Synthesis of C-Glycoinositols from C-Glycosylcrotylstannanes - The

May 22, 2018 - A strategy for the synthesis of C-pseudodisaccharides that centers on the reaction of a C-linked crotyltin and a substituted pent-4-ena...
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Article Cite This: J. Org. Chem. 2018, 83, 6534−6540

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Synthesis of C‑Glycoinositols from C‑Glycosylcrotylstannanes Ahmad S. Altiti and David R. Mootoo* Department of Chemistry, Hunter College, 695 Park Avenue, New York, New York 10065, United States The Graduate Center, CUNY, 365 Fifth Avenue, New York, New York 10016, United States

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ABSTRACT: A strategy for the synthesis of C-pseudodisaccharides that centers on the reaction of a C-linked crotyltin and a substituted pent-4-enal and a ring-closing metathesis−alkene dihydroxylation sequence on the derived crotylation products is illustrated in the preparation of analogues of the insulin modulatory inositol galactosamine-β-(1 → 4)-3-O-methyl-D-chiro-inositol (β-INS-2). The modularity of this approach and versatility of the pivotal crotylation products make this a potentially general methodology for diverse libraries of C-glycoinositols.

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INTRODUCTION Inositol hexosamines (IHs) have attracted attention as leads to antidiabetic therapies because of their ability to activate phosphatases involved in glucose metabolism (Scheme 1).1−4

basis of this effect, we have been interested in using Cglycosides of INS-2 as conformational probes.11,12 In this context, C-INS-2 3 was shown to activate PDHP comparable to INS-2 but failed to activate PP2Cα, which may be due to the greater flexibility of the intersaccharide linkage in the Cglycoside. For a closer examination of the binding of the inositol segment of these INS-2 analogues we sought C-glycosyl inositols with inositol modifications. Our recently reported crotylation methodology for glycomimetics appeared wellsuited to such structures.13,14 Given the implication of IHs and IH containing glycans in other cellular and disease pathways, including pathogen infection and virulence, this methodology is relevant to other areas of glycobiology research.15−19 Herein, we illustrate its application to C-glycosides of INS-2. The crotylation strategy centers on the reaction of C-glycosyl crotylating agents with relatively simple oxygenated alkenals to give products that can be rapidly fashioned into glycoinositol analogues with diverse inositol ring substitutes. Noteworthy features of this strategy are easy access to the crotyltin and aldehyde precursors, modularity of the synthetic plan, and versatility of the crotylation products.

Scheme 1. Crotylation Path to Inositol Hexosamine Mimetics

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RESULTS AND DISCUSSION While other crotylating agents are conceivable, tin-based reagents were chosen because of their ease of preparation and stability.20,21 The requisite C-glycosyl crotyltin 10 was prepared following an established protocol on a xanthate precursor (Scheme 2).22 Thus, the 2-phthalimido-β-C-allyl glycoside 823 was transformed in 72% yield to the E/Z mixture of allylic alcohols 9 via the cross-metathesis (CM) with the bis tert-butyldimethylsilyl ether of (Z)-1,4-but-2-enediol and desilylation of the product. Thermal rearrangement on the

Galactosyamino and glucosylamino glycosides of inositols 1 with varying stereochemistry have been examined.5−10 One of the more well-known analogues is galactosamine-β-(1 → 4)-3O-methyl-D-chiro-inositol (INS-2) 2, which is reported to be both insulin-mimetic and insulin-sensitizing in diabetic rats. This activity was attributed to allosteric activation of pyruvate dehydrogenase phosphatase (PDHP) and protein phosphatase 2Cα (PP2Cα). Toward the understanding of the molecular © 2018 American Chemical Society

Received: April 4, 2018 Published: May 22, 2018 6534

DOI: 10.1021/acs.joc.8b00845 J. Org. Chem. 2018, 83, 6534−6540

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The Journal of Organic Chemistry

Scheme 4. Synthesis of Inositol Ring Analogues of C-INS-2

Scheme 2. Synthesis of Crotyltin 10

xanthate derivative of 924 and in situ treatment of the resulting allyl dithiocarbonate with Bu3SnH in the presence of AIBN gave crotyltin 10 as a 2:1 mixture of E/Z isomers. This material was purified using standard extraction and chromatography procedures and could be stored at −4 °C for several months. Aldehyde 11, the partner for crotyltin 10, was prepared from 25 D-lyxose via a known synthesis (Scheme 3). For the Scheme 3. Reaction of Crotyltin 10 and Aldehyde 11

a

crotylation reaction, E/Z-10 was added to a preincubated mixture of 11 and BF3·OEt2 in dichloromethane at −78 °C. A chromatographically inseparable mixture of crotylation products was obtained. For separation, this mixture was converted to the acetate derivatives 12 (27%) and 13 (54%). The stereochemistry of these products was deduced from NMR analysis of subsequent cyclic derivatives (vide infra), which also indicated that epimerization at the α-carbon in the aldehyde during the crotylation reaction was not in play. The exclusive production of syn diastereomers with respect to the newly formed C−C bond in the crotylation reaction follows the trend observed for simpler crotylation substrates, i.e., both E and Z crotyltins favor syn products. This behavior has been explained by open transition-state models.13,26−28 However, the selectivity (i.e., 2:1) with respect to the two syn products was modest. Stereochemical control of this reaction through the use of chelating and chiral Lewis acids and/or other metalating entities is envisaged.29,30 The acetates 12 and 13 were next transformed to the inositol ring and “ring-opened” inositol analogues of C-INS-2 (Scheme 4). Thus, RCM on 12 using Grubbs II catalyst, Upjon dihydroxylation on the RCM product 14, and acetylation of the resulting diol provided the tri-O-acetate 15. The inositol

Inositol rings in 14, 15, 18, and 19 are numbered differently.

segment in 15 was assigned as D-chiro based on the absolute stereochemistry in the aldehyde precursor, vicinal JH,H coupling constants for 15, and a H2/H4 NOE in the alkene precursor 14. Removal of the protecting groups in 15 provided β-Cgalactosaminoinositol 16 with matching stereochemistry to CINS-2. Similarly, RCM on 13 provided 17, on which the dihydroxylation−acetylation sequence led to a 3:1 mixture of triacetates 18 and 19, with C-neo- and C-epi inositol motifs, respectively. To illustrate the synthesis of “ring-opened” inositol analogues, crotylation product 13 was transformed to 21 (Scheme 5). Thus, ozonolysis of 13, reduction of the resulting dialdehyde, and acetylation of the derived diol provided tri-Oacetate 20. Removal of alcohol protecting groups as for the cyclic analogue 16 led to 21.

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CONCLUSION In conclusion, the preparation of inositol ring and “ringopened” C-glycoside analogues of INS-2 illustrates the use glycosyl crotylating agents for the synthesis of stereochemically rich disaccharide-like mimetics. The central crotylation products in this methodology are potentially relay compounds 6535

DOI: 10.1021/acs.joc.8b00845 J. Org. Chem. 2018, 83, 6534−6540

Article

The Journal of Organic Chemistry Scheme 5. Synthesis of “Ring-Opened” Inositol Analogues

nitrogen for 30 min. Then Grubbs I catalyst (27 mg, 0.033 mmol) was added and the reaction mixture heated at 40 °C for 16 h under nitrogen. Excess solvent was removed in vacuo, and the residue was purified by FCC to give a homogeneous product with Rf = 0.43 (15% EtOAc/PE). A mixture of this material in THF (10 mL) and 1 M TBAF in THF (9 mL, 9.0 mmol) was stirred at rt for 2 h then diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified by FCC to give E/Z-9 (825 mg, 72% yield) as a 3:1 E/Z mixture: Rf = 0.10 (30% EtOAc/PE). For E-9: 1H NMR (500 MHz, CDCl3) δ 7.77 (m, 1H), 7.64 (m, 3H), 7.30 (m, 11H), 6.93 (m, 4H), 5.56 (m, 1H), 5.42 (m, 1H), 4.89 (app d, J = 11.7 Hz, 1H), 4.55 (m, 3H), 4.42 (ABq, J = 11.4, Δδ = 0.06, 2H), 4.26 (dd, J = 8.1, 2.9 Hz, 1H), 4.21 (app d, J = 12.1 Hz, 1H), 4.15 (dt, J = 10.6, 5.4 Hz, 1H), 4.02 (m, 1H), 3.75 (t, J = 5.9 Hz, 1H), 3.66 (t, J = 6.6 Hz, 1H), 3.54 (m, 2H), 2.21 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 168.8, 168.4, 138.8, 138.2, 138.0, 134.2, 134.1, 131.9, 131.8, 128.6, 128.4, 128.2, 128.1, 128.0, 127.8, 127.7, 123.6, 123.3, 77.7, 75.2, 74.6, 73.7, 72.6, 71.5, 69.2, 63.7, 62.7, 52.8, 35.9. For Z-9: Rf = 0.13 (30% EtOAc/PE); 1 H NMR (500 MHz, CDCl3) δ 7.77 (m, 1H), 7.65 (m, 3H), 7.30 (m, 11H), 6.95 (m, 4H), 5.59 (m, 1H), 5.40 (m, 1H), 4.87 (app d, J = 11.7 Hz, 1H), 4.40 (ABq, J = 11.9, Δδ = 0.11, 2H), 4.26 (dd, J = 9.4, 2.7 Hz, 1H), 4.20 (app d, J = 12.1, 1H), 4.09 (m, 1H), 3.95 (m, 3H), 3.56 (dd, J = 8.1, 6.2 Hz, 1H), 3.44 (dd, J = 8.3, 6.5 Hz, 1H), 2.19 (m, 3H); 13 C NMR (125 MHz, CDCl3) δ 167.5, 137.5, 136.8, 136.6, 133.1, 132.9, 130.6, 130.5, 127.4, 127.3, 127.0, 126.8, 126.7, 126.6, 126.5, 126.3, 122.5, 122.2, 81.8, 76.3, 76.1, 73.7, 73.4, 72.4, 71.3, 70.3, 68.1, 61.5, 56.8, 51.6, 29.3. HRMS (ESI) m/z calcd for C39H39O7NNa [M + Na]+ 656.2619, found 656.2630. Synthesis of (E/Z)-Tributyl[4-(3,4,6-tri-O-benzyl-2-N-phthalimido-β-C-D-galactopyran-osyl)but-2-en-1-yl]stannane (E/Z10). To a solution of E/Z-9 (330 mg, 0.52 mmol) in dry DMF (4.5 mL) was added under nitrogen at 0 °C carbon disulfide (200 μL, 3.12 mmol). The solution was stirred at this temperature for 15 min, at which point sodium hydride (60% suspension in mineral oil, 25 mg, 1.04 mmol) was introduced. After an additional 30 min, MeI (350 μL, 5.20 mmol) was added. The mixture was stirred for 20 min at 0 °C, warmed to rt over 30 min, then diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), and concentrated in vacuo. FCC of the residue provided the derived xanthate (280 mg, 74%) as a 3:1 E/Z mixture: Rf = 0.42 (30% EtOAc/hexane). For E-xanthate: 1H NMR (500 MHz, CDCl3) δ 7.77 (m, 1H), 7.63 (m, 3H), 7.28 (m, 11H), 6.95 (m, 4H), 5.72 (m, 1H), 5.49 (m, 1H), 4.88 (app d, J = 11.7 Hz, 1H), 4.64 (m, 2H), 4.54 (m, 3H), 4.41 (ABq, dd = 0.05 ppm, J = 11.8 Hz, 2H), 4.28 (dd, J = 10.8, 2.8 Hz, 1H), 4.22 (app d, J = 12.1 Hz, 1H), 4.11 (m, 1H), 4.00 (bd, J = 2.3 Hz, 1H), 3.67 (t, J = 6.6 Hz, 1H), 3.54 (m, 2H), 2.41 (s, 3H), 2.28 (m, 1H), 2.20 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 215.5, 168.8, 168.3, 138.8, 138.2, 138.0, 134.2, 134.1, 132.7, 131.9, 131.8, 128.7, 128.5, 128.4, 128.1, 128.0, 127.8, 127.7, 125.1, 123.6, 123.3, 77.6, 77.3, 77.1, 75.1, 74.7, 74.0, 73.7, 72.7, 72.6, 71.5, 69.2, 53.1, 36.1, 19.1; HRMS (ESI) m/z calcd for C42H75O8NNa [M + Na]+ 744.5385, found 744.5388. A solution of the product from the previous step (280 mg, 0.39 mmol) in dry toluene (10 mL) was purged with nitrogen and heated at reflux for 3 h. The reaction mixture was then cooled to rt, a mixture of Bu3SnH (0.20 mL, 0.75 mmol) and AIBN (2 mg) in toluene (2 mL) was added dropwise over 5 min, and heating was continued for 30 min. The solvent was evaporated in vacuo and the product purified by FCC to give E/Z-10 (277 mg, 81%): E/Z ca. 2:1; Rf = 0.53 (20% EtOAc/ hexane). For E-10: 1H NMR (500 MHz, CDCl3) δ 7.76 (m, 1H), 7.60 (m, 3H), 7.40−7.20 (m, 10H), 6.93 (m, 5H), 5.29 (m, 1H), 5.03 (m, 1H), 4.88 (m, 1H), 4.60−4.21 (m, 7H), 4.1−3.9 (m, 2H), 3.65 (m, 1H), 3.53 (m, 2H), 2.01 (m, 2H), 1.57 (m, 4H), 1.33−1.08 (m, 11H), 0.86−0.61 (m, 12H); 13C NMR (125 MHz, CDCl3) δ 168.8, 168.5, 138.9, 138.3, 138.1, 134.0, 133.9, 133.8, 132.1, 131.6, 130.2, 128.7, 128.6, 128.5, 128.4, 128.3, 128.1, 127.9, 127.7, 127.6, 123.5, 123.2, 120.8, 77.9, 77.8, 77.7, 77.3, 77.1, 76.2, 74.6, 73.7, 72.8, 72.6, 71.5, 69.2, 53.5, 36.7, 32.1, 30.9, 29.9, 29.6, 29.2, 29.2, 29.1, 28.0, 27.7, 27.4,

to more diverse glycoinositols, as a variety of different reaction strategies on the versatile diene functionality can be envisaged. In addition, starting with related O-glycosyl crotylating agents can provide a nonconventional synthesis of unusual Oglycoinositols.31 These synthetic directions and biological assays on these novel INS-2 analogues are underway and will be reported in due course.

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EXPERIMENTAL SECTION

General Experimental Details. Unless otherwise stated, all reactions were carried out under a nitrogen atmosphere in oven-dried glassware using standard syringe and septa techniques. Unless otherwise stated, NMR spectra were obtained on 500 or 600 MHz instruments. Chemical shifts are relative to the deuterated solvent peak or the tetramethylsilane (TMS) peak at (δ 0.00) and are reported in parts per million (ppm). Assignments for selected nuclei were determined from 1H COSY and HSQC experiments. High-resolution mass spectrometry (HRMS) measurements were acquired on an Agilent 6500 Series QToF mass spectrometer using an electrospray ionization (ESI) source in positive-ion mode. Thin-layer chromatography (TLC) was done on 0.25 mm thick precoated silica gel HF254 aluminum sheets. Chromatograms were observed under UV (short and long wavelength) light and/or were visualized by heating plates that were dipped in a solution of ammonium (VI) molybdate tetrahydrate (12.5 g) and cerium(IV) sulfate tetrahydrate (5.0 g) in 10% aqueous sulfuric acid (500 mL). Unless otherwise stated, flash column chromatography (FCC) was performed using silica gel 60 (230−400 mesh) and employed a stepwise solvent polarity gradient, correlated with TLC mobility. Hexanes and petroleum ether (PE) used for FCC had a boiling point in the 35−60 °C range. Synthesis of 3-[3,4,6-Tri-O-benzyl-2-deoxy-2-phthalimido-βC-D-galactopyranosyl]propene (8). To a solution of 723 (475 mg, 1.0 mmol) in pyridine (1 mL) and Et3N (0.2 mL) was added phthalic anhydride (296 mg, 2.0 mmol). The reaction mixture was stirred at rt for 16 h, at which time pyridine (1 mL) and Ac2O (1 mL) were added. The mixture was maintained at rt for an additional 16 h. The volatiles were removed in vacuo, and the residue was purified by FCC to give 8 (425 mg, 61%): Rf = 0.37 (20% EtOAc/PE); 1H NMR (500 MHz, C6D6) δ 7.46−6.85 (m, 19H), 5.90 (m, 1H), 5.15 (t, J = 10.5 Hz, 1H), 4.88 (dd, J = 43.1, 17.1 Hz, 2H), 4.77 (ABq, J = 11.5 Hz, Δδ = 0.38 ppm, 2H), 4.49 (m, 2H), 4.30 (m, 3H), 4.06 (m, 2H), 3.82 (t, J = 8.0 Hz, 1H), 3.73 (t, J = 5.5 Hz, 1H), 3.67 (m, 1H), 2.38 (m, 2H); 13C NMR (125 MHz, C6D6) δ 169.2, 168.4, 139.9, 139.3, 139.0, 134.8, 134.0, 133.9, 133.8, 132.7, 132.6, 129.0, 128.9, 128.8, 128.7, 128.5, 128.3, 128.0, 127.9, 123.7, 123.3, 117.2, 78.8, 77.8, 76.1, 75.3, 73.9, 73.7, 71.7, 69.7, 53.8, 38.2; HRMS (ESI) m/z calcd for C38H37O6NNa [M + Na]+ 626.2513, found 626.2533. Synthesis of (E/Z)-4-[3,4,6-Tri-O-benzyl-2-deoxy-2-N-phthalimido-β-C-D-galactopyranosyl]-2-buten-1-ol (9). A solution of 8 (1.10 g, 1.82 mmol) and (Z)-1,4-di(tert-butyldimethylsilyloxy)but-2ene (630 mg, 2.0 mmol) in dry CH2Cl2 (60 mL) was purged with 6536

DOI: 10.1021/acs.joc.8b00845 J. Org. Chem. 2018, 83, 6534−6540

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The Journal of Organic Chemistry

filtered, and evaporated in vacuo. The residue was taken up in EtOAc (2 mL) and treated with Ac2O (50 μL) and DMAP (2 mg) at rt for 15 min. Removal of the volatiles under reduced pressure and purification of the residue by FCC gave 15 (28 mg, 82% from 14): Rf = 0.29 (30% EtOAc/PE); 1H NMR (500 MHz, C6D6) δ 7.55−6.96 (m, 29H), 6.05 (t, J = 3.5 Hz, 1H, H6), 5.95 (t, J = 10.1 Hz, 1H, H3), 5.80 (dd, J = 11.7, 3.0 Hz, 1H, H5), 5.11 (t, J = 10.4 Hz, 1H, H2′), 5.02 (app d, J = 11.6 Hz, 1H, PhCH), 4.75 (m, 1H, H1′), 4.73−4.63 (m, 5H, H3′, 4 × PhCH), 4.50 (app d, J = 11.7 Hz, 1H, PhCH), 4.42 (m, 2H, PhCH2), 4.36 (app d, J = 12.1, 1H, PhCH), 4.33 (app d, J = 11.7, 1H, PhCH), 4.16 (d, J = 2.4 Hz, 1H, H4′), 4.10 (app d, J = 12.1 Hz, 1H, PhCH), 3.95−3.86 (m, 5H, H1, 2, 5′, CH2-6′), 2.72 (m, 1H, H4), 2.24 (m, 1H, Ha), 2.04 (s, 3H), 1.84 (m, 1H, Ha), 1.74 (s, 3H), 1.72 (s, 3H); 13C NMR (125 MHz, C6D6) δ 170.1, 169.6, 169.5, 168.8, 168.7, 140.0, 139.5, 139.2, 139.0, 138.7, 133.9, 132.9, 132.5, 129.0, 128.9, 128.8, 128.7, 128.1, 128.0, 127.9, 127.8, 127.7, 123.6, 123.3, 79.6, 78.3, 77.3, 75.1, 74.6, 73.9, 73.6, 73.5, 73.1, 72.2, 71.9, 71.5, 69.4, 69.3, 54.7, 37.7, 30.5, 21.1. 20.8, 20.7; HRMS (ESI) m/z calcd for C62H63NO14Na [M + Na]+1068.4141, found 1068.4125. Synthesis of 4-C-(2-Amino-2-deoxy-β-D-galactopyranosyl)-Dchiro-inositol (16). A mixture of 15 (20 mg, 0.019 mmol), palladium black (10 mg), cyclohexene (0.2 mL), 1 M HCl (100 μL), and MeOH (2 mL) was heated, under nitrogen, at 65 °C for 4 h. The suspension was then filtered through a pad of Celite and the filtrate evaporated under reduced pressure. The residue was taken up in EtOAc (1 mL) and treated with Ac2O (100 μL) and DMAP (1 mg) for 16 h at rt. MeOH (0.5 mL) was then added to the reaction mixture, and the volatiles were removed in vacuo. FCC of the residue afforded the octaO-acetate derivative (14 mg, 91%): Rf = 0.33 (70% EtOAc/hexane); 1 H NMR (500 MHz, CDCl3) δ 7.75 (m, 2H, Ar), 7.69 (m, 2H, Ar), 5.74 (dd, J = 2.9, 9.2 Hz, 1H, H3′), 5.41 (d, J = 2.9 Hz, 1H, H4′), 5.23 (m, 1H, H1) 5.18 (dd, J = 2.1, 3.9 Hz, 1H, H6), 5.11 (m, 2H, H2, 3), 4.98 (dd, J = 2.5, 9.3 Hz, 1H, H5), 4.29 (t, J = 8.7 Hz, 1H, H1′), 4.21 (t, J = 8.6 Hz, 1H, H2′), 4.14 (m, 1H, H6′), 4.00 (m, 2H, H5′, 6′), 2.31 (m, 1H), 2.08 (s, 3H, OAc), 2.07 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.02 (s, 3H, OAc), 2.00 (s, 3H, OAc), 1.93 (s, 3H, OAc), 1.92 (s, 3H, OAc), 1.78 (s, 3H, OAc), 1.63 (m, 1H, Ha), 1.39 (m, 1H, Ha); 13 C NMR (125 MHz, CDCl3) δ 170.2, 170.1, 170.0, 169.5, 169.4, 168.0, 167.8, 134.8, 134.6, 131.2, 123.9, 123.7, 74.3, 74.0, 71.2, 70.8, 69.9, 68.6, 67.9, 67.7, 67.3, 61.6, 52.0, 30.9, 21.2, 21.0, 20.9, 20.8, 20.7; HRMS (ESI) m/z calcd for C37H43NO19Na [M + Na]+ 828.2327, found 828.2318. A mixture of the material (10.0 mg, 0.017 mmol) from the previous step, H2NNH2·H2O (0.1 mL) and EtOH (2 mL), was heated, under nitrogen, at 90 °C for 45 min. The suspension was then filtered through a pad of Celite and the filtrate evaporated under reduced pressure. The residue was loaded on a silica gel column and the column was eluted successively with CHCl3/DMF/MeOH (8:1:1) and MeOH/H2O (1:1). The combined eluate was evaporated in vacuo and purified by preparative reversed-phase HPLC (XBridge Prep C-18 5 μm OBD 19 × 150 mm); 0−35% gradient of acetonitrile in aqueous trifluoroacetic acid (0.05%) and a flow rate of 20 mL/min, with automated MS fraction monitoring. The fractions containing the desired compounds were collected and the volatiles were removed by SpeedVac. The resultant solution was lyophilized to give 16 (1.9 mg, 46%): Rf 0.15 [pyridine/2-propanol/H2O/HOAc (8:8:4:1); visualized with the standard TLC stain or ninhydrin];7 1H NMR (600 MHz, D2O, external standard: C6H6) δ 4.02 (t, J = 3.6 Hz, 1H, H1), 3.97 (t, J = 3.6 Hz, 1H, H6), 3.89 (d, J = 3.2 Hz, 1H, H4′), 3.85 (dd, J = 3.0, 10.5 Hz, 1H, H5), 3.80−3.68 (m, 3H, H2, 5′, 6′), 3.65 (m, 1H, H6′), 3.45 (m, 2H, H3, 3′), 3.46 (bt, J = 9.2 Hz, 1H, H1′), 2.78 (t, J = 10.0 Hz, 1H, H2′), 2.09 (m, 1H, Ha), 1.97 (m, 1H, H4), 1.88 (m, 1H, Ha); 13 C NMR (150 MHz, D2O, external standard: C6D6) δ 13CNMR (150 MHz, CDCl3) δ 79.4, 79.3, 74.7, 73.0, 72.6, 72.4, 71.4, 70.8, 69.2, 62.3, 53.4, 40.2, 30.9; HRMS (ESI) m/z calcd for for C13H26NO9 [M + H]+ 340.1602, found 340.1604. Synthesis of β-C-Galactosamino Cyclohexene (17). A solution of 13 (55 mg, 0.058 mmol) in CH2Cl2 (10 mL) was subjected to the RCM procedure described for the synthesis of 14. FCC of the crude reaction product give 17 (47 mg, 89%): Rf = 0.1 (20% EtOAc/

27.3, 27.0, 17.7, 13.9, 9.23. For E/Z-10: HRMS (ESI) m/z calcd for C51H65NO6SnNa (ESI, MNa+) 930.3738, found 930.3757. Synthesis of Homoallylic Acetates 12 and 13. To a solution of 1125 (25 mg. 0.083 mmol) in CH2Cl2 (2 mL) was added BF3·OEt2 (21 μL, 0.160 mmol) at −78 °C. After 15 min, a solution of E/Z-10 (50 mg, 0.055 mmol) in CH2Cl2 (1 mL) was added dropwise over 30 min. The reaction mixture was maintained at −78 °C for 2 h, then diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. FCC of the crude product afforded an inseparable mixture (Rf = 0.21; 20% EtOAc/PE), which was taken up in EtOAc (1 mL) and treated with DMAP (1 mg) and Ac2O (50 μL). The reaction mixture was stirred at rt for 5 min, excess solvent was evaporated in vacuo, and the residue was purified by FCC to give 12 (14 mg, 27%) and 13 (28 mg, 54%). For 12: Rf = 0.41 (30% EtOAc/ hexane); 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 7.2 Hz, 1H), 7.63 (m, 3H), 7.30−6.90 (m, 25H), 5.80 (m, 1H), 5.22 (m, 3H), 5.00 (dd, J = 1.6, 10.3 Hz, 1H), 4.94 (dd, J = 2.2, 9.5 Hz, 1H), 4.87 (m, 2H), 4.62−4.46 (m, 4H), 4.42−4.43 (m, 4H), 4.19 (m, 3H), 4.00 (m, 2H), 3.68 (t, J = 6.3 Hz, 1H), 3.58 (m, 3H), 3.47 (m, 1H), 2.90 (m, 1H), 1.86 (s, 3H), 1.63 (m, 1H), 1.14 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 171.1, 168.6, 168.4, 138.9, 138.8, 138.4, 138.2, 138.0, 137.9, 137.6, 135.8, 134.1, 134.0, 132.0, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 123.7, 123.3, 119.6, 119.1, 80.9, 80.5, 77.8, 77.3, 77.1, 74.8, 74.7, 74.2, 73.7, 73.4, 72.8, 71.4, 70.4, 69.2, 53.4, 41.1, 29.9, 21.3; HRMS (ESI) m/z calcd for C60H61O10NNa [M + Na]+ 978.4188, found 978.4189. For 13: Rf = 0.50 (30% EtOAc/ hexane); 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.2 Hz, 1H), 7.51 (m, 3H), 7.30−6.95 (m, 25H), 5.64 (m, 1H), 5.55 (m, 1H), 5.18 (d, J = 10.4 Hz, 1H), 5.04 (d, J = 17.3 Hz, 1H), 4.91 (m, 4H), 4.53 (m, 3H), 4.43 (m, 4H), 4.30 (m, 2H), 4.25 (m, 2H), 4.15 (m, 1H), 4.11 (m, 1H), 3.60 (m, 4H), 3.51 (dd, J = 4.7, 8.3 Hz, 1H), 2.51 (m, 1H), 1.78 (s, 3H), 1.76 (m, 1H). 1.65 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 170.1, 168.6, 168.5, 138.9, 138.8, 138.6, 138.4, 138.1, 134.9, 134.0, 131.9, 131.8, 128.6, 128.5, 128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 123.2, 119.5, 116.6, 80.9, 80.7, 77.7, 77.1, 74.9, 74.5, 73.6, 73.1, 72.6, 71.4, 70.1, 68.9, 53.9, 42.4, 29.9, 21.1; HRMS (ESI, MNa+) m/z calcd for C60H61O10NNa [M + Na]+ 978.4188, found 978.4203. Synthesis of β-C-Galactosamino Cyclohexene (14). A solution of 12 (48 mg, 0.050 mmol) in CH2Cl2 (10 mL) was purged with nitrogen for 30 min. Then Grubbs II catalyst (4.5 mg, 0.005 mmol) was added and the reaction stirred under nitrogen at 40 °C for 6 h. At that time, another portion of catalyst (4.5 mg, 0.005 mmol) was introduced and stirring continued at 40 °C for an additional 12 h. The volatiles were then removed in vacuo, and the residue was purified by FCC to give 14 (40 mg, 86%): Rf = 0.21 (20% EtOAc/PE); 1H NMR (500 MHz, C6D6) δ 7.40−6.80 (m, 29H. Ar), 6.00 (dd, J = 10.0, 2.5 Hz, 1H, H5), 5.73 (dd, J = 9.4, 8.1 Hz, 1H, H3), 5.64 (ddd, J = 10.0, 4.8, 2.5 Hz, 1H, H6), 5.16 (t, J = 10.5 Hz, 1H, H2′), 4.94 (app d, J = 11.5 Hz, 1H, PhCH), 4.67 (dt, J = 9.9, 2.0 Hz, 1H, H1′), 4.58 (app d, J = 12.3 Hz, 1H, PhCH), 4.55 (app d, J = 11.5 Hz, 1H, PhCH), 4.50 (dd, J = 10.8, 2.6 Hz, 1H, H3′), 4.46 (app d, J = 12.3 Hz, 1H, PhCH), 4.41 (app d, J = 12.2 Hz, 1H, PhCH), 4.34−4.28 (m, 4H, 4 × PhCH), 4.05 (app d, J = 12.1 Hz, 1H, PhCH), 4.02 (d, J = 2.5 Hz, 1H, H4′), 3.90 (m, 1H, H1), 3.79 (m, 1H, H5′), 3.71 (m, 2H, CH2−6′), 3.51 (dd, J = 9.4, 3.6 Hz, 1H, H2), 2.83 (m, 1H, H4), 2.13 (ddd, J = 13.5, 9.5, 3.5 Hz, 1H, Ha), 1.81 (m, 1H, Ha′), 1.47 (s, 3H, OAc); 13C NMR (125 MHz, C6D6) δ 170.0, 169.2, 168.5, 140.1, 139.8, 139.7, 139.4, 138.9, 133.8, 133.7, 132.7, 132.5, 132.4, 129.0, 127.9, 127.8, 127.7, 125.4, 123.7, 123.4, 80.1, 78.9, 77.9, 75.3, 74.4, 73.8, 73.7, 72.5, 72.4, 72.3, 72.1, 71.7, 69.7, 53.8, 39.8, 34.6, 20.8; HRMS (ESI) m/z calcd for C58H57NO10Na [M + Na]+ 950.3875, found 950.3858. Synthesis of D-chiro-Inositol Tri-O-acetate (15). To a solution of 14 (31.0 mg, 0.033 mmol) in acetone/H2O 4:1 (1.0 mL) were added 50% aqueous NMNO (50 μL, 0.2 μmol) and 2.5% OsO4 in tBuOH (100 μL, 0.01 μmol). The reaction mixture was stirred at rt for 20 h. Na2SO3 (50 mg) was then added and stirring continued for 30 min. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), 6537

DOI: 10.1021/acs.joc.8b00845 J. Org. Chem. 2018, 83, 6534−6540

Article

The Journal of Organic Chemistry hexane); 1H NMR (500 MHz, C6D6) δ 7.60−6.90 (m, 29H), 5.72 (d, J = 10.0 Hz, 1H), 5.59 (d, J = 10.0 Hz, 1H), 5.19 (t, J = 10.4 Hz, 1H), 5.07 (m, 2H), 4.86 (ABq, J = 12.4 Hz, Δδ = 0.12 ppm, 2H), 4.67 (m, 2H), 4.58 (br d, J = 10.5 Hz, 1H), 4.53 (app d, J = 11.6 Hz, 1H), 4.42−4.32 (m, 5H), 4.15 (m, 2H), 4.09 (br s, 1H), 3.92 (m, 1H), 3.83 (m, 2H), 3.30 (br s, 1H), 2.03 (m, 1H), 1.92 (s, 3H), 1.76 (m, 1H); 13 C NMR (125 MHz, C6D6) δ 170.5, 169.0, 168.5, 140.2, 139.8, 139.6, 139.4, 138.9, 134.1, 133.5, 134.1, 133.9, 131.3, 129.0, 127.9, 127.7, 127.0, 123.7, 123.3, 78.6, 77.7, 77.6, 76.2, 75.8, 75.6, 75.3, 74.3, 73.9, 73.6, 71.6, 71.2, 69.7, 54.4, 35.6, 35.1, 21.2; HRMS (ESI) m/z calcd for C58H57NO12Na [M + Na]+ 982.3773, found 982.3782. Synthesis of C-neo-Inositol Tri-O-acetate (18) and C-epiInositol Tri-O-acetate (19). Alkene 17 (44.0 mg, 0.047 mmol) was subjected to the dihydroxylation−acetylation procedure described for the synthesis of 15. The crude product was purified by FCC to give a mixture of 18:19 (42.5 mg, 86%, respectively ratio 3:1). For 18: Rf = 0.12 (20% acetone/hexane); 1H NMR (500 MHz, C6D6) δ 7.55−6.92 (m, 29H), 6.09 (t, J = 2.8 Hz, 1H, H2), 5.92 (dd, J = 10.6, 3.2 Hz, 1H, H3), 5.19 (dd, J = 11.8, 2.1 Hz, 1H, H6), 5.13 (t, J = 10.4 Hz, 1H, H2′), 5.01 (app d, J = 11.6 Hz, 1H, PhCH), 4.79 (app d, J = 12.3 Hz, 1H, PhCH), 4.64 (m, 2H, 2xPhCH), 4.56 (m, 3H, 1′, 3′, PhCH), 4.40 (m, 5H, 5, 4 × PhCH), 4.18 (d, J = 2.3 Hz, 1H, H4′), 4.12 (app d, J = 12.2 Hz, 1H, PhCH), 3.94 (t, J = 8.8 Hz, 1H, H5′), 3.90 (m, 2H, H4, H6′), 3.72 (dd, J = 8.2, 5.5 Hz, 1H, H6′), 2.90 (m, 1H, H1), 1.88 (m, 2H, CH2-a), 1.85 (s, 3H, OAc), 1.77 (s, 3H, OAc), 1.74 (s, 3H, OAc); 1 H NMR (600 MHz, CDCl3) δ 7.80−6.85 (m, 29H), 5.47 (t, J = 3.1 Hz, 1H, H2), 5.25 (dd, J = 3.1, 10.5 Hz, 1H, H3), 4.87 (app d, J = 10.5 Hz, 1H, PhCH), 4.66 (app d, J = 12.1 Hz, 1H, PhCH), 4.59 (dd, J = 2.3, 11.8 Hz, 1H, H6), 4.56−4.46 (m, 6H, PhCH), 4.42 (m, 2H, H2′, PhCH), 4.30 (dd, J = 2.8, 10.8 Hz, 1H, H3′), 4.22 (app d, J = 12.1 Hz, 1H, PhCH), 4.11 (dt, partially buried, J = 2.3, 9.7 Hz, 1H, H1′), 4.08 (d, J = 2.4 Hz, 1H, H4′), 4.03 (t, J = 2.9 Hz, 1H, H5), 3.70 (t, J = 6.3 Hz, 1H, H5′), 3.65 (m, 3H, CH2-6′, H4), 2.50 (m, 1H, H1), 1.95 (s, 3H, OAc) 1.92 (s, 3H, OAc), 1.67 (s, 3H, OAc), 1.42 (m, 1H, Ha), 1.22 (m, 1H, Ha); 13C NMR (125 MHz, C6D6) δ 170.4, 170.1, 169.8, 169.0, 168.7, 139.9, 139.6, 139.5, 139.3, 139.0, 134.0 (two peaks), 132.6, 132.4, 129.0, 128.9, 128.8, 128.1, 128.0, 127.9, 127.8, 127.7, 123.6, 123.4, 78.4, 77.8, 77.5, 76.3, 76.2, 75.2 (two peaks), 73.9, 73.6, 73.5, 73.1, 72.7, 71.6, 71.3, 69.3, 54.8, 37.0, 30.6, 21.1, 20.7 (two peaks); HRMS (ESI) m/z calcd for C62H63NO14Na [M + Na]+ 1068.4141, found 1068.4125. For 19: Rf = 0.14 (20% acetone/ hexane); 1H NMR (600 MHz, C6D6) δ 7.43 (m, 3H), 7.35 (m, 5H), 7.24 (m, 4H), 7.15 (m, 6H), 7.08 (m, 4H), 6.97 (m, 2H), 6.85 (m, 5H), 6.12 (t, J = 2.8 Hz, 1H, H3), 5.11 (overlapping dd, J = 2.9, 12.4 Hz, 2H, H2, 6), 4.98 (t, J = 10.3 Hz, 1H, H2′), 4.88 (app d, J = 11.9 Hz, 1H, PhCH), 4.86 (app d, J = 12.4 Hz, 1H, PhCH), 4.60 (app d, J = 12.6 Hz, 1H, PhCH), 4.54 (app d, J = 11.6 Hz, 1H, PhCH), 4.49 (m, 2H, PhCH, H1′), 4.40 (m, 3H, PhCH × 2, H3′), 4.31 (m, 2H, PhCH, H5), 4.04 (app d, J = 12.2 Hz, 1H, PhCH), 3.96 (app d, J = 11.5 Hz, 1H, PhCH), 3.85 (m, 2H, H4′, 6′), 3.71 (t, J = 6.4 Hz, 1H. H5′), 3.61 (dd, J = 6.2, 9.1 Hz, 1H, H6′), 3.25 (t, J = 2.8 Hz, 1H, H4), 3.21 (tdd, J = 2.3, 5.3, 12.0 Hz, 1H, H1), 2.16 (ddd, J = 2.3, 10.9, 14.2 Hz, 1H, Ha), 1.82 (s, 3H, Ac), 1.80 (s, 3H, Ac), 1.77 (s, 3H), 1.72 (ddd, J = 2.0, 5.3, 14.2 Hz, 1H, Ha); 1H NMR (600 MHz, CDCl3) δ 7.82−692 (m, 29H), 5.67 (t, J = 2.70 Hz, 1H, H3), 4.88 (app d, J = 11.6 Hz, PhCH), 4.73 (dd, J = 2.9, 12.0 Hz, 1H, H6), 4.70 (app d partially buried, J = 11.9 Hz, 1H, PhCH), 4.68 (dd, partially buried, J = 3.2, 11.6 Hz, 1H, H2), 4.55−4.45 (m, 5H, PhCH), 4.42 (t, J = 10.3 Hz, 1H, H2′), 4.38 (app d, J = 11.4 Hz, 1H, PhCH), 4.26 (app d, J = 11.6 Hz, 1H, PhCH), 4.22 (m, 2H, H3′, PhCH), 4.10 (m, 2H, H5, H1′), 3.99 (d, J = 2.4 Hz, 1H, H4′), 3.66 (t, J = 6.5 Hz, 1H, H5′), 3.52 (m, 2H, CH2-6′), 3.33 (t, J = 2.9 Hz, H4), 2.78 (m, 1H, H1), 1.96 (s, 3H, OAc) 1.91 (s, 3H, OAc), 1.81 (m, 1H, Ha), 1.73 (s, 3H, OAc),1.44 (m, 1H, Ha); 13C NMR (150 MHz, C6D6) δ 170.3, 169.7, 169.5, 168.2, 167.7, 139.8, 139.1, 138.8, 138.3, 138.2, 133.4, 133.3, 131.9, 131.8, 128.3, 128.2, 128.1, 127.8, 127.7, 127.5, 127.2, 126.9, 123.1, 122.5, 77.8, 76.1, 75.7, 74.3, 74.0, 73.2, 73.1, 72.8, 71.0, 70.9, 69.6, 67.4, 53.9, 32.1, 27.4, 20.4, 20.3, 20.1. HRMS (ESI) m/z calcd for C62H63NO14Na [M + Na]+ 1068.4141, found 1068.4149.

Synthesis of Tri-O-acetate 20. A stream of O3/O2 was bubbled through a solution of 13 (25 mg, 0.026 mmol) in CH2Cl2 (2 mL) at −78 °C for 5 min. Then PPh3 (50 mg, 0.19 mmol) was added and the reaction mixture warmed to rt and stirred for 2 h at this temperature. Removal of the solvent in vacuo and FCC of the residue afforded the derived aldehyde (24 mg, 96%) as a colorless oil: Rf = 0.46 (40% EtOAc/hexane); 1H NMR (500 MHz, CDCl3) δ 9.53 (bs, 1H), 9.49 (bs, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.72 (m, 3H), 7.40−7.20 (m, 18H), 7.18 (m, 2H), 7.05 (m, 5H), 5.38 (dd, J = 4.5, 8.3 Hz, 1H), 4.93 (apparent d, J = 11.6 Hz, 1H), 4.67−4.55 (m, 5H), 4.44 (m, 3H), 4.32 (m, 3H), 4.22 (t, J = 10.0 Hz, 1H), 4.10 (d, J = 2.2 Hz, 1H), 4.00 (dd, J = 2.3, 8.3 Hz, 1H), 3.94 (m, 1H), 3.72 (t, J = 6.5 Hz, 1H), 3.57 (m, 2H), 2.90 (m, 1H), 2.07 (m, 1H), 1.79 (s, 3H), 1.54 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 200.9 (two peaks), 169.5, 168.6, 168.2, 138.6, 138.1, 137.8, 137.1, 134.2, 134.1, 131.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 123.7, 123.2, 81.2, 80.5, 77.6, 74.8, 74.7, 73.6, 73.3, 72.5 (two peaks), 71.4, 70.0, 68.7, 53.1, 49.6, 26.9, 20.6; HRMS (ESI) m/z calcd for C58H57NO12Na [M + Na]+ 982.3773, found 982.3782. A solution of the material from the previous step (20 mg, 0.021 mmol) in EtOH (2 mL) was treated with NaBH4 (5 mg, 0.13 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred at this temperature for 30 min. Saturated aqueous NH4Cl (0.5 mL) was then added slowly at 0 °C and the mixture extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was taken up in EtOAc (1 mL) and treated with Ac2O (100 μL) and DMAP (1.0 mg) for 3 h at rt. MeOH (0.1 mL) was then added to the reaction mixture, and the volatiles were removed in vacuo. FCC of the residue afforded 20 (18 mg, 83% over two steps): Rf = 0.08 (40% EtOAc/hexane); 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 7.3 Hz, 1H), 7.48 (m, 2H), 7.48 (d, J = 7.3 Hz, 1H), 7.30−6.95 (m, 25H), 5.06 (m, 1H), 4.86 (app d, J = 11.6 Hz, 1H), 4.56−4.37 (m, 7H), 4.34 (app d, J = 11.7 Hz, 1H), 4.25 (app d, J = 11.4 Hz, 1H), 4.20 (m, 3H), 4.12 (t, J = 10.0 Hz, 1H), 4.02 (m, 2H), 3.82 (m, 2H), 3.60 (t, J = 5.3 Hz, 1H), 3.55 (m, 2H), 3.45 (m, 2H), 2.24 (m, 1H), 1.89 (s, 3H), 1.81 (s, 3H), 1.73 (m, partially buried, 1H), 1.70 (s, 3H), 1.44 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 171.1, 171.0, 170.2, 168.5, 168.3, 138.8, 138.2, 137.9, 137.8, 137.7, 134.2, 134.1, 131.7, 128.6, 128.5, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 123.6, 123.1, 77.8, 77.4, 77.1, 76.6, 76.4, 74.8, 73.7, 73.5, 72.5, 71.9, 71.6, 71.3, 68.9, 65.2, 62.6, 53.6, 37.1, 29.3, 21.1, 21.0, 20.9. Synthesis of 4-C-(2-Amino-2-deoxy-β-D-galactopyranosyl)hexitol (21). A mixture of 20 (15 mg, 0.014 mmol), palladium black (6.0 mg), cyclohexene (0.5 mL), 1 M methanolic HCl (100 μL), and MeOH (2 mL) was heated under nitrogen at 65 °C for 4 h. The suspension was then filtered through a pad of Celite and the filtrate evaporated under reduced pressure. The residue was taken up in EtOAc (1 mL) and treated with Ac2O (0.1 mL) and DMAP (1 mg) for 16 h at rt. MeOH (100 μL) was then added to the reaction mixture, and the volatiles were removed in vacuo. FCC of the residue afforded the octa-O-acetate derivative (8.5 mg, 75% over two steps): Rf = 0.0.35 (70% EtOAc/hexane); 1H NMR (600 MHz, CDCl3) δ 7.79 (m, 2H), 7.70 (m, 2H), 5.71 (dd, J = 3.4, 10.6 Hz, 1H), 5.42 (dd, J = 0.8, 3.4 Hz, 1H), 5.10 (m, 2H), 5.02 (m, 1H), 4.32 (m, 2H), 4.17 (m, 2H), 4.10−3.92 (m, 4H), 3.88 (dd, J = 8.0, 10.6, 1H), 2.14 (s, 3H), 2.06 (m, 1H), 1.99 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H), 1.93 (s, 3H), 1.92 (s, 3H), 1.78 (s, 3H), 1.75 (s, 3H), 1.52 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 170.5, 170.1, 170.0, 169.4, 168.2, 168.1, 134.7, 134.5, 131.8, 131.3, 123.8, 75.5, 74.3, 70.4, 70.1, 68.8, 67.4, 64.2, 61.9, 51.7, 37.1, 29.1, 21.1, 21.0, 20.9, 20.8, 20.6; HRMS (ESI) m/z calcd for C37H45NO19Na [M + Na]+ 830.2478, found 830.2475. A mixture of the octa-O-acetate from the previous step (8.5 mg, 0.01 mmol), H2NNH2.H2O (100 μL), and EtOH (2.0 mL) was heated under nitrogen at 90 °C for 45 min. The suspension was then filtered through a pad of Celite and the filtrate evaporated under reduced pressure. The residue was purified following the protocol used for 16 to give 21 (1.4 mg 39%): Rf 0.40 [pyridine/2-propanol/H2O/HOAc (8:8:4:1); visualized with the standard TLC stain or ninhydrin]; 1H NMR (600 MHz, D2O, external standard: C6H6) δ 3.80 (bd, J = 2.3 Hz, 1H), 3.77 (m, 1H), 3.71 (bd, J = 8.7 Hz, 1H), 3.65 (dd, J = 2.3, 6538

DOI: 10.1021/acs.joc.8b00845 J. Org. Chem. 2018, 83, 6534−6540

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The Journal of Organic Chemistry 11.8 Hz, 1H), 3.64−3.47 (m, 8H), 3.42 (t, J = 9.5 Hz, 1H), 2.89 (t, J = 10.1 Hz, 1H), 2.05 (m, 1H), 1.88 (bd, J = 14.9 Hz, 1H), 1.2 (m, 1H); 13 C NMR (150 MHz, D2O, external standard: C6D6) δ 78.8, 76.8, 73.1, 72.2, 71.3, 71.0, 68.1, 63.4, 61.9, 61.4, 53.3, 38.7, 27.6; HRMS (ESI) m/z calcd for C13H27NO9Na [M + Na]+ 364.1578, found 364.1580.

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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/acs.joc.8b00845. NMR spectra of all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

David R. Mootoo: 0000-0002-5159-1299 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (CHE-1301330). A Research Centers in Minority Institutions Program grant from the National Institute of Health Disparities (MD007599) of the National Institutes of Health (NIH), which supports the infrastructure at Hunter College is also acknowledged. We thank Ms. Rong Wang and Dr. George Sukenick in the Nuclear Magnetic Core Facility of Memorial Sloan Kettering Cancer Center for help in purification of 16 and 21.

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REFERENCES

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DOI: 10.1021/acs.joc.8b00845 J. Org. Chem. 2018, 83, 6534−6540