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Abstract: A simple and efficient method for the stereoselective synthesis of isoxazoline/isoxazole-fused iminosugar derivatives has been developed usi...
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Note Cite This: J. Org. Chem. 2018, 83, 1558−1564

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Iminosugar C‑Nitromethyl Glycoside: Stereoselective Synthesis of Isoxazoline and Isoxazole-Fused Bicyclic Iminosugars Sure Siva Prasad and Sundarababu Baskaran* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India S Supporting Information *

ABSTRACT: A simple and efficient method for the stereoselective synthesis of isoxazoline/isoxazole-fused iminosugar derivatives has been developed using intramolecular nitrile oxide cycloaddition (INOC) as a key step. Iminosugar Cnitromethyl glycosides, derived from simple carbohydrates, served as excellent nitrile oxide precursors in 1,3-dipolar cycloaddition reactions. N-Alkenyl iminosugar C-nitromethyl glycosides afforded novel isoxazoline-fused indolizidine-, pyrrolizidine-, and quinolizidine-based iminosugars in excellent yields with a high degree of stereoselectivity, whereas Nalkynyl iminosugar C-nitromethyl glycosides furnished the corresponding isoxazole containing tricyclic iminosugars in very good yields.

G

clinical trials for the treatment of hepatitis C virus (HCV), HIV, and dengue virus infections due to its strong and selective inhibition of endoplasmic reticulum α-glucosidase compared to the parent molecule.7 In addition, castanospermine, swainsonine, and their derivatives exhibit promising immunosuppressive activities.8 In general, simple structural and stereochemical modification of iminosugar can drastically alter its biological activity, potency, and/or specificity.3 The structural diversity of iminosugars coupled with their intriguing biological activities has inspired extensive efforts toward the synthesis of novel bicyclic iminosugar derivatives.9 Isoxazoline and isoxazole are common structural frameworks present in many biologically active molecules and natural products exhibiting analgesic, hypoglycemic, anticancer, and anti-inflammatory activities.10 In addition, isoxazoline derivatives are versatile intermediates in the synthesis of α,βunsaturated ketones, β-amino acids, γ-amino alcohols, and βhydroxyketones.11,12 In general, isoxazoline and isoxazole are synthesized by the 1,3-dipolar cycloaddition reaction of nitrile oxide with alkene and alkyne, respectively.12 Like aldoxime, the nitromethyl derivative also serves as an ideal precursor for the generation of nitrile oxide (1,3-dipole) under dehydrative conditions.13 Our sustained interest toward the synthesis of biologically significant iminosugars14 has recently resulted in the development of a novel and facile one-pot strategy for the stereoselective synthesis of novel iminosugar C-nitromethyl glycosides and subsequent single-step transformations to structurally unique bicyclic iminosugars (Scheme 1).15 Though the 1,3-dipolar cycloaddition of nitrone has been extensively applied in the synthesis of iminosugars,16 the intramolecular

lycosidases and glycosyltransferases are ubiquitous in many living organisms and play a vital role in various biological processes.1 These carbohydrate-processing enzymes have also been implicated in numerous diseases and metabolic disorders such as viral infections, diabetes, and cancers.1,2 Iminosugars are the most fascinating class of sugar-mimics, exhibiting inhibition against a wide variety of glycosidases and glycosyltransferases even in a femtomolar range.3 Naturally occurring bicyclic iminosugars and their structural analogues have evoked considerable interest among synthetic and medicinal chemists due to their specific glycosidase inhibitory activities.2,3 Intriguingly, iminosugars casuarine (1) and hyacinthacine A2 (2) are strong inhibitors of amyloglucosidase,4 whereas castanospermine (3) is a potent inhibitor of αglucosidases (Figure 1).5 Similarly, swainsonine (4) is a potent inhibitor of α-mannosidases,6a and steviamine (5) is a known inhibitor of β-galactosidase.6b Conspicuously, swainsonine (4) is in phase II clinical trials for the treatment of renal cell carcinoma and colorectal cancer.3,6c Moreover, celgosivir (6), an O-butyrate derivative of castanospermine, is in phase II

Figure 1. Biologically active and pharmaceutically important bicyclic iminosugars. © 2018 American Chemical Society

Received: November 6, 2017 Published: January 9, 2018 1558

DOI: 10.1021/acs.joc.7b02803 J. Org. Chem. 2018, 83, 1558−1564

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The Journal of Organic Chemistry Scheme 1. One-Pot Synthesis of Functionalized Bicyclic Iminosugars from C-nitromethyl Glycoside 8

Table 1. Synthesis of Isoxazoline-Fused Indolizidine-Based Iminosugar

a

entry

reagent

temp (°C)

T (h)

1 2 3 4

(Boc)2O (4 equiv)/DMAP (catalyst) (Boc)2O (4 equiv)/DMAP (catalyst) PhNCO (4 equiv)/Et3N (1 equiv) PhNCO (4 equiv)/Et3N (1 equiv)

28 28 28 80

12 13 8 3

yield (%)a

product 10 11 12 12

(viscous liquid) (viscous liquid) (crystalline solid) (crystalline solid)

76 74 82 90

Isolated yield after column chromatography.

Scheme 2. Plausible Reaction Pathway to Iminosugar 12

the corresponding tricyclic iminosugar 11 in 74% yield with a good stereoselectivity (entry 2).18 Intriguingly, C-nitromethyl glycoside 8 on exposure to phenyl isocyanate (PhNCO) and triethylamine in toluene at rt afforded the corresponding 1,3-dipolar adduct 12 as a white crystalline solid in 82% yield (Table 1, entry 3). Moreover, the reaction of iminosugar C-nitromethyl glycoside 8 with PhNCO was found to be facile (3 h) at 80 °C, and the desired adduct 12 was isolated in an excellent yield (Table 1, entry 4). The structure of the cyclized product 12 was established using 1H NMR, 13C NMR, 2D NMR, and HRMS data, and the stereochemistry was unambiguously confirmed by single-crystal X-ray analysis.19 The nitrile oxide cycloaddition reaction appears to proceed through the transition state of lower energy (8c) rather than the sterically less favored transition state (8b) (Scheme 2).20 Encouraged by this facile stereoselective intramolecular nitrile oxide cycloaddition reaction, the generality and scope of this method were further investigated with various

nitrile oxide cycloaddition (INOC) has not been explored in the synthesis of functionalized iminosugars. It is anticipated that the nitromethyl side chain present in iminosugar N-allyl-C-glycoside 8 could serve as a source of nitrile oxide under dehydrative conditions, and thus the synthetic versatility of iminosugar C-nitromethyl glycosides could be further explored in the stereoselective synthesis of isoxazoline-fused bicyclic iminosugars using INOC as a key step. Thus, treatment of iminosugar N-allyl-C-nitromethyl glycoside 8 with (Boc)2O and DMAP in toluene at rt resulted in the generation of nitrile oxide 8a, which by ensuing intramolecular 1,3-dipolar cycloaddition afforded a novel isoxazoline-fused indolizidine derivative 10 in 76% yield as a viscous liquid (Table 1, entry 1). The 1H and 13C NMR spectra of the crude reaction mixture revealed that the INOC reaction is highly diastereoselective (>19:1).17 Under similar reaction conditions, iminosugar N-cinnamyl-C-nitromethyl glycoside 9 furnished 1559

DOI: 10.1021/acs.joc.7b02803 J. Org. Chem. 2018, 83, 1558−1564

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The Journal of Organic Chemistry iminosugar N-allyl/homoallyl/propargyl C-nitromethyl glycosides, and the results are summarized in Table 2.

Under the reaction conditions, the iminosugar N-allyl-Cnitromethyl glycosides 13 and 15 furnished the corresponding isoxazoline-fused polyhydroxylated indolizidine derivative 14 and pyrrolizidine derivative 16, respectively, in good yields (Table 2, entries 1 and 2). Similarly, iminosugar N-homoallylC-nitromethyl glycosides 17 and 19 smoothly underwent stereoselective 1,3-dipolar addition, resulting in isoxazolinefused quinolizidine and indolizidine derivatives 18 and 20, respectively, in excellent yields (Table 2, entries 3 and 4). The stereochemical outcome of this INOC reaction can be rationalized based on the six-membered chair-like transition state (TS) models as shown in Scheme 3. The nitrile oxide functional group present in 17a could approach the terminal double bond through an endo and exo fashion, leading to sixmembered chair-like transition states 17b and 17c, respectively. Due to steric interactions in TS 17b, the TS 17c is energetically favored21 and thus the reaction leads to cyclic adduct 18 with a good selectivity.22 The structure and relative stereochemistry of the iminosugars 18 and 20 were further unambiguously confirmed by singlecrystal X-ray analyses.19 Under similar reaction conditions, the N-propargyl iminosugars 21 and 23 afforded the corresponding isoxazole-fused indolizidine derivative 22 and pyrrolizidine derivative 24, respectively, in very good yields (Table 2, entries 5 and 6). Deprotection of acetonide in 22 using 6 N HCl resulted in a novel iminosugar 25 in 95% yield (Scheme 4).

Table 2. Synthesis of Isoxazoline and Isoxazole-Fused Bicyclic Iminosugar Derivativesa

Scheme 4. Deprotection of Acetonide in 22

Moreover, the synthetic utility of isoxazoline-fused iminosugar 10 was further shown in the stereoselective synthesis of functionalized indolizidine derivative 26 (Scheme 5). Thus, Scheme 5. Synthesis of Indolizidine Derivative 26 from Iminosugar 10

a

Reaction conditions: starting material (1 equiv), PhNCO (4 equiv), and Et3N (1 equiv) in dry toluene (5 mL) at 80 °C. bIsolated yield after column chromatography.

reductive cleavage of isoxazoline in iminosugar 10 under catalytic hydrogenation11e using H2−Pd/C followed by protection with (Boc)2O−triethylamine in the presence of a

Scheme 3. Rationalization of Stereochemical Outcome Based on Six-Membered Chair-Like TS

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DOI: 10.1021/acs.joc.7b02803 J. Org. Chem. 2018, 83, 1558−1564

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The Journal of Organic Chemistry

as described earlier, N-trans-cinnamyl iminosugar C-nitromethyl glycoside 9 (60 mg, 0.17 mmol) was allowed to react with (Boc)2O (156 μL, 0.68 mmol) and DMAP (0.1 equiv) at rt for 13 h. Purification of the crude product by column chromatography over silica gel (gradient elution with 20−30% EtOAc in hexane) afforded the isoxazoline-fused indolizidine based iminosugar 11 in 74% yield (55 mg) as a colorless viscous liquid: [α]22 D +30.5 (c 0.5, CHCl3); IR (neat) 3038, 2988, 1737, 1632, 1604, 1467, 1378, 1267 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.43−7.32 (m, 5H), 5.32 (d, J = 13.0 Hz, 1H), 5.00 (ddd, J = 10.0, 6.0, 4.0 Hz, 1H), 4.54 (t, J = 4.5 Hz, 1H), 4.24 (dd, J = 9.0, 4.5 Hz, 1H), 3.93−3.85 (m, 1H), 3.38 (d, J = 8.5 Hz, 1H), 3.24 (t, J = 7.5 Hz, 1H), 3.20 (dd, J = 10.5, 6.0 Hz, 1H), 2.81 (t, J = 10.5 Hz, 1H), 2.64 (t, J = 9.0 Hz, 1H), 1.61 (s, 3H), 1.49 (s, 9H), 1.39 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 170.7, 152.9, 136.9, 128.8, 126.9, 110.9, 87.9, 83.1, 74.8, 73.7, 70.7, 60.3, 60.1, 54.0, 49.7, 28.2, 27.9, 26.2 ppm; HRMS (ESI) m/z calcd for C23H31N2O6 [M+ + H] 431.2182, found 431.2164. General Procedure for the Synthesis of Isoxazoline/ Isoxazole-Fused Bicyclic Iminosugars (12, 14, 16, 18, 20, 22, and 24) from C-Nitromethyl Glycosides (8, 13, 15, 17, 19, 21, and 23). To a stirred solution of azeotropically dried N-allyl iminosugar C-nitromethyl glycoside 8 (80 mg, 0.29 mmol) in dry toluene (5 mL) were slowly added phenyl isocyanate (129 μL, 1.17 mmol) and triethylamine (40 μL, 0.29 mmol) dropwise at room temperature under N2, and the resulting mixture was stirred further for 3 h at 80 °C. After completion of the reaction, as indicated by TLC, toluene was removed under reduced pressure to give the crude product, which was purified by column chromatography over silica gel (gradient elution with 25−30% EtOAc in hexane) to afford the isoxazoline-fused indolizidine based iminosugar 12 in 90% yield (98 mg) as a white crystalline solid. (3aR,4R,7aS,10bS,10cS)-2,2-Dimethyl-3a,4,5,7,7a,8,10b,10c-octahydro-[1,3]dioxolo[4,5-g]isoxazolo[3,4-a]indolizin-4-yl Phenylcarbamate (12): mp 210−212 °C; [α]30 D +55.8 (c 1.0, CHCl3); IR (KBr) 3314, 3054, 2925, 1731, 1602, 1540, 1445, 1378 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.4 Hz, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.92 (brs, 1H), 5.26−5.21 (m, 1H), 4.55 (t, J = 4.4 Hz, 1H), 4.53−4.50 (m, 1H), 4.23 (dd, J = 8.8, 4.8 Hz, 1H), 3.90−3.83 (m, 2H), 3.29 (d, J = 9.6 Hz, 1H), 3.26 (t, J = 6.8 Hz, 1H), 3.23 (dd, J = 10.4, 6.0 Hz, 1H), 2.76 (t, J = 10.0 Hz, 1H), 2.47 (t, J = 8.4 Hz, 1H), 1.62 (s, 3H), 1.41 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.1, 152.5, 137.6, 129.2, 123.8, 118.7, 110.7, 74.9, 74.5, 72.7, 68.9, 59.9, 54.6, 54.4, 49.8, 28.3, 26.3 ppm; HRMS (ESI) m/z calcd for C19H23N3O5Na [M+ + Na] 396.1524, found 396.1530. (3aS,4R,7aR,10bR,10cR)-2,2-Dimethyl-3a,4,5,7,7a,8,10b,10c-octahydro-[1,3]dioxolo[4,5-g]isoxazolo[3,4-a]indolizin-4-yl Phenylcarbamate (14). Following the general procedure as described earlier, the N-allyl iminosugar C-nitromethyl glycoside 13 (80 mg, 0.29 mmol) was allowed to react with PhNCO (129 μL, 1.17 mmol) and Et3N (40 μL, 0.29 mmol) for 4 h. After column chromatography over silica gel, the product 14 (83 mg, 76%) was obtained as a white semisolid: Rf = 0.3 in 30% EtOAc in hexane; [α]30 D −57.5 (c 1.0, CHCl3); IR (KBr) 3315, 2926, 1730, 1600, 1542, 1445, 1378 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.86 (brs, 1H), 5.23 (s, 1H), 4.52 (t, J = 7.6, 1H), 4.30− 4.25 (m, 2H), 4.00−3.82 (m, 2H), 3.27 (t, J = 7.6 Hz, 1H), 3.15−3.00 (m, 2H), 3.94 (dd, J = 12.8, 2.8 Hz, 1H), 2.38 (t, J = 8.4 Hz, 1H), 1.56 (s, 3H), 1.38 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.6, 152.4, 137.6, 129.3, 123.9, 118.8, 109.8, 75.6, 73.5, 72.9, 69.9, 60.8, 54.9, 54.4, 52.7, 28.3, 26.3 ppm; HRMS (ESI) m/z calcd for C19H23N3O5Na [M+ + Na] 396.1524, found 396.1530. (S)-1-((3aS,6R,6aR,9aS,9bS)-8,8-Dimethyl-3a,4,6,6a,9a,9b-hexahydro-3H-[1,3]dioxolo[4,5-a]isoxazolo[4,3-f ]pyrrolizin-6-yl)ethyl Phenylcarbamate (16). The reaction of N-allyl iminosugar Cnitromethyl glycoside 15 (80 mg, 0.28 mmol) with PhNCO (122 μL, 1.12 mmol) and Et3N (39 μL, 0.28 mmol) was carried out for 4 h following the general procedure. The crude compound was purified by column chromatography over silica gel to give a white solid 16 (89 mg) in 82% yield: Rf = 0.3 in 30% EtOAc in hexane; mp 168−170 °C; [α]29 D −12.0 (c 1.0, CHCl3); IR (KBr) 3336, 3055, 2926, 1730, 1602, 1533, 1449, 1376 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J =

catalytic amount of DMAP furnished bicyclic iminosugar 26 in 74% yield as a single isomer (Scheme 5). In conclusion, we have demonstrated the synthetic utility of N-alkenyl/alkynyl iminosugar C-nitromethyl glycosides in the stereoselective synthesis of isoxazoline/isoxazole-fused iminosugar derivatives using the INOC reaction as a key step. Salient features of this novel transformation are (i) facile and highly stereoselective, and furnishing the product in excellent yield, (ii) provide an easy access to synthetically challenging novel isoxazoline-fused indolizidine-, pyrrolizidine-, and quinolizidine-based iminosugars, and (iii) N-alkyne iminosugar Cnitromethyl glycosides provide direct access to isoxazole-fused iminosugars in very good yields. Moreover, the isoxazoline ring undergoes a facile reductive cleavage to provide functionalized bicyclic iminosugar derivatives in high yields.

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EXPERIMENTAL SECTION

General Information. All of the solvents were distilled prior to use. Dry solvents were prepared according to the standard procedures. All other reagents were used as received from either Aldrich or Lancaster chemical companies. Reactions requiring an inert atmosphere were carried out under a nitrogen atmosphere. Infrared (IR) spectra were recorded on a JASCO 4100 FT-IR spectrometer. 1H NMR spectra were measured on Bruker AVANCE 400 and 500 MHz spectrometers. Chemical shifts were reported in ppm from tetramethylsilane in the case of CDCl3 as an internal standard. 13C NMR spectra were recorded on Bruker 100 and 125 MHz spectrometers with complete proton decoupling. Chemical shifts were reported in ppm from the residual solvent as an internal standard. The high-resolution mass spectra (HRMS) were performed on a Micromass Q-TOF spectrometer equipped with a Harvard apparatus syringe pump. Optical rotations were measured on a JASCO P-2000 polarimeter. X-ray crystallographic data were recorded using a BrukerAXS Kappa CCD diffractometer with graphite-monochromatic Mo Kα radiation (λ = 0.7107 Å). The structures were solved by direct methods (SHELXS-97) and refined by full-matrix least-squares techniques against F2 (SHELXL-97). Hydrogen atoms were inserted from geometry consideration using the HFIX option of the program. For thin-layer chromatography (TLC) analysis throughout this work, E-merck precoated TLC plates (silica gel 60 F254 grade, 0.25 mm) were used. Acme (India) silica gel (100−200 mesh) was used for column chromatography. Procedure for the Synthesis of tert-Butyl (3aR,4R,7aS,10bS,10cS)-2,2-Dimethyl-3a,4,5,7,7a,8,10b,10c-octahydro-[1,3]dioxolo[4,5-g]isoxazolo[3,4-a]indolizin-4-yl Carbonate (10). To a stirred solution of azeotropically dried N-allyl iminosugar C-nitromethyl glycoside 8 (80 mg, 0.29 mmol) in dry toluene (5 mL) were slowly added (Boc)2O (268 μL, 1.17 mmol) and DMAP (5 mg, 0.029 mmol, 0.1 equiv) at room temperature under N2, and the resulting mixture was stirred further for 12 h at rt. After completion of the reaction, as indicated by TLC, the solvent was removed under reduced pressure to give the crude product. Purification of the crude product by column chromatography over silica gel (gradient elution with 20−30% EtOAc in hexane) afforded the isoxazoline-fused indolizidine based iminosugar 10 in 76% yield (78 mg) as a colorless viscous liquid: [α]30 D +61.7 (c 0.5, CHCl3); IR (neat) 2937, 1740, 1637, 1420, 1376, 1217, 1159, 1048 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.97 (ddd, J = 9.6, 6.0, 4.4 Hz, 1H), 4.50 (t, J = 4.4 Hz, 1H), 4.49−4.44 (m, 1H), 4.16 (dd, J = 8.8, 4.4 Hz, 1H), 3.89−3.79 (m, 2H), 3.26 (d, J = 8.8 Hz, 1H), 3.24−3.20 (m, 1H), 3.17 (dd, J = 10.8, 6.0 Hz, 1H), 2.74 (t, J = 10.0 Hz, 1H), 2.44 (t, J = 8.4 Hz, 1H), 1.56 (s, 3H), 1.46 (s, 9H), 1.35 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.1, 152.9, 110.8, 83.0, 74.8, 73.7, 72.7, 70.7, 59.8, 54.6, 54.4, 49.6, 28.2, 27.8, 26.2 ppm; HRMS (ESI) m/z calcd for C17H26N2O6Na [M+ + Na] 377.1689, found 377.1684. tert-Butyl (3aR,4R,7aS,8S,10bS,10cS)-2,2-Dimethyl-8-phenyl3a,4,5,7,7a,8,10b,10c-octahydro-[1,3]dioxolo[4,5-g]isoxazolo[3,4-a]indolizin-4-yl Carbonate (11). Following a similar procedure 1561

DOI: 10.1021/acs.joc.7b02803 J. Org. Chem. 2018, 83, 1558−1564

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The Journal of Organic Chemistry

82% yield (88 mg): Rf = 0.3 in 30% EtOAc in hexane; mp 168−170 °C; [α]29 D +29.8 (c 1.0, CHCl3); IR (KBr) 3424, 3055, 2926, 1732, 1628, 1603, 1533, 1449, 1376 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.24−7.17 (m, 3H), 6.97 (t, J = 7.6 Hz, 1H), 5.19−5.11 (m, 1H), 4.59 (dd, J = 7.2, 3.6 Hz, 1H), 4.53 (d, J = 3.2 Hz, 1H), 4.44 (t, J = 7.6 Hz, 1H), 3.86 (d, J = 12.8 Hz, 1H), 3.72 (d, J = 13.2 Hz, 1H), 3.24 (dd, J = 9.6, 8.0 Hz, 1H), 1.50 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H), 1.24 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 169.2, 152.8, 149.2, 137.8, 129.1, 123.7, 121.1, 118.7, 115.0, 84.4, 82.5, 71.2, 70.5, 65.7, 43.8, 27.5, 25.4, 18.6 ppm; HRMS (ESI) m/z calcd for C20H24N3O5 [M+ + H] 386.1710, found 386.1707. Synthesis of (7R,8S,9S,9aS)-8,9-Dihydroxy-4,6,7,8,9,9ahexahydroisoxazolo[3,4-a]indolizin-7-yl Phenylcarbamate (25). A stirred solution of iminosugar derivative 22 (50 mg, 0.13 mmol) in 5 mL of methanol was treated with 6 N HCl (0.2 mL), and the resultant mixture was stirred at rt for 12 h. The solvent was removed under reduced pressure, and the resultant residue was dissolved in dichloromethane (25 mL), washed with a saturated solution of sodium hydrogen carbonate (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 25 as an off-white solid (42 mg) in 95% yield: Rf = 0.3 in 80% EtOAc in hexane; mp 162−164 °C; [α]23 D −8.4 (c 0.5, MeOH); IR (KBr) 3465, 3052, 2987, 1681, 1419, 1370, 1210, 1032 cm−1; 1H NMR (500 MHz, CD3OD) δ 8.26 (t, J = 1.0 Hz, 1H), 7.43 (dd, J = 9.0, 1.0 Hz, 2H), 7.30−7.25 (m, 2H), 7.02 (tt, J = 14.0, 1.0 Hz, 1H), 4.92 (ddd, J = 10.5, 5.0, 2.5 Hz, 1H), 4.27 (t, J = 2.5 Hz, 1H), 4.05−4.00 (m, 2H), 3.73 (dt, J = 12.0, 1.0 Hz, 1H), 3.63 (dd, J = 10.0, 2.5 Hz, 1H), 3.18 (t, J = 11.0 Hz, 1H), 3.05 (dd, J = 11.5, 5.0 Hz, 1H) ppm; 13C NMR (125 MHz, CD3OD) δ 172.1, 155.1, 150.1, 140.2, 129.9, 124.3, 122.5, 119.9, 71.4, 71.3, 70.7, 59.1, 48.3, 47.2 ppm; HRMS (ESI) calcd for C16H17N3O5Na [M+ + Na] 354.1066, found 354.1031. Synthesis of tert-Butyl (3aR,4R,8S,9S,9aS,9bS)-4-(tert-Butoxycarbonyloxy)-8-((tert-butoxycarbonyloxy)methyl)-2,2-dimethyloctahydro-[1,3]dioxolo[4,5-g]indolizin-9-ylcarbamate (26). To a solution of isoxazoline-fused iminosugar 10 (80 mg, 0.22 mmol) in dry ethyl acetate (6 mL) was added Pd/C (10%, 15 mg), and the resultant mixture was stirred at rt for 16 h under H2. The catalyst was filtered through a pad of Celite and washed with ethyl acetate, and the combined filtrate was concentrated under reduced pressure. The crude product was dissolved in dry DCM (3 mL) and treated with (Boc)2O (202 μL, 0.88 mmol), Et3N (30 μL, 0.22 mmol), and DMAP (10 mg) at 0 °C. The reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was diluted with DCM (50 mL), washed with aqueous NaHCO3, dried over anhydrous Mg2SO4, filtered, and concentrated under reduced pressure. Purification of residue by column chromatography on silica gel eluting with 15% ethyl acetate in hexane gave 26 as a colorless viscous liquid in 74% yield (90 mg): Rf = 0.3 in 25% EtOAc in hexane; [α]22 D +26 (c 0.5, CHCl3); IR (neat) 3214, 2982, 1745, 1692, 1500, 1370, 1255, 1158, 1050 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.95−4.90 (m, 1H), 4.68 (d, J = 6.8 Hz, 1H), 4.45 (t, J = 4.4 Hz, 1H), 4.12 (dd, J = 11.2, 4.0 Hz, 1H), 4.05 (dd, J = 8.8, 4.8 Hz, 1H), 4.00 (dd, J = 11.2, 6.4 Hz, 1H), 3.95 (dd, J = 16.4, 8.8 Hz, 1H), 3.26 (t, J = 8.8 Hz, 1H), 3.03 (dd, J = 9.6, 5.2 Hz, 1H), 2.76− 2.67 (m, 1H), 2.39 (t, J = 10.4 Hz, 1H), 2.29 (t, J = 8.0 Hz, 1H), 2.13 (t, J = 8.4 Hz, 1H), 1.55 (s, 3H), 1.48 (s, 9H), 1.46 (s, 9H), 1.44 (s, 9H), 1.36 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 156.0, 153.4, 152.8, 110.4, 82.9, 82.2, 79.8, 77.7, 73.3, 70.9, 67.6, 66.1, 56.9, 55.8, 50.3, 37.2, 28.4, 28.3, 27.8, 27.8, 26.5 ppm; HRMS (ESI) m/z calcd for C27H47N2O10 [M+ + H] 559.3231, found 559.3212.

8.0 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.07 (tt, J = 7.2, 1.2 Hz, 1H), 6.88 (brs, 1H), 5.19−5.10 (m, 1H), 4.80 (dd, J = 6.4, 2.0 Hz, 1H), 4.54−4.48 (m, 2H), 4.35 (s, 1H), 4.05−3.94 (m, 1H), 3.89 (dd, J = 12.0, 8.0 Hz, 1H), 3.31 (t, J = 7.6 Hz, 1H), 3.20 (dd, J = 10.0, 8.8 Hz, 1H), 2.42 (t, J = 8.8 Hz, 1H), 1.55 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.33 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.7, 152.7, 137.7, 129.2, 123.8, 118.7, 114.6, 85.1, 81.9, 73.3, 70.4, 70.2, 63.1, 54.3, 50.9, 27.7, 25.5, 18.4 ppm; HRMS (ESI) m/z calcd for C20H26N3O5 [M+ + H] 388.1867, found 388.1857. (3aR,8R,8aR,11aS,11bS)-3a,10,10-Trimethyl3a,4,5,7,8,8a,11a,11b-octahydro-3H-[1,3]dioxolo[4,5-a]isoxazolo[4,3-h]quinolizin-8-yl Phenylcarbamate (18). Following the general procedure, the reaction of N-homoallyl iminosugar C-nitromethyl glycoside 17 (80 mg, 0.27 mmol) with PhNCO (116 μL, 1.08 mmol) and Et3N (37 μL, 0.27 mmol) was carried out for 3 h. After column chromatography, product 18 (92 mg) was obtained as a white crystalline solid in 85% yield: Rf = 0.2 in 30% EtOAc in hexane; mp 208−210 °C; [α]34 D +31.0 (c 1.0, CHCl3); IR (KBr) 3054, 2986, 2930, 2855, 1739, 1600, 1528, 1443 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 6.92 (brs, 1H), 5.19−5.14 (m, 1H), 4.61−4.55 (m, 2H), 4.27 (d, J = 8.0 Hz, 1H), 3.87 (d, J = 7.5 Hz, 1H), 2.98 (dd, J = 10.5, 5.0 Hz, 1H), 2.91 (d, J = 8.0 Hz, 1H), 2.83 (dt, J = 12.0, 3.5 Hz, 1H), 2.62 (t, J = 10.5 Hz, 1H), 2.55 (dd, J = 12.5, 3.5 Hz, 1H), 1.90−1.81 (m, 2H), 1.58 (s, 3H), 1.42 (s, 3H), 1.27 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 161.2, 152.3, 137.6, 129.2, 123.8, 118.6, 110.7, 82.2, 74.8, 73.5, 67.9, 59.5, 52.5, 50.9, 49.3, 36.5, 28.4, 26.4, 20.6 ppm; HRMS (ESI) m/z calcd for C21H28N3O5 [M+ + H] 402.2029, found 402.2056. (S)-1-((3aR,7R,7aR,10aS,10bS)-3a,9,9-Trimethyl3,3a,4,5,7,7a,10a,10b-octahydro-[1,3]dioxolo[4,5-a]isoxazolo[4,3g]indolizin-7-yl)ethyl Phenylcarbamate (20). Under similar reaction conditions, the reaction of N-homoallyl iminosugar C-nitromethyl glycoside 19 (80 mg, 0.25 mmol) with PhNCO (111 μL, 1.02 mmol) and Et3N (35 μL, 0.25 mmol) for 4 h afforded compound 20 (90 mg) as a white crystalline solid in 87% yield: Rf = 0.3 in 30% EtOAc in hexane; mp 208−210 °C; [α]28 D −48.8 (c 1.0, CHCl3); IR (KBr) 3054, 2986, 1734, 1600, 1527, 1443 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.82 (brs, 1H), 5.16 (quintet, J = 6.4 Hz, 1H), 4.74 (t, J = 6.8 Hz, 1H), 4.57 (dd, J = 7.2, 4.0 Hz, 1H), 4.25 (d, J = 7.6 Hz, 1H), 3.81 (d, J = 8.0 Hz, 1H), 3.16 (d, J = 6.4 Hz, 1H), 3.02−2.98 (m, 1H), 2.96 (t, J = 4.4 Hz, 1H), 2.54 (td, J = 12.0, 2.4 Hz, 1H), 1.86 (dt, J = 12.8, 2.4 Hz, 1H), 1.78−1.70 (m, 1H), 1.53 (s, 3H), 1.37 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.25 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 160.3, 152.9, 137.9, 129.1, 123.5, 118.7, 114.5, 81.8, 79.2, 78.1, 70.3, 69.9, 64.4, 49.7, 45.9, 37.6, 27.3, 25.3, 20.9, 15.2 ppm; HRMS (ESI) m/z calcd for C22H30N3O5 [M+ + H] 416.2185, found 416.2176. (3aR,4R,10bS,10cS)-2,2-Dimethyl-3a,4,5,7,10b,10c-hexahydro[1,3]dioxolo[4,5-g]isoxazolo[3,4-a]indolizin-4-yl Phenylcarbamate (22). Following a similar procedure, exposure of N-propargyl iminosugar C-nitromethyl glycoside 21 (80 mg, 0.296 mmol) to PhNCO (129 μL, 1.18 mmol) and Et3N (41 μL, 0.296 mmol) for 3 h furnished adduct 22 (95 mg) as an off-white solid in 86% yield: Rf = 0.3 in 40% EtOAc in hexane; mp 179−181 °C; [α]29 D −61.5 (c 1.0, CHCl3); IR (KBr) 3690, 3054, 2986, 1734, 1628, 1603, 1547, 1423 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.2, 1H), 6.92 (brs, 1H), 5.31−5.25 (m, 1H), 4.58 (t, J = 4.4 Hz, 1H), 4.35 (dd, J = 8.4, 4.4 Hz, 1H), 3.98 (d, J = 11.6 Hz, 1H), 3.78 (dd, J = 8.4, 1.2 Hz, 1H), 3.60 (dt, J = 12.0, 1.2 Hz, 1H), 3.27 (dd, J = 10.4, 6.0 Hz, 1H), 2.98 (t, J = 10.0 Hz, 1H), 1.63 (s, 3H), 1.44 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 169.9, 152.5, 148.3, 137.7, 129.3, 123.9, 118.8, 110.9, 75.6, 74.0, 69.0, 60.9, 49.4, 48.0, 28.3, 26.3 ppm; HRMS (ESI) m/z calcd for C19H22N3O5 [M+ + H] 372.1554, found 372.1551. (S)-1-((6R,6aR,9aS,9bS)-8,8-Dimethyl-6,6a,9a,9b-tetrahydro-4H[1,3]dioxolo[4,5-a]isoxazolo[4,3-f ]pyrrolizin-6-yl)ethyl Phenylcarbamate (24). The reaction of N-propargyl iminosugar C-nitromethyl glycoside 23 (80 mg, 0.28 mmol) with PhNCO (122 μL, 1.12 mmol) and Et3N (39 μL, 0.28 mmol) was carried out for 4 h. The product 24 was obtained after column chromatography as an off-white solid in

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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.7b02803. Copies of NMR spectra of all new compounds, crystal data and ORTEP diagrams, optimized geometries, reaction progress for 18, and Cartesian coordinates (PDF) Crystallographic data for 12, 18, and 20 (CIF) 1562

DOI: 10.1021/acs.joc.7b02803 J. Org. Chem. 2018, 83, 1558−1564

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The Journal of Organic Chemistry

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sundarababu Baskaran: 0000-0002-7636-2812 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank DST-SERB (EMR/2016/004040), India, for financial support and DST-FIST for providing instrument facilities. S.S.P. thanks CSIR-New Delhi for a research fellowship. We thank Mr. V. Ram Kumar and Dr. P. K. Sudhadevi Antharjanam for single-crystal X-ray analyses and Dr. E. Varathan for DFT calculations.

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DOI: 10.1021/acs.joc.7b02803 J. Org. Chem. 2018, 83, 1558−1564

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The Journal of Organic Chemistry (17) The 1H NMR and 13C NMR spectra of the crude reaction mixture of 10 are provided in the Supporting Information. (18) The structure and relative stereochemistry of adduct 11 were assigned based on 2D NMR spectra. (See the Supporting Information.) (19) The ORTEP diagram and crystallographic data are given in the Supporting Information. (20) (a) Su, D.; Wang, X.; Shao, C.; Xu, J.; Zhu, R.; Hu, Y. J. Org. Chem. 2011, 76, 188. (b) Kozikowski, A. P.; Stein, P. D. J. Org. Chem. 1984, 49, 2301. (c) Saha, A.; Bhattacharjya, A. Chem. Commun. 1997, 495. (d) Huang, K. S.-L.; Lee, E. H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 2000, 65, 499. (21) The transition state (TS) geometry and activation energies of 17b and 17c were calculated using DFT (B3LYP/6-31G*), and the results are summarized in the Supporting Information. (22) Inoue, A.; Kanematsu, M.; Mori, S.; Yoshida, M.; Shishido, K. Synlett 2013, 24, 61.

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DOI: 10.1021/acs.joc.7b02803 J. Org. Chem. 2018, 83, 1558−1564