Construction of the DEF-Benzoxocin Ring System of Nogalamycin and

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Article Cite This: J. Org. Chem. 2019, 84, 173−180

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Construction of the DEF−Benzoxocin Ring System of Nogalamycin and Menogaril via a Reductive Heck Cyclization Ruogu Peng and Michael S. VanNieuwenhze* Department of Chemistry, Indiana University-Bloomington 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States

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ABSTRACT: Construction of the DEF-ring system of nogalamycin and menogaril has been achieved with a novel reductive Heck cyclization approach. Our strategy exploited the stereoelectronic preferences dictated by the anomeric effect for introduction of an O-glycosidic bond in order to direct the introduction of a bridging C-glycosidic bond with the desired stereochemistry. Our strategy relied upon a stereoselective O-aryl glycosylation reaction and a highly efficient selenoxide elimination to provide the key substrate for study of the reductive Heck cyclization reaction. The cyclization proceeded smoothly under the optimized conditions, in a yield comparable to that achieved in our previously reported model study.

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INTRODUCTION Nogalamycin 1, a member of the anthracycline family, was isolated in 1968 by Wiley from Streptomyces nogalator.1 The unique dumbbell-like structure of nogalamycin differentiates it from the more common daunomycin-type anthracyclines, which have only one carbohydrate unit attached to the central chromophore.2 Besides its potent biological activity versus Gram-positive bacteria, nogalamycin also shows prominent cytotoxicity against L1210 and KB cell lines in vitro.3,4 Chemical modification of nogalamycin led to the discovery of a semisynthetic derivative, 7-con-O-methylnogarol (menogaril) 2. Menogaril was found to possess even better antitumor activity and was finally evaluated in a phase II clinical trial.5 Since their discovery, several studies directed at the total synthesis of nogalamycin and menogaril have been reported.6−24 A total synthesis of menogaril has been reported by Terashima14 and Hauser,16,23 but a total synthesis of nogalamycin has not yet been reported. Most of these studies were focused on developing an efficient synthesis of the synthetically interesting DEF−benzoxocin ring system (Figure 1), in which the E-ring is formed by attaching the F-ring unit (also called nogalamine) to the anthracycline aglycone via an aryl C-glycosidic linkage and a α-O-glycosidic linkage. In all reports where the DEF−benzoxocin ring system has been successfully constructed, the aryl C-glycosidic bond was always formed prior to the formation of the O-glycosidic bond. We have sought to develop a novel route for construction of the DEF-ring system, which would eventually lead to the completion of the total synthesis of nogalamycin. We decided to reverse the previously adopted order of glycosidic bond © 2018 American Chemical Society

Figure 1. Structures of the bridged anthracycline antitumor antibiotics nogalamycin (1) and menogaril (2).

formation in DEF-ring construction by forming the Oglycosidic bond first in order to take advantage of the stereochemical preferences imposed by the anomeric effect. The desired and thermodynamically more stable α-Oglycosidic bond could then direct formation of the C-aryl glycosidic bond with the desired stereochemistry. Only two reports were found that employed this strategy in their attempts to construct the DEF-ring system, but both failed to give the desired cyclization product (Scheme 1).8,24 One report attempted to exploit the Friedel−Crafts alkylation through activation of the exocyclic double bond of 3 with an acid or an electrophile, followed by nucleophilic capture by the aromatic ring. However, no cyclization was observed and exocyclic olefin 5 was obtained as the major product (Scheme 1).8 The second report attempted an intramolecular radical Received: October 5, 2018 Published: December 9, 2018 173

DOI: 10.1021/acs.joc.8b02575 J. Org. Chem. 2019, 84, 173−180

The Journal of Organic Chemistry

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RESULTS AND DISCUSSION Our retrosynthetic analysis is illustrated in Scheme 3. The principal challenge embedded in this approach would be the enantioselective synthesis of a precursor with the L-gluco relative configuration, since L-glucose and its derivatives are not readily available from commercial sources. The target substrate for the reductive Heck cyclization 15 could be derived from an α-selective glycosylation reaction between phenol 16 and 3-amino-3-deoxy-α-L-glucoside derivatives 17. F-ring precursor 17 would be synthesized from diol 18, the one carbon homologue of 19. To prepare 19, readily available Darabinose 20 was chosen as the starting material to take advantage of the chirality within its structure, a strategy that was exploited in the Terashima synthesis of menogaril.10 Following literature precedent, epoxide 21 was synthesized in 5 steps from D-arabinose (Scheme 4).10,40 Nucelophilic ring-

Scheme 1. Previous Attempts at Generating the DEF-Ring System of Nogalamycin through Formation of a CGlycosidic Bond

cyclization of aryl bromide 6 onto an exocyclic 5,6′-olefin. In this example, direct reduction product 7 was obtained as the major product.24 Inspired by the application of the Heck cyclization to construct quaternary carbon centers,25−38 we were intrigued to explore its potential for construction of the DEF-ring system. In a recent Communication, we reported a model study of this novel reductive Heck cyclization approach (Scheme 2).39 The

Scheme 4. Attempt To Generate an F-Ring Nogalamine Precursor from Arabinose

Scheme 2. Construction of the DEF-Ring System of Nogalamycin via Reductive Heck Cyclization

opening of the epoxide was achieved with sodium azide,40 followed by bis-benzylation of the diol intermediate to give 22. Hydrolysis of 22 under acidic conditions led to hemiacetal 23. However, attempted Wittig olefination of 23 to provide terminal alkene 24 failed to give any desired product. IR analysis of the major reaction product revealed an unidentified terminal alkene lacking the azide group. This product was believed to arise from the facile elimination of the azide group under the basic Wittig olefination conditions.41 To avoid the problematic elimination side reaction, the azide 22 was reduced to the corresponding primary amine by LAH, and intermediate amine was then protected by the 2naphthylsulfonyl group to give 25 (Scheme 5).42 After hydrolysis and Wittig olefination, 26 was obtained in good yield without evidence of any elimination product(s). The alkenol 26 was oxidized to aldehyde 27 under the Parikh− Doering conditions43 and then transformed to the corresponding dimethoxy acetal. Dihydroxylation under the Upjohn

desired cyclization product was formed in good yield under the optimized conditions. Encouraged by the success of the model study, we then explored the construction of an authentic DEFring structure containing all of the functionality present in the bridging carbohydrate subunit (F-ring) of nogalamycin.

Scheme 3. Retrosynthetic Analysis for the Synthesis of the DEF-Ring System of Nogalamycin

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DOI: 10.1021/acs.joc.8b02575 J. Org. Chem. 2019, 84, 173−180

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The Journal of Organic Chemistry

The α-glycoside 32 was further deacetylated, and the resulting primary alcohol 34 was converted into iodide 35 (Scheme 6). However, attempted elimination of the iodide to

Scheme 5. Synthetic Routes Utilized for Preparation of FRing Glycosyl Donors

Scheme 6. Conversion of 32 into the Reductive Heck Cyclization Precursor

conditions44 resulted in isolation of a single diastereomer 28 in 74% yield after silica gel purification. The diol product stereochemistry was assigned according to literature precedent.45−47 The diol 28 was cyclized under acidic conditions and diacetylated to give 3-amino-3-deoxy-α-L-glucose derivative 29 as an anomeric mixture. Thioglycosylation of 29 gave thioglycoside 30 as pure α-anomer after chromatographic purification.48 A second potential glycosyl donor 31 was synthesized as an anomeric mixture via a selective deacetylation.49 Employing the glycosylation conditions reported by van der Marel, the desired α-glycoside 32 was obtained in 65% yield via thioglycoside 30 and phenol 16, with an anomeric ratio of 5:1 favoring the desired α anomer.50 Glycosylation of 30 activated by NIS/TMSOTf gave an unfavorable ratio of isolated products (1:2). Compounds 29 and 31 were also tested as glycosyl donors, activated either by TMSOTf51 or via the Mitsunobu conditions,52 respectively, but both gave an unfavorable product ratio along with a low yield of the desired α-anomer (Table 1).

form alkene 38 with DBU led to exclusive formation of 37, the intramolecular substitution product. Subjecting 35 to AgF in pyridine provided the same result.53 To avoid the intramolecular substitution, we decided to explore the utility of a selenoxide elimination reaction to install the desired exocyclic olefin in 38.54−56 Initial attempts to transform iodide 35 to selenide 36 still gave 37 as the major product under typical conditions for nucleophilic displacement by selenide anion (PhSeSePh/NaBH 4 /THF/EtOH 57 and PhSeH/Et 3 N/ THF58). Finally, we found that selenide displacement utilizing PhSeH and KOH in DMF gave the desired phenylselenide 36 in high yield. We noted, that it was critical to have excess phenylselenol present in the reaction mixture, relative to base, in order to suppress formation of the intramolecular nucleophilic displacement product 37. The selenide 36 was then oxidized to the corresponding selenoxide by NaIO4, followed by elimination in diisopropylamine/toluene mixture to give alkene 38 in good yield. With 38 in hand, reductive Heck cyclization was conducted under the optimized conditions identified in the model study (Scheme 7).39 The desired cyclization product 39 was isolated in 59% yield, along with the direct reduction product 40 isolated in 19% yield. Stoichiometric palladium catalysis gave a higher ratio of 39:40 (6:1), but the isolated yield of 39 (65%) only improved slightly compared to the catalytic version. In our earlier model study, (1-naphthyl)3P provided comparable yields of reductive Heck cyclization products. When (1naphthyl)3P was used, however, along with a stoichiometric palladium catalyst, a lower yield of 39 (34%) was obtained after isolation.

Table 1. Glycosylation Conditions Explored for Preparation of the DEF-Ring System Precursor

entry

sub

1

30

2 3 4

30 29 31

conditions Ph2SO, Tf2O, TTBP, 4 Å MS, DCM/Et2O, −78 °C to rt NIS, TMSOTf, 4 Å MS, DCM, −40 °C TMSOTf, 4 Å MS, DCM, 0 °C to rt ADDP, PBu3, 4 Å MS, THF, −78 °C to rt

% yielda (32,33)

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63, 13

CONCLUSION The reductive Heck cyclization approach has proven to be a viable way to construct the DEF-ring system in nogalamycin, with an efficiency comparable to that observed in our previously reported model system.39 In this example, we have successfully exploited the stereochemical preferences

25, 53 13, 43 20, 51

a

Isolated yields of 32 and 33, except in entry 3, which were determined by NMR. 175

DOI: 10.1021/acs.joc.8b02575 J. Org. Chem. 2019, 84, 173−180

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The Journal of Organic Chemistry

3.38 (td, J = 9.8, 5.2 Hz, 1H), 3.24−3.10 (m, 2H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 137.9, 137.6, 128.5, 128.4, 128.2, 128.1, 127.9, 127.8, 105.1, 79.8, 76.1, 74.6, 73.3, 67.5, 64.5, 57.0. IR (film, cm−1) υmax: 3032, 2868, 2105, 1455, 1267, 1079, 738, 698. HRMS-ESI (m/ z): [M + Na]+ Calcd for C20H23N3O4Na, 392.1586; found, 392.1581. Methyl 2,4-Di-O-benzyl-3-deoxy-3-(2-naphthylsulfonyl)aminoβ-D-xylopyranoside (25). Azide 22 (10.45 g, 28 mmol) was dissolved in THF (100 mL), and the solution was cooled to 0 °C. To the solution was added solid LiAlH4 (3.2 g, 84 mmol) in small portions, and the reaction was stirred at room temperature for 30 min. The reaction was diluted with ether and cooled back to 0 °C. To the mixture were added water (4 mL), 10% NaOH (4 mL), and then water (8 mL) again. The resulted suspension was dried by MgSO4, filtered through Celite, and concentrated to give the crude amine product as a thick colorless oil (9.71 g). The crude product was used for the next step without further purification. The crude amine product was dissolved in DCM (108 mL) and cooled to 0 °C. To the solution was added Et3N (10 mL, 72 mmol), followed by 2-naphthylsulfonyl chloride (9.7 g, 43 mmol) in small portions. The reaction was stirred at room temperature for 96 h and then washed with a mixture of 1 M NaOH (150 mL) and ice. The aqueous phase was further extracted with DCM (100 mL × 2). The combined organic phase was dried with MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 4:1, then hexane:EtOAc:DCM = 3:1:1 and 3:1:2) to give a solid, which was triturated by DCM:hexane to give 25 as a white solid (10.5 g, 71% for 2 steps). [α]26D: −18.5 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.43 (s, 1H), 7.97−7.82 (m, 3H), 7.77 (dd, J = 8.7, 1.7 Hz, 1H), 7.64 (ddd, J = 15.0, 13.7, 6.8 Hz, 2H), 7.28−7.19 (m, 5H), 7.14 (t, J = 7.3 Hz, 1H), 7.08 (t, J = 7.3 Hz, 2H), 6.91 (d, J = 7.2 Hz, 2H), 5.47 (d, J = 8.6 Hz, 1H), 4.56−4.43 (m, 3H), 4.26 (ABq, J = 12.0 Hz, 2H), 3.90 (dd, J = 12.6, 2.7 Hz, 1H), 3.74 (dt, J = 8.7, 4.3 Hz, 1H), 3.57 (dd, J = 12.6, 3.3 Hz, 1H), 3.47−3.40 (m, 1H), 3.38 (s, 3H), 3.05−2.92 (m, 1H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 137.8, 137.5, 137.2, 134.8, 132.1, 129.5, 129.2, 128.8, 128.3, 128.2, 128.1, 127.9, 127.9, 127.6, 127.6, 122.3, 101.0, 74.6, 74.4, 71.9, 71.6, 59.5, 55.7, 50.8. IR (film, cm−1) υmax: 3288, 3030, 2869, 1453, 1324, 1159, 1075, 747. HRMS-ESI 9m/z): [M + Na]+ Calcd for C30H31NO6SNa, 556.1770; found, 556.1744. N-((2S,3R,4S)-2,4-Bis(benzyloxy)-1-hydroxyhex-5-en-3-yl)naphthalene-2-sulfonamide (26). Compound 25 (6.43 g, 12 mmol) was suspended in AcOH (64 mL), followed by the addition of 4 M HCl (12.8 mL). The reaction was stirred at 80 °C for 45 min and then cooled back to room temperature. The mixture was azeotroped by toluene until the removal of all of the AcOH and water. The pale green solid obtained was first triturated by a mixture of toluene (20 mL) and hexane (20 mL). Filtration of the suspension gave a solid, which was further triturated by a mixture of EtOAc (9 mL) and hexane (18 mL) to give the hemiacetal product (4.85 g, 77%). A suspension of Ph3P+CH3Br− (22.19 g, 62 mmol) in THF (95 mL) was cooled to −78 °C, followed by dropwise addition of KHMDS in PhMe (0.5 M, 124 mL, 62 mmol). The mixture was stirred at room temperature for 40 min and cooled back to −78 °C. A solution of hemiacetal product from the previous step (4.96 g, 9.6 mmol) in THF (95 mL) was added, followed by a wash in THF (15 mL). The reaction was allowed to warm up to room temperature and stirred for 45 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (DCM:EtOAc = 100:0, then 100:3 and 100:4) to give 26 as a white wax (3.73 g, 75%). [α]26D: −14.5 (c 0.5, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.37 (s, 1H), 7.92−7.70 (m, 4H), 7.65−7.50 (m, 2H), 7.33−7.09 (m, 7H), 7.06−6.94 (m, 2H), 5.59−5.43 (m, 1H), 5.28 (d, J = 8.9 Hz, 1H), 5.07−5.00 (m, 2H), 4.47 (ABq, J = 11.6 Hz, 2H), 4.20 (ABq, J = 11.6 Hz, 2H), 3.84 (dd, J = 7.7, 5.2 Hz, 1H), 3.74−3.63 (m, 4H), 2.57 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 137.8, 137.7, 137.3, 134.9, 134.6, 131.9, 129.1, 129.0, 128.5, 128.3, 128.1, 128.0, 127.8, 127.7, 127.6 (2 C), 127.5, 127.3, 122.6, 119.7, 78.8, 78.2, 72.3, 70.1,

Scheme 7. Conditions for Construction of the DEF-Ring System via Reductive Heck Cyclization

dictated by the anomeric effect to facilitate construction of the bridged bicyclic DEF-ring system of nogalamycin in good yield with the desired absolute stereochemistry. These results have provided the foundation for additional effort directed at the synthesis of the full anthracycline core structure of nogalamycin. Results of these investigations will be reported in due course.

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EXPERIMENTAL SECTION

General Methods. Unless otherwise noted, all reactions were carried out in oven-dried glassware under an atmosphere of argon. Anhydrous solvents were bought from Aldrich in Sure/Seal bottles. All commercially available reagents were used as received. 1 H NMR and 13C NMR spectra were measured at 400 and 100 MHz, respectively. Chemical shifts are reported relative to the internal TMS standard or the solvent residue peak. Analytical thin layer chromatography (TLC) was performed using Whatman glass plates coated with a 0.25 mm thickness of silica gel containing PF 254 indicator, and compounds were visualized with UV light, cerium molybdate stain. Preparatory HPLC purifications (Phenomenex Luna normal phase column, 10 μ particle size, 100 Å pore size, 250 mm length × 22.0 mm diameter) were performed with an Agilent 1100 Series HPLC purification system. Flash chromatography purifications were performed using Silicycle 60 Å, 35−75 μm silica gel. ESI-HRMS were recorded with a Waters/Micromass LCT Classic time-of-flight mass spectrometer. Methyl 3-Azido-2,4-di-O-benzyl-3-deoxy-β-D-xylopyranoside (22). To a stirred solution of epoxide 21 (6.68 g, 46 mmol) in DMF (90 mL) were added NH4Cl (8.73 g, 160 mmol) and NaN3 (5.95 g, 92 mmol). The reaction mixture was heated at 95 °C for 23 h and then cooled to room temperature. The mixture was diluted with EtOAc (150 mL) and filtered through a pad of Celite (top) and silica (bottom). The filter cake was further washed with EtOAc (250 mL × 3). The filtrate was dried by MgSO4, concentrated, and then azeotroped with toluene to give the crude diol product as a pale yellow oil. To a stirred solution of the above crude diol product in DMF (60 mL) was added NaH (5.86 g, 60% suspension in oil, 147 mmol) at 0 °C. The stirring was continued at the same temperature for another 20 min before a dropwise addition of BnBr (16.3 mL, 137 mmoL). Then the reaction was warmed up to room temperature. After 1 h, the reaction was quenched with MeOH (20 mL), diluted with icy water, and extracted with DCM. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product, which was purified by flash chromatography (hexane:EtOAc = 30:1, then 20:1, 15:1, and 10:1) to give 22 as a white wax (14.73 g, 87% for 2 steps). [α]26D: −20.2 (c 0.8, acetone). Lit. [α]15D: −21.2 (c 0.82, acetone).40 1H NMR (CDCl3, 400 MHz, δ): 7.43−7.25 (m, 10H), 4.73 (ABq, J = 11.0 Hz, 2H), 4.71 (ABq, J = 10.8 Hz, 2H), 4.23 (d, J = 7.5 Hz, 1H), 3.92 (dd, J = 11.6, 5.1 Hz, 1H), 3.52 (s, 3H), 3.50 (t, J = 9.6 Hz, 1H), 176

DOI: 10.1021/acs.joc.8b02575 J. Org. Chem. 2019, 84, 173−180

Article

The Journal of Organic Chemistry 60.5, 56.9. IR (film, cm−1) υmax: 3518, 3287, 3030, 2870, 1453, 1156, 1074, 746. HRMS-ESI (m/z): [M + Na]+ Calcd for C30H31NO5SNa, 540.1821; found, 540.1794. N-((2S,3R,4S)-2,4-Bis(benzyloxy)-1-oxohex-5-en-3-yl)naphthalene-2-sulfonamide (27). To a stirred solution of alcohol 26 (1.86 g, 3.6 mmol) in DCM (28 mL) were added DMSO (2.56 mL, 36 mmol) and iPr2NEt (2.51 mL, 14.4 mmol) in an ice bath. Then, Py·SO3 (1.72 g, 10.8 mmol) was added in small portions. The reaction was stirred at 0 °C for 1 h before being diluted with DCM and washed with brine. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 5:1, then 4:1) to give the aldehyde 27 as a colorless oil (1.75 g, 95%). [α]26D: + 10.5 (c 0.5, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 9.53 (s, 1H), 8.34 (s, 1H), 7.96−7.82 (m, 3H), 7.74 (dd, J = 8.7, 1.7 Hz, 1H), 7.68−7.55 (m, 2H), 7.24 (tt, J = 7.4, 5.7 Hz, 9H), 5.46 (ddd, J = 17.5, 10.3, 7.4 Hz, 1H), 5.39 (d, J = 9.0 Hz, 1H), 5.13 (d, J = 17.2 Hz, 1H), 5.00 (d, J = 10.4 Hz, 1H), 4.52 (ABq, J = 11.7 Hz, 2H), 4.30 (ABq, J = 11.3 Hz, 2H),4.10 (dd, J = 7.2, 2.3 Hz, 1H), 3.84 (d, J = 4.7 Hz, 1H), 3.79−3.69 (m, 1H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 200.6, 136.9, 136.7, 134.7, 133.5, 131.9, 129.3, 129.2, 128.8, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.8, 127.5, 122.4, 119.8, 81.4, 76.9, 72.9, 70.5, 58.7. IR (film, cm−1) υmax: 3285, 3060, 2867, 1729, 1454, 1334, 1160, 748. HRMS-ESI (m/z): [M + Na]+ Calcd for C30H29NO5SNa, 538.1664; found, 538.1644. N-((2S,3R,4R,5S)-2,4-Bis(benzyloxy)-5,6-dihydroxy-1,1-dimethoxyhexan-3-yl)naph- thalene-2-sulfonamide (28). Aldehyde 27 (1.75 g, 3.4 mmol) was dissolved in HC(OMe)3 (29 mL). To this solution was added TsOH·H2O (0.064 g, 0.34 mmol), and the reaction was stirred at room temperature for 30 min. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase was dried by MgSO4, filtered, and concentrated to give the dimethylacetal product as a colorless oil (2.07 g), which was used for the next step without further purification. Dimethylacetal product (2.07 g) from the previous step was dissolved in a mixture of acetone (32 mL) and water (8 mL). To the solution were added NMO (0.8 g, 6.8 mmol) and OsO4 (2.5% in tBuOH, 2.66 mL, 0.17 mmol). The reaction was stirred at room temperature for 24 h before being quenched by 5% Na2S2O3 (100 mL). The mixture was extracted with EtOAc, and the organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 2:1, then 1:1) to give the diol 28 as a clear oil (1.56 g, 77% for 2 steps from the aldehyde). [α]26D: +1.5 (c 0.5, CHCl3). 1 H NMR (CDCl3, 400 MHz, δ): 8.43 (d, J = 1.0 Hz, 1H), 7.91 (dd, J = 16.2, 7.5 Hz, 3H), 7.80 (dd, J = 8.7, 1.8 Hz, 1H), 7.70−7.55 (m, 2H), 7.30−7.20 (m, 6H), 7.19−7.07 (m, 4H), 5.94 (d, J = 9.7 Hz, 1H), 4.53 (ABq, J = 11.1 Hz, 2H), 4.36 (ABq, J = 11.5 Hz, 2H), 4.18 (d, J = 7.4 Hz, 1H), 3.98 (dt, J = 9.7, 2.9 Hz, 1H), 3.78 (dt, J = 8.4, 4.2 Hz, 1H), 3.66 (d, J = 11.1 Hz, 1H), 3.42 (dd, J = 7.3, 2.5 Hz, 2H), 3.39−3.30 (m, 2H), 3.26 (s, 3H), 3.18 (s, 3H), 1.98 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 137.5, 137.3, 137.3, 134.7, 132.0, 129.4, 129.1, 128.8, 128.5, 128.3 (2 C), 128.0, 127.9, 127.8, 127.7, 127.7, 122.6, 105.9, 77.2, 76.6, 73.9, 72.7, 71.7, 63.7, 56.4, 55.1, 53.3. IR (film, cm−1) υmax: 3473, 3320, 3030, 2935, 1454, 1330, 1074, 748. HRMS-ESI (m/z): [M + Na]+ Calcd for C32H37NO8SNa, 618.2138; found, 618.2111. Acetyl 6-O-Acetyl-2,4-di-O-benzyl-3-deoxy-3-(2naphthylsulfonyl)amino-L-gluco- pyranoside (29) and Phenyl 6O-Acetyl-2,4-di-O-benzyl-3-deoxy-3-(2-naphthyl sulfonyl)amino-1thio-α-L-glucopyranoside (30). Diol 28 (1.55 g, 2.6 mmol) was dissolved in 80% AcOH (45 mL), and the reaction was stirred at 80 °C for 2 h. The mixture was concentrated and then azeotroped with toluene to give an colorless oil (1.4 g) as the crude 2,4-di-O-benzyl-3deoxy-3-(2-naphthyl)amino-L-glucopyranoside product. The crude product was used for the next step without further purification. To a solution of the crude product from the previous step in DCM (90 mL) were added pyridine (3.67 mL, 46 mmol) and Ac2O (2.65 mL, 28 mmol) in an ice bath. The reaction was stirred at room temperature for 18 h before being diluted with DCM. The mixture

was washed with saturated aqueous NaHCO3. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (DCM:EtOAc = 100:2) to give anomeric glycosyl acetate 29 as a white wax (1.29 g, 80% for 2 steps). To a mixture of 29 (0.4 g, 0.63 mmol) and powdered 4 Å molecular sieves (2.6 g) was added DCE (15 mL). Then, PhSTMS (0.49 mL, 2.57 mmol) and TMSOTf (0.24 mL, 1.26 mmol) were added. The reaction was stirred at 78 °C for 1.5 h before being cooled to room temperature and filtrated through Celite. To the filtrate was added ice, followed by saturated aqueous NaHCO3. The mixture was extracted with DCM, and the organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (DCM:EtOAc = 100:2) to give 30 as a white wax (0.387 g, 90%). [α]26D: −161.3 (c 2.0, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.47 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.85−7.77 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.59 (dt, J = 15.0, 6.3 Hz, 2H), 7.37 (dd, J = 6.5, 3.1 Hz, 2H), 7.29−7.17 (m, 8H), 7.13 (t, J = 7.4 Hz, 2H), 6.94 (d, J = 7.2 Hz, 2H), 5.53 (d, J = 5.2 Hz, 1H), 4.86 (d, J = 10.6 Hz, 1H), 4.66 (d, J = 8.0 Hz, 1H), 4.47−4.38 (m, 2H), 4.24−4.11 (m, 2H), 4.16 (ABq, J = 11.7 Hz, 2H), 3.94 (dd, J = 17.7, 8.4 Hz, 1H), 3.62 (dd, J = 9.7, 5.3 Hz, 1H), 3.48−3.40 (m, 1H), 1.95 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 170.5, 138.1, 137.1, 136.7, 134.6, 133.2, 132.1, 132.0, 129.2, 128.9, 128.9, 128.5, 128.4, 128.4, 128.2, 128.0, 127.8, 127.8, 127.4, 127.3, 122.7, 86.4, 77.1, 76.5, 74.4, 71.6, 69.9, 63.1, 57.6, 20.7. IR (film, cm−1) υmax: 3288, 3059, 2907, 1739, 1454, 1156, 1076, 743. HRMS-ESI (m/z): [M + Na]+ Calcd for C38H37NO7S2Na, 706.1909; found, 706.1922. 2-Bromo-4-methoxyphenyl 6-O-Acetyl-2,4-di-O-benzyl-3-deoxy3-(2-naphthyl sulfonyl)amino-α-L-glucopyranoside (32) and 2Bromo-4-methoxyphenyl 6-O-Acetyl-2,4-di-O-benzyl-3-deoxy-3(2-naphthylsulfonyl)amino-β-L-glucopyranoside (33). A mixture of thioglycoside 30 (75 mg, 0.11 mmol), TTBP (153 mg, 0.44 mmol), and diphenylsulfoxide (109 mg, 0.39 mmol) was azeotroped by toluene 3 times. Then, DCM (3.9 mL), ether (3.9 mL), and freshly activated 4 Å molecular sieves (1.6 g) were added. The mixture was cooled to −78 °C, and Tf2O (45 μL, 0.26 mmol) was added dropwise. Ten minutes later, phenol 16 (88 mg, 0.44 mmol) (azeotroped by toluene 3 times) in DCM (3 mL) was added dropwise. The reaction was allowed to warm up to room temperature overnight, diluted with DCM, and filtered. The filtrate was washed with saturated aqueous NaHCO3, and the organic phase was dried over MgSO4. After solvent evaporation, the residue was purified by flash chromatography (hexane:EtOAc = 3:1, then 2:1 and 1:1) to give the β glycoside 33 (10.6 mg, 13%) as a colorless oil and the α glycoside 32 (53 mg, 63%) as a pale yellow oil. The α glycoside 32: [α]26D: −138.5 (c 1.04, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.55 (s, 1H), 7.93−7.84 (m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.58 (td, J = 13.5, 6.2 Hz, 2H), 7.41 (d, J = 6.5 Hz, 2H), 7.37−7.26 (m, 3H), 7.11 (t, J = 7.3 Hz, 1H), 7.05−7.01 (m, 3H), 6.87−6.76 (m, 3H), 6.64 (dd, J = 9.0, 3.0 Hz, 1H), 5.16 (d, J = 3.1 Hz, 1H), 4.84 (d, J = 7.5 Hz, 1H), 4.83 (ABq, J = 10.3 Hz,2H), 4.27−4.13 (m, 3H), 4.09− 4.00 (m, 2H), 3.98 (d, J = 9.8 Hz, 1H), 3.72 (s, 3H), 3.52 (t, J = 9.7 Hz, 1H), 3.37 (dd, J = 10.6, 3.1 Hz, 1H), 1.99 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 170.5, 155.1, 147.2, 137.5, 137.2, 137.0, 134.7, 132.0, 129.3, 128.9, 128.7, 128.5, 128.4, 128.2, 128.1, 127.8, 127.7, 127.7, 127.2, 123.2, 118.5, 116.3, 113.7, 113.1, 95.4, 77.1, 76.6, 75.1, 72.1, 70.2, 62.6, 57.1, 55.8, 20.8. IR (film, cm−1) υmax: 3283, 3033, 2934, 1740, 1491, 1216, 1075, 809. HRMS-ESI (m/z): [M + Na]+ Calcd for C39H38NO9SBrNa, 798.1348; found, 798.1327. The β glycoside 33: [α]26D: +23 (c 0.2, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.56 (s, 1H), 7.94−7.86 (m, 4H), 7.67−7.58 (m, 2H), 7.25−7.16 (m, 5H), 7.14−7.12 (m, 2H), 7.09 (d, J = 2.9 Hz, 1H), 7.06−7.00 (m, 2H), 6.99 (d, J = 9.1 Hz, 1H), 6.77 (dd, J = 9.1, 3.0 Hz, 1H), 5.78 (d, J = 9.9 Hz, 1H), 5.28 (d, J = 3.5 Hz, 1H), 4.62 (ABq, J = 10.9 Hz, 2H), 4.42−4.24 (m, 3H), 4.04 (d, J = 10.2 Hz, 2H), 3.99−3.89 (m, 2H), 3.75 (s, 3H), 3.56−3.51 (m, 1H), 1.67 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 170.5, 155.2, 146.5, 137.9, 137.1, 136.9, 134.8, 132.1, 129.7, 129.3, 128.9, 128.5, 128.3, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 122.4, 118.4, 116.6, 113.9, 177

DOI: 10.1021/acs.joc.8b02575 J. Org. Chem. 2019, 84, 173−180

Article

The Journal of Organic Chemistry

noside (36). Benzeneselenol (112 μL, 1.04 mmoL) was dissolved in DMF (2 mL), and the solution was cooled in an ice bath. To the solution was added 1 M KOH (0.8 mL, 0.78 mmol) dropwise. Ten minutes later, iodide 35 (112 mg, 0.13 mmol) in DMF (1.5 mL, followed by 1 mL wash twice) was added. The reaction was then stirred at room temperature for 1.5 h before being diluted with DCM. The mixture was washed with saturated aqueous NH4Cl. The organic phase was dried over MgSO4, filtered, and evaporated to give a residue, which was purified by flash chromatography (DCM:EtOAc = 100:0, then 100:2) to give the product 36 (103 mg, 90%) as a white solid. [α]26D: −149.1 (c 0.44, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.55 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.65−7.49 (m, 3H), 7.38−7.22 (m, 7H), 7.18−7.07 (m, 4H), 7.00 (t, J = 7.3 Hz, 2H), 6.90 (d, J = 9.0 Hz, 1H), 6.81 (d, J = 7.4 Hz, 2H), 6.66 (dd, J = 9.0, 2.6 Hz, 1H), 5.19 (d, J = 7.6 Hz, 1H), 5.10 (d, J = 10.5 Hz, 1H), 4.81 (ABq, J = 10.4 Hz, 2H), 4.22−4.15 (m, 1H), 4.08−3.98 (m, 2H), 3.72 (s, 3H), 3.45 (t, J = 9.5 Hz, 1H), 3.37 (dd, J = 10.6, 2.6 Hz, 1H), 3.24−3.21 (m, 1H), 2.98−2.82 (m, 2H). 13 C{1H} NMR (CDCl3, 100 MHz, δ): 155.0, 147.2, 137.6, 137.4, 137.0, 134.7, 132.4, 132.0, 130.4, 129.3, 129.0, 128.8, 128.8, 128.7, 128.4, 128.4, 128.1, 127.9, 127.9, 127.7, 127.1, 126.8, 123.2, 118.4, 116.7, 113.7, 113.0, 95.3, 80.5, 77.3, 75.0, 72.0, 71.4, 56.9, 55.8, 29.9. IR (film, cm−1) υmax: 3271, 3054, 2921, 1574, 1474, 1020, 733. HRMS-ESI (m/z): [M + Na]+ Calcd for C43H40NO7SSeBrNa, 896.0772; found, 896.0755. (1S,3S,4S,5R,8R)-4,8-Bis(benzyloxy)-3-(2-bromo-4-methoxyphenoxy)-6-(naphthalen-2- ylsulfonyl)-2-oxa-6-azabicyclo[3.2.1]octane (37). Iodide 35 (10 mg, 0.012 mmol) was dissolved in MeCN (1 mL), and DBU (50 μL, 0.312 mmol) was added. The mixture was stirred at room temperature for 20 min before being stirred at 40 °C overnight and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc = 5:2) to give the product 37 (7.7 mg, 91%) as a colorless oil. [α]26D: −22 (c 0.2, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.30 (s, 1H), 7.93 (dd, J = 20.4, 7.9 Hz, 2H), 7.83 (d, J = 8.7 Hz, 1H), 7.73−7.63 (m, 2H), 7.60 (dd, J = 8.6, 1.7 Hz, 1H), 7.47 (d, J = 6.8 Hz, 2H), 7.40−7.26 (m, 4H), 7.14 (t, J = 7.1 Hz, 1H), 7.07−7.01 (m, 5H), 6.76 (dd, J = 9.0, 3.0 Hz, 1H), 5.40 (d, J = 2.8 Hz, 1H), 5.06 (ABq, J = 11.6 Hz, 2H), 4.47 (ABq, J = 12.1 Hz, 2H), 4.39 (s, 1H), 4.36 (t, J = 4.4 Hz, 1H), 4.19−4.10 (m, 1H), 3.77 (s, 3H), 3.66 (d, J = 11.7 Hz, 1H), 3.30 (dd, J = 11.7, 3.5 Hz, 1H), 2.96 (dd, J = 4.4, 2.1 Hz, 1H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 155.9, 148.5, 138.6, 137.1, 135.0, 134.4, 132.1, 129.9, 129.3, 129.1, 128.5, 128.3, 128.2, 128.2, 128.1, 128.0, 127.9, 127.6, 127.6, 121.7, 120.8, 118.2, 114.3, 113.9, 98.2, 76.4, 75.5, 74.4, 74.1, 72.0, 55.8, 55.5, 48.8. IR (film, cm−1) υmax: 3052, 2914, 1501, 1152, 1024, 903. HRMS-ESI (m/z): [M + Na]+ Calcd for C37H34NO7SBrNa, 738.1137; found, 738.1155. 2-Bromo-4-methoxyphenyl 2,4-Di-O-benzyl-3-deoxy-3-(2naphthylsulfonyl)amino-α-L-xylo-hex-5-enopyranoside (38). To a mixture of selenide 36 (34 mg, 0.039 mmol) in DCM (4 mL), MeOH (4 mL), and water (1.2 mL) were added NaHCO3 (32 mg, 0.39 mmol) and NaIO4 (250 mg, 1.17 mmol) in an ice bath. The reaction was stirred at room temperature for 80 min and diluted with DCM. The mixture was washed with saturated aqueous NaHCO3, and the organic phase was separated and dried over MgSO4. Solvent evaporation gave the crude selenoxide product as colorless oil, which was used directly for the next step. The selenoxide was dissolved in a mixture of toluene (6 mL) and iPr2NH (4 mL). The reaction was stirred at 90 °C for 4.5 h and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc = 3:1, then 2:1, buffered with 1% Et3N) to give alkene 38 as a white wax (24.7 mg, 89% for 2 steps). [α]26D: −105.9 (c 0.5, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.51 (d, J = 1.4 Hz, 1H), 7.86 (dd, J = 8.7, 1.9 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.58−7.50 (m, 2H), 7.39−7.26 (m, 5H), 7.13−7.06 (m, 1H), 7.08−7.04 (m, 2H), 7.02 (d, J = 3.0 Hz, 1H), 6.97−6.90 (m, 3H), 6.69 (dd, J = 9.0, 3.0 Hz, 1H), 5.23 (d, J = 3.0 Hz, 1H), 4.80 (s, 1H), 4.74−4.66 (m, 2H), 4.54 (t, J = 1.4 Hz, 1H), 4.24−4.13 (m, 3H), 3.90 (d, J = 9.7 Hz, 1H), 3.72 (s, 3H), 3.55 (dd, J = 10.3, 3.0 Hz, 1H). 13C{1H} NMR (CDCl3, 100 MHz, δ):

112.4, 97.7, 78.2, 77.2, 76.1, 73.6, 72.0, 62.2, 58.4, 55.9, 20.4. IR (film, cm−1) υmax: 3233, 2939, 1477, 1053, 735. HRMS-ESI (m/z): [M + Na]+ Calcd for C39H38NO9SBrNa, 798.1348; found, 798.1351. Glycosylation via the Mitsunobe Conditions. To a solution of 29 (200 mg, 0.32 mmol) in DMF (4.6 mL) was added hydrazine acetate (35 mg, 0.38 mmol) at room temperature. The reaction was stirred for 4 h before being diluted by EtOAc and washed by water three times. The organic phase was dried by MgSO4, filtered, and concentrated to give the crude product of anomeric 31 (170 mg, 91%) as a white wax, which was used directly for the next step. Compound 31 (14 mg, 0.024 mmol), phenol 16 (19 mg, 0.096 mmol), PBu3 (18 μL, 0.072 mmol), and powdered 4 Å molecular sieves (0.2 g) were mixed in THF (1 mL) and stirred at room temperature for 5 min. Then the mixture was cooled to −78 °C, and ADDP (18 mg, 0.072 mmol) in THF (0.5 mL) was added dropwise. The reaction was allowed to warm up to room temperature overnight, diluted with DCM, and filtered. The filtrate was washed with saturated aqueous NaHCO3, and the organic phase was dried over MgSO4. After solvent evaporation, the residue was purified by flash chromatography (hexane:EtOAc = 3:1, then 2:1, 1:1) to give the β glycoside 33 (9.4 mg, 51%) as a colorless oil and the α glycoside 32 (3.6 mg, 20%) as a pale yellow oil. 2-Bromo-4-methoxyphenyl 2,4-di-O-Benzyl-3-deoxy-3-(2naphthylsulfonyl)amino-α- L-gluco- pyranoside (34). To a solution of α glycoside 32 (134 mg, 0.17 mmol) in THF (4 mL) and MeOH (4 mL) was added NaOMe (47 mg, 0.85 mmol) in an ice bath. The reaction was stirred at room temperature for 3 h before being quenched with saturated aqueous NH4Cl. The mixture was extracted with DCM, and the organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 2:1, then 1:1) to give 34 as a white wax (108 mg, 85%). [α]26D: −134 (c 1.04, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.55 (s, 1H), 7.88 (dd, J = 10.7, 3.8 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.65−7.49 (m, 3H), 7.41 (d, J = 6.3 Hz, 2H), 7.36−7.26 (m, 3H), 7.09 (t, J = 7.3 Hz, 1H), 7.02−6.98 (m, 3H), 6.83 (d, J = 7.4 Hz, 2H), 6.77 (d, J = 9.1 Hz, 1H), 6.63 (dd, J = 9.0, 2.9 Hz, 1H), 5.15 (d, J = 3.0 Hz, 1H), 5.12 (d, J = 7.7 Hz, 1H), 4.85 (ABq, J = 10.6 Hz, 2H), 4.24−4.17 (m, 1H), 4.07 (s, 2H), 3.81 (d, J = 9.8 Hz, 1H), 3.75−3.62 (m, 4H), 3.58 (t, J = 9.8 Hz, 1H), 3.34 (dd, J = 10.6, 3.1 Hz, 1H), 1.50 (t, J = 4 Hz, 1H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 155.0, 147.2, 137.7, 137.5, 137.1, 134.7, 132.0, 129.3, 128.8, 128.7, 128.5, 128.3, 128.1, 128.0, 127.8, 127.7, 127.7, 127.1, 123.2, 118.5, 116.2, 113.7, 113.1, 95.5, 77.3, 75.9, 74.8, 72.3, 72.1, 61.3, 56.9, 55.8. IR (film, cm−1) υmax: 3250, 3070, 2907, 1503, 1413, 1203, 1071, 820. HRMS-ESI (m/z): [M + Na]+ Calcd for C37H36NO8SBrNa, 756.1243; found, 756.1264. 2-Bromo-4-methoxyphenyl 2,4-di-O-Benzyl-6-deoxy-6-iodo-3deoxy-3-(2-naphthyl sulfonyl)amino-α-L-gluco-pyranoside (35). To a solution of PPh3 (232 mg, 0.89 mmol) and imidazole (100 mg, 1.47 mmol) in DCM (8 mL) was added I2 (187 mg, 0.74 mmol). Ten minutes later, alcohol 34 (108 mg, 0.15 mmol) in DCM (3 mL, followed by 2 mL wash twice) was added. The reaction was stirred at 35 °C for 18 h and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc = 2:1, then 1:1) to give the iodide 35 as a clear oil (112 mg, 90%). [α]26D: −127.6 (c 0.9, CHCl3). 1 H NMR (CDCl3, 400 MHz, δ): 8.56 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.65−7.50 (m, 3H), 7.45 (d, J = 6.7 Hz, 2H), 7.36−7.28 (m, 3H), 7.08 (t, J = 7.4 Hz, 1H),7.00−6.96 (m, 3H), 6.86 (d, J = 9.1 Hz, 1H), 6.80 (d, J = 7.3 Hz, 2H), 6.64 (dd, J = 9.0, 2.9 Hz, 1H), 5.29−5.25 (m, 2H), 5.15 (d, J = 2.6 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 4.26−4.19 (m, 1H), 4.07 (s, 2H), 3.71 (s, 3H), 3.59−3.49 (m, 1H), 3.46−3.29 (m, 4H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 155.1, 147.2, 137.4, 137.4, 137.0, 134.7, 132.0, 129.3, 128.9, 128.9, 128.7, 128.5, 128.4, 128.1, 128.1, 127.9, 127.7, 127.2, 123.2, 118.5, 116.9, 113.7, 113.0, 95.5, 81.0, 77.4, 75.7, 72.2, 70.4, 56.6, 55.8, 7.7. IR (film, cm−1) υmax: 3275, 2925, 1490, 1155, 1076, 811. HRMSESI (m/z): [M + Na]+ Calcd for C37H35NO7SBrINa, 866.0260; found, 866.0264. 2-Bromo-4-methoxyphenyl 2,4-di-O-Benzyl-3-deoxy-3-(2naphthylsulfonyl)amino-6- deoxy-6-phenylseleno-α-L-gluco-pyra178

DOI: 10.1021/acs.joc.8b02575 J. Org. Chem. 2019, 84, 173−180

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155.1, 152.1, 146.9, 137.7, 137.4, 137.1, 134.7, 132.0, 129.3, 128.8, 128.7, 128.4, 128.2, 128.2, 127.8, 127.7, 127.7, 127.1, 123.0, 118.5, 116.8, 113.6, 113.2, 98.4, 95.6, 77.2, 77.2, 73.4, 72.3, 56.7, 55.8. IR (film, cm−1) υmax: 3279, 3054, 2925, 1664, 1492, 1156, 907. HRMSESI (m/z): [M + Na]+ Calcd for C37H34NO7SBrNa, 738.1137; found, 738.1122. (2S,3S,4R,5R,6S)-4-N-(2-Naphthylsulfonyl)amino-3,5-dibenzyloxy-6-methyl-8-meth-oxy-3,4,5,6-tetrahydro-2,6-epoxy-2H-1-benzoxocin (39) and 4-Methoxyphenyl 2,4-Di-O-benzyl-3-deoxy-3-(2naphthylsulfonyl)amino-α-L-xylo-hex-5-enopyranoside (40). Alkene 38 (34 mg, 0.048 mmol), Pd2(dba)3 (4.4 mg, 0.0048 mmol), (o-Tol)3P (11.6 mg, 0.038 mmol), and HCOONa (6.5 mg, 0.096 mmol) were weighed into a 10 mL round-bottom flask. DMF (1.8 mL, degassed by bubbling with Ar for 15 min) was added. The flask was evacuated under vacuum for 30 s, and Ar was then introduced. This procedure was repeated 3 times. Then, the reaction was stirred in a 90 °C oil bath for 15 h and cooled to room temperature. The reaction mixture was diluted with EtOAc, filtrated through silica and concentrated. The residue was purified by flash chromatography (DCM:EtOAc = 100:0, then 100:2) to give an inseparable mixture of 39 and 40. This mixture was further purified by normal phase HPLC (DCM:EtOAc = 98.5:1.5) to give 39 (17.9 mg, 59%) and 40 (5.8 mg, 19%). 39: Colorless oil. [α]26D: −66 (c 0.25, CHCl3). 1H NMR (CDCl3, 400 MHz, δ): 8.27 (s, 1H), 7.75−7.66 (m, 3H), 7.58−7.48 (m, 3H), 7.26−7.16 (m, 8H), 6.99−6.97 (m, 2H), 6.79−6.74 (m, 2H), 6.54 (d, J = 2.4 Hz, 1H), 5.41 (d, J = 3.6 Hz, 1H), 4.75 (ABq, J = 11.2 Hz, 2H), 4.58 (d, J = 7.8 Hz, 1H), 4.20 (ABq, J = 11.8 Hz, 2H), 3.64 (s, 3H), 3.55 (dd, J = 10.3, 3.6 Hz, 1 H), 3.53 (d, J = 9.8 Hz, 1 H), 3.39 (td, J = 10.1, 7.5 Hz, 1H), 1.51 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz, δ): 153.1, 144.2, 138.4, 137.8, 137.2, 134.6, 131.9, 129.2, 128.9, 128.4, 128.3, 128.3, 128.0, 127.8, 127.7, 127.6, 127.5, 127.2, 122.9, 122.6, 116.2, 115.5, 111.8, 91.8, 84.1, 78.6, 75.7, 75.1, 71.3, 58.0, 55.5, 23.7. IR (film, cm−1) υmax: 3247, 3050, 2950, 1503, 1208, 1094, 826, 751. HRMS-ESI (m/z): [M + Na]+ Calcd for C37H35NO7SNa, 660.2032; found, 660.2020. 40: White wax. [α]26D: −102 (c 0.1, DCM). 1H NMR (CDCl3, 400 MHz, δ): 8.49 (s, 1H), 7.89−7.83 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.60−7.51 (m, 2H), 7.25−7.10 (m, 8H), 7.01 (d, J = 7.4 Hz, 2H), 6.84 (ABq, J = 9.0 Hz, 4H), 5.26 (d, J = 3.2 Hz, 1H), 4.79 (s, 1H), 4.62 (d, J = 7.1 Hz, 1H), 4.59(ABq, J = 11.3 Hz, 2H), 4.58 (s, 1H), 4.27 (ABq, J = 12 Hz, 2H), 4.17 (td, J = 10.1, 7.1 Hz, 1H), 3.85 (d, J = 10.1 Hz, 1H), 3.76 (s, 3H), 3.56 (dd, J = 10.3, 3.3 Hz, 1H). 13 C{1H} NMR (CDCl3, 100 MHz, δ):155.2, 152.2, 150.4, 138.5, 137.2, 137.1, 134.6, 132.0, 129.2, 128.9, 128.41, 128.38, 128.36, 128.2, 128.0, 127.9, 127.84, 127.81, 127.2, 122.9, 118.3, 114.4, 98.4, 95.9, 77.1, 77.0, 73.2, 72.3, 57.2, 55.6. IR (film, cm−1) υmax: 3294, 3076, 2887, 1494, 1340, 1144, 913. HRMS-ESI (m/z): [M + Na]+ Calcd for C37H35NO7SNa, 660.2032; found, 660.2052.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02575.

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REFERENCES

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DOI: 10.1021/acs.joc.8b02575 J. Org. Chem. 2019, 84, 173−180

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The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.8b02575 J. Org. Chem. 2019, 84, 173−180