One-Pot Synthesis of Structurally Diverse ... - ACS Publications

Article Cite This: J. Org. Chem. 2018, 83, 9604−9618

pubs.acs.org/joc

One-Pot Synthesis of Structurally Diverse Iminosugar-Based Hybrid Molecules Sure Siva Prasad, Narra Rajashekar Reddy, and Sundarababu Baskaran* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India

Downloaded via UNIV OF SOUTH DAKOTA on September 8, 2018 at 07:30:58 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: A one-pot iminium-ion-based strategy has been developed for the synthesis of structurally novel iminosugarbased hybrid molecules. Iminium ion derived from L-rhamnose lactol-mesylate reacted with electron-rich aromatic systems in an inter/intra molecular fashion to furnish pyrrolidine-based iminosugar C-aryl glycosides with a high degree of stereoselectivity. Iminium ion also reacted readily with active methylene compounds such as 4-hydroxycoumarin, 4-hydroxyquinolinone, and lawsone to provide iminosugar C-coumarin/quinolinone/naphthoquinonyl glycosides in very good yields. Azomethine ylide generated from an iminium ion derivative underwent dipolar cycloaddition reaction with 1,4-quinones to furnish novel isopyrrolonaphtho/anthroquinon-based iminosugar-hybrids. The preliminary cytotoxic activities of some of the synthesized iminosugar-hybrids have been assayed against various human cancer cell lines and some of the hybrid molecules exhibited promising anticancer activities.

■

INTRODUCTION Iminosugars, widely present in various plants and microorganisms, are an important class of carbohydrate mimics in which the endocyclic oxygen atom is replaced with a nitrogen atom.1 Because of their structural resemblance to the oxacarbenium-ion-like transition state that occurs during the enzymatic hydrolysis of carbohydrates, iminosugars exhibit selective inhibitory activities against therapeutically significant carbohydrate-processing enzymes including glycosidases, glycosyltransferase, and nucleoside-processing enzymes such as nucleoside hydrolase and purine nucleoside phosphorylase (PNP).1,2 As a result, iminosugars serve as potential lead molecules for the treatment of diabetes, viral infections, inflammation, tumor growth and metastasis, and lysosomal storage disorders.3,4 Structure−activity relationship (SAR) studies on iminosugars revealed that the structural modifications and/or introduction of hydrophobic substituents at N-/ C1-position significantly alter their potency and specificity toward the glycosidase inhibitory activities.1−5 The hydrophobically modified 1-deoxynojirimycin (DNJ) derivatives,3 Glyset (N-hydroxyethyl-DNJ), and Zavesca (N-butyl-DNJ) have already been approved for the oral treatment of type II diabetes and Gaucher disease, respectively (Figure 1). The glycoconjugates, derived from polyhydroxylated pyrrolidine and piperidine with aryl/heteroaryl substitution at C-1 anomeric position, are stable toward various chemical and enzymatic degradations.6−10 These iminosugar C-aryl/heteroaryl-based glycoconjugates are known to display a wide range © 2018 American Chemical Society

of biological activities, for instance, the naturally occurring iminosugar C-aryl glycosides, radicamine A and radicamine B (Figure 1), show potent α-glucosidase inhibitory activities.8 Likewise, the synthetic iminosugar forodesine, a potent purine nucleoside phosphorylase inhibitor, exhibits a very strong antitumor activity, and consequently, it is in phase II clinical trials for the treatment of T-cell acute lymphocytic leukemia.6 Moreover, the synthetic pyrrolidine C-aryl glycosides are potent α-L-fucosidase inhibitors.9 Due to the broad spectrum of biological activities coupled with a wide variety of therapeutic applications, several synthetic approaches have been reported for the stereocontrolled synthesis of iminosugar C-aryl/heteroaryl/alkyl glycosides.1,6,10 However, development of simple and efficient strategies, which provide structurally diverse and biologically relevant molecules, are much sought after. Iminium ion has long been used as a key intermediate for the synthesis of nitrogen heterocycles, particularly in the synthesis of biologically important alkaloids through carbon− carbon and carbon−heteroatom bond-forming reactions.11 The Mannich,12 aza-Cope,13 Beckmann,14 and Pictet− Spengler15 reactions exemplify the significance of iminium ion chemistry in organic synthesis. As part of our ongoing research,16 we recently reported an iminium-ion-based one-pot methodology for the stereoselective synthesis of iminosugar CReceived: March 25, 2018 Published: August 13, 2018 9604

DOI: 10.1021/acs.joc.8b00748 J. Org. Chem. 2018, 83, 9604−9618

Article

The Journal of Organic Chemistry

Figure 1. Biologically active and pharmaceutically important iminosugars.

Scheme 1. Facile Synthesis of Polyhydroxy Tetrahydroindolizine

Scheme 2. Synthesis of Iminosugar 2-Acyl Indolizidine

Scheme 3. Divergent Synthesis of Polycyclic Iminosugars from Iminosugar C-Nitromethyl Glycosides

alkynyl glycosides using copper acetylide as a carbon

The synthetic power of the iminium ion chemistry was

nucleophile (Scheme 1).The synthetic usefulness of iminosu-

further demonstrated in the short and efficient synthesis of

gar N-allyl-C-alkynyl glycosides was further shown in the

iminosugar 2-acyl indolizidines in a stereoselective manner.

synthesis of conformationally locked 1-vinyl tetrahydroindoli-

This iminium ion strategy involves aza-Cope rearrangement

zine derivatives using ring closing metathesis (RCM) reaction

followed by intramolecular Mannich cyclization as key steps

as a key step (Scheme 1).

17

(Scheme 2).18 9605


Article


Consequently, we envisaged that iminosugar C-coumarin/ quinolinone/naphthoquinonyl glycosides could display a broad spectrum of biological activities. Thus, active methylene pharmacophores such as 4-hydroxycoumarin, 4-hydroxyquinolinone, and lawsone could serve as a carbon nucleophile in our one-pot iminium ion reaction, leading to a new class of biologically significant novel iminosugar-based hybrid molecules (Figure 3). The main objective of the present study is to explore the iminium ion strategy toward the stereoselective synthesis of iminosugar-based hybrid molecules using electron-rich aromatic ring systems and active methylene compounds as carbon nucleophiles.

Moreover, the one-pot iminium ion method has recently been exploited in the stereoselective synthesis of novel iminosugar C-nitromethyl glycosides using nitromethane as a carbon nucleophile, whose synthetic versatility was further demonstrated in the single-step synthesis of a wide variety of bi/tricyclic iminosugar derivatives (Scheme 3).19 Iminosugar C-nitromethyl glycoside, under SET oxidative cyclization conditions, furnished cyclopropane-fused iminosugar 7, whereas upon exposure to (Boc)2O/DMAP underwent intramolecular nitrile oxide cycloaddition (INOC) reaction leading to isoxazoline-fused indolizidine derivative 8. Intriguingly, under reagent-free conditions, the N-allyl-C-nitromethyl glycoside resulted in an intramolecular nitronate-olefin cycloaddition to iminosugar-oxime 9. Moreover, N-propargyl-Cnitromethyl glycoside 10, upon exposure to TsN3/CuI, underwent an unprecedented ketenimine-acryl amidineMichael addition cascade reaction to give bicyclic amidine 11 (Scheme 3). 3-Alkyl-substituted active methylene compounds, such as 4hydroxycoumarin, 4-hydroxy-quinolin-2(1H)-one, and 2-hydroxy-1,4-naphthoquinone are important class of pharmacophores present in many natural as well as in synthetic drug molecules (Figure 2).20 They elicited much interest due to

■

RESULTS AND DISCUSSION A recent study from our lab showed that iminium ions, derived from D-ribose tosylate, underwent smooth reaction with electron-rich aromatic ring systems in a inter/intramolecular fashion to furnish piperidine-based iminosugar C-aryl glycosides and iminosugar hybrid molecules, respectively, under mild conditions (Scheme 4).25 Scheme 4. One-Pot Synthesis of Novel Iminosugar C-Aryl Glycosides

Figure 2. Coumarin-, quinolinone-, and quinone-based biologically active molecules.

their promising therapeutic applications as α-glucosidase inhibitors, analgesic, antipyretic, anticancer, anti-HIV, antiviral, antibacterial and anti-inflammatory agents, and effectively used in the treatment of central nervous system (CNS) disorders.20,21 Furthermore, many natural and synthetic quinone, coumarin, and quinolinone derivatives have been extensively studied due to their ability to interfere with enzymes that are crucial for DNA replication in cells, and thus they are found to exhibit cytotoxic activity against a wide variety of cancer cell lines.20,21 In recent years, hybrid molecules, having a combination of two distinct molecular scaffolds, received considerable attention due to their dual mode of action and/or enhanced biological activities.22 As a result, various hybrid molecules have been synthesized from carbohydrates, steroids, quinones, peptides, and lactams.23 Interestingly, hybrid molecules bearing iminosugar and carbasugar are found to exhibit better glycosidase inhibitor activities than the parent compounds.24

Since a wide variety of pyrrolidine-based iminosugar C-aryl glycosides are known to exhibit a broad spectrum of biological activities,7−9 it was our interest to explore iminium-ion-based strategy toward the synthesis of pyrrolidine-based C-aryl glycosides. Intriguingly, the iminium ion 15, derived from Lrhamnose lactol-mesylate 14 and benzylamine at 80 °C in DMF, upon exposure to resorcinol at room temperature underwent smooth arylation reaction to furnish the corresponding pyrrolidine-based iminosugar C-aryl glycoside 16 as a single diastereomer in 80% yield (Scheme 5). Under similar reaction conditions, the heteroaromatic compound, indole underwent one-pot arylation reaction with lactol-mesylate 14 to give the corresponding iminosugar C-aryl

Figure 3. Proposed synthesis of novel iminosugar-based hybrid molecules. 9606


Article


(Pictet−Spengler-type cyclization),26 leading to a novel pyrrolidine-based tetracyclic hybrid molecule (Scheme 7). Thus, L-rhamnose lactol-mesylate 14, on exposure to tryptamine in DMF at 80 °C, underwent smooth domino cyclization to provide a pyrrolidine iminosugar-based novel tetracyclic hybrid 18 as a single diastereomer in 78% yield (Scheme 7). Similarly, reaction of L-rhamnose mesylate 14 with dopamine afforded the corresponding tricyclic iminosugar-hybrid 19 in very good yield (Scheme 7). The structure and relative stereochemisty of the cyclized products 18 and 19 were unambiguously established by 1H, 13C, and 2D NMR spectral analyses (see SI). Intriguingly, the tetracyclic derivative 18 is an iminosugar analogue of antileishmanial agent (+)-harmicine,27 whereas tricyclic compound 19 is an analogue of (−)-trolline, an antiviral and antibacterial agent.28 Moreover, the lactol-mesylate 2018 derived from D-mannose, on exposure to tryptamine in toluene at 100 °C, furnished the corresponding piperidine iminosugar-based tetracyclic hybrid derivative 21 in 66% yield (Scheme 7). Synthesis of Iminosugar C-Coumarinyl/Quinolinonyl/ Naphthoquinonyl Glycosides. Intriguingly, the addition of active methylene compound, 4-hydroxycoumarin, to the in situ generated iminium ion 22a, derived from D-ribose tosylate, resulted in a smooth one-pot alkylation reaction to give the corresponding iminosugar β-C-coumarinyl glycoside 22 as a single diastereomer in excellent yield (Scheme 8). The stereoselective formation of β-C-coumarinyl glycoside 22 can be envisaged due to the preferencial addition of coumarinyl nucleophile to iminium ion 22a through si-face attack (pseudoequatorial approach) rather than a sterically hindered re-face attack (pseudoaxial approach) (Scheme 8).29 The structure and the relative stereochemistry of the iminosugar 22 were established using 1H NMR, 13C NMR,

Scheme 5. One-Pot Synthesis of Pyrrolidine-Based Iminosugar β-C-Aryl Glycoside 16

glycoside 17 in good yield with a high degree of regio- and stereoselectivity (Scheme 6). Scheme 6. Synthesis of Pyrrolidine-Based Iminosugar β-CAryl Glycoside 17

Encouraged by the facile intermolecular arylation reaction of the in situ generated iminium ion 15, we envisaged that the use of electron-rich aromatic ring system, bearing an aminoethyl group, could trigger an intramolecular arylation reaction

Scheme 7. Domino Synthesis of Iminosugar-Based Hybrid Molecules

9607


Article

The Journal of Organic Chemistry Scheme 8. Synthesis of Iminosugar β-C-Coumarinyl Glycoside 22

Scheme 10. Synthesis of Pyrrolidine-Based Iminosugar β-CCoumarinyl Glycoside 37

2D NMR, IR, and high-resolution mass spectra (HRMS) spectroscopic data (see SI) and further unambiguously confirmed by single-crystal X-ray analysis.30 The scope of this one-pot transformation was further tested with various heteroaromatic systems and amines, and the results are summarized in Table 1. The iminium ion, derived from D-ribose tosylate and cyclopropylamine, on treatment with 4-hydroxycoumarin resulted in the isolation of iminosugar β-C-coumarinyl glycoside 23 in 75% yield (Table 1, entry 1). Similarly, iminium ion 22a on reaction with 4-hydroxyquinolinone derivatives 24, 26, 28, and 30 afforded the corresponding iminosugar β-C-quinolinonyl glycosides 25, 27, 29, and 31, respectively, in good yields (Table 1, entries 2−5). Under similar conditions, iminium ion 22a underwent smooth reaction with lawsone (32) to furnish the corresponding naphthoquinone containing iminosugar β-C-glycoside 33 as a single diastereomer in 80% yield (Table 1, entry 6). Similarly, iminium ion generated from D-lyxose tosylate 35 and benzylamine on treatment with 4-hydroxycoumarin and Et3N underwent facile alkylation reaction to furnish the corresponding iminosugar α-C-coumarinyl glycoside 36 in 82% yield with excellent stereoselectivity (Scheme 9).

Figure 4. Biologically active isopyrrolonaphthoquinones.

integrase,32 and GR30921X exhibits activity against solid tumors, including human colon HT29, mouse sarcoma 180, and rat hepatoma D23, whereas its prodrug GR63178A showed promising anticancer activities in phase II clinical trials.33 Therefore, isopyrrolonaphthoquinone containing molecule could lead to a possible drug candidate for the treatment of metabolic disorders such as cancer and diabetes.31−33 Since 1,3-dipolar cycloaddition of azomethine ylide with 1,4naphthoquinones is one of the most efficient synthetic pathways to make isopyrrolonaphthoquinone derivatives,34 it was anticipated that the one-pot iminium ion approach could provide an easy access to biologically important iminosugarfused isopyrrolonaphthoquinone derivatives via [3 + 2]cycloaddition of azomethine ylide. Intriguingly, the D-ribose tosylate 1 on treatment with glycine methyl ester and Et3N in toluene at 120 °C resulted in the generation of azomethine ylide 38, which on subsequent reaction with 1,4-naphthoquinone furnished a novel iminosugar-isopyrrolonaphthoquinone hybrid molecule 39 in 50% yield (Scheme 11). The structure of the cyclized adduct 39 was unambiguously confirmed by single crystal X-ray analysis.30 The scope of the reaction was further tested with 1,4anthraquinone, and the corresponding pentacyclic adduct 40 was obtained in 47% yield. Under similar reaction conditions, azomethine ylide, derived from D-lyxose tosylate 35 and glycine methyl ester, underwent smooth reaction with 1,4naphthoquinone and 1,4-anthraquinone to furnish the corresponding iminosugar hybrid molecules 41 and 42, respectively, in moderate yields. Similarly, azomethine ylide,

Scheme 9. Synthesis of Iminosugar α-C-Coumarinyl Glycoside 36

Likewise, L-rhamnose mesylate 14 was exposed to allylamine, and the resultant in situ generated iminium ion was allowed to react with 4-hydroxycoumarin at room temperature to furnish a pyrrolidine-based iminosugar β-C-coumarinyl glycoside 37 as a single diastereomer in 65% yield (Scheme 10). Synthesis of Iminosugar Isopyrrolonaphthoquinone Hybrid. Isopyrrolonaphthoquinone is a common structural scaffold present in various biologically active molecules such as bhimamycin C, biscogniauxone, GR30921X, and GR63178A (Figure 4).31−33 Biscogniauxone is found to be a glycogen synthase kinase (GSK-3β) inhibitor,31 bhimamycin C is an inhibitor of HIV-1 9608


Article

The Journal of Organic Chemistry Table 1. One-Pot Synthesis of Novel Iminosugar β-CCoumarinyl/Quinolinonyl/Naphthoquinonyl Glycosidesa

Since imidazole-fused polyhydroxylated piperidine, nagstatine (Figure 1), is known to exhibit promising anticancer activities,1 our one-pot iminium ion strategy was further explored in the synthesis of conformationally locked benzimidazole-fused iminosugars. Thus, D-ribose tosylate 1 on reaction with o-phenylenediamine, in the presence of 10 mol% of Sc(OTf)3 in dry toluene at 80 °C, afforded a novel cyclized product, benzimidazole-fused tricyclic iminosugar 44 in 60% yield (Scheme 13). Under similar reaction conditions, reaction of o-phenylenediamine with D-lyxose tosylate 35 afforded tricyclic iminosugar 45 in 58% yield, whereas L-rhamnose mesylate 14 gave the corresponding pyrrolidine-iminosugar 46 in 55% yield. The structure of the cyclized adduct 46 was unambiguously confirmed by single crystal X-ray analysis.30 In order to evaluate the biological significance of iminosugar-based hybrid molecules, the protecting groups were removed under mild conditions. Thus, the deprotection of isopropylidene group in compound 22 was realized using 6 N HCl in MeOH at room temperature to furnish the corresponding N-alkyl trihydroxy-piperidine derivative 47 as the hydrochloride salt in excellent yield. Moreover, catalytic hydrogenation of 22 with H2-Pd/C in 6 N HCl and MeOH at 50 °C afforded the trihydroxy-piperidine C-coumarinyl derivative 48 as the hydrochloride salt in 85% yield (Scheme 14). Preliminary cytotoxicity evaluation of some of the synthesized molecules was carried out against various human cancer cell lines by the MTT assay method35 and their IC50 values are summarized in Table 2. Among the iminosugar C-coumarinyl glycosides (47, 48 and 49) screened, the hydrophobically modified N-benzyl iminosugar C-coumarinyl glycoside 47 showed better activities against tested cancer cell lines compared to N-unsubstituted iminosugars 48 and 49 (Table 2, entries 1−3). Moreover, the iminosugar-isopyrrolonaphthoquinone hybrid 50 showed moderate activity against MCF-7, HT-29, and HCT-116 cancer cell lines (Table 2, entry 4). With these promising results, synthesis of a library of iminosugar-based hybrid analogs and their SAR studies are being pursued to improve their efficacy.

■

CONCLUSIONS In summary, a simple and efficient one-pot iminium-ion-based method has been developed for the stereoselective synthesis of a new class of pyrrolidine-based iminosugar C-aryl glycosides. Intriguingly, L-rhamnose lactol-mesylate 14 on exposure to tryptamine underwent smooth domino cyclization to provide a novel pyrrolidine iminosugar-based tetracyclic hybrid 18, an analogue of antileishmanial agent (+)-harmicine, in very good yield. Similarly, reaction of L-rhamnose mesylate 14 with dopamine afforded the corresponding tricyclic iminosugarhybrid 19, an analogue of antiviral and antibacterial agent tetrahydroisoquinoline alkaloid (−)-trolline, in excellent yield. The synthetic power of this iminium ion strategy was further explored in the stereoselective synthesis of novel iminosugar Ccoumarinyl/quinolinonyl/naphthoquinonyl glycosides in good yields. Moreover, one-pot synthesis of structurally novel and biologically important iminosugar-isopyrrolonaphthoquinone hybrids has also been achieved using [3 + 2]-cycloaddition of azomethine ylide as a key step. The usefulness of this iminium ion method was further shown in the synthesis of conformationally locked benzimidzole-fused iminosugars. Remarkably,

a Reaction conditions: Starting material 1 (0.29 mmol), amine (0.58 mmol), nucleophile (0.29 mmol), and Et3N (0.29 mmol) in dry DCM (2 mL) at rt. bIsolated yield after column chromatography.

generated from L-rhamnose lactol-mesylate 14, reacted with 1,4-naphthoquinone to afford the corresponding isopyrrolonaphthoquinone fused polyhydroxylated pyrrolidine derivative 43 in 45% yield (Scheme 11). The formation of iminosugar-isopyrrolonaphthoquinonebased hybrid molecule 39 can be rationalized by the following mechanism (Scheme 12). The ribose tosylate 1 upon reaction with glycine methyl ester would lead to a cyclic iminium ion B, via imine intermediate A, which on subsequent deprotonation in the presence of base would generate an azomethine ylide 38. Azomethine ylide 38 could then undergo [3 + 2]-cycloaddition reaction with 1,4-naphthoquinone to give the adduct C, which on ensuing aerobic oxidation could lead to tetracyclic iminosugar hybrid 39 (Scheme 12). 9609


Article

The Journal of Organic Chemistry Scheme 11. Synthesis of Iminosugar-Isopyrrolonaphthoquinone Hybrid 39

a

Reaction conditions: 1 (0.58 mmol), glycine methyl ester hydrochloride (1.16 mmol), Et3N (1.74 mmol), and quinone (1.16 mmol) in 6 mL of dry toluene at 120 °C. bIsolated yield after column chromatography.

Scheme 12. Plausible Mechanism for the Formation of Iminosugar Hybrid 39

currently being pursued to identify more potent anticancer molecules.

Scheme 13. Synthesis of Benzimidazole-Fused Iminosugar 44

■

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. 1 H 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 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. Xray crystallographic data were recorded using a Bruker-AXS 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

the hydrophobically modified iminosugar N-benzyl-C-coumarinyl glycoside 47 exhibited promising anticancer activities against various cancer cell lines (MCF-7, HT-29 and HCT116). Similarly, the iminosugar-isopyrrolonaphthoquinone hybrid 50 showed moderate activity against MCF-7, HCT116, and HT-29 cancer cell lines. Synthesis of novel iminosugar-based hybrid analogs and their SAR studies are 9610


Article

The Journal of Organic Chemistry Scheme 14. Debenzylation and Acetonide Deprotection in 22

Table 2. In Vitro Cytotoxicity Studies of Synthesized Compounds against Human Cancer Cell Lines

7.76 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.30−7.20 (m, 7H), 7.20−7.14 (m, 1H), 4.84 (t, J = 6.0 Hz, 1H), 4.63 (dd, J = 6.5, 2.0 Hz, 1H), 4.34 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 13.5 Hz, 1H), 3.86 (d, J = 14.0 Hz, 1H), 3.77 (s, 1H), 3.20 (dd, J = 6.5, 2.0 Hz, 1H), 2.67 (brs, 1H), 1.62 (s, 3H), 1.36 (s, 3H), 1.28 (d, J = 6.0 Hz, 3H) ppm; 13 C NMR (125 MHz, CDCl3) δ 138.0, 137.1, 129.6, 128.4, 127.4, 126.2, 122.6, 122.3, 119.9, 119.7, 115.8, 112.6, 111.5, 85.3, 81.8, 74.0, 68.1, 67.4, 58.5, 27.7, 25.3, 19.2 ppm; HRMS (ESI) calcd for C24H29N2O3 [M+ + H] 393.2178, found 393.2148. Procedure for the Synthesis of Iminosugar Hybrid Molecule 18. To a stirred solution of azeotropically dried L-rhamnose mesylate 14 (100 mg, 0.35 mmol) in dry DMF (2 mL), tryptamine (112 mg, 0.70 mmol) was added, and the resultant mixture was stirred for 24 h at 80 °C. After completion of the reaction as indicated by TLC, saturated NH4Cl (10 mL) was added to the reaction mixture and extracted with DCM (3 × 20 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product, which on column chromatographic purification over silica gel using 50−55% EtOAc in hexane as eluent afforded the iminosugar hybrid molecule 18 (89 mg, 78%) as a colorless solid: Mp 218−220 °C; [α]25 D −118.7 (c 0.5, CHCl3); IR (KBr): 3514, 3243, 2981, 2923, 1449, 1377, 1214, 1071, 864, 767 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.33 (s,1H), 7.47 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.18−7.13 (m, 1H), 7.09 (t, J = 7.2 Hz, 1H), 4.62 (dd, J = 7.2, 3.2 Hz, 1H), 4.48 (t, J = 7.2 Hz, 1H), 4.16 (t, J = 5.6 Hz, 1H), 3.77 (dt, J = 7.6, 1.6 Hz, 1H), 3.42 (dd, J = 10.4, 6.0 Hz, 1H), 2.99 (t, J = 4.0 Hz, 1H), 2.95−2.85 (m, 1H), 2.80−2.72 (m, 1H), 2.69 (dd, J = 11.2, 4.4 Hz, 1H), 2.47 (brs, 1H), 1.60 (s, 3H), 1.39 (s, 3H), 1.33 (d, J = 6.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 136.0, 133.0, 127.0, 121.7, 119.6, 118.3, 114.5, 111.1, 108.6, 82.1, 80.8, 72.4, 67.6, 66.5, 48.0, 27.7, 25.7, 22.5, 20.3 ppm; HRMS (ESI) calcd for C19H25N2O3 [M+ + H] 329.1865, found 329.1859. Procedure for the Synthesis of Iminosugar Hybrid Molecule 19. To a stirred solution of azeotropically dried L-rhamnose lactolmesylate 14 (100 mg, 0.35 mmol) in dry DMF (2 mL), dopamine hydrochloride (133 mg, 0.7 mmol) and Et3N (97 μL, 0.7 mmol) were added at rt, and the resultant mixture was stirred for 24 h at 80 °C. After completion of the reaction as indicated by TLC, saturated NH4Cl (10 mL) was added to the reaction mixture and extracted with DCM (3 × 20 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product, which on column chromatographic purification over silica gel using 50−55% EtOAc in hexane as eluent afforded the hybrid iminosugar 19 (90 mg, 80%) as a yellow color solid: Mp 65− 67 °C; [α]23 D −61.0 (c 0.5, CHCl3); IR (KBr): 3438, 3021, 2982, 1580, 1531, 1428, 1266, 1133, 1043, 930, 766 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.79 (s, 1H), 6.48 (s, 1H), 4.48 (dd, J = 6.8, 3.6 Hz, 1H), 4.40 (t, J = 7.2 Hz, 1H), 4.10 (quintet, J = 6.0 Hz, 1H), 3.94 (brs, 2H), 3.58 (d, J = 6.8 Hz, 1H), 3.42 (dd, J = 9.2, 6.4 Hz, 1H), 2.90−2.80 (m, 2H), 2.71 (dd, J = 10.8, 3.6 Hz, 1H), 2.67−2.58 (m, 1H), 2.18 (s, 1H), 1.56 (s, 3H), 1.37 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 143.5, 142.5, 127.9, 126.1,

IC50 (μg/mL) entry

compd

MCF-7

HCT-116

HT-29

A-549

1 2 3 4

47 48 49 50

26.22 100.64 251.22 53.81

44.33 69.78 198.87 55.57

41.05 60.57 360.25 61.75

215.94 302.62 263.07 100.66

thin-layer chromatography (TLC) analysis throughout this work, Emerck 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. General Procedure for the Synthesis of Pyrrolidine-Based Iminosugar C-Aryl Glycosides 16 and 17. To a stirred solution of azeotropically dried L-rhamnose lactol-mesylate 14 (100 mg, 0.35 mmol) in dry DMF (2 mL) was slowly added benzylamine (77 μL, 0.7 mmol), and the resultant mixture was stirred at 80 °C for about 2 h. To this stirred solution, resorcinol (39 mg, 0.35 mmol) was added, and the resultant mixture was stirred further for 24 h at rt. After completion of the reaction, as indicated by TLC, reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. Purification of the crude product by column chromatography over silica gel (gradient elution with 20−25% EtOAc in hexane) afforded the iminosugar C-aryl glycoside 16 in 80% yield (107 mg) as a colorless solid. 4-((3aS,4S,6R,6aR)-5-Benzyl-6-((S)-1-hydroxyethyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-4-yl)benzene-1,3-diol (16). Mp 124−126 °C; [α]23 D +13.6 (c 0.5, CHCl3); IR (KBr): 3398, 3056, 2985, 1513, 1462, 1376, 1267, 1159, 1089, 970, 750 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.35−7.30 (m, 3H), 7.24−7.20 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 6.34 (dd, J = 8.4, 2.0 Hz, 1H), 4.56 (dd, J = 6.4, 2.8 Hz, 1H), 4.51 (t, J = 6.4 Hz, 1H), 4.06 (d, J = 14.0 Hz, 1H), 3.95 (quintet, J = 6.0 Hz, 1H), 3.84 (d, J = 5.6 Hz, 1H), 3.71 (d, J = 13.6 Hz, 1H), 3.17 (dd, J = 5.2, 3.2 Hz, 1H), 1.41 (s, 3H), 1.26 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.9, 157.3, 133.7, 130.7, 130.4, 128.7, 128.4, 114.1, 113.4, 107.3, 104.1, 83.4, 79.9, 73.5, 70.9, 67.3, 55.9, 27.7, 25.6, 19.1 ppm; HRMS (ESI) calcd for C22H28NO5 [M+ + H] 386.1967, found 386.1938. (R)-1-((3aR,4R,6S,6aS)-5-benzyl-6-(1H-Indol-3-yl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-4-yl)ethanol (17). Following the general procedure as described earlier, the L-rhamnose lactolmesylate 14 (100 mg, 0.35 mmol) was allowed to react with benzylamine (77 μL, 0.7 mmol) and indole (42 mg, 0.35 mmol) for 24 h. After column chromatography over silica gel, the product 17 (96 mg, 70%) was obtained as colorless solid: Mp 138−140 °C; [α]23 D −16.7 (c 1.0, CHCl3); IR (KBr): 3435, 3019, 2927, 1518, 1447, 1379, 1079, 924, 766 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 9611


Article


added, and the resultant mixture was stirred for 24 h at 100 °C. After completion of the reaction as indicated by TLC, saturated NH4Cl (10 mL) was added to the reaction mixture and extracted with DCM (3 × 20 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product, which on column chromatographic purification over silica gel using 10−25% EtOAc in hexane as eluent afforded the iminosugar hybrid molecule 21 (73 mg, 66%) as a colorless liquid; [α]25 D −113.6 (c 0.8, CHCl3); IR (neat): 3448, 3024, 2918, 2311, 1701, 1635, 1441, 1351, 1252, 1041, 951 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.44 (s,1H), 7.48 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 4.33 (t, J = 4.6 Hz, 1H), 4.20−4.24 (m, 2H), 3.92−4.00 (m, 2H), 3.64 (d, J = 9.2 Hz, 1H), 3.28−3.36 (m, 2H), 2.83−2.88 (m, 2H), 2.74−2.78 (m, 1H), 2.58 (td, J = 3.6, 14.9 Hz, 1H), 1.64 (s, 3H), 1.46 (s, 3H), 0.93 (s, 9H), 0.12 (s, 6H) ppm; 13 C NMR (100 MHz, CDCl3) δ 136.2, 133.7, 126.5, 119.3, 118.1, 111.0, 110.1, 108.0, 76.8, 69.0, 63.3, 63.2, 60.7, 47.3, 29.8, 28.3, 26.3, 25.9, 21.9, −5.3 ppm; HRMS (ESI) calcd for C25H38N2O3 [M++Na] 481.2499, found 481.2488. General Procedure A for the Synthesis of Iminosugar CCoumarinyl/Quinolinonyl/Naphthoquinonyl Glycosides (22, 23, 25, 27, 29, 31, 33, and 34). To a stirred solution of azeotropically dried D-ribose tosylate 1 (100 mg, 0.29 mmol) in dry DCM (2 mL) was slowly added benzylamine (63 μL, 0.58 mmol), and the resultant mixture was stirred at room temperature for about 2 h. To this stirred solution, 4-hydroxycoumarin (47 mg, 0.29 mmol) and Et3N (40 μL, 0.29 mmol) were added, and the resultant mixture was stirred further at rt for 9 h. After completion of the reaction, as indicated by TLC, reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with DCM (3 × 15 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. Purification of the crude product by column chromatography over silica gel (gradient elution with 60−65% EtOAc in hexane) afforded the pure iminosugar Ccoumarinyl glycoside 22 (100 mg, 82%) as a colorless solid. 3-((3aS,4S,7R,7aR)-5-Benzyl-7-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-4-yl)-4-hydroxy-2H-chromen-2-one (22). Mp 173−175 °C; [α]30 D +1.7 (c 1.0, CHCl3); IR (KBr): 3457, 3058, 2989, 1692, 1630, 1611, 1536, 1422, 1270, 1110, 1032, 895 cm−1;1H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 7.52− 7.40 (m, 6H), 7.24−7.19 (m, 2H), 5.56 (s, 1H), 4.58 (dd, J = 8.0, 4.4 Hz, 1H), 4.36 (t, J = 4.0 Hz, 1H), 4.31 (d, J = 8.4 Hz, 1H), 4.29−4.22 (m, 1H), 4.24 (d, J = 13.2 Hz, 1H), 4.08 (d, J = 12.8 Hz, 1H), 3.02 (dd, J = 11.6, 4.4 Hz, 1H), 2.76 (t, J = 11.2 Hz, 1H), 1.47 (s, 3H), 1.24 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 173.8, 163.6, 154.1, 131.7, 131.1, 129.6, 129.3, 128.6, 124.3, 122.5, 121.8, 116.0, 109.3, 88.9, 74.8, 74.4, 61.9, 60.5, 55.7, 49.5, 27.7, 26.2 ppm; HRMS (ESI) calcd for C24H26NO6 [M+ + H] 424.1760, found 424.1770. 3-((3aS,4S,7R,7aR)-5-Cyclopropyl-7-hydroxy-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-4-hydroxy-2H-chromen-2one (23). The reaction of D-ribose tosylate 1 (100 mg, 0.29 mmol) with cyclopropylamine (41 μL, 0.58 mmol), 4-hydroxycoumarin (47 mg, 0.29 mmol), and Et3N (40 μL, 0.29 mmol) was carried out for 12 h at rt following the general procedure A. The crude compound was purified by column chromatography over silica gel to give a colorless liquid 23 (81 mg) in 75% yield: Rf = 0.3 in 60% EtOAc in hexane; [α]28 D +57.5 (c 1.0, CHCl3); IR (neat): 3401, 3055, 2987, 1678, 1612, 1419, 1383, 1216, 1038, 740 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 7.6, 1.2 Hz, 1H), 7.52−7.47 (m, 1H), 7.26−7.21 (m, 2H), 7.07 (s, 1H), 4.98 (dd, J = 6.8, 3.6 Hz, 1H), 4.72 (d, J = 3.6 Hz, 1H), 4.34 (t, J = 4.2 Hz, 1H), 4.00 (dt, J = 11.2, 4.0 Hz, 1H), 3.15 (dd, J = 10.8, 3.2 Hz, 1H), 3.09 (t, J = 11.2 Hz, 1H), 2.57−2.52 (m, 1H), 1.60 (s, 3H), 1.39 (s, 3H), 0.79−0.67 (m, 3H), 0.64−0.57 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 169.9, 162.9, 153.6, 132.2, 123.7, 123.6, 117.8, 116.5, 109.6, 95.1, 75.6, 71.7, 64.8, 61.7, 50.3, 40.6, 26.8, 24.9, 5.2, 5.1 ppm; HRMS (ESI) calcd for C20H24NO6 [M+ + H] 374.1604, found 374.1618. 3-((3aS,4S,7R,7aR)-5-Benzyl-7-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-4-yl)-4-hydroxyquinolin-2(1H)-one (25). The reaction of D-ribose tosylate 1 (100 mg, 0.29 mmol) with

115.4, 114.5, 112.0, 82.4, 82.2, 73.2, 69.6, 68.4, 49.3, 28.4, 27.6, 25.6, 21.1 ppm; HRMS (ESI) calcd for C17H24NO5 [M+ + H] 322.1654, found 322.1672. Synthesis of Lactol-Mesylate 20 from D-Mannose: Procedure for the Synthesis of Compound 20b. To a stirred solution of compound 20a (2 g, 7.62 mmol) in dry DMF (30 mL) was added imidazole (625 mg, 9.15 mmol), TBDMSCl (1.2 g, 8.3 mmol), and the resultant mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ether (100 mL), and the organic layer was washed with water (2 × 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude compound. Chromatographic purification of the crude compound over silica gel (gradient elution with 15−20% EtOAc in hexane) afforded the pure compound 20b (2.4 g, 86%) as a white solid. [α]25 D = +42.61 (c 1, CHCl3); TLC: Rf 0.60 (7:3 hexanes/EtOAc); IR (KBr disc): 3442, 3054, 2958, 2955, 2886, 2844, 1743, 1458, 1421, 1367, 1260, 1241, 1152, 1115, 1018, 958 cm−1; 1H NMR (500 MHz, CDCl3) δ 6.06 (s, 1H), 4.85 (dd, J = 5.5, 3.5 Hz, 1H), 4.61 (d, J = 6.0 Hz, 1H), 4.0 (q, J = 7 Hz, 1H), 3.96 (dd, J = 8.5, 3.5 Hz, 1H), 3.77 (dd, J = 10, 3.5 Hz, 1H), 3.78 (dd, J = 10, 4.0 Hz, 1H), 2.66 (d, J = 6.5 Hz, 1H), 1.97 (d, J = 1 Hz, 3H), 1.45 (s, 3H), 1.32 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.4, 113.2, 100.8, 84.9, 80.8, 79.9, 69.1, 64.1, 26.1, 25.9, 24.9, 21.1, 18.4, −5.3, −5.5; HRMS (ESI) calcd for C17H33O7Si [M+ + H] 377.1996, found 377.2002. Procedure for the Synthesis Compound 20c. To a stirred solution of compound 20b (1.5 g, 3.9 mmol) in dry DCM (20 mL) at 0 °C was added Et3N (0.7 mL, 5.1 mmol) followed by MsCl (0.35 mL, 4.5 mmol). The resultant reaction mixture was stirred for 30 min at 0 °C, and then the reaction mixture was diluted with DCM (50 mL) and water (25 mL). The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Chromatographic purification of the crude compound over silica gel (gradient elution with 15−20% EtOAc in hexane) yielded the pure compound 20c (1.6 g, 89%) as a liquid. [α]25 D = +24.16 (c 1, CHCl3); TLC: Rf 0.60 (7:3 hexanes/EtOAc); IR (neat): 3470, 3041, 2869, 2801, 1745, 1631, 1450, 1390, 1341, 1223, 1151, 1120, 1005, 943, 739, 514; 1H NMR (400 MHz, CDCl3) δ 6.13 (s, 1H), 4.83 (t, J = 1 Hz, 2H), 4.69 (d, J = 6.0 Hz, 1H), 4.37 (dd, J = 7.6, 3.6 Hz, 1H), 4.09−4.12 (m, 1H), 3.88 (dd, J = 12, 3 Hz, 1H), 3.67 (d, J = 1.5 Hz, 1 H) 3.08 (s, 3H), 2.04 (s, 3H), 1.47 (s, 3H), 1.32 (s, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.3, 113.5, 100.3, 84.9, 80.3, 79.1, 62.5, 38.7, 26.2, 25.9, 25.0, 21.1, 18.4, −5.3, −5.5; HRMS (ESI) calcd for C18H34O9SNaSi [M+ + Na] 477.6034, found 477.6019. Procedure for the Synthesis Compound 20. To a stirred solution of compound 20c (1.0 g, 2.2 mmol) in dry MeOH (10 mL) at 0 °C was added NaOMe (12 mg, 0.22 mmol). The resultant mixture was stirred at room temperature for 8 h, and then the solvent MeOH was removed completely and water (10 mL) was added. The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Chromatographic purification of the crude compound over silica gel (gradient elution with 20−25% EtOAc in Hexane) yielded the pure compound 20 (845 mg, 95%) as a white solid. [α]24 D = 5.52 (c 1, CHCl3); IR (KBr disc): 3651, 3522, 3482, 3012, 2896, 2954, 2902, 2852, 2801, 1602, 1412, 1406, 1348, 1259, 1211, 1115, 1045, 1025, 957 cm−1 ; 1H NMR (400 MHz, CDCl3) δ 5.2 (s, 1H) 4.71−4.77 (m, 2H), 4.53 (d, J = 5.8 Hz, 1H), 4.36 (dd, J = 7.1, 3.5 Hz, 1H), 4.01 (dd, J = 12.0, 1.9 Hz, 1H), 3.77− 3.83 (m, 1H), 3.14 (s, 3H), 2.62 (s, 1H), 1.38 (s, 3H), 1.23 (s, 3H), 0.81 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 112.9, 101.2, 85.4, 81.0, 79.4, 77.7, 62.9, 38.6, 26.1, 25.9, 24.8, 18.4, −5.2, −5.3; HRMS (ESI) calcd for C16H33O8SSi [M + + H] 413.1665, found 413.1661. Procedure for the Synthesis of Iminosugar Hybrid Molecule (21). To a stirred solution of azeotropically dried D-mannose mesylate 20 (100 mg, 0.24 mmol) in dry toluene (2 mL), tryptamine (112 mg, 0.48 mmol) and trifluoroacetic acid (TFA) (5 μL, 0.048 mmol) were 9612


Article

The Journal of Organic Chemistry benzylamine (63 μL, 0.58 mmol), 4-hydroxyquinolinone 24 (47 mg, 0.29 mmol), and Et3N (40 μL, 0.29 mmol) was carried out for 12 h following a similar procedure A. After column chromatography, the product 25 (94 mg) was obtained in 77% yield as a yellow color semisolid: Rf = 0.3 in 70% EtOAc in hexane; [α]28 D −13.3 (c 1.0, CHCl3); IR (neat): 3450, 3056, 2987, 1645, 1608, 1497, 1391, 1265, 1048, 895, 739 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.51−7.44 (m,1H), 7.40−7.26 (m, 6H), 7.21 (t, J = 7.2 Hz, 1H), 4.80 (brs, 1H), 4.50 (dd, J = 7.2, 5.2 Hz, 1H), 4.42 (t, J = 4.4 Hz, 1H), 4.38 (d, J = 7.2 Hz, 1H), 4.11 (d, J = 13.2 Hz, 1H), 4.06 (t, J = 4.4 Hz, 1H), 3.41 (d, J = 13.2 Hz, 1H), 3.00 (dd, J = 11.2, 4.4 Hz, 1H), 2.53 (t, J = 11.2 Hz, 1H), 1.76 (s, 3H), 1.36 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.6, 163.6, 138.7, 135.5, 131.1, 129.9, 128.9, 128.1, 123.1, 122.0, 116.0, 115.9, 110.5, 106.1, 78.2, 74.6, 65.8, 60.9, 59.4, 50.9, 27.8, 26.3 ppm; HRMS (ESI) calcd for C24H27N2O5 [M+ + H] 423.1920, found 423.1933. 3-((3aS,4S,7R,7aR)-5-Benzyl-7-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-4-yl)-4-hydroxy-7-methoxyquinolin2(1H)-one (27). The reaction of D-ribose tosylate 1 (100 mg, 0.29 mmol) with benzylamine (63 μL, 0.58 mmol), 4-hydroxy-7methoxyquinolin-2(1H)-one 26 (55 mg, 0.29 mmol) and Et3N (40 μL, 0.29 mmol) was carried out following the general procedure A for 14 h. After column chromatography, the product 27 (96 mg) was obtained as a yellow color viscous liquid in 74% yield: Rf = 0.2 in EtOAc; [α]28 D −4.3 (c 1.0, CHCl3); IR (neat): 3400, 3054, 2986, 1716, 1644, 1422, 1216, 1171, 1052, 895, 739 cm−1; 1H NMR (500 MHz, CDCl3) δ 12.14 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.30−7.10 (m, 5H), 6.80−6.70 (m, 2H), 4.69 (brs, 1H), 4.38−4.30 (m, 2H), 4.20 (d, J = 7.5 Hz, 1H), 4.01−3.95 (m, 2H), 3.78 (s, 3H), 3.29 (d, J = 13.0 Hz, 1H), 2.90 (dd, J = 11.0, 8.0 Hz, 1H), 2.40 (t, J = 11.0 Hz, 1H), 1.66 (s, 3H), 1.26 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 165.1, 163.8, 162.4, 140.6, 135.6, 129.9, 128.8, 128.0, 124.5, 111.5, 110.4, 109.9, 103.7, 98.2, 78.4, 74.8, 65.7, 60.6, 59.1, 55.6, 51.2, 27.9, 26.3 ppm; HRMS (ESI) calcd for C25H29N2O6 [M+ + H] 453.2026, found 453.2026. 3-((3aS,4S,7R,7aR)-5-Benzyl-7-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-4-yl)-4-hydroxybenzo[h]quinolin-2(1H)one (29). Following a similar procedure, exposure of D-ribose tosylate 1 (100 mg, 0.29 mmol) with benzylamine (63 μL, 0.58 mmol), 4hydroxybenzo[h]quinolin-2(1H)-one 28 (61 mg, 0.29 mmol) and Et3N (40 μL, 0.29 mmol) was carried out for 10 h. The product 29 was obtained as a light yellow solid in 75% yield (102 mg): Rf = 0.3 in EtOAc; Mp 148−150 °C; [α]27 D +6.8 (c 1.0, CHCl3); IR (KBr): 3425, 3019, 2989, 1638, 1602, 1435, 1218, 1071, 1038, 892, 739 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.18 (s, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.92−7.88 (m, 1H), 7.69−7.60 (m, 3H), 7.30−7.20 (m, 5H), 4.89 (brs, 1H), 4.68 (t, J = 6.0 Hz, 1H), 4.57 (d, J = 6.4 Hz, 1H), 4.45 (t, J = 4.8 Hz, 1H), 4.15−4.08 (m, 2H), 3.49 (d, J = 12.8 Hz, 1H), 3.01 (dd, J = 11.2, 4.4 Hz, 1H), 2.61 (t, J = 11.2 Hz, 1H), 1.73 (s, 3H), 1.35 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.7, 164.5, 136.2, 135.1, 134.7, 129.9, 128.8, 128.6, 128.1, 127.9, 126.8, 122.9, 122.5, 122.4, 119.7, 111.9, 110.3, 105.7, 78.2, 74.1, 65.9, 60.8, 59.8, 50.6, 27.9, 26.0 ppm; HRMS (ESI) calcd for C28H29N2O5 [M+ + H] 473.2076, found 473.2072. 3-((3aS,4S,7R,7aR)-5-Benzyl-7-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-4-yl)-4-hydroxy-6-methyl-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (31). Under similar reaction conditions, the reaction of D-ribose tosylate 1 (100 mg, 0.29 mmol) with benzylamine (63 μL, 0.58 mmol), 4-hydroxy-6-methyl-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione 30 (70 mg, 0.29 mmol), and Et3N (40 μL, 0.29 mmol) was carried out for 14 h. The product 31 was obtained after column chromatography as a yellow color viscous liquid in 70% yield (102 mg): Rf = 0.2 in EtOAc; [α]28 D −21.7 (c 1.0, CHCl3); IR (neat): 3443, 3054, 2986, 1728, 1672, 1577, 1438, 1041, 895, 742 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 7.5 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H), 4.88 (dd, J = 8.5, 4.5 Hz, 1H), 4.49 (t, J = 4.0 Hz, 1H), 4.07 (quintet, J = 5.0 Hz, 1H), 3.92 (d, J = 8.5 Hz, 1H), 3.87 (d, J = 13.0 Hz, 1H), 3.76 (s, 3H), 3.15 (d, J = 12.5 Hz, 1H), 2.93 (dd, J =

10.5, 5.0 Hz, 1H), 2.27 (t, J = 11.0 Hz, 1H), 1.65 (s, 3H), 1.36 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 167.5, 163.2, 158.8, 139.1, 138.8, 134.2, 129.1, 128.2, 126.9, 124.8, 124.4, 115.1, 114.4, 113.7, 109.7, 100.8, 100.1, 75.8, 74.9, 66.4, 60.0, 58.0, 54.3, 29.5, 28.0, 26.6 ppm; HRMS (ESI) calcd for C28H29N2O7 [M+ + H] 505.1975, found 505.1981. 2-((3aS,4S,7R,7aR)-5-Benzyl-7-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-hydroxynaphthalene-1,4-dione (33). The reaction of D-ribose tosylate 1 (100 mg, 0.29 mmol) with benzylamine (63 μL, 0.58 mmol), 2-hydroxy-1,4-naphthoquinone 32 (50 mg, 0.29 mmol), and Et3N (40 μL, 0.29 mmol) was carried out following the general procedure A for 10 h. After column chromatography, the product 33 (100 mg) was obtained as an orange color solid in 80% yield: Rf = 0.2 in EtOAc; Mp 132−134 °C; [α]28 D −61.5 (c 1.0, CHCl3); IR (KBr): 3440, 1712, 1645, 1535, 1428, 1387, 1043, 924, 767 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.62 (td, J = 7.6, 1.2 Hz, 1H), 7.49 (td, J = 7.6, 1.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.2 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H), 4.75 (dd, J = 8.0, 4.8 Hz, 1H), 4.68−4.60 (m, 3H), 4.49 (t, J = 4.0 Hz, 1H), 4.43 (d, J = 12.8 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H), 3.89 (dd, J = 10.8, 3.2 Hz, 1H), 2.87 (t, J = 11.2 Hz, 1H), 1.64 (s, 3H), 1.34 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 184.6, 181.5, 170.5, 134.4, 134.0, 131.8, 131.7, 131.4, 129.9, 129.1, 129.0, 126.3, 126.2, 111.1, 110.5, 75.2, 74.8, 63.6, 59.5, 57.1, 49.9, 27.8, 26.4 ppm; HRMS (ESI) calcd for C25H26NO6 [M+ + H] 436.1760, found 436.1759. 2-((3aS,4S,7R,7aR)-5-Hexyl-7-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-hydroxynaphthalene-1,4-dione (34). Following the general procedure A as described earlier, D-ribose tosylate 1(100 mg, 0.29 mmol) was allowed to react with hexylamine (76 μL, 0.58 mmol), 2-hydroxy-1,4-naphthoquinone 32 (50 mg, 0.29 mmol), and Et3N (40 μL, 0.29 mmol) for 12 h. After column chromatography over silica gel, the product 34 (97 mg, 78%) was obtained as an orange color solid: Rf = 0.1 in EtOAc; Mp 90−92 °C; [α]25 D −19.2 (c 1.0, CHCl3); IR (KBr): 3440, 3054, 1679, 1538, 1428, 1387, 1266, 1047, 760 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 4.87 (dd, J = 8.0, 4.0 Hz, 1H), 4.80−4.75 (m, 1H), 4.61 (d, J = 8.8 Hz, 1H), 4.55 (t, J = 4.0 Hz, 1H), 4.12 (dd, J = 11.2, 4.8 Hz, 1H), 3.20 (t, J = 10.8 Hz, 1H), 3.00 (td, J = 12.0, 4.4 Hz, 1H), 2.78 (td, J = 12.0, 4.4 Hz, 1H), 1.70 (s, 3H), 1.60−1.40 (m, 2H), 1.37 (s, 3H), 1.05 (s, 6H), 0.633 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 185.6, 181.4, 170.6, 134.6, 134.0, 131.8, 131.3, 126.4, 125.9, 110.9, 109.2, 74.7, 74.0, 63.5, 59.1, 53.4, 51.8, 31.1, 27.9, 26.4, 26.3, 22.6, 22.3, 13.8 ppm; HRMS (ESI) m/z calcd for C24H32NO6 [M+ + H] 430.2230, found 430.2239. 3-((3aR,4R,7R,7aS)-5-Benzyl-7-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-4-yl)-4-hydroxy-2H-chromen-2-one (36). The reaction of D-lyxose tosylate (100 mg, 0.29 mmol) with benzylamine (63 μL, 0.58 mmol), 4-hydroxycoumarin (47 mg, 0.29 mmol), and Et3N (40 μL, 0.29 mmol) was carried out for 11 h at rt following the general procedure A. The crude compound was purified by column chromatography over silica gel to give a white solid 36 (100 mg) in 82% yield: Rf = 0.3 in 60% EtOAc in hexane; Mp 222− 224 °C; [α]30 D +1.8 (c 1.0, CHCl3); IR (KBr): 3453, 3054, 1677, 1641, 1103, 1037, 895 cm−1; 1H NMR (400 MHz, CD3OD) δ 8.00 (dd, J = 8.0, 1.6 Hz, 1H), 7.60−7.53 (m, 1H), 7.48−7.40 (m, 5H), 7.32−7.27 (m, 2H), 4.73 (dd, J = 8.4, 4.4 Hz, 1H), 4.55 (d, J = 5.6 Hz, 1H), 4.53 (s, 1H), 4.30 (t, J = 4.0 Hz, 1H), 4.28−4.25 (m, 1H), 4.00 (d, J = 13.2 Hz, 1H), 3.40 (dd, J = 12.8, 1.2 Hz, 1H), 3.34−3.30 (m, 1H), 1.67 (s, 3H), 1.36 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 177.7, 167.8, 155.9, 133.2, 131.8, 131.7, 131.0, 130.7, 125.6, 124.7, 123.0, 117.8, 112.2, 92.7, 76.4, 76.3, 64.5, 63.9, 57.1, 52.9, 28.4, 26.8 ppm; HRMS (ESI) calcd for C24H26NO6 [M+ + H] 424.1760, found 424.1745. 3-((3aS,4S,6R,6aR)-5-Allyl-6-((S)-1-hydroxyethyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-4-yl)-4-hydroxy-2H-chromen-2-one (37). To a stirred solution of azeotropically dried Lrhamnose lactol-mesylate 14 (100 mg, 0.35 mmol) in dry DMF (2 mL) was slowly added allylamine (52 μL, 0.7 mmol), and the 9613


Article

The Journal of Organic Chemistry resultant mixture was stirred for 2 h at 80 °C. To this stirred solution, 4-hydroxycoumarin (57 mg, 0.35 mmol) and Et3N (49 μL, 0.35 mmol) were added, and the resultant mixture was stirred further at room temperature for 10 h. After completion of the reaction, as indicated by TLC, reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with DCM (3 × 15 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. Purification of the crude product by column chromatography over silica gel (gradient elution with 20−25% EtOAc in hexane) afforded the pyrrolidine-based iminosugar C-coumarinyl glycoside 37 (88 mg, 65%) as a yellow color viscous liquid: [α]32 D +50.1 (c 1.0, CHCl3); IR (neat): 3375, 1713, 1646, 1605, 1429, 1215, 1038, 863, 761 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.20− 7.10 (m, 2H), 6.00−5.90 (m, 1H), 5.51−5.40 (m, 2H), 4.86 (d, J = 3.6 Hz, 1H), 4.78 (t, J = 5.2 Hz, 1H), 4.55 (t, J = 5.2 Hz, 1H), 4.26 (quintet, J = 6.0 Hz, 1H), 3.85 (d, J =7.2 Hz, 2H), 3.33 (dd, J = 8.0, 4.4 Hz, 1H), 1.58 (s, 3H), 1.40 (d, J = 6.0 Hz, 3H), 1.30 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 173.4, 164.1, 153.9, 131.8, 126.9, 125.7, 123.9, 123.3, 119.9, 116.7, 113.7, 91.9, 83.9, 81.3, 73.0, 69.1, 67.7, 57.1, 27.7, 25.5, 21.1 ppm; HRMS (ESI) calcd for C21H26NO6 [M+ + H] 388.1760, found 388.1757. General Procedure B for the Synthesis of Iminosugar Isopyrrolonaphtho/Anthroquinone Hybrid Molecules (39− 43). To a suspension of glycine methylester hydrochloride (146 mg, 1.16 mmol) in dry toluene (6 mL) was added Et3N (1.74 mmol, 242 μL). After 5 min, D-ribose tosylate 1 (200 mg, 0.58 mmol) was added, and the resulting mixture was stirred for 2 h at 120 °C. To this stirred solution, 1,4-naphthoquinone (185 mg, 1.16 mmol) was added, and the resultant mixture was stirred further 12 h at 120 °C. After completion of the reaction, as indicated by TLC, reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with DCM (3 × 10 mL). Combined organic layer were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. Purification of the crude product by column chromatography over silica gel (gradient elution with 35−40% EtOAc in hexane) afforded the iminosugar hybrid 39 (115 mg) as a brownish yellow color solid in 50% yield. Iminosugar Isopyrrolonaphthoquinone Hybrid 39. Rf = 0.3 in 50% EtOAc in hexane; Mp 196−198 °C; [α]26 D −38.2 (c 1.0, CHCl3); IR (KBr): 3468, 3055, 1717, 1667, 1599, 1428, 1151, 896, 753 cm−1; 1 H NMR (400 MHz, CDCl3) δ 8.20−8.15 (m, 2H), 7.71−7.67 (m, 2H), 6.10 (d, J = 7.2 Hz, 1H), 4.74 (d, J = 6.4 Hz, 1H), 4.60 (dd, J = 17.6, 10.0 Hz, 1H), 4.03 (s, 3H), 3.98−3.90 (m, 2H), 2.79 (brs, 1H), 1.54 (s, 3H), 1.45 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 180.6, 178.9, 161.1, 135.5, 134.5, 133.7, 133.5, 132.8, 127.4, 126.8, 124.5, 123.3, 120.4, 110.9, 72.5, 68.1, 67.7, 53.1, 44.7, 26.2, 24.5 ppm; HRMS (ESI) calcd for C21H19NO7Na [M+ + Na] 420.1059, found 420.1069. Iminosugar Isopyrroloanthroquinone Hybrid 40. Following the general procedure B as described earlier, the D-ribose tosylate 1 (200 mg, 0.58 mmol) was allowed to react with glycine methyl ester hydrochloride (146 mg, 1.16 mmol), Et3N (1.74 mmol, 242 μL), and 1,4-anthraquinone (241 mg, 1.16 mmol) for 16 h. After column chromatography, product 40 (121 mg) as a brown color solid in 47% yield: Rf = 0.3 in 30% EtOAc in hexane; Mp 178−180 °C; [α]25 D −16.1 (c 0.5, CHCl3); IR (KBr): 3457, 3021, 1714, 1667, 1439, 1169, 1037, 924, 765 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.67 (s, 1H), 8.01 (dd, J = 6.0, 3.2 Hz, 2H), 7.62 (dd, J = 6.0, 3.2 Hz, 2H), 6.18 (d, J = 7.6 Hz, 1H), 4.76 (dd, J = 7.6, 2.0 Hz, 1H), 4.65− 4.57 (m, 2H), 4.05 (s, 3H), 4.00−3.93 (m, 2H), 1.56 (s, 3H), 1.48 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 180.5, 178.9, 161.2, 135.0, 134.8, 132.8, 131.9, 131.1, 130.1, 129.6, 129.5, 129.3, 129.2, 128.9, 124.6, 124.2, 121.3, 110.9, 72.5, 68.2, 67.8, 53.1, 44.7, 26.2, 24.5 ppm; HRMS (ESI) calcd for C25H22NO7 [M+ + H] 448.1396, found 448.1403. Iminosugar Isopyrrolonaphthoquinone Hybrid 41. Under similar reaction conditions, the reaction of D-lyxose tosylate 35 (200 mg, 0.58 mmol) with glycine methyl ester hydrochloride (146 mg, 1.16 mmol), Et3N (1.74 mmol, 242 μL), and 1,4-naphthoquinone (185 mg, 1.16

mmol) was carried out for 16 h affording compound 41 (117 mg) as a brown color viscous liquid in 51% yield: Rf = 0.3 in 50% EtOAc in hexane; [α]26 D −114.4 (c 1.0, CHCl3); IR (neat): 3473, 3055, 1717, 1666, 1430, 1145, 1016, 897, 750 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.19−8.12 (m, 2H), 7.71−7.64 (m, 2H), 6.06 (d, J = 6.8 Hz, 1H), 4.65 (ddd, J = 14.0, 3.6, 1.6 Hz, 1H), 4.49 (ddd, J = 7.2, 2.8, 1.6 Hz, 1H), 4.38 (dd, J = 4.8, 3.2 Hz, 1H), 3.99 (s, 3H), 1.49 (s, 3H), 1.41 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 180.8, 179.1, 161.5, 135.6, 134.6, 133.6, 133.5, 133.4, 127.4, 126.8, 125.2, 123.3, 120.5, 110.0, 74.1, 67.6, 67.2, 53.0, 46.2, 26.6, 24.3 ppm; HRMS (ESI) calcd for C21H19NO7Na [M+ + Na] 420.1059, found 420.1066. Iminosugar Isopyrroloanthroquinone Hybrid 42. The reaction of D-lyxose tosylate 35 (200 mg, 0.58 mmol) with glycine methylester hydrochloride (146 mg, 1.16 mmol), Et3N (1.74 mmol, 242 μL) and 1,4-anthraquinone (241 mg, 1.16 mmol) was carried out for 16 h. The product 42 was obtained after column chromatography as a yellow color viscous liquid in 50% yield (129 mg): Rf = 0.3 in 40% EtOAc in hexane; [α]25 D −26.1 (c 0.5, CHCl3); IR (neat): 3456, 3056, 1718, 1669, 1616, 1435, 1170, 1032, 895, 760 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 6.4 Hz, 2H), 8.04 (dd, J = 4.8, 3.2 Hz, 2H), 7.65 (dd, J = 5.2, 3.2 Hz, 2H), 6.19 (d, J = 6.8 Hz, 1H), 4.67 (dd, J = 14.0, 3.6 Hz, 1H), 4.50 (d, J = 7.2 Hz, 1H), 4.41 (s, 1H), 4.26 (d, J = 14.4 Hz, 1H), 4.06 (s, 3H), 2.24 (s, 1H), 1.55 (s, 3H), 1.46 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 180.6, 178.9, 161.5, 134.8, 134.7, 133.7, 131.8, 131.0, 130.0, 130.0, 129.5, 129.2, 129.1, 128.8, 125.4, 124.0, 121.2, 109.9, 74.0, 67.6, 67.3, 52.9, 46.3, 26.6, 24.3 ppm; HRMS (ESI) calcd for C25H21NO7Na [M+ + Na] 470.1216, found 470.1208. Iminosugar Isopyrrolonaphthoquinone Hybrid 43. Under similar reaction conditions, the reaction of L-rhamnose mesylate 14 (200 mg, 0.71 mmol) with glycine methyl ester hydrochloride (177 mg, 1.42 mmol), Et3N (2.13 mmol, 296 μL), and 1,4-naphthoquinone (227 mg, 1.42 mmol) was carried out for 18 h affording compound 43 (131 mg) as a brown color solid in 45% yield: Rf = 0.3 in 50% EtOAc in hexane; [α]26 D − 35.7 (c 1.0, CHCl3); IR (KBr): 3434, 3050, 1714, 1665, 1516, 1439, 1126, 1049, 870, 760 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05−7.99 (m, 1H), 7.95−7.90 (m, 1H), 7.71−7.66 (m, 2H), 5.75 (d, J = 5.2 Hz, 1H), 5.14 (d, J = 5.2 Hz, 1H), 5.06 (d, J = 4.0 Hz, 1H), 4.23 (s, 1H), 3.98 (s, 3H), 3.61 (s, 1H), 1.41 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.09 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ179.6, 178.3, 160.8, 143.6, 135.4, 133.7, 133.6, 133.6, 127.4, 127.3, 127.1, 121.1, 116.6, 112.4, 85.4, 75.9, 71.3, 68.1, 52.7, 27.2, 26.1, 19.3 ppm; HRMS (ESI) calcd for C22H22NO7 [M+ + H] 412.1396, found 412.1402. General Procedure for the Synthesis of BenzimidazoleFused Tricyclic Iminosugars (44−46). To a stirred solution of azeotropically dried D-ribose tosylate 1 (100 mg, 0.29 mmol) in dry toluene (2 mL), o-phenylenediamine (37 mg, 0.35 mmol) and Sc(OTf)3 (14 mg, 10 mol%) were added at rt, and the resultant mixture was stirred for 28 h at 80 °C. After completion of the reaction, as indicated by TLC, reaction mixture was diluted with saturated NaHCO3 solution (5 mL) and extracted with DCM (3 × 10 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. Purification of the crude product by column chromatography over silica gel (gradient elution with 30−35% EtOAc in hexane) afforded the iminosugar 44 (45 mg, 60%) as a colorless solid. Benzimidazole-Fused Tricyclic Iminosugar 44. Mp 178−180 °C; [α]24 D −11.7 (c 1.0, CHCl3); IR (KBr): 3384, 2988, 2928, 1455, 1377, 1220, 1088, 868, 748 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.34−7.28 (m, 2H), 5.52 (d, J = 6.0 Hz, 1H), 4.81 (d, J = 4.5 Hz, 1H), 4.33 (dd, J = 11.5, 4.0 Hz, 1H), 4.25−4.20 (m, 1H), 4.12 (dd, J = 11.0, 10.0 Hz, 1H), 3.39 (brs, 1H), 1.46 (s, 3H), 1.34 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 147.8, 142.6, 133.8, 123.7, 123.3, 119.9, 111.4, 109.9, 74.8, 70.1, 66.5, 42.8, 26.6, 25.1 ppm; HRMS (ESI) calcd for C14H17N2O3 [M+ + H] 261.1239, found 261.1259. Benzimidazole-Fused Tricyclic Iminosugar 45. Following the general procedure, the reaction of D-lyxose tosylate 35(100 mg, 0.29 mmol) with o-phenylenediamine (37 mg, 0.35 mmol) and Sc(OTf)3 9614


Article

The Journal of Organic Chemistry (14 mg, 10 mol%) was carried out for 28 h at 80 °C. After column chromatography, product 45 (44 mg) was obtained as a light yellow color solidin 58% yield: Rf = 0.3 in 50% EtOAc in hexane; Mp 182− 184 °C; [α]25 D −1.3 (c 1.0, CHCl3); IR (KBr): 3397, 2985, 2895, 1458, 1378, 1086, 1037, 868, 746 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.26−7.18 (m, 2H), 5.39 (d, J = 6.0 Hz, 1H), 4.64 (t, J = 4.5 Hz, 1H), 4.53 (s, 1H), 4.25 (dd, J = 12.5, 2.0 Hz, 1H), 4.20 (dd, J = 12.5, 1.5 Hz, 1H), 4.17 (brs, 1H), 1.39 (s, 3H), 1.27 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 148.2, 141.6, 134.1, 123.5, 123.1, 119.3, 110.8, 109.9, 75.5, 69.2, 66.1, 44.4, 27.1, 25.1 ppm; HRMS (ESI) calcd for C14H17N2O3 [M+ + H] 261.1239, found 261.1259. Benzimidazole-Fused Tricyclic Iminosugar 46. The reaction of Lrhamnose mesylate 14 (100 mg, 0.35 mmol) with o-phenylenediamine (38 mg, 0.35 mmol) and Sc(OTf)3 (17 mg, 10 mol%) was carried out under similar reaction conditions for 28 h. The product 46 was obtained in 55% yield (53 mg) as a yellow color solid: Rf = 0.2 in 50% EtOAc in hexane; Mp 208−210 °C; [α]25 D −24.5 (c 1.0, CHCl3); IR (KBr): 3440, 3022, 2982, 1451, 1379, 1216, 1152, 1046, 868, 754 cm−1; 1H NMR (400 MHz, CD3OD) δ 7.70−7.64 (m, 1H), 7.60− 7.57 (m, 1H), 7.31−7.25 (m, 2H), 5.66 (d, J = 5.2 Hz, 1H), 5.24 (d, J = 5.2 Hz, 1H), 4.66 (d, J = 3.2 Hz, 1H), 4.30−4.22 (m, 1H), 1.43 (s, 3H), 1.26 (d, J = 6.8 Hz, 3H), 1.10 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 160.3, 148.7, 133.8, 124.4, 123.9, 120.4, 113.7, 113.4, 87.1, 75.8, 68.9, 68.7, 27.5, 26.3, 20.7 ppm; HRMS (ESI) calcd for C15H19N2O3 [M+ + H] 275.1396, found 275.1385. 3-((2S,3S,4R,5R)-1-Benzyl-3,4,5-trihydroxypiperidin-2-yl)-4-hydroxy-2H-chromen-2-one hydrochloride (47). To the stirred solution of compound 22 (100 mg, 0.23 mmol) in 10 mL of methanol was added 6 N HCl (0.5 mL), and the resultant mixture was stirred at rt for 6 h. The solvent was removed under reduced pressure and further evaporation under high vacuo afforded N-benzyl-Ccoumarinyl trihydroxy-piperidine hydrochloride 47 in 95% yield (93 mg) as a colorless moisture sensitive solid, [α]28 D −21.2 (c 1.0, MeOH); IR (KBr): 3465, 3052, 1679, 1612, 1419, 1370, 1210, 1032, 740 cm−1; 1H NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.46 (s, 1H), 7.20−7.12 (m, 7H), 4.59 (s,1H), 4.24 (s, 1H), 4.1−3.83 (m, 4H), 3.02 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 172.8, 165.0, 154.5, 134.5, 132.5, 130.9, 129.8, 129.6, 125.6, 124.8, 117.7, 117.2, 97.2, 71.3, 68.0, 65.7, 60.0, 59.0, 51.6 ppm; HRMS (ESI) calcd for C21H22NO6 [M+ + H] 384.1447, found 384.1454. Procedure C for Debenzylation and Deprotection of Acetonide. To the stirred solution of iminosugar 22 (100 mg, 0.23 mmol) in 10 mL of methanol were added 6 N HCl (0.5 mL) and Pd/C (10 mg), and the resulting mixture was stirred at 50 °C for 6 h under H2. The catalyst was filtered through a pad of Celite bed. The resulting solvent was removed under reduced pressure and further dried under high vacuo affording C-coumarinyl trihydroxy-piperidine hydrochloride 48 in 85% yield (66 mg) as a colorless moisture sensitive solid. 4-Hydroxy-3-((2S,3S,4R,5R)-3,4,5-trihydroxypiperidin-2-yl)-2Hchromen-2-one hydrochloride (48). [α]28 D −11.2 (c 1.0, MeOH); IR (KBr): 3450, 3028, 1680, 1260, 1033 cm−1; 1H NMR (400 MHz, CD3OD) δ 7.72 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.11− 7.04 (m, 2H), 4.49 (d, J = 10.4 Hz, 1H), 4.0 (dd, J = 10.4, 2.0 Hz, 2H), 3.88 (s, 1H), 3.76−3.71 (m, 1H), 2.94 (d, J = 8 Hz, 2H) ppm; 13 C NMR (100 MHz, CD3OD) δ 167.6, 164.9, 154.6, 134.8, 125.9, 125.1, 117.9, 117.0, 98.1, 72.4, 67.6, 66.7, 51.2, 44.3 ppm; HRMS (ESI) calcd for C14H15NO6Na [M+ + Na] 316.0797, found 316.0811. 4-Hydroxy-3-((2R,3R,4S,5R)-3,4,5-trihydroxypiperidin-2-yl)-2Hchromen-2-one hydrochloride (49). Following the general procedure C as described earlier, the reaction of iminosugar 36 (100 mg, 0.23 mmol) with 6 N HCl (0.5 mL) and Pd/C (10 mg) was carried out for 6 h. The product 49 (64 mg) obtained as a colorless moisture sensitive solid in 82% yield; [α]28 D +17.9 (c 1.0, MeOH); IR (KBr): 3465, 3021, 2985, 2859, 1676, 1605, 1333, 1158, 1020 cm−1; 1H NMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 7.18 (m, 2H), 4.59 (s, 1H), 4.38 (s, 1H), 4.00−3.88 (m, 2H), 3.12 (d, J = 16 Hz, 2H) ppm; 13 C NMR (100 MHz, CD3OD) δ 166.9, 164.6, 153.9, 134.7, 125.8,

124.7, 117.7, 116.7, 98.2, 70.2, 67.5, 64.8, 51.7, 46.2 ppm; HRMS (ESI) calcd for C14H15NO6Na [M+ + Na] 316.0796, found 316.0811. (1R,2S,3R)-Methyl-1,2,3-trihydroxy-7,14-dioxo-1,2,3,4,7,14hexahydronaphtho[2,3-f ]pyrido[2,1-a]isoindole-6-carboxylate (50). To a stirred solution of iminosugar 42 (50 mg, 0.11 mmol) in MeOH (5 mL) was added 2 N HCl (0.2 mL) at 0 °C, and the resulting mixture was stirred at rt for 2 h. The solvent was removed under reduce pressure. 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 40% ethyl acetate in hexane gave 50 (36 mg) as a yellow color solid in 80% yield: Mp 210−212 °C; [α]24 D +51.3 (c 0.15, CHCl3); IR (KBr): 3442, 3022, 1710, 1646, 1524, 1430, 1216, 1042, 924, 770 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.72 (d, J = 4.8 Hz, 2H), 8.06−8.02 (m, 2H), 7.69−7.65 (m, 2H), 6.91(s, 1H), 5.28 (d, J = 4.0 Hz, 1H), 4.58−4.55 (m, 1H), 4.49 (dd, J = 11.6, 2.4 Hz, 1H), 4.40−4.37 (m, 1H), 4.36 (t, J = 2.4 Hz, 1H), 4.05 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ182.5, 178.7, 161.5, 140.1, 135.3, 134.8, 131.9, 130.6, 130.2, 130.2, 129.9, 129.7, 129.6, 129.5, 124.7, 124.5, 121.2, 67.5, 66.9, 63.2, 53.0, 48.0 ppm; HRMS (ESI) calcd for C22H18NO7[M+ + H] 408.1083, found 408.1076.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00748. Copies of NMR spectra of all new compounds and preliminary cyctotoxicity studies (PDF) ORTEP diagram and crystallographic data for 22 (CIF) ORTEP diagram and crystallographic data for 39 (CIF) ORTEP diagram and crystallographic data for 46 (CIF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sundarababu Baskaran: 0000-0002-7636-2812 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank DST-SERB (EMR/2016/004040), India, for financial support and DST-FIST for providing instrument facilities. S.S.P. and N.R.R. thank CSIR-New Delhi for research fellowships. We thank Mr. V. Ram Kumar for single-crystal Xray analysis and Dr. Ashish D. Wadhwani, Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, Ooty, Tamil Nadu for cytotoxicity studies.

■

REFERENCES

(1) (a) Compain, P.; Martin, O. R. Iminosugars: From Synthesis to Therapeutic Applications; Wiley: Chichester, 2007. (b) Bols, M.; Lopez, O.; Ortega-Caballero, F. In Glycosidase Inhibitors: Structure, Activity, Synthesis, and Medical Relevance; Elsevier Ltd.: Amsterdam, 2007; pp 815−884. (c) Horne, G.; Wilson, F. X.; Tinsley, J.; Williams, D. H.; Storer, R. Iminosugars Past, Present and Future: Medicines for Tomorrow. Drug Discovery Today 2011, 16, 107−118. (2) (a) Greimel, P.; Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Iminosugars and Relatives as Antiviral and Potential Anti-Infective Agents. Curr. Top. Med. Chem. 2003, 3, 513−523. (b) Butters, T. D.; Dwek, R. A.; Platt, F. M. Inhibition of Glycosphingolipid Biosynthesis: Application to Lysosomal Storage Disorders. Chem. Rev. 2000, 100, 4683−46962.

9615


Article

The Journal of Organic Chemistry (3) (a) Steinmann, E.; Whitfield, T.; Kallis, T.; Dwek, R. A.; Zitzmann, N.; Pietschmann, T.; Bartenschlager, T. Antiviral Effects of Amantadine and Iminosugar Derivatives Against Hepatitis C. Hepatology 2007, 46, 330−338. (b) Weiss, M.; Hettmer, S.; Smith, P.; Ladisch, S. Inhibition of Melanoma Tumor Growth by aNovel Inhibitor of Glucosylceramide Synthase. Cancer Res. 2003, 63, 3654− 3658. (c) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond. Wiley-VCH: Weinheim, Germany, 1999; p 397 . (d) Tyrrell, B. E.; Sayce, A. C.; Warfield, K. L.; Miller, J. L.; Zitzmann, N. Iminosugars: Promising Therapeutics for Influenza Infection. Crit. Rev. Microbiol. 2017, 43, 521−545. (e) Aoki, K.; Nakamura, A.; Ito, S.; Nezu, U.; Iwasaki, T.; Takahashi, M.; Kimura, M.; Terauchi, Y. Administration of Miglitol Until 30min After the Start of aMeal is Effective in Type 2 Diabetic Patients. Diabetes Res. Clin. Pract. 2007, 78, 30−33. (f) Alfonso, P.; Pampin, S.; Estrada, J.; Rodriguez-Rey, J. C.; Giraldo, P.; Sancho, J.; Pocovi, M. Miglustat (NB-DNJ) Works as a Chaperone for Mutated Acid β-Glucosidase in Cells Transfected with Several Gaucher Disease Mutations. Blood Cells, Mol., Dis. 2005, 35, 268−276. (4) (a) Nash, R. J.; Kato, A.; Yu, C.-Y.; Fleet, G. W. J. Iminosugars as Therapeutic Agents: Recent Advances and Promising Trends. Future Med. Chem. 2011, 3, 1513−1521. (b) Weiss, M.; Hettmer, S.; Smith, P.; Ladisch, S. Inhibition of Melanoma Tumor Growth by aNovel Inhibitor of Glucosylceramide Synthase. Cancer Res. 2003, 63, 3654− 3658. (c) Wang, G.-N.; Xiong, Y.-L.; Ye, J.; Zhang, L.-H.; Ye, X.-S. Synthetic N-Alkylated Iminosugars as New Potential Immunosuppressive Agents. ACS Med. Chem. Lett. 2011, 2, 682−686. (5) (a) Kato, A.; Okaki, T.; Ifuku, S.; Sato, K.; Hirokami, Y.; Iwaki, R.; Kamori, A.; Nakagawa, S.; Adachi, I.; Kiria, P. G.; Onomura, O.; Minato, D.; Sugimoto, K.; Matsuya, Y.; Toyooka, N. Synthesis and Biological Evaluation of N-(2-fluorophenyl)-2β-Deoxyfuconojirimycin Acetamide as aPotent Inhibitor for α-l-Fucosidases. Bioorg. Med. Chem. 2013, 21, 6565−6573. (b) Hottin, A.; Carrion-Jimenez, S.; Moreno-Clavijo, E.; Moreno-Vargas, A. J.; Carmona, A. T.; Robina, I.; Behr, J.-B. Expanding the Library of Divalent Fucosidase Inhibitors with Polyamino and Triazole-Benzyl Bridged Bispyrrolidines. Org. Biomol. Chem. 2016, 14, 3212−3220. (6) (a) Bergeron-Brlek, M.; Meanwell, M.; Britton, R. Direct Synthesis of Imino-C-Nucleoside Analogues and other Biologically Active Iminosugars. Nat. Commun. 2015, 6, 6903. (b) Compain, P.; Chagnault, V.; Martin, O. R. Tactics and Strategies for the Synthesis of Iminosugar C-Glycosides: AReview. Tetrahedron: Asymmetry 2009, 20, 672−711. (c) Kicska, G. A.; Long, L.; Horig, H.; Fairchild, C.; Tyler, P. C.; Furneaux, R. H.; Schramm, V. L.; Kaufman, H. L.; Immucillin, H. APowerful Transition-State Analog Inhibitor of Purine Nucleoside Phosphorylase, Selectively Inhibits Human T Lymphocytes. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 4593−4598. (d) Balakrishnan, K.; Ravandi, F.; Bantia, S.; Franklin, A.; Gandhi, V. Preclinical and Clinical Evaluation of Forodesine in Pediatric and Adult B-Cell Acute Lymphoblastic Leukemia. Clin. Lymphoma, Myeloma Leuk. 2013, 13, 458−466. (e) Robak, P.; Robak, T. Older and New Purine Nucleoside Analogs for Patients with Acute Leukemias. Cancer Treat. Rev. 2013, 39, 851−861. (7) (a) Horne, G.; Wilson, F. X. Therapeutic Applications of Iminosugars: Current Perspectives and Future Opportunities. Prog. Med. Chem. 2011, 50, 135−176. (b) Yokoyama, M.; Akiba, T.; Ochiai, Y.; Momotake, A.; Togo, H. A Convenient Method for CAzanucleosides Synthesis. J. Org. Chem. 1996, 61, 6079−6082. (c) Evans, G. B.; Furneaux, R. H.; Hutchison, T. L.; Kezar, H. S.; Morris, P. E., Jr.; Schramm, V. L.; Tyler, P. C. Addition of Lithiated 9Deazapurine Derivatives to a Carbohydrate Cyclic Imine: Convergent Synthesis of the Aza-C-nucleoside Immucillins. J. Org. Chem. 2001, 66, 5723−5730. (8) (a) Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.; Kusano, G. Two New Pyrrolidine Alkaloids, Radicamines A and B, as Inhibitors of α-Glucosidase from Lobelia Chinensis Lour. Chem. Pharm. Bull. 2001, 49, 1362−1365. (b) Asano, N. Glycosidase Inhibitors: Update and Perspectives on Practical Use. Glycobiology 2003, 13, 93R−104R.

(9) (a) Kotland, A.; Accadbled, F.; Robeyns, K.; Behr, J.-B. Synthesis and Fucosidase Inhibitory Study of Unnatural Pyrrolidine Alkaloid 4epi-(+)-Codonopsinine. J. Org. Chem. 2011, 76, 4094−4098. (b) Ak, A.; Prudent, S.; Le Nouen, D.; Defoin, A.; Tarnus, C. Synthesis of Allcis 2,5-Imino-2,5-dideoxy-fucitol and its Evaluation as a Potent Fucosidase and Galactosidase Inhibitor. Bioorg. Med. Chem. Lett. 2010, 20, 7410−7413. (10) (a) Khangarot, R. K.; Kaliappan, K. P. A Stereoselective Route to Aza-C-aryl Glycosides from Arynes and Chiral Nitrones. Eur. J. Org. Chem. 2012, 2012, 5844−5854. (b) Zhao, H.; Wang, W.-B.; Nakagawa, S.; Jia, Y.-M.; Hu, X.-G.; Fleet, G. W. J.; Wilson, F. X.; Nash, R. J.; Kato, A.; Yu, C.-Y. Novel 2-Aryl-3,4,5-trihydroxypiperidines: Synthesis and Glycosidase Inhibition. Chin. Chem. Lett. 2013, 24, 1059−1063. (c) Lingamurthy, M.; Jagadeesh, Y.; Ramakrishna, K.; Rao, B. V. DDQ-Promoted Benzylic/Allylic sp3 C-H Activation for the Stereoselective Intramolecular C-N Bond Formation: Applications to the Total Synthesis of (−)-Codonopsinine, (+)-5-epi-Codonopsinine, (+)-Radicamine B, and (−)-Codonopsinol. J. Org. Chem. 2016, 81, 1367−1377. (11) (a) Royer, J.; Bonin, M.; Micouin, L. Chiral Heterocycles by Iminiumion Cyclization. Chem. Rev. 2004, 104, 2311−2352. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Cyclizations of N-Acyliminium Ions. Chem. Rev. 2004, 104, 1431−1628. (c) Chang, S.-M.; Christian, W.; Wu, M.-H.; Chen, T.-L.; Lin, Y.-W.; Suen, C.-S.; Pidugu, H. B.; Detroja, D.; Shah, A.; Hwang, M.-J.; Su, T.-L.; Lee, T.-C. Novel Indolizino[8,7-b]indole Hybrids as Anti-small Cell Lung Cancer Agents: Regioselective Modulation of Topoisomerase II Inhibitory and DNA Crosslinking Activities. Eur. J. Med. Chem. 2017, 127, 235−249. (d) Noble, A.; Anderson, J. C. Nitro-Mannich Reaction. Chem. Rev. 2013, 113, 2887−2939. (e) Barber, D. M.; Duris, A.; Thompson, A. L.; Sanganee, H. J.; Dixon, D. J. One-Pot Asymmetric Nitro-Mannich/Hydroamination Cascades for the Synthesis of Pyrrolidine Derivatives: Combining Organocatalysis and Gold Catalysis. ACS Catal. 2014, 4, 634−638. (12) Keinman, E. F. In Comprehensive Organic Synthesis; Trost, B. M., Flemming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 893. (13) Overman, L. E.; Mendelson, L. T.; Jacobsen, E. J. Synthesis Applications of Aza-Cope Rearrangements. 12. Applications of Cationic Aza-Cope Rearrangements for Alkaloid Synthesis. Stereoselective Preparation of cis-3a-Aryloctahydroindoles and a New Short Route to Amaryllidaceae alkaloids. J. Am. Chem. Soc. 1983, 105, 6629−6637. (14) Donaruma, L. G.; Heldt, W. Z. The Beckmann Rearrangement. In Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, 1960; Vol 11, pp 1−156. (15) (a) Pictet, A.; Spengler, T. Formation of Isoquinoline Derivatives by the Action of Methylal on Phenylethylamine, Phenylalanine and Tyrosine. Ber. Dtsch. Chem. Ges. 1911, 44, 2030−2036. (b) Mons, E.; Wanner, M. J.; Ingemann, S.; van Maarseveen, J. H.; Hiemstra, H. Organocatalytic Enantioselective Pictet-Spengler Reactions for the Syntheses of 1-Substituted 1,2,3,4Tetrahydroisoquinolines. J. Org. Chem. 2014, 79, 7380−7390. (16) (a) Aravind, A.; Kumar, P. S.; Sankar, M. G.; Baskaran, S. Diversity-oriented Synthesis of Useful Chiral Building Blocks from DMannitol. Eur. J. Org. Chem. 2011, 2011, 6980−6988. (b) Kumar, P. S.; Banerjee, A.; Baskaran, S. Regioselective Oxidative Cleavage of Benzylidene Acetals: Synthesis of α- and β-Benzoyloxy Carboxylic Acids.Angew. Angew. Chem., Int. Ed. 2010, 49, 804−807. (c) Aravind, A.; Sankar, M. G.; Varghese, B.; Baskaran, S. Regioselective Reductive Cleavage of Bis-benzylidene Acetal: Stereoselective Synthesis of Anticancer Agent OGT2378 and Glycosidase Inhibitor 1,4-Dideoxy1,4-imino-L-xylitol. J. Org. Chem. 2009, 74, 2858−2861. (17) Senthilkumar, S.; Prasad, S. S.; Das, A.; Baskaran, S. One-Pot Synthesis of Hydrophobically Modified Iminosugar C-Alkynyl Glycosides: Facile Synthesis of Polyhydroxy Tetrahydroindolizines. Chem. - Eur. J. 2015, 21, 15914−15918. 9616


Article


Int. Ed. 2005, 44, 2001−2004. (c) Hottin, A.; Scandolera, A.; Duca, L.; Wright, D. W.; Davies, G. J.; Behr, J.-B. A Second-Generation Ferrocene−Iminosugar Hybrid with Improved Fucosidase Binding Properties. Bioorg. Med. Chem. Lett. 2016, 26, 1546−1549. (25) Senthilkumar, S.; Prasad, S. S.; Kumar, P. S.; Baskaran, S. A Diversity Oriented One-pot Synthesis of Novel Iminosugar CGlycosides. Chem. Commun. 2014, 50, 1549−1551. (26) Stockigt, J.; Antonchick, A. P.; Wu, F.-R.; Waldmann, H. The Pictet-Spengler Reaction in Nature and in Organic Chemistry. Angew. Chem., Int. Ed. 2011, 50, 8538−8564. (27) (a) Lood, C. S.; Koskinen, A. M. P. Harmicine, a Tetracyclic Tetrahydro-β-Carboline: From the First Synthetic Precedent to Isolation from Natural Sources to Target-Oriented Synthesis. Chem. Heterocycl. Compd. 2015, 50, 1367−1387. (b) Spindola, H. M.; Vendramini-Costa, D. B.; Rodrigues, M. T.; Foglio, M. A.; Pilli, R. A.; Carvalho, J. E. The antinociceptive activity of harmicine on chemicalinduced neurogenic and inflammatory pain models in mice. Pharmacol., Biochem. Behav. 2012, 102, 133−138. (28) (a) Lin, W.; Ma, S. Enantioselective Synthesis of Naturally Occurring Isoquinoline Alkaloids: (S)-(−)-Trolline and (R)(+)-Oleracein E. Org. Chem. Front. 2017, 4, 958−966. (b) Wang, R. F.; Yang, X. W.; Ma, C. M.; Cai, S. Q.; Li, J. N.; Shoyama, Y. A Bioactive Alkaloid from the Flowers of Trollius Chinensis. Heterocycles 2004, 35, 1443−1448. (29) (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. Synthesis of 1,5-Dideoxy-1,5-iminoribitol C-Glycosides through a Nitrone-Olefin Cycloaddition Domino Strategy: Identification of Pharmacological Chaperones of Mutant Human Lysosomal β-Galactosidase. J. Org. Chem. 2014, 79, 4398− 4404. (b) Yuan, W.; Xia, J.; Zhang, X.; Liang, P.; Zhang, J.; Jiao, W.; Shao, H. An Efficient Method for the Stereoselective Synthesis of NSubstituted Trihydroxypiperidine Derivatives Promoted by p-TsOH. Tetrahedron 2016, 72, 3994−4000. (c) Hu, X.-G.; Daryl Ariawan, A.; Hunter, L. A D-Ribose-derived α-Amino Nitrile as a Versatile Intermediate for the Collective Synthesis of Piperidine-type Iminosugar C-Glycosides. Tetrahedron Lett. 2014, 55, 7222−7225. (30) The ORTEP diagram and crystallographic data are given in the Supporting Information. (31) Wu, B.; Wiese, J.; Schmaljohann, R.; Imhoff, J. F.; Wu, B. Biscogniauxone, a New Isopyrrolonaphthoquinone Compound from the Fungus Biscogniauxia mediterraneaIsolated from Deep-Sea Sediments. Mar. Drugs 2016, 14, 204. (32) (a) Fotso, S.; Maskey, R. P.; Gruen-wollny, I.; Schulz, K.-p.; Munk, M.; Laatsch, H.; Bhimamycin, A.-E. and Bhimanone: Isolation, Structure Elucidation and Biological Activity of Novel Quinone Antibiotics from a Terrestrial Streptomycete. J. Antibiot. 2003, 56, 931−941. (b) Verschueren, W. G.; Dierynck, I.; Amssoms, K. I. E.; Hu, L.; Boonants, P. M. J. G.; Pille, G. M. E.; Daeyaert, F. F. D.; Hertogs, K.; Surleraux, D. L. N. G.; Wigerinck, P. B. T. P. Design and Optimization of Tricyclic Phthalimide Analogues as Novel Inhibitors of HIV-1 Integrase. J. Med. Chem. 2005, 48, 1930−1940. (33) (a) Boven, E.; Erkelens, C. A. M.; Luning, M.; Pinedo, H. M. Activity of GR30921X (NSC 382057) and GR63178A (NSC D611615) in Human Ovarian Cancer Lines. Br. J. Cancer 1990, 61, 709−711. (b) French, R. C.; Cummings, J.; Nicolson, M.; Smyth, J. F. Stability of GR63178A, ANovel Pentacyclic Pyrroloquinone Anticancer Compound, in Aqueous Solutions and Biological Fluids. J. Pharm. Pharmacol. 1993, 45, 10−15. (c) Kaye, S. B.; Brampton, M.; Harper, P.; Smyth, J.; Kerr, D. J.; Gore, M.; Green, J. A.; Gilby, E.; Crawford, S. M.; Rustin, G. J. Phase II Trials of Fosquidone, (GR63178A), in Colorectal, Renal and Non-Small Cell Lung Cancer. CRC Phase II Clinical Trials Committee. Br. J. Cancer 1992, 65, 624− 625. (34) (a) Li, Y.-J.; Huang, H.-M.; Dong, H.-Q.; Jia, J.-H.; Han, L.; Ye, Q.; Gao, J.-R. The Synthesis of Benzo[f]isoindole-1,3-dicarboxylates viaan I2-Induced 1,3-Dipolar Cycloaddition Reaction. J. Org. Chem. 2013, 78, 9424−9430. (b) Healy, M. P.; Giblin, G. M. P.; Price, H. S. Benzoisoindole Derivatives as Prostanoid EP4 Receptor Agonists,

(18) Chinthapally, K.; Karthik, R.; Senthilkumar, S.; Baskaran, S. A Short and Efficient Synthesis of Iminosugar 2-Acyl Indolizidine. Chem. - Eur. J. 2017, 23, 533−536. (19) (a) Prasad, S. S.; Senthilkumar, S.; Srivastava, A.; Baskaran, S. Iminosugar C-Nitromethyl Glycosidesand Divergent Synthesis of Bicyclic Iminosugars. Org. Lett. 2017, 19, 4403−4406. (b) Prasad, S. S.; Baskaran, S. Iminosugar C-Nitromethyl Glycoside: Stereoselective Synthesis of Isoxazoline and Isoxazole Fused Bicyclic Iminosugars. J. Org. Chem. 2018, 83, 1558−1564. (20) (a) Jung, J.-C.; Park, O.-S. Synthetic Approaches and Biological Activities of 4-Hydroxycoumarin Derivatives. Molecules 2009, 14, 4790−4803. (b) March, S.; Pelletier, S. M. C.; Plant, A. Expedient Synthesis of Substituted 4-Hydroxy-quinolin-2(1H)-ones. Tetrahedron Lett. 2015, 56, 5859−5863. (c) de Carvalho da Silva, F.; Ferreira, V. F. Natural Naphthoquinones with Great Importance in Medicinal Chemistry. Curr. Org. Synth. 2016, 13, 334−371. (d) Abdou, M. M. Chemistry of 4-Hydroxy-2(1H)-quinolone. Part 1: Synthesis and Reactions. Arabian J. Chem. 2017, 10, S3324−S3337. (e) Shen, Q.; Shao, J.-L.; Peng, Q.; Zhang, W.-J.; Ma, L.; Chan, A. S. C.; Gu, L.-Q. Hydroxycoumarin Derivatives: Novel and Potent α-Glucosidase Inhibitors. J. Med. Chem. 2010, 53, 8252−8259. (21) (a) Thone, J.; Linker, R. A. Laquinimod in the Treatment of Multiple Sclerosis: AReview of the Data So Far. Drug Des., Dev. Ther. 2016, 10, 1111−1118. (b) Dang, Y.-P.; Chen, Y.-F.; Li, Y.-Q.; Zhao, L. Developments of Anticoagulants and New Agents with AntiCoagulant Effects in Deep Vein Thrombosis. Mini-Rev. Med. Chem. 2017, 17, 338−350. (c) Kirkiacharian, B. S.; De Clercq, E.; Kurkjian, R.; Pannecouque, C. New Synthesis and Anti-HIV and Antiviral Properties of 3-Arylsulfonyl Derivatives of 4-Hydroxycoumarin and 4Hydroxyquinolone. Pharm. Chem. J. 2008, 42, 265−270. (d) Xu, H.; Chen, Q.; Wang, H.; Xu, P.; Yuan, R.; Li, X.; Bai, L.; Xue, M. Inhibitory Effects of Lapachol on Rat C6 Glioma in Vitro and In Vivo by Targeting DNA Topoisomerase I and Topoisomerase II. J. Exp. Clin. Cancer Res. 2016, 35, 178. (e) Tandon, V. K.; Kumar, S. Recent Development on Naphthoquinone Derivatives and their Therapeutic Applications as Anticancer Agents. Expert Opin. Ther. Pat. 2013, 23, 1087−1108. (f) Beretta, G. L.; Supino, R.; Zunino, F.; Ribaudo, G.; Zagotto, G.; Menegazzo, I.; Capranico, G. Synthesis and Evaluation of New Naphthalene and Naphthoquinone Derivatives as Anticancer Agents. Arch. Pharm. 2017, 350, e1600286. (22) (a) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Natural Product Hybrids as New Leads for Drug Discovery. Angew. Chem., Int. Ed. 2003, 42, 3996−4028. (b) Mehta, G.; Singh, V. Hybrid Systems throughNatural Product Leads: An Approach towardsNew Molecular Entities. Chem. Soc. Rev. 2002, 31, 324−334. (c) Decker, M. Hybrid Molecules Incorporating Natural Products: Applications in Cancer Therapy, Neurodegenerative Disorders and Beyond. Curr. Med. Chem. 2011, 18, 1464−1475. (23) (a) Tietze, L. F.; Feuerstein, T.; Fecher, A.; Haunert, F.; Panknin, O.; Borchers, U.; Schuberth, I.; Alves, F. Proof of Principle in the Selective Treatment of Cancer by Antibody Directed Enzyme Prodrug Therapy. The Development of a Highly Potent Prodrug. Angew. Chem. 2002, 114, 785−787; Angew. Chem., Int. Ed. 2002, 41, 759−761. (b) Kuduk, S. D.; Harris, T. C.; Zheng, F. F.; SeppLorenzino, L.; Ouerfelli, Q.; Rosen, N.; Danishefsky, S. J. Synthesis and Evaluation of Geldanamycin-Testosterone Hybrids. Bioorg. Med. Chem. Lett. 2000, 10, 1303−1306. (c) Fortin, S.; Berube, G. Advances in the Development of Hybrid Anticancer Drugs. Expert Opin. Drug Discovery 2013, 8, 1029−1047. (d) Baraldi, P. G.; Preti, D.; Fruttarolo, F.; Tabrizi, M. A.; Romagnoli, R. Hybrid Molecules Between Distamycin A and Active Moieties of Antitumor Agents. Bioorg. Med. Chem. 2007, 15, 17−35. (e) Bolton, J. L.; Dunlap, T. Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects. Chem. Res. Toxicol. 2017, 30, 13−37. (24) (a) Mehta, G.; Ramesh, S. S. Polycyclitols. Novel Conduritol and Carbasugar Hybrids as a New Class of Potent Glycosidase Inhibitors. Chem. Commun. 2000, 2429−2430. (b) Reddy, B. G.; Vankar, Y. D. The Synthesis of Hybrids of D-Galactose with 1Deoxynojirimycin Analogs as Glycosidase Inhibitors. Angew. Chem., 9617


Article

The Journal of Organic Chemistry their Preparation, Pharmaceutical Compositions, and Use for the Treatment of Pain. WO2007088189A1, August 9, 2007. (35) Denizot, F.; Lang, R. Rapid Colorimetric Assay for Cell Growth and Survival. Modifications to the Tetrazolium Dye Procedure Giving Improved Sensitivity and Reliability. J. Immunol. Methods 1986, 89, 271−277.

9618


One-Pot Synthesis of Structurally Diverse ... - ACS Publications

Recommend Documents