55.2 (OCH3), 70.7 (CH2PMP), 73.0/74.6/ 75.2 (CH2Ph), 74.5 (C-4), 75.1 (C-5), 79.3 (C-2), 81.7 (C-3), 102.5 (C-1), 113.8/127.5/127.56/127.62/128.1/128.2/128.3/ 128.4/129.6 (d, arom.), 129.5/138.38/138.39/138.7/159.3 (s, arom.). HRMS (ESI) m/z: [M + Na] + calcd for C36H38O7SiNa, 605.2510; found, 605.2501. Minor Isomer α-20. Colorless needles (from n-hexane− AcOEt). mp 106−107 °C. [α]25 D −52.6 (c = 0.52, CHCl3). IR (KBr): 1613, 1095, 1072 cm−1. 1H NMR (800 MHz, CDCl3): δ 2.31 (1H, dd, J = 4.6, 2.8, H-7a), 2.43 (1H, dd-like, J = 4.5, 4.3, H-7b), 2.85 (1H, dd, J = 6.6, 1.0, H-5), 3.25 (1H, ddd, J = 6.6, 4.3, 2.8, H-6), 3.46 (1H, dd, J = 9.7, 2.9, H-3), 3.75 (1H, dd, J = 2.9, 1.0, H-4), 3.79 (3H, s, OCH3), 3.92 (1H, dd, J = 9.7, 7.7, H-2), 4.42 (1H, d, J = 7.7, H-1), 4.61/4.95 (each 1H, d, J = 11.7, CH2PMP), 4.70/4.98 (each d, J = 12.0, CH2Ph), 4.70/4.80 (each 1H, d, J = 11.8, CH2Ph), 4.75/4.93 (each 1H, d, J = 10.8, CH2Ph), 6.84 (2H, d-like, J = 8.7, arom.), 7.26− 7.37 (17H, m, arom.). 13C NMR (200 MHz, CDCl3): δ 43.4 (C-7), 52.3 (C-6), 55.2 (OCH3), 70.7 (CH2PMP), 73.5/74.1/ 75.2 (CH2Ph), 74.4 (C-4), 77.0 (C-5), 79.4 (C-2), 81.9 (C-3), 102.3 (C-1), 113.7/127.5/127.6/127.7/127.8/128.1/128.2/ 128.3/128.4/128.7/129.7 (d, arom.), 129.6/138.1/138.4/ 138.6/159.2 (s, arom). HRMS (ESI) m/z: [M + Na]+ calcd for C36H38O7SiNa, 605.2510; found, 605.2500. S-Alkylation of Thiosugar (7b) with Epoxide (β-20) in HFIP. A mixture of epoxide β-20 (2.2 g, 3.78 mmol), thiosugar (7b, 8.0 g, 19.0 mmol), and HFIP (30 mL) was heated under reflux for 8 h. After being cooled with cold water, the reaction mixture was acidified with 5% methanolic hydrogen chloride to ca. pH 3. The mixture was immediately neutralized with NaHCO3 with ice cooling. The resulting suspension was filtered by suction, and the filter cake was washed with CHCl3. The combined filtrate and washings were condensed in vacuo to give a colorless oil (11.5 g), which on column chromatography (CHCl3/MeOH = 100/1 → 30/1 → 10/1) gave 1,4-dideoxy-1,4-{(R)-[7-deoxy-2,3,4-tri-O-benzyl-1-O-(pmethoxybenzyl)-β-D-glycero-β-D-galacto-heptopyranose-7-yl]episulfoniumylidene}-2,3,5-tri-O-benzyl-D-arabinitol chloride (α-19, 2.94 g, 75%), a ca. 3:1 mixture of α-19 and its βisomer (β-19, 360 mg, 9%), a ca. 1:1 mixture of α-19 and β-19 (38 mg, 1%), and thiosugar (7b, 6.2 g). Major Isomer α-19. Colorless amorphous. [α]21 D −300.6 (c = 1.2, CHCl3). IR (KBr): 3206, 1613, 1072 cm−1. 1H NMR (800 MHz, CDCl3): δ 3.59 (1H, dd, J = 9.7, 2.9, H-5′), 3.69 (1H, dd, J = 10.2, 9.2, H-5a), 3.71 (1H, dd, J = 10.2, 6.4, H5b), 3.74 (3H, s, OCH3), 3.76 (1H, dd, J = 7.0, 0.9, H-3′), 3.79 (1H, dd, J = 9.7, 7.8, H-6′), 3.82 (1H, dd, J = 12.6, 3.4, H-1′a), 4.01 (1H, br dd-like, J = ca. 9.2, 6.4, H-4), 4.08 (1H, dd, J = 13.2, 1.6, H-1a), 4.12 (1H, dd-like, J = ca. 1.8, 1.8, H-3), 4.25 (1H, dd, J = 2.9, 0.9, H-4′), 4.29 (1H, dd, J = 12.6, 9.0, H-1′b), 4.35/4.45 (each 1H, d, J = 11.8, CH2Ph), 4.38 (1H, ddd, J = 9.0, 7.0. 3.4, H-2′), 4.39 (1H, m, H-2), 4.46 (1H, dd-like, J = ca. 13.2, 4.2, H-1b), 4.49/4.55 (each 1H, d, J = 12.0, CH2Ph), 4.50/4.57 (each 1H, d, J = 12.1, CH2Ph), 4.49 (1H, d, J = 7.8, H-7′), 4.57/4.69 (each 1H, d, J = 11.6, CH2PMP), 4.67/4.97 (each 1H, d, J = 10.8, CH2Ph), 4.73 (2H, s-like, CH2Ph), 4.76/ 4.85 (each 1H, d, J = 11.0, CH2Ph), 6.78 (2H, d-like, J = 8.7,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b00610. 1

H and 13C NMR spectra for all new compounds (PDF)

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DOI: 10.1021/acsomega.9b00610 ACS Omega 2019, 4, 7533−7542

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Genzoh Tanabe: 0000-0002-7954-8874 Fumihiro Ishikawa: 0000-0002-8681-9396 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by a Grant-in-Aid for scientific research from the Japan Society for the Promotion of Science [JSPS (KAKENHI), 17K08377 (GT)] and by a grant from the Hoansha Foundation, 2017-2020. We are also thankful for the financial support extended by the Antiaging Project for Private Universities.

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