Iminosugar C-Nitromethyl Glycoside: Stereoselective Synthesis of

Subscriber access provided by READING UNIV

Note

Iminosugar C-Nitromethyl Glycoside: Stereoselective Synthesis of Isoxazoline and Isoxazole-Fused Bicyclic Iminosugars Sure Siva Prasad, and Sundarababu Baskaran J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02803 • Publication Date (Web): 09 Jan 2018 Downloaded from http://pubs.acs.org on January 10, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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

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 C-nitromethyl 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 high degree of stereoselectivity, whereas N-alkynyl iminosugar C-nitromethyl glycosides furnished the corresponding isoxazole containing tricyclic iminosugars in very good yields.

Glycosidases and glycosyltransferases are ubiquitous in many living organisms and play 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, exhibit 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 α-glucosidases (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), a Obutyrate derivative of castanospermine, is in phase II clinical trials for the treatment of hepatitis 1 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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 towards the synthesis of novel bicyclic iminosugar derivatives. 9

Figure 1. Biologically active and pharmaceutically important bicyclic iminosugars. Isoxazoline and isoxazole are common structural frameworks present in many biologically active molecules and natural products exhibiting analgesic, hypoglycemic, anticancer and antiinflammatory activities.10 In addition, isoxazoline derivatives are versatile intermediates in the synthesis of α,β-unsaturated ketones, β-amino acids, γ-amino alcohols and β-hydroxyketones.11,12 In general, isoxazoline and isoxazole are synthesized by 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 nitrile oxide cycloaddition (INOC) has not been explored in the synthesis of functionalized iminosugars.

2 ACS Paragon Plus Environment

Page 2 of 16

Page 3 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 1. One-pot synthesis of functionalized bicyclic iminosugars from C-nitromethyl glycoside 8

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 on ensuing intramolecular 1,3dipolar 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 the corresponding tricyclic iminosugar 11 in 74% yield with good stereoselectivity (entry 2).18 Table 1. Synthesis of isoxazoline fused indolizidine-based iminosugar

a

Temp

Entry

Reagent

1

(Boc)2O (4 equiv)/DMAP (cat)

28

12

2

(Boc)2O (4 equiv)/DMAP (cat)

28

13

3

PhNCO (4 equiv)/Et3N (1 equiv)

28

8

4

PhNCO (4 equiv)/Et3N (1 equiv)

80

3

(oC)

T (h)

Product 10 (viscous liquid) 11 (viscous liquid) 12 (crystalline solid) 12 (crystalline solid)

Isolated yield after column chromatography.


Yield (%)a 76

74

82

90


Page 4 of 16

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 Cnitromethyl glycoside 8 with PhNCO was found to be facile (3 h) at 80 oC and the desired adduct 12 was isolated in excellent yield (Table 1, entry 4). The structure of the cyclized product 12 was established using 1H NMR,

13

C 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 sterically less favored transition state 8b (Scheme 2).20 Scheme 2. Plausible reaction pathway to iminosugar 12

Encouraged by this facile stereoselective intramolecular nitrile oxide cycloaddition reaction, the generality and scope of this method was further investigated with various iminosugar Nallyl/homoallyl/propargyl C-nitromethyl glycosides and the results are summarized in Table 2. Under the reaction conditions, the iminosugar N-allyl-C-nitromethyl 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-homoallyl-C-nitromethyl

glycosides

17

and

19

smoothly

underwent

stereoselective 1,3-dipolar addition, resulting in isoxazoline-fused quinolizidine and indolizidine derivatives 18 and 20, respectively, in excellent yields (Table 2, entries 3 and 4).


Page 5 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 2. Synthesis of isoxazoline and isoxazole-fused bicyclic iminosugar derivativesa

a

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

The stereochemical outcome of this INOC reaction can be rationalized based on the sixmembered 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 endo- and exofashion, leading to six-membered 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 good selectivity.22



Scheme 3. Rationalization of stereochemical outcome based on six membered chair-like TS

The structure and relative stereochemistry of the iminosugars 18 and 20 were further unambiguously confirmed by single crystal 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). 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, 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 catalytic amount of DMAP furnished bicyclic iminosugar 26 in 74% yield as a single isomer (Scheme 5). Scheme 5. Synthesis of indolizidine derivative 26 from iminosugar 10

In conclusion, we have demonstrated the synthetic utility of N-alkenyl/alkynyl iminosugar Cnitromethyl glycosides in the stereoselective synthesis of isoxazoline/isoxzole-fused iminosugar derivatives using INOC reaction as a key step. Salient features of this novel transformation are i) facile, highly stereoselective and furnishes the product in excellent yield, ii) provides an easy access to synthetically challenging novel isoxazoline-fused indolizidine, pyrrolizidine and quinolizidine-based iminosugars and iii) N-alkyne iminosugar C-nitromethyl glycosides provide direct access to isoxazole-fused iminosugars in very good yields. Moreover, the isoxazoline ring 6 ACS Paragon Plus Environment

Page 6 of 16

Page 7 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


undergoes facile reductive cleavage to provide functionalized bicyclic iminosugar derivatives in high yields. EXPERIMENTAL SECTION General Information. All 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 inert atmosphere were carried out under nitrogen atmosphere. Infrared (IR) spectra were recorded on a JASCO 4100 FT-IR spectrometer. 1H NMR spectra were measured on Bruker AVANCE 400 MHz and 500 MHz spectrometers. Chemical shifts were reported in ppm from tetramethylsilane in the case of CDCl3 as an internal standard.

13

C NMR spectra were recorded on Bruker 100 MHz 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 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 Bruker-AXS Kappa CCD-Diffract meter with graphite-monochromatic MoKα 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), (Boc)2O (268 µL, 1.17 mmol) and DMAP (5 mg, 0.029 mmol, 0.1 equiv) were slowly added at room temperature under N 2 and the resulting mixture was stirred further for 12 h at rt. After completion of the reaction, as indicated by TLC, 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) 7 ACS Paragon Plus Environment


Page 8 of 16

as a colorless viscous liquid; [α]30D +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;

13

C 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-phenyl

3a,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 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]22D +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;

13

C 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): (3aR,4R,7aS,10bS,10cS)-2,2-Dimethyl-3a,4,5,7,7a,8,10b,10c-octahydro-[1,3]dioxolo[4,5g]isoxazolo[3,4-a]indolizin-4-yl phenylcarbamate (12). To a stirred solution of azeotropically dried N-allyl iminosugar C-nitromethyl glycoside 8 (80 mg, 0.29 mmol) in dry toluene (5 mL), phenyl isocyanate (129 µL, 1.17 mmol) and triethylamine (40 µL, 0.29 mmol) were slowly added drop wise 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 8 ACS Paragon Plus Environment

Page 9 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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; m.p. 210 – 212 °C; [α]30D +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 Et 3N (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]30D -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;

13

C

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[4,5a]isoxazolo[4,3-f]pyrrolizin-6-yl)ethyl phenylcarbamate (16). The reaction of N-allyl iminosugar C-nitromethyl 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); m.p. 168 – 170 °C; [α]29D -12.0 (c 1.0, 9 ACS Paragon Plus Environment


CHCl3); IR (KBr): 3336, 3055, 2926, 1730, 1602, 1533, 1449, 1376 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 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; 13

C 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-Trimethyl-3a,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 Et 3N (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); m.p. 208 – 210°C; [α]34D +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;

13

C 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-Trimethyl-3,3a,4,5,7,7a,10a,10b-octahydro[1,3]dioxolo[4,5-a]isoxazolo[4,3-g]indolizin-7-yl)ethyl phenylcarbamate (20). Under similar reaction conditions, N-homoallyl iminosugar C-nitromethyl glycoside 19 (80 mg, 0.25 mmol) on reaction with PhNCO (111 µL, 1.02 mmol) and Et 3N (35 µL, 0.25 mmol) for 4 h afforded compound 20 (90 mg) as a white crystalline solid (Rf = 0.3 in 30% EtOAc in hexane) in 87% yield); m.p. 208 – 210 °C; [α]28D -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 10 ACS Paragon Plus Environment

Page 10 of 16

Page 11 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(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;

13

C 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[4,5g]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 Et 3N (41 µL, 0.296 mmol) for 3 h furnished adduct 22 (95 mg) as a off-white solid in 86% yield (Rf = 0.3 in 40% EtOAc in hexane); m.p. 179 – 181 °C; [α]29D 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;

13

C

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[4,5a]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 a off-white solid (Rf = 0.3 in 30% EtOAc in hexane) in 82% yield (88 mg); m.p. 168 – 170 °C; [α]29D +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, 11 ACS Paragon Plus Environment


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-4,6,7,8,9,9a-hexahydroisoxazolo[3,4-a]indolizin7-yl phenylcarbamate (25). To a stirred solution of iminosugar derivative 22 (50 mg, 0.13 mmol) in 5 mL of methanol, was treated with 6N HCl (0.2 mL) and the resultant mixture was stirred at rt for 12 h. Solvent was removed under reduced pressure and the resultant residue was dissolved in dichloromethane (25 mL) and washed with saturated solution of sodium hydrogen carbonate (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 25 as a off-white solid (42 mg) in 95% yield (Rf = 0.3 in 80% EtOAc in hexane); m.p. 162 – 164 °C; [α]23D ‒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-butoxy carbonyloxy)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 atmosphere. The catalyst was filtered through a pad of Celite, 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 oC. The reaction mixture was allowed to stirr at rt for 2 h. The reaction mixture was diluted with DCM (50 mL) and 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 (Rf = 0.3 in 25% EtOAc in hexane) in 74% yield (90 mg); [α]22D +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), 12 ACS Paragon Plus Environment

Page 12 of 16

Page 13 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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;

13

C 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. Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Copies of NMR spectra of all new compounds (PDF) ORTEP diagram and crystallographic data for 12, 18 and 20 (CIF) Corresponding Author *E-mail: [email protected] Acknowledgements We thank DST-SERB (EMR/2016/004040), India for financial support and DST-FIST for providing instruments 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. References 1.

(a) Gloster, T. M.; Davies, G. J. Org. Biomol. Chem. 2010, 8, 305. (b) Bols, M.; Lopez, O.; Ortega-Caballero, F. In Glycosidase inhibitors: structure, activity, synthesis, and medical relevance, Elsevier Ltd.: 2007; pp 815-884. (c) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199.

2.

(a) Somsak, L.; Nagy, V.; Hadady, Z.; Docsa, T.; Gergely, P. Curr. Pharm. Des. 2003, 9, 1177. (b) Greimel, P.; Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top. Med. Chem 2003, 3, 513. (c) De Clercq, E. Med. Res. Rev. 2000, 20, 323. (d) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100, 4683. (e) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935. (f) Tyrrell, B. E.; Sayce, A. C.; Warfield, K. L.; Miller, J. L.; Zitzmann, N. Crit. Rev. Microbiol. 2017, 43, 521. (g) Saha, N.; Chattopadhyay, S. K.



Beilstein J. Org. Chem. 2014, 10, 3104. (h) Malinowski, M.; Rowicki, T.; Guzik, P.; Wielechowska, M.; Sobiepanek, A.; Sas, W. Eur. J. Org. Chem. 2016, 3642. 3.

(a) Horne, G.; Wilson, F. X.; Tinsley, J.; Williams, D. H.; Storer, R. Drug Discovery Today 2011, 16, 107. (b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. F. Tetrahedron: Asymmetry 2000, 11, 1645. (c) Compain, P.; Martin, O. R. Iminosugars: From synthesis to therapeutic applications; Wiley, 2007. (d) Li, Q.; Ye, X.-S. Isr. J. Chem. 2015, 55, 336. (e) Pawar, N. J.; Parihar, V. S.; Khan, A.; Joshi, R.; Dhavale, D. D. J. Med. Chem. 2015, 58, 7820. (f) Szczesniak, P.; Stecko, S.; Maziarz, E.; Staszewska-Krajewska, O.; Furman, B. J. Org. Chem. 2014, 79, 10487. (g) Vieira Da Cruz, A.; Kanazawa, A.; Poisson, J.-F.; Behr, J.B.; Py, S. J. Org. Chem. 2017, 82, 9866.

4.

(a) Kato, A.; Kano, E.; Adachi, I.; Molyneux, R. J.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Wormald, M. R.; Kizu, H.; Ikeda, K.; Asano, N. Tetrahedron: Asymmetry 2003, 14, 325. (b) Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1.

5.

(a) Molyneux, R. J.; Roitman, J. N.; Dunnheim, G.; Szumilo, T.; Elbein, A. D. Arch. Biochem. Biophys. 1986, 251, 450. (b) Kato, A.; Hirokami, Y.; Kinami, K.; Tsuji, Y.; Miyawaki, S.; Adachi, I.; Hollinshead, J.; Nash, R. J.; Kiappes, J. L.; Zitzmann, N.; Cha, J. K.; Molyneux, R. J.; Fleet, G. W. J.; Asano, N. Phytochemistry 2015, 111, 124.

6.

(a) Dorling, P. R.; Huxtable, C. R.; Colegate, S. M. Biochem. J. 1980, 191, 649. (b) Hu, X.G.; Bartholomew, B.; Nash, R. J.; Wilson, F. X.; Fleet, G. W. J.; Nakagawa, S.; Kato, A.; Jia, Y.-M.; van Well, R.; Yu, C.-Y. Org. Lett. 2010, 12, 2562. (c) Goss, P. E.; Baptiste, J.; Fernandes, B.; Baker, M.; Dennis, J. W. Cancer Res 1994, 54, 1450.

7.

(a) Whitby, K.; Taylor, D.; Patel, D.; Ahmed, P.; Tyms, A. S. Antiviral Chem. Chemother. 2004, 15, 141. (b) Rathore, A. P. S.; Paradkar, P. N.; Watanabe, S.; Tan, K. H.; Sung, C.; Connolly, J. E.; Low, J.; Ooi, E. E.; Vasudevan, S. G. Antiviral Res. 2011, 92, 453. (c) Low, J. G.; Sung, C.; Wijaya, L.; Wei, Y.; Rathore, A. P. S.; Watanabe, S.; Tan, B. H.; Toh, L.; Chua, L. T.; Hou, Y. a.; Chow, A.; Howe, S.; Chan, W. K.; Tan, K. H.; Chung, J. S.; Cherng, B. P.; Lye, D. C.; Tambayah, P. A.; Ng, L. C.; Connolly, J.; Hibberd, M. L.; Leo, Y. S.; Cheung, Y. B.; Ooi, E. E.; Vasudevan, S. G. Lancet Infect. Dis. 2014, 14, 706.

8.

(a) Walter, S.; Fassbender, K.; Gulbins, E.; Liu, Y.; Rieschel, M.; Herten, M.; Bertsch, T.; Engelhardt, B. J. Neuroimmunol. 2002, 132, 1. (b) Galustian, C.; Foulds, S.; Dye, J. F.; 14 ACS Paragon Plus Environment

Page 14 of 16

Page 15 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Guillou, P. J. Immunopharmacology 1994, 27, 165. (c) Kumar, K. S. A.; Rathee, J. S.; Subramanian, M.; Chattopadhyay, S. J. Org. Chem. 2013, 78, 7406. (d) Li, Q.; Ye, X.-S. Isr. J. Chem. 2015, 55, 336. (e) Pawar, N. J.; Parihar, V. S.; Khan, A.; Joshi, R.; Dhavale, D. D. J. Med. Chem. 2015, 58, 7820. 9.

(a) Vajaria, B. N.; Patel, P. S. Glycoconjugate J. 2017, 34, 147. (b) Whitby, K.; Taylor, D.; Patel, D.; Ahmed, P.; Tyms, A. S. Antiviral Chem. Chemother. 2004, 15, 141. (c) Malik, M.; Witkowski, G.; Ceborska, M.; Jarosz, S. Org. Lett. 2013,15, 6214. (d) Chen, W. A.; Chen, C.-W.; Lee, H.-Y.; Cheng, W.-C. In Inspired from naturally occurring bicyclic iminosugars to develop new molecular scaffolds and libraries, American Chemical Society: 2017; pp ORGN-391. (e) Bergeron-Brlek, M.; Meanwell, M.; Britton, R. Nat. Commun. 2015, 6, 6903. (f) Abrar Alam, M.; Kumar, A.; Vankar, Y. D. Eur. J. Org. Chem. 2008, 4972.

10. (a) Hajlaoui, K.; Guesmi, A.; Ben Hamadi, N.; Msaddek, M. Heterocycl. Commun. 2017, 23, 225. (b) Prajapti, S. K.; Shrivastava, S.; Bihade, U.; Gupta, A. K.; Naidu, V. G. M.; Banerjee, U. C.; Babu, B. N. Med Chem Comm 2015, 6, 839. (c) Proksch, P.; Putz, A.; Ortlepp, S.; Kjer, J.; Bayer, M. Phytochem. Rev. 2010, 9, 475. (d) Quadrelli, P.; Mella, M.; Legnani, L.; Al-Saad, D. Eur. J. Org. Chem. 2013, 4655. (e) Chalyk, B. A.; Kandaurova, I. Y.; Hrebeniuk, K. V.; Manoilenko, O. V.; Kulik, I. B.; Iminov, R. T.; Kubyshkin, V.; Tverdokhlebov, A. V.; Ablialimov, O. K.; Mykhailiuk, P. K. RSC Adv. 2016, 6, 25713. (f) Joshi, V. D.; Kshirsagar, M. D.; Singhal, S. J. Chem. Pharm. Res. 2012, 4, 3234. 11. (a) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J. Am. Chem. Soc. 2005, 127, 5376. (b) Aschwanden, P.; Kvrno, L.; Geisser, R. W.; Kleinbeck, F.; Carreira, E. M. Org. Lett. 2005, 7, 5741. (c) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. J. Org. Chem. 2010, 75, 1961. (d) Ono, N., Ed. The Nitro Group in Organic Synthesis; Wiley & Sons, 2001. (e) Majumdar, S.; Hossain, J.; Natarajan, R.; Banerjee, A. K.; Maiti, D. K. RSC Adv., 2015, 5, 106289. 12. (a) Namboothiri, I. N. N.; Rastogi, N. Top. Heterocycl. Chem. 2008, 12, 1. (b) Padwa, A.; Pearson, W. H.; Editors, Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products. Wiley: 2002; p 940 pp. (c) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247. (d) Kadowaki, A.; Nagata, Y.; Uno, H.; Kamimura, A. Tetrahedron Lett. 2007, 48, 1823. 13. (a) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc.1960, 82, 5339. (b) Larsen, K. E.; Torssell, K. B. G. Tetrahedron 1984, 40, 2985. (c) Basel, Y.; Hassner, A. Synthesis 1997, 15 ACS Paragon Plus Environment


309. (d) Shimizu, T.; Hayashi, Y.; Shibafuchi, H.; Teramura, K. Bull. Chem. Soc. Jpn. 1986, 59, 2827. 14. (a) Chinthapally, K.; Karthik, R.; Senthilkumar, S.; Baskaran, S. Chem. - Eur. J. 2017, 23, 533. (b) Senthilkumar, S.; Prasad, S. S.; Das, A.; Baskaran, S. Chem. - Eur. J. 2015, 21, 15914. (c) Senthilkumar, S.; Prasad, S. S.; Kumar, P. S.; Baskaran, S. Chem. Commun. 2014, 50, 1549. (d) Aravind, A.; Kumar, P. S.; Sankar, M. G.; Baskaran, S. Eur. J. Org. Chem. 2011, 2011, 6980. (e) Kumar, P. S.; Banerjee, A.; Baskaran, S. Angew. Chem., Int. Ed. 2010, 49, 804. (f) Aravind, A.; Sankar, M. G.; Varghese, B.; Baskaran, S. J. Org. Chem. 2009, 74, 2858. 15. Prasad, S. S.; Senthilkumar, S.; Srivastava, A.; Baskaran, S. Org. Lett. 2017, 19, 4403. 16. (a) Siriwardena, A.; Sonawane, D. P.; Bande, O. P.; Markad, P. R.; Yonekawa, S.; Tropak, M. B.; Ghosh, S.; Chopade, B. A.; Mahuran, D. J.; Dhavale, D. D. J. Org. Chem. 2014, 79, 4398. (b) Xu, W.-Y.; Ren, I.; Jia, Y.-M.; Zhang, W.; Kato, A.; Yu, C.-Y. Org. Biomol. Chem. 2013, 11, 4622. (c) Duff, F. J.; Vivien, V.; Wightman, R. H. Chem. Commun. 2000, 2127. (d) Khangarot, R. K.; Kaliappan, K. P. Eur. J. Org. Chem. 2012, 2012, 5844. (e) Cardona, F.; Lalli, D.; Faggi, C.; Goti, A.; Brandi, A. J. Org. Chem. 2008, 73, 1999. (f) Gkizis, P.; Argyropoulos, N. G.; Coutouli-Argyropoulou, E. Tetrahedron 2013, 69, 8921. 17. The 1H NMR and 13C NMR spectra of crude reaction mixture of 10 are provided in SI. 18. The structure and relative stereochemistry of adduct 11 were assigned based on 2D NMR spectra (see SI). 19. The ORTEP diagram and crystallographic data are given in SI. 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 SI. 22. Inoue, A.; Kanematsu, M.; Mori, S.; Yoshida, M.; Shishido, K. Synlett 2013, 24, 61.


Page 16 of 16

Iminosugar C-Nitromethyl Glycoside: Stereoselective Synthesis of

Recommend Documents