European Journal of Medicinal Chemistry 70 (2013) 380e392

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European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Original article

Aziridines from alkenyl-b-D-galactopyranoside derivatives: Stereoselective synthesis and in vitro selective anticancer activity José M. Vega-Pérez a, *, Carlos Palo-Nieto a, Margarita Vega-Holm a, Purificación Góngora-Vargas a, José Manuel Calderón-Montaño b, Estefanía Burgos-Morón b, Miguel López-Lázaro b, Fernando Iglesias-Guerra a, * a b

Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, 41071 Sevilla, Spain Departamento de Farmacología, Facultad de Farmacia, Universidad de Sevilla, 41071 Sevilla, Spain

a r t i c l e i n f o

a b s t r a c t

Article history: Received 8 April 2013 Received in revised form 3 October 2013 Accepted 7 October 2013 Available online 16 October 2013

A series of new aziridines b-D-galactopyranoside derivatives were synthesized from alkenyl b-D-galactopyranosides employing Sharpless conditions. The structures of the compounds were established by 1 H NMR, 13C NMR, MS, HRMS and elemental analysis. The stereoselectivity of the reaction and the structural requirements of the alkenyl precursor for improving diastereoisomeric excesses of the direct aziridination reaction were also studied. The new compounds were subjected to a preliminary screening for cytotoxic activity against human lung cancer cells vs. human non-malignant lung cells. Terminal aziridine derivatives showed activity and, most notably, selectivity. One of the most active and selective compounds was also evaluated against breast cancer cells, melanoma cells, and non-malignant cells from the same origin. Its cytotoxic activity was similar to that of the positive controls, displaying a highly selective cytotoxic activity against both types of cancer cells. Ó 2013 Elsevier Masson SAS. All rights reserved.

Keywords: Cancer Stereoselective synthesis Aziridine carbohydrate derivative Selective cytotoxic activity

1. Introduction Aziridine moiety, a three-membered heterocycle, analogue to epoxide with a nitrogen group replacing the oxygen, is an important scaffold in organic synthesis [1]. The chemistry of aziridines has attracted considerable attention over the last few decades, and it is profoundly dependent on their ability to undergo nucleophilic ring opening, both stereo- and regioselectively [2]. This allows the installation of a wide range of functional groups in a 1, 2relationship to nitrogen, and provides access to an important pool of nitrogen-containing compounds [3e7]. This makes them versatile synthetic intermediates that are used for the synthesis of biologically active products [8e16]. Besides their importance as reactive intermediates, many aziridine-containing compounds have demonstrated to possess biological activity, essentially due to the presence of the aziridine ring. In this sense this functional group is present in different types of compounds with antitumoral activity, such as mitomycins [17e23], * Corresponding authors. E-mail addresses: [email protected] (J.M. Vega-Pérez), [email protected] (F. IglesiasGuerra). 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.10.020

benzoquinones [24e26], azinomycins [27e30] and epothilones [31] derivatives. Other natural and/or synthesized aziridine-containing compounds, with different structures (lipids, steroids, amino acids, as well as their peptide derivatives), have also shown to be promising candidates for the development of new drugs against several diseases, especially neoplasms [32]. The work presented here is included in a research line of our group aimed at the synthesis of new compounds with potential antitumor activity, possessing different chemical structures. We recently described the synthesis of new isoprenyl-thiourea and urea derivatives designed to act as farnesyl diphosphate analogues, and evaluated their cytotoxic activity, with promising results [33]. General structure 1, Fig. 1. An important objective in the design of new chemotherapeutic agents is to increase their specificity avoiding the death of healthy cells. In this regard, an usual approach followed in the search of promising leading compounds, both with antitumor [34] and antiviral [35] activity, is to attach the biologically active residue to different carbohydrate templates, trying to improve physicochemical and biological properties (carbohydrate moiety is found in

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381

Fig. 1. General backbone for new isoprenyl thiourea and urea derivatives. Fig. 2. General backbone for new glycosylglycerol derivatives.

many natural anticancer products [36]) and to influence the specificity and consequently to decrease the cytotoxicity. We have prepared a variety of new glycosylglycerol derivatives and 1-OAcyl-3-O-b-D-glycosyl-sn-glycerol analogues by stereoselective dihydroxylation of a range of alkenyl b-D-hexopyranosides under Donohoe’s conditions, (general structure 2, Fig. 2) and presented our preliminary results of cytotoxicity and selectivity assays [37]. Among all the tested compounds, the best results for both antitumor activity and selectivity were those of galacto glycosylglycerol derivatives. The inherent toxic effect of aziridines has promoted intensive studies aimed at obtaining new derivatives and evaluating their pharmacological activity and selectivity, to procure substances that can be used as chemotherapeutic agents. Our contribution in this line, presented here, is to combine in a general scaffold (3) the aziridine ring (crucial for the antitumor activity of various compounds) and the galacto moiety as the carbohydrate template, in order to obtain new potentially active compounds and study their activityeselectivity profile, Fig. 3. This paper therefore has a dual purpose. On one hand, the development of a synthetic methodology for the stereoselective azidirination reaction of alkenyl glycosides (galacto derivatives). Interestingly, this is the first time carbohydrates are used to induce chirality in direct aziridination reactions of alkenes. And on the other hand, the evaluation of antitumor activity and analysis of the structureeactivity relationship of these compounds. 2. Results & discussion 2.1. Chemistry From a range of alkenyl galactopyranosides previously described by us [37,38], we proceeded to the aziridination reaction using the conditions described by Sharpless, who uses TsNClNa as a nitrogen source and a bromine-based catalyst system: phenyltrimethylammonium tribromide, PhNMeþ 3 Br3 (also known as PTAB) [39], and to evaluate the stereoselectivity of the process. Our goal was to make an initial screening to identify the structural requirements that provided greater chemical and stereochemical yields. For this we used as precursors a set of different functionalized alkenes which differ in the substituents of the olefin moiety as well as in the presence of a protective group on the sugar residue. Scheme 1 outlines the direct aziridination reaction of alkenes 4e13. The new aziridine derivatives 14e23 were isolated in satisfactory chemical yields (60e90%). Stereochemical yields obtained (de’s) were established by 1H NMR and are summarized in Table 1. For the analysis of the diastereoisomeric excesses, the aziridinyl b-D-galactopyranosides were divided into two groups according to the structure of the precursor olefin residue. The first group comprises those terminal aziridines (compounds 14e16, entries 1e3, Table 1); the second group comprises those not terminal aziridines with substituted 2-position of the aziridine moiety (compounds 17e23, entries 4e10, Table 1). As can be seen in Table 1, compounds obtained with largest diastereoisomeric excesses were compounds 14e16 (derived from terminal olefins), with values between 77%

and 99%. However, the obtained excesses fall drastically (9e31%) for compounds with any substituents at 2 position of the aziridine, 17, 20e23. Note that if the alkenyl residue has a Ph group at 2-position of the olefin, the reaction does not evolve to the aziridine compound, but to intermediate products (compounds 18 and 19, entries 5 and 6, Table 1). These intermediate were isolated by column chromatography and identified by mass spectroscopy. Fig. 4 shows the proposed structure for these products, according to mass spectrometry data. Analyzing in turn the stereoselectivity differences obtained in the terminal alkenes, we see that compound 14 obtained in 99% de (R1 ¼ Me) has the sugar hydroxyl groups benzylated, while in compound 16 (R1 ¼ Me) these groups are free. De decreases in this case to 77% (compare entry 1 vs entry 3, Table 1). The same happens with non-terminal aziridines (entry 7 vs entry 4, entry 10 vs entry 9). This leads us to think that the protection of positions 2 and 3 of the sugar could help increase the stereoselectivity of the process. Based on these results we decided to address the stereoselective preparation of new aziridines with general backbone 24, Fig. 5. As precursors for the synthesis of the aziridines, we needed terminal olefines with different R groups on their first carbon; to obtain them we started from the alkenyl b-D-galactopiranoside 5 and through a three-step synthetic sequence, involving oxidative cleavage of the alkene, Grignard reagents addition and subsequent oxidation of the generated alcohol, we obtained the new derivatives with keto function in the aglycon (compounds 31e34, Scheme 2). By subsequent Wittig reaction, we got the precursor alkene. All these compounds were isolated in high chemical yields. The structures of the new compounds were confirmed by analysis of their NMR spectra. 1H NMR spectra show as features the following signals: the aldehydic proton at 9.67 ppm (compound 25), the signal for CH(OH) proton at 3.8e3.6 ppm and the signal for the hydroxilic proton at 3.0e2.7 ppm (compounds 26e30), both at the aglycon moiety. 13C NMR spectra show the signals for carbonyl carbon at 201 ppm (compound 25) and at 209 ppm (compounds 31e34). In case of compound 28, with R ¼ tBu, the oxidation reaction was not successfully, possibly due to steric problems. Wittig reaction was carried out with compounds 31e34 in order to prepare the appropriate olefins according to the general backbone above mentioned (Fig. 5). Compounds 35e38 were obtained in high yields and were used as precursors for the synthesis of the

Fig. 3. General backbone for new aziridine-containing galactopyranoside derivatives.

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Scheme 1. Synthesis of aziridinyl galactopyranoside derivatives (14e23). Reagent and conditions: Substrate (1 mmol), TsNClNa (1.1 mmol), PTAB (10 mmol %), CH3CN, 20  C, 12 h.

aziridines (Sharpless conditions [39]) to obtain compounds 39e42 in high yields (Scheme 3). The stereoselectivity of this reaction was almost complete so these compounds were obtained as practically one stereoisomer (Table 2). The structures of the new azirinide derivatives were confirmed by their NMR analysis (1H and 13C). Table 3 summarizes spectroscopic data for the aziridine group in compounds 14e17, 20e23 and 39e42. In order to assess how the loss of the aziridine ring affected both biological activity (IC50) and selectivity, we subjected two aziridines to the opening reaction. The chosen aziridines had the general scaffold but different R; CH3 in one (compound 14) and CH2(CH2)12CH3 in the other one (compound 16) and two different amines were used as nucleophiles. The obtained products, 43 and 44, were also subjected to bioassay (Scheme 4). 2.2. In vitro cytotoxic activity To examine the cytotoxic activity of our compounds against cancer cells they were tested in vitro against A549 human lung cancer cells by using the MTT method. To evaluate the selectivity of our compounds, they were also tested in an MTT assay against MRC5 human non-malignant lung fibroblasts (for conditions of the MTT assay, see the Exptl. Sect.). Data were averaged from at least three independent experiments and are expressed as means  standard error of the means (SEM). Cisplatin was used as positive control. Table 1 Asymmetric synthesis of aziridine b-D-galactopyranosides derivatives (14e23). Entry

Compound

R1

R2

R3

R4

R5

Yielda (%)

Deb (%)

1 2 3 4 5 6 7 8 9 10

14 15 16 17 18 19 20 21 22 23

Me H Me H H H H H H H

H H H Me H H Me H H H

H H H Me Ph Ph Me n-C7H15 Me Me

Bn Bn H H H Bn Bn H H Bn

Bn Bn H H H Bn Bn Bn H Bn

67 74 65 87 Intermediate Intermediate 67 72 59 69

>99 77 77 23 Intermediate Intermediate 31 33 9 28

We carried out these early biological tests of the aziridines 14e 17, 20e23 and 39e42 and ring-opening compounds 43 and 44. The viability of human lung cancer cells A549 and human nonmalignant lung fibroblasts MRC5 treated for 48 h with several concentrations of each compound is shown in Figs. 6e19 (see Supporting information). Data (IC50) observed for compounds submitted to antitumoral assay are presented in Table 4. Analyzing the collected data shown in Figs. 6e19 and in Table 4 we can consider three types of profiles for the pair cytotoxic activity/selectivity of 14e17, 20e23 y 39e42. The best profile was observed in compounds 14, 15, 21 and 41. They were not only our most active compounds (IC50 73e235 mM, entries 1, 2, 6 and 11, Table 4) but also the most selective, presenting such selectivity from low product concentrations (see Figs. 6, 7, 11 and 16). For the IC50 values of these products, survival percentage of healthy cells is in the 90e100% range. The most selective compounds were 14 and 41 which at concentrations around 300 mM, achieve a viability of cancer cells about 30e40% with little affection on the viability of normal cells (Figs. 6 and 16), maintaining this selectivity even with high concentrations. The second type of observed behaviour was for compounds 16, 17 and 22, with activity (IC50 154, 389 and 351 mM respectively, entries 3, 4 and 7, Table 4) but with worse selectivity (Figs. 8, 9 and 12). Finally, compounds 20, 23, 39, and 40, with higher values of IC50 (580->1000 mM, entries 5, 8, 9 and 10, Table 4), showed low cytotoxic activity. From the structural point of view, the most active compounds (14, 15 and 41) were terminal aziridines with the sugar moiety diO-protected with R: Methyl, H and Nonyl respectively at 1-position

a

Yields after column chromatography. Diastereoisomeric excesses were determined by 1H NMR spectroscopy of the reaction mixture. b

Fig. 4. Proposed structure for compounds 18 and 19.

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Fig. 5. General backbone for new aziridinyl carbohydrate derived.

of the aziridine ring. The highest activity was found when R: H, in compound 15 (IC50 73 mM, entry 2, Table 4). Compounds 14 and 41 (R: Methyl and R: Nonyl respectively), showed similar IC50 (150 mM). The replacement of this substituent for a phenyl group (compound 39) or by a propyl group (compound 40), brings a decrease in the cytotoxic activity, with IC50 increasing almost to 600 mM (entries 9 and 10). It’s worth noting that the debenzylated compund analogue to 14, compound 16, showed similar activity (IC50 154 mM vs 153 mM, entries 1 vs 3) but a worse selectivity profile (Fig. 6 vs Fig. 8). In the first group of aziridines, those showing the best profile, is compound 21 with an IC50 (235 mM) slightly higher than those of its group (compounds 14, 15 and 41) (entry 6 vs entries 1, 2 and 11). This compound is a di-O-protected non-terminal aziridine, with an heptyl group at 2-position of the aziridine moiety. However, for other non-terminal aziridines, compounds 20 and 23, high IC50 were observed, with values > 800 mM (entries 5 and 8). Their analogues with positions 2 and 3 of the sugar deprotected, compounds 17 and 22, were more active, IC50 about 350e380 mM (entries 4 and 7). Compounds 43 and 44, obtained from the ring opening reaction with amines, were also subjected to biological assay. They were more cytotoxic against MRC5 cells than A549 cells (entries 13 and 14), and compound 44 stood out for its toxicity. As a result of this study, we chose compound 14, one of the most active but, especially, one of the most selective. We then conducted a preliminary study of its antitumor activity against other tumor types. To check whether this selectivity against cancer cells was repeated in other types of cancer, compound 14 was subjected to in vitro assays using MTT methodology versus breast cancer cells

383

and melanoma, and their corresponding nonmalignant cell lines (Figs. 20 and 21, Supporting information). Data (IC50) observed for compound 14 submitted to antitumoral assay against tumoral breast cancer and melanoma are presented in Table 5. As shown in the viability graphs (Figs. 20 and 21), compound 14 also has a high selectivity for MCF7 breast cancer cells and UACC-62 melanoma cells. For breast cancer cells it presents a selectivity profile similar to that lung cancer cells; at the IC50 value the percentage of survival of nonmalignant cells is around 80% (Fig. 20). In the case of melanoma cells selectivity is better, from the lowest concentrations tested. At the highest concentration (1.0 mM, Fig. 21) it was not cytotoxic to normal skin cells (VH-10), while the viability of the melanoma cells (UACC-62) was only 10%. Therefore, we can say that this compound was highly selective against melanoma cells UACC-62. From the data collected in Table 5 we see that compound 14 was, for these tumor cells (breast and melanoma), more active than the positive control used in each case (cisplatin and 5-fluorouracil respectively) and clearly more selective than the positive control against cells of breast cancer. 3. Conclusions Focused on the design of new compounds with cytotoxic activity and based on the fact that many aziridine-containing compounds have demonstrated to possess biological activity, essentially due to the presence of the aziridine ring, our first objective was to prepare new aziridinic compounds derived from sugar. We performed direct aziridination reaction on alkenes using different alkenyl b-Dgalactopyranosides (acting as chiral templates) through an easy and high yielded reaction. A range of aziridinyl derivatives differently substituted in positions 1 and 2 of the aziridine ring and with positions 2 and 3 of the sugar either free or di-O-protected were synthesized. Those terminal aziridines with protected sugar and the 1-position of the aziridine ring substituted were obtained as a single diastereoisomer, independently of the nature of the substituent. Our next aim was to assess the cytotoxic activity of these compounds, for which they were tested in vitro against human A549 lung cancer cells by using the MTT method. To evaluate their selectivity they were also tested in an MTT assay against MRC5 human non-malignant lung fibroblasts.

Scheme 2. Synthesis of new galactopyranoside derivatives (31-34). Reagent and conditions: (i) Substrate (1 mmol), Me3NO (2 mmol), OsO4 catalytic, CH2Cl2. NaIO4 (2 mmol), H2O (ii) Substrate (1 mmol), RMgBr (2 mmol), N2, THF, 78  C, 12h (iii) Substrate (1 mmol), PCC (2 mmol), CH2Cl2.

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Scheme 3. Synthesis of aziridinyl galactopyranoside derivatives (39e42). Reagent and conditions: (i) Substrate (1 mmol), CH3P(C6H5)3Br (1.2 mmol), nBuLi (2.3 mmol), THF, 70 / rt (ii) Substrate (1 mmol), TsNClNa (1.1 mmol), PTAB (10 mmol %), CH3CN, 20  C, 12 h.

The best compounds (higher activity and selectivity) were terminal aziridines with the sugar moiety di-O-protected, with R: H, Methyl and Nonyl at 1-position of aziridine ring, being the activity higher when R: H. The presence of a Ph or a Propyl groups in the aziridine considerably decreases activity. In general, nonterminal aziridines showed higher IC50 values and yet the activity of these products was higher for unprotected derivatives than for dibencilated ones. Aziridines were submitted to ring opening reaction with Nnucleophiles and the obtained compounds were subjected to biological assays. They showed higher cytotoxicity against nonmalignant cells than to human lung cancer cells. We selected compound 14 (one of the most active against lung cancer cells, and one of the most selective) and subjected it to similar tests of antitumor activity against both breast and melanona cancer cells. The results showed that compound 14 is very active and selective against these types of cancer. To sum up, compound 14 has been shown to possess a high selectivity against 3 different types of cancer cells: lung, breast and skin. These are initial results that are still under study, in order to understand the mechanism of action of this substance, besides trying to get other sugar-derived aziridines with antitumor activity. 4. Experimental section

measurements with resolutions of 10,000. NMR spectra were recorded at 25  C on a Bruker AMX500 spectrometer and on a Bruker AV500 spectrometer at 500 MHz for 1H and 125 MHz for 13C. The chemical shifts are reported in ppm on the d scale relative to TMS. COSY, DEPT, HSQC, and NOESY experiments were performed to assign the signals in the NMR spectra. 4.1.2. Methodology for the synthesis of alkenyl b-Dgalactopyranoside derivatives (35e38) 4.1.2.1. 2-Oxoethyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (25). To a solution of olefin (1.0 mmol) and trimethylamine-N-oxide (2.0 mmol) in dichloromethane (20 mL), was added catalytic OsO4, and the reaction mixture was stirred at room temperature for 2 h. After this time sodium bisulphite was added and stirring for 15 min and washed with water. The organic phase was concentrated under reduced pressure. To a solution of the resultant diol in ethanol (40 mL) a solution of sodium periodate (2.0 mmol) in distilled water was added and stirring for 2 h. The ethanol was evaporated and the aqueous phase was extracted with dichloromethane and the organic phase was concentrated to dryness. The solid was purified by column chromatography using hexane-ethyl acetate (1:1) as eluent (0.416 g, 85% yield). Mp 122e 123  C; [a]D ¼ þ43.5 (c 1.0, CH2Cl2); MS (FAB): m/z 513 (50%) [M þ Na]þ; 1H NMR (500 MHz, CDCl3, d ppm): 9.67 (s, 1H, OCH2COH), 7.8e7.3 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 4.93 (d, 1H,

4.1. Chemistry 4.1.1. General All reagents, solvents, and starting materials were obtained from commercial suppliers and used without further purification. Evaporations were conducted under reduced pressure. Reactions were monitored by thin layer chromatography (TLC) using Kieselgel 60 F254 (E. Merck) plates and UV detector for visualization. Flash column chromatography was performed on Silica Gel 60 (E. Merck). Yields are of purified products. Melting points were obtained on a Stuart Melting Point Apparatus SMP 10 and are uncorrected. Optical rotations were obtained on a Perkin Elmer Polarimeter Model 341 at 25  C. Mass spectra were recorded on a Micromass AUTOSPECQ mass spectrometer: EI at 70 eV and CI at 150 eV, HR mass

Table 2 Asymmetric synthesis of aziridine b-D-galactopyranosides derivatives (39e42). Entry

Compound

Yielda (%)

Deb (%)

1 2 3 4

39 40 41 42

70 75 72 68

>99 >99 >99 >99

a

Yields after column chromatography. Diastereoisomeric excesses were determined by 1H NMR spectroscopy of the reaction mixture. b

Table 3 NMR spectroscopic data (d [ppm]) for the aziridine group in compounds 14e17, 20e 23 and 39e42.

Entry Compound 10 -H 1 2 3 4 5 6 7 8 9 10 11 12

14 15 16 17 20 21 22 23 39 40 41 42

e 4.29e4.37 e 3.23 3.23 2.93e2.97 3.06 3.00 e e e e

20 -H

NSO2PhCH3 10 -C 20 -C NSO2PhCH3

2.50, 2.50 3.79e3.90 2.54, 2.67 e e 2.93e2.97 2.48 2.90 2.73, 3.04 2.45, 2.60 2.44, 2.60 2.44, 2.60

2.36 1.55 2.41 2.41 2.26 2.37 2.38 2.28 2.36 2.35 2.34 2.34

48.6 49.2 49.4 50.3 50.6 48.0 46.2 47.0 53.6 68.9 52.4 52.4

38.6 33.2 38.4 49.5 51.0 46.6 43.2 43.4 37.5 38.2 38.1 38.1

21.5 21.6 21.5 21.5 21.3 21.5 21.8 21.5 21.5 21.5 21.5 21.5

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Scheme 4. Aziridine ring opening with N-nucleophiles. Reagent and conditions: (i) Substrate (1 mmol), amine (2 mmol), acetonitrile, reflux.

Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 4.85 (d, 1H, Jgem ¼ 11.0 Hz, 2PhCHAHBO), 4.80 (d, 1H, Jgem ¼ 11.0 Hz, 3-PhCHAHBO), 4.75 (d, 1H, Jgem ¼ 11.0 Hz, 3-PhCHAHBO), 4.46 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.29e 4.20 (m, 3H, H-6e, OCH2CHO), 4.13 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.01 (dd, 1H, J5,6a ¼ 1.7 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.94 (dd, 1H, J1,2 ¼ 7.7 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.58 (m, 1H, H-3), 3.33 (s, 1H, H-5). 13 C NMR (125 MHz, CDCl3, d ppm):d 201.2 (OCH2CHO), 129.0e126.4 (3Ph), 103.9 (C-1), 101.3 (PhCH), 79.1 (C-3), 78.2 (C-2), 75.4 (2PhCH2O), 74.4 (OCH2CHO), 73.7 (C-4), 72.0 (3-PhCH2O), 69.0 (C6), 66.7 (C-5). HRMS (FAB): calcd. for C29H30O7Na 513.1889; found, 513.1885 [M þ Na]þ. Anal. Calcd. for C29H30O7: C, 71.00; H, 6.16. Found: C, 70.93; H, 6.09. 4.1.2.2. Reaction of the aldehyde 33 with Grignard reagents (26e30). To a cooled solution (78  C) of the aldehyde 25 (1.0 mmol) in THF (30 mL) under argon atmosphere, the appropriate RMgBr (2.0 mmol) was added and the mixture was stirred at this temperature for 12 h. The reaction mixture was diluted in dichloromethane and washed successively with an aqueous saturated solution of ammonium chloride and with water, dried over MgSO4, filtered and the filtrate was evaporated to dryness under reduced pressure. The resultant crude was purified by column chromatography. 4.1.2.2.1. 2-Hydroxy-2-phenylethyl 2,3-di-O-benzyl-4,6-O-(S)benzylidene-b-D-galactopyranoside (26). Two stereoisomers were Table 4 Cytotoxic activity data (MTT assay). Entry

Compound

IC50 (mM) SEM A549 cells

IC50 (mM) SEM MRC5 cells

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

14 15 16 17 20 21 22 23 39 40 41 42 43 44 Cisplatin

153  44 73  13 154  10 389  16 >1000 235  118 351  63 804  99 599  91 579  54 154  16 w1000 492  41 15  4 13  5

>1000 183  20 312  27 567  12 >1000 >1000 544  32 >1000 570  46 793  20 575  31 w1000 156  81 20 139  51

obtained in a 1.7:1 ratio (26% de). The pure diastereomeric mixture was obtained as a solid by column chromatography using hexaneethyl acetate (2:1) as eluent (0.465 g, 82% yield). Mp 143e144  C; [a]D ¼ þ25.5 (c 1.0, CH2Cl2); MS (FAB): m/z 591 (100%) [M þ Na]þ. 1 H NMR (500 MHz, CDCl3, d ppm): 7.6e7.3 (m, 20H, Ph), 5.51 (s, 0.37H, PhCH minor), 5.50 (s, 0.63H, PhCH major), 4.93e4.76 [m, 5H, 2-PhCH2O, 3-PhCH2O, OCH2CH(OH)Ph], 4.53 (d, 0.63H, J1,2 ¼ 7.6 Hz, H-1 major), 4.48 (d, 0.37H, J1,2 ¼ 7.6 Hz, H-1 minor), 4.32 (dd, 0.37H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e minor), 4.28 (dd, 0.63H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e major), 4.14 (m, 1H, H-4), 4.10e 4.00 [m, 1.63H, H-6a, OCHAHBCH(OH)Ph major], 3.96e3.88 (m, 1.37H, H-2, OCHAHBCH(OH)Ph minor ], 3.80 [m, 0.37H, OCHAHBCH(OH)Ph minor], 3.60 [m, 2H, H-3, OCHAHBCH(OH)Ph major, OCH2CH(OH)Ph minor], 3.39 (s, 0.37H, H-5 minor), 3.35 (s, 0.63H, H-5 major), 3.30 [d, 0.63H, JH,OH ¼ 2.7 Hz, OCH2CH(OH)Ph major]. 13 C NMR (125 MHz, CDCl3): d 128.9e126.1 (4Ph), 104.1 (C-1), 101.4 (PhCH major), 101.3 (PhCH minor), 79.6 (C-3 major), 79.3 (C-3 minor), 78.4 (C-2 major), 78.3 (C-2 minor), 77.1 [OCH2CH(OH)Ph major], 76.4 [OCH2CH(OH)Ph minor], 75.6 (2-PhCH2O major), 75.4 (2-PhCH2O minor), 73.7 (C-4 major), 73.6 (C-4 minor), 73.1 [OCH2CH(OH)Ph major], 72.9 [OCH2CH(OH)Ph minor], 71.9 (3PhCH2O minor), 71.8 (3-PhCH2O major), 69.2 (C-6 major), 69.0 (C6 minor), 66.7 (C-5 minor), 66.6 (C-5 major). HRMS (FAB): calcd. for C35H36O7Na 591.2359; found, 591.2365 [M þ Na]þ. Anal. Calcd. for C35H36O7: C, 73.92; H, 6.38. Found: C, 74.01; H, 6.34. 4.1.2.2.2. 2-Hydroxypentyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (27). Two stereoisomers were obtained in a 1.3:1 ratio (13% de). The pure diastereomeric mixture was obtained as a solid by column chromatography using hexaneethyl acetate (2:1) as eluent (0.485 g, 91% yield). Mp 121e122  C; [a]D ¼ þ37.5 (c 1.0, CH2Cl2); MS (FAB): m/z 557 (90%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 4.90e4.84 (m, 2H, 2-PhCH2O), 4.79e4.73 (m, 2H, 3PhCH2O), 4.45 (d, 0.43H, J1,2 ¼ 7.8 Hz, H-1 minor), 4.42 (dd, 0.57H, J1,2 ¼ 7.8 Hz, H-1 major), 4.29 (m, 1H, H-6e), 4.13 (m, 1H, H-4), 4.01 (m, 1H, H-6a), 3.94 [dd, 0.43H, Jgem ¼ 10.6 Hz, J ¼ 2.7 Hz, OCHAHBCH(OH)CH2CH2CH3 minor], 3.88 (m, 1H, H-2), 3.82e3.78 [m, 1.57H, OCHAHBCH(OH)CH2CH2CH3 major, OCH2CH(OH)CH2CH2CH3], 3.65 [dd, 0.57H, Jgem ¼ 11.4 Hz, J ¼ 8.1 Hz, OCHAHBCH(OH)CH2CH2CH3 major], 3.58 (m, 1H, H-3), 3.46 [dd, 0.45H, Jgem ¼ 10.6 Hz, J ¼ 8.1 Hz, OCHAHBCH(OH)CH2CH2CH3 minor], 3.36 (s, 0.57H, H-5 major), 3.34 (s, 0.43H, H-5 minor), 3.00 [s, 0.57H, OCH2CH(OH)CH2CH2CH3 major], 2.76 [s, 0.43H, OCH2CH(OH)CH2CH2CH3 minor], 1.51e1.33

386

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Table 5 Cytotoxic activity data (MTT assay). Entry

Compound

IC50 (mM) SEM MCF-7 cells

IC50 (mM) SEM MCF-10 cells

IC50 (mM) SEM UACC-62 cells

IC50 (mM) SEM VH-10 cells

1 2 3

14 Cisplatin 5-Fluorouracil

12  2 25  2 e

567  114 23  4 e

196  190 e 264  66

>1000 e >1000

[m, 4H, OCH2CH(OH)CH2CH2CH3], 0.93 [m, 3H, OCH2CH(OH) CH2CH2CH3].13C NMR (125 MHz, CDCl3, d ppm): 138.6e126.4 (3Ph), 104.24 (C-1 major), 104.22 (C-1 minor), 101.30 (PhCH minor), 101.27 (PhCH major), 79.6 (C-3 minor), 79.5 (C-3 major), 78.5 (C-2 minor), 78.4 (C-2 major), 76.1 [OCH2CH(OH)CH2CH2CH3 major], 75.6 (2PhCH2O minor), 75.5 (2-PhCH2O major), 75.4 [OCH2CH(OH) CH2CH2CH3 minor], 73.7 (C-4), 71.9 (3-PhCH2O major), 71.8 (3PhCH2O minor), 70.4 [OCH2CH(OH)CH2CH2CH3 minor], 76.2 [OCH2CH(OH)CH2CH2CH3 major], 69.2 (C-6 minor), 69.1 (C-6 major), 66.6 (C-5 major), 66.5 (C-5 minor), 35.0 [OCH2CH(OH) CH2CH2CH3 major], 34.9 [OCH2CH(OH)CH2CH2CH3 minor], 18.7 [OCH2CH(OH)CH2CH2CH3], 14.0 [OCH2CH(OH)CH2CH2CH3]. HRMS (FAB): calcd. for C32H38O7Na 557.2515; found, 557.2512 [M þ Na]þ. Anal. Calcd. for C32H38O7: C, 71.89; H, 7.16. Found: C, 71.74; H, 7.08. 4.1.2.2.3. 2-Hydroxy-3,3-dimethylbutyl 2,3-di-O-benzyl-4,6-O(S)-benzylidene-b-D-galactopyranoside (28). Two stereoisomers were obtained in a 1.5:1 ratio (20% de). The pure diastereomeric mixture was obtained as a syrup by column chromatography using hexane-ethyl acetate (2.5:1) as eluent (0.411 g, 75% yield). Mp 144e 145  C; [a]D ¼ þ23.3 (c 1.0, CH2Cl2); MS (FAB): m/z 571 (100%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 4.92e4.83 (m, 2H, 2-PhCH2O), 4.80e4.73 (m, 2H, 3-PhCH2O), 4.46 (d, 0.4H, J1,2 ¼ 7.8 Hz, H-1 minor), 4.41 (dd, 0.6H, J1,2 ¼ 7.8 Hz, H-1 major), 4.31 (m, 1H, H-6e), 4.13 (m, 1H, H-4), 4.09 [m, 0.4H, OCHAHBCH(OH)C(CH3)3 minor], 4.01 (m, 1H, H-6a), 3.93e 3.83 [m, 1.6H, H-2, OCHAHBCH(OH)C(CH3)3 major], 3.70 [dd, 0.6H, Jgem ¼ 10.5 Hz, J ¼ 9.1 Hz, OCHAHBCH(OH)C(CH3)3 major], 3.58 (m, 1H, H-3), 3.51e3.44 [m, 1.4H, OCHAHBCH(OH)C(CH3)3 minor, OCH2CH(OH)C(CH3)3], 3.36 (s, 0.6H, H-5 major), 3.34 (s, 0.4H, H-5 minor), 3.03 [s, 0.6H, OCH2CH(OH)C(CH3)3 major], 2.81 [s, 0.4H, OCH2CH(OH)C(CH3)3 minor], 0.94 [s, 5.4H, OCH2CH(OH)C(CH3)3 major], 0.92 [s, 3.6H, OCH2CH(OH)C(CH3)3 minor].13C NMR (125 MHz, CDCl3, d ppm): 138.7e126.4 (3Ph), 104.2 (C-1 minor), 104.1 (C-1 major), 101.4 (PhCH minor), 101.3 (PhCH major), 79.6 (C3 minor), 79.4 (C-3 major), 78.5 (C-2 minor), 78.4 (C-2 major), 77.8 [OCH2CH(OH)C(CH3)3 minor], 77.4 [OCH2CH(OH)C(CH3)3 major], 75.6 (2-PhCH2O minor), 75.4 (2-PhCH2O major), 73.72 (C-4 major), 73.67 (C-4 major), 72.9 [OCH2CH(OH)C(CH3)3 major], 72.4 [OCH2CH(OH)C(CH3)3 minor], 71.9 (3-PhCH2O major), 71.8 (3-PhCH2O minor), 69.2 (C-6 minor), 69.1 (C-6 major), 66.6 (C-5 major), 66.5 (C-5 minor), 33.31 [OCH2CH(OH)C(CH3)3 major], 33.29 [OCH2CH(OH)C(CH3)3 minor], 26.1 [OCH2CH(OH)C(CH3)3]. HRMS (FAB): calcd. for C33H40O7Na 571.2672; found, 571.2695 [M þ Na]þ. Anal. Calcd. for C33H40O7: C, 72.24; H, 7.35. Found: C, 72.32; H, 7.11. 4.1.2.2.4. 2-Hydroxyundecyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (29). Two stereoisomers were obtained in a 1.6:1 ratio (23% de). The pure diastereomeric mixture was obtained as a syrup by column chromatography using hexaneethyl acetate (2.5:1) as eluent (0.494 g, 80% yield); [a]D ¼ þ12.6 (c 1.0, CH2Cl2); MS (FAB): m/z 641 (100%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 4.86 (m, 2H, 2-PhCH2O), 4.76 (m, 2H, 3-PhCH2O), 4.45 (d, 0.38H, J1,2 ¼ 7.8 Hz, H-1 minor), 4.42 (dd, 0.62H, J1,2 ¼ 7.8 Hz, H-1 major), 4.29 (d, 1H, J6e,6a ¼ 12.4 Hz, H-6e), 4.12 (m, 1H, H-4), 4.01 (m, 1H, H6a), 3.93 [dd, 0.38H, Jgem ¼ 10.5 Hz, J ¼ 2.6 Hz, OCHAHBCH(OH) CH2(CH2)7CH3 minor], 3.87 (m, 1H, H-2), 3.82e3.77 [m, 1.62H,

OCHAHBCH(OH)CH2(CH2)7CH3 major, OCH2CH(OH)CH2(CH2)7CH3], 3.64 [dd, 0.62H, Jgem ¼ 11.3 Hz, J ¼ 8.1 Hz, OCHAHBCH(OH) CH2(CH2)7CH3 major], 3.58 (m, 1H, H-3), 3.46 [dd, 0.38H, Jgem ¼ 10.6 Hz, J ¼ 8.1 Hz, OCHAHBCH(OH)CH2(CH2)7CH3 minor], 3.36 (s, 0.62H, H-5 major), 3.34 (s, 0.38H, H-5 minor), 3.00 [s, 0.62H, OCH2CH(OH)CH2(CH2)7CH3 major], 2.75 [s, 0.38H, OCH2CH(OH)CH2(CH2)7CH3 minor], 1.50e1.20 [m, 16H, OCH2CH(OH)CH2(CH2)7CH3], 0.88 [t, 3H, J ¼ 7.0 Hz, OCH2CH(OH) CH2(CH2)7CH3].13C NMR (125 MHz, CDCl3, d ppm): 138.6e126.5 (3Ph), 104.3 (C-1 major), 104.2 (C-1 minor), 101.32 (PhCH minor), 101.28 (PhCH major), 79.6 (C-3 minor), 79.5 (C-3 major), 78.5 (C-2 minor), 78.4 (C-2 major), 76.1 [OCH2CH(OH)CH2(CH2)7CH3 minor], 75.6 (2-PhCH2O minor), 75.5 (2-PhCH2O major), 75.4 [OCH2CH(OH) CH2(CH2)7CH3 major], 73.7 (C-4), 71.9 (3-PhCH2O major), 71.8 (3PhCH2O minor), 70.7 [OCH2C(OH)CH2(CH2)7CH3 minor], 70.4 [OCH2C(OH)CH2(CH2)7CH3 major], 69.2 (C-6 minor), 69.1 (C-6 major), 66.6 (C-5 major), 66.5 (C-5 minor), 32.9e22.7 [OCH2C(OH) CH2(CH2)7CH3], 14.1 [OCH2C(OH)CH2(CH2)7CH3]. HRMS (FAB): calcd. for C38H50O7Na 641.3454; found, 641.3431 [M þ Na]þ. 4.1.2.2.5. 2-Hydroxyhexadecyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (30). Two stereoisomers were obtained in a 1.2:1 ratio (9% de). The pure diastereomeric mixture was obtained as a syrup by column chromatography using hexane-ethyl acetate (2.5:1) as eluent (0.357 g, 52% yield); [a]D ¼ þ35.2 (c 1.0, CH2Cl2); MS (FAB): m/z 711 (50%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 4.86 (m, 2H, 2PhCH2O), 4.76 (m, 2H, 3-PhCH2O), 4.45 (d, 0.45H, J1,2 ¼ 7.7 Hz, H-1 minor), 4.42 (dd, 0.55H, J1,2 ¼ 7.7 Hz, H-1 major), 4.29 (d, 1H, J6e,6a ¼ 12.4 Hz, H-6e), 4.12 (m, 1H, H-4), 4.01 (d, 1H, J6e,6a ¼ 12.4 Hz, H-6a), 3.93 [dd, 0.45H, Jgem ¼ 10.6 Hz, J ¼ 2.6 Hz, OCHAHBCH(OH) CH2(CH2)12CH3 minor], 3.88 (m, 1H, H-2), 3.82e3.76 [m, 1.55H, OCHAHBCH(OH)CH2(CH2)12CH3 major, OCH2CH(OH)CH2(CH2)12CH3], 3.64 [dd, 0.55H, Jgem ¼ 11.3 Hz, J ¼ 8.2 Hz, OCHAHBCH(OH) CH2(CH2)12CH3 major], 3.58 (m, 1H, H-3), 3.46 [dd, 0.45H, Jgem ¼ 10.6 Hz, J ¼ 8.2 Hz, OCHAHBCH(OH)CH2(CH2)12CH3 minor], 3.36 (s, 0.55H, H-5 major), 3.34 (s, 0.45H, H-5 minor), 3.01 [s, 0.55H, OCH2CH(OH)CH2(CH2)12CH3 major], 2.75 [s, 0.45H, OCH2CH(OH) CH2(CH2)12CH3 minor], 1.22 [m, 2H, OCH2CH(OH)CH2(CH2)12CH3], 1.34e1.24 [m, 24H, OCH2CH(OH)CH2(CH2)12CH3], 0.88 [t, 3H, J 7.0 Hz, OCH2CH(OH)CH2(CH2)12CH3].13C NMR (125 MHz, CDCl3, d PPM): 128.9e126.4 (3Ph), 104.3 (C-1 major), 104.2 (C-1 minor), 101.3 (PhCH minor), 101.2 (PhCH major), 79.6 (C-3 minor), 79.5 (C-3 major), 78.5 (C-2 minor), 78.4 (C-2 major), 76.1 [OCH2CH(OH)CH2(CH2)12CH3 minor], 75.6 (2-PhCH2O minor), 75.5 (2-PhCH2O major), 75.4 [OCH2CH(OH)CH2(CH2)12CH3 major], 73.7 (C-4), 71.9 (3-PhCH2O major), 71.8 (3-PhCH2O minor), 70.7 [OCH2C(OH)CH2(CH2)12CH3 minor], 70.4 [OCH2C(OH)CH2(CH2)12CH3 major], 69.2 (C-6 minor), 69.1 (C-6 major), 66.6 (C-5 major), 66.5 (C-5 minor), 32.9 [OCH2C(OH)CH2(CH2)12CH3 major], 32.9 [OCH2C(OH)CH2(CH2)12CH3 minor], 31.9e22.7 [OCH2C(OH)CH2(CH2)12CH3], 14.1 [OCH2C(OH) CH2(CH2)12CH3]. HRMS (FAB): calcd. for C43H60O7Na 711.4237; found, 711.4222 [M þ Na]þ. 4.1.2.3. Oxidation reaction with PCC (31e34). To a solution of the appropriate 2-hydroxyalkyl derivative (1.0 mmol) in dichloromethane (20 mL), molecular sieve 4 A and PCC (2.0 mmol) were

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 70 (2013) 380e392

added and the mixture was stirred at room temperature overnight. The resultant crude was filtered by silica flash column using diethylether as solvent and the resultant crude was purified by column chromatography. 4.1.2.3.1. 2-Oxo-2-phenylethyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (31). The solid was purified by column chromatography using hexane-ethyl acetate (2.5:1) as eluent (0.441 g, 78% yield). Mp 154e155  C; [a]D ¼ þ15.5 (c 0.5, CH2Cl2); MS (FAB): m/z 589 (30%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.5e7.2 (m, 20H, Ph), 5.49 (s, 1H, PhCH), 5.10 (d, 1H, Jgem ¼ 16.0 Hz, OCHAHBCOPh), 5.02 (d, 1H, Jgem ¼ 11.0 Hz, 2PhCHAHBO), 4.86 (d, 1H, Jgem ¼ 16.0 Hz, OCHAHBCOPh), 4.79e4.73 (m, 3H, 2-PhCHAHBO, 3-PhCH2O), 4.60 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.29 (dd, 1H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e), 4.10 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.01 (dd, 1H, J5,6a ¼ 1.7 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.94 (dd, 1H, J1,2 ¼ 7.7 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.58 (dd, 1H, J2,3 ¼ 9.6 Hz, J3,4 ¼ 3.7 Hz, H-3), 3.34 (s, 1H, H-5). 13C NMR (125 MHz, CDCl3): d 195.4 (OCH2COPh), 138.8e126.5 (4Ph), 103.2 (C-1), 101.3 (PhCH), 79.0 (C-3), 78.2 (C-2), 75.2 (2-PhCH2O), 73.9 (C-4), 72.2 (3-PhCH2O), 71.1 (OCH2COPh), 69.0 (C-6), 66.6 (C5). HRMS (FAB): calcd. for C35H34O7Na 589.2200; found 589.2184 [M þ Na]þ. Anal. Calcd. for C35H34O7: C, 74.19; H, 6.05. Found: C, 74.05; H, 6.20. 4.1.2.3.2. 2-Oxopentyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-bD-galactopyranoside (32). The solid was purified by column chromatography using hexane-ethyl acetate (2:1) as eluent (0.441 g, 83% yield). Mp 132e133  C; [a]D ¼ þ29.0 (c 0.5, CH2Cl2); MS (FAB): m/z 555 (80%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.3 (m, 15H, Ph), 5.52 (s, 1H, PhCH), 4.98 (d, 1H, Jgem ¼ 11.0 Hz, 2PhCHAHBO), 4.95 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 4.77 (d, 1H, Jgem ¼ 12.0 Hz, 3-PhCHAHBO), 4.75 (d, 1H, Jgem ¼ 12.0 Hz, 3PhCHAHBO), 4.44 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.33 (d, 1H, Jgem ¼ 16.5 Hz, OCHAHBCOCH2CH2CH3), 4.25 (dd, 1H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e), 4.14 (d, 1H, Jgem ¼ 16.5 Hz, OCHAHBCOCH2CH2CH3), 4.11 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.00 (dd, 1H, J5,6a ¼ 1.7 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.90 (dd, 1H, J1,2 ¼ 7.7 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.58 (m, 1H, H-3), 3.32 (s, 1H, H-5), 2.68 (m, 1H, OCH2COCHAHBCH2CH3), 2.56 (m, 1H, OCH2COCHAHBCH2CH3), 1.64 (m, 2H, OCH2COCH2CH2CH3), 0.93 (t, 3H, J ¼ 7.40 Hz, OCH2COCH2CH2CH3). 13C NMR (125 MHz, CDCl3, d ppm): 209.1 (OCH2COCH2CH2CH3), 128.9e126.4 (3Ph), 103.4 (C1), 101.3 (PhCH), 79.2 (C-3), 78.2 (C-2), 75.3 (2-PhCH2O), 74.1 (OCH2COCH2CH2CH3), 73.7 (C-4), 72.0 (3-PhCH2O), 69.0 (C-6), 66.6 (C-5), 41.0 (OCH2COCH2CH2CH3), 16.4 (OCH2COCH2CH2CH3), 13.7 (OCH2COCH2CH2CH3). HRMS (FAB): calcd. for C32H36O7Na 555.2359; found, 555.2371 [M þ Na]þ. Anal. Calcd. for C32H36O7: C, 72.16; H, 6.81. Found: C, 72.05; H, 6.73. 4.1.2.3.3. 2-Oxoundecyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-bD-galactopyranoside (33). The solid was purified by column chromatography using hexane-ethyl acetate (3:1) as eluent (0.498 g, 82% yield). Mp 122e123  C; [a]D ¼ þ21.2 (c 1.0, CH2Cl2); MS (FAB): m/z 639 (100%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 4.97 (d, 1H, Jgem ¼ 11.0 Hz, 2PhCHAHBO), 4.84 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 4.76 (d, 1H, Jgem ¼ 12.0 Hz, 3-PhCHAHBO), 4.75 (d, 1H, Jgem ¼ 12.0 Hz, 3PhCHAHBO), 4.43 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.32 [d, 1H, Jgem ¼ 16.5 Hz, OCHAHBCOCH2(CH2)7CH3], 4.26 (dd, 1H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e), 4.24 [d, 1H, Jgem ¼ 16.5 Hz, OCHAHBCOCH2(CH2)7CH3], 4.12 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.01 (dd, 1H, J5,6a ¼ 1.7 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.92 (dd, 1H, J1,2 ¼ 7.7 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.57 (m, 1H, H-3), 3.32 (s, 1H, H-5), 2.63 [m, 1H, OCH2COCHAHB(CH2)7CH3], 2.55 [m, 1H, OCH2COCHAHB(CH2)7CH3], 1.24 [m, 14H, OCH2COCH2(CH2)7CH3], 0.88 [t, 3H, J ¼ 7.4 Hz, OCH2COCH2(CH2)7CH3]. 13C NMR (125 MHz, CDCl3, d ppm): 209.2 [OCH2COCH2(CH2)7CH3], 128.9e126.4 (3Ph), 103.3 (C-1), 101.3

387

(PhCH), 79.2 (C-3), 78.2 (C-2), 75.3 (2-PhCH2O), 74.1 [OCH2COCH2(CH2)7CH3], 73.7 (C-4), 72.0 (3-PhCH2O), 69.1 (C-6), 66.6 (C-5), 39.2 [OCH2COCH2(CH2)7CH3], 31.8e22.6 [OCH2COCH2(CH2)7CH3], 14.1 [OCH2COCH2(CH2)7CH3]. HRMS (FAB): calcd. for C38H48O7Na 639.3298; found, 639.3281 [M þ Na]þ. Anal. Calcd. for C38H48O7: C, 74.00; H, 7.84. Found: C, 74.04; H, 7.80. 4.1.2.3.4. 2-Oxohexadecyl 2,3-di-O-benzyl-4,6-O-(S)-benzylideneb-D-galactopyranoside (34). The solid was purified by column chromatography using hexane-ethyl acetate (2.5:1) as eluent (0.470 g, 75% yield). Mp 136e137  C; [a]D ¼ þ12.2 (c 1, CH2Cl2); MS (FAB): m/z 709 (80%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 4.97 (d, 1H, Jgem ¼ 10.9 Hz, 2-PhCHAHBO), 4.85 (d, 1H, Jgem ¼ 10.9 Hz, 2-PhCHAHBO), 4.78 (d, 1H, Jgem ¼ 12.3 Hz, 3PhCHAHBO), 4.75 (d, 1H, Jgem ¼ 12.3 Hz, 3-PhCHAHBO), 4.44 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.34 [d, 1H, Jgem ¼ 16.5 Hz, OCHAHBCOCH2(CH2)12CH3], 4.26 (dd, 1H, J5,6e ¼ 1.2 Hz, J6e,6a ¼ 12.3 Hz, H-6e), 4.15 [d, 1H, Jgem ¼ 16.5 Hz, OCHAHBCOCH2(CH2)12CH3], 4.12 (d, 1H, J3,4 ¼ 3.6 Hz, H-4), 4.00 (dd, 1H, J5,6a ¼ 1.4 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.93 (dd, 1H, J1,2 ¼ 7.7 Hz, J2,3 ¼ 9.7 Hz, H-2), 3.58 (dd, 1H, J2,3 ¼ 9.7 Hz, J3,4 ¼ 3.6 Hz, H-3), 3.32 (s, 1H, H-5), 2.65 [m, 1H, OCH2COCHAHB(CH2)12CH3], 2.55 [m, 1H, OCH2COCHAHB(CH2)12CH3], 1.6e1.2 [m, 24H, OCH2COCH2(CH2)12CH3], 0.88 [t, 3H, J ¼ 7.0 Hz, OCH2COCH2(CH2)12CH3]. 13C NMR (125 MHz, CDCl3, d ppm): 209.3 [OCH2COCH2(CH2)12CH3], 138.7e126.4 (3Ph), 103.3 (C-1), 101.3 (PhCH), 79.2 (C-3), 78.2 (C-2), 75.3 (2-PhCH2O), 74.1 [OCH2COCH2(CH2)12CH3], 73.7 (C-4), 72.0 (3-PhCH2O), 69.1 (C-6), 66.6 (C-5), 39.2 [OCH2COCH2(CH2)12CH3], 31.9e22.7 [OCH2COCH2(CH2)12CH3], 14.1 [OCH2COCH2(CH2)12CH3]. HRMS (FAB): calcd. for C43H58O7Na 709.4080; found, 709.4070 [M þ Na]þ. Anal. Calcd. for C43H58O7: C, 75.19; H, 8.51. Found: C, 75.07; H, 8.35. 4.1.2.4. Wittig reaction (35e38). A suspension of methyl (triphenyl)phosphonium bromide (1.2 mmol) in dry THF (40 mL) was cooled to 70  C, then a 2.5 M solution of n-butyllithium in hexane (2.3 mmol) was added dropwise under argon atmosphere, maintaining the temperature at 70  C. The mixture was stirred until it became bright red (ylide formation, w1 h) and allowed to slowly warm up to 30  C, the keto derivate (1.0 mmol) was added, and the mixture was stirred for 1 h at 30  C and left to stand for 12 h at 20  C. The reaction mixture was concentrated and the resultant crude was purified by column chromatography. 4.1.2.4.1. 2-Phenylallyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-bD-galactopyranoside (35). The solid was purified by column chromatography using hexane-ethyl acetate (4:1) as eluent(0.372 g, 65% yield). Mp 155e156  C; [a]D ¼ þ8.3 (c 0.5, CH2Cl2); MS (FAB): m/z 587 (20%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 20H, Ph), 5.56 [s, 1H, OCH2C(Ph)]CHAHB], 5.51 (s, 1H, PhCH), 5.45 [s, 1H, OCH2C(Ph)]CHAHB], 4.87 [d, 1H, Jgem 12.6 Hz, OCHAHBC(Ph)]CH2], 4.78e4.70 (m, 3H, 2-PhCHAHBO, 3-PhCH2O), 4.67 (d, 1H, Jgem ¼ 10.8 Hz, 2-PhCHAHBO), 4.54 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.51 [d, 1H, Jgem ¼ 12.6 Hz, OCHAHBC(Ph)]CH2], 4.33 (dd, 1H, J5,6e ¼ 1.3 Hz, J6e,6a ¼ 12.3 Hz, H-6e), 4.11 (d, 1H, J3,4 ¼ 3.6 Hz, H-4), 4.04 (dd, 1H, J5,6a ¼ 1.7 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.89 (dd, 1H, J1,2 ¼ 7.7 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.57 (dd, 1H, J2,3 ¼ 9.6 Hz, J3,4 ¼ 3.6 Hz, H-3), 3.34 (s, 1H, H-5). 13C NMR (125 MHz, CDCl3): d 143.5 [OCH2C(Ph)]CH2], 129.0e126.2 (4Ph), 114.9 [OCH2C(Ph)] CH2], 102.3 (C-1), 101.3 (PhCH), 79.4 (C-3), 78.4 (C-2), 75.2 (2PhCH2O), 74.0 (C-4), 72.0 (3-PhCH2O), 70.4 [OCH2C(Ph)]CH2], 69.2 (C-6), 66.5 (C-5). HRMS (FAB): calcd. for C36H36O6Na 587.2410; found, 587.2399 [M þ Na]þ. Anal. Calcd. for C36H36O6: C, 76.57; H, 6.43. Found: C, 76.53; H, 6.52. 4.1.2.4.2. 2-Propylallyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-bD-galactopyranoside (36). The solid was purified by column chromatography using hexane-ethyl acetate (3.5:1) as eluent (0.344 g, 65% yield). Mp 138e139  C; [a]D ¼ þ18.6 (c 0.5, CH2Cl2); MS (FAB):

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m/z 553 (20%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.50 (s, 1H, PhCH), 5.09 [s, 1H, OCH2C(CH2CH2CH3)] CHAHB], 4.95 (d, 1H, Jgem ¼ 10.8 Hz, 2-PhCHAHBO), 4.91 [s, 1H, OCH2C(CH2CH2CH3)]CHAHB,], 4.81e4.73 (m, 3H, 2-PhCHAHBO, 3PhCH2O), 4.42 (d, 1H, J1,2 ¼ 7.8 Hz, H-1), 4.37 [d, 1H, Jgem ¼ 12.6 Hz, OCHAHBC(CH2CH2CH3)]CH2], 4.31 (dd, 1H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e), 4.11 (d, 1H, J ¼ 3.7 Hz, H-4), 4.07 [d, 1H, Jgem ¼ 12.6 Hz, OCHAHBC(CH2CH2CH3)]CH2], 4.02 (dd, 1H, J5,6a ¼ 1.7 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.88 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.57 (dd, 1H, J2,3 ¼ 9.6 Hz, J3,4 ¼ 3.7 Hz, H-3), 3.31 (s, 1H, H-5), 2.08 [m, 2H, OCH2C(CH2CH2CH3)]CH2], 1.48 [m, 2H, OCH2C(CH2CH2CH3)]CH2], 0.88 [t, 3H, J ¼ 7.40 Hz, OCH2C(CH2CH2CH3)]CH2]. 13C NMR (125 MHz, CDCl3, d ppm): 145.3 [OCH2C(CH2CH2CH3)]CH2], 128.8e126.5 (3Ph), 111.9 [OCH2C(CH2CH2CH3)]CH2], 102.2 (C-1), 101.3 (PhCH), 79.4 (C-3), 78.4 (C-2), 75.3 (2-PhCH2O), 74.1 (C-4), 72.0 (3-PhCH2O), 71.6 [OCH2C(CH2CH2CH3)]CH2], 69.2 (C-6), 66.4 (C-5), 35.2 [OCH2C(CH2CH2CH3)]CH2], 20.6 [OCH2C(CH2CH2CH3)]CH2], 13.8 [OCH2C(CH2CH2CH3)]CH2]. HRMS (FAB): calcd. for C33H38O6Na 553.2566; found, 553.2579 [M þ Na]þ. Anal. Calcd. for C33H38O6: C, 74.69; H, 7.22. Found: C, 74.78; H, 7.10. 4.1.2.4.3. 2-Nonylallyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-bD-galactopyranoside (37). The solid was purified by column chromatography using hexane-ethyl acetate (4:1) as eluent (0.456 g, 74% yield). Mp 126e127  C; [a]D ¼ þ32.1 (c 0.5, CH2Cl2); MS (FAB): m/z 639 (60%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 5.08 [s, 1H, OCH2C(CH2(CH2)7CH3)] CHAHB], 4.94 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 4.90 [s, 1H, OCH2C(CH2(CH2)7CH3)]CHAHB], 4.79 (d, 1H, Jgem ¼ 11.0 Hz, 2PhCHAHBO), 4.76 (d, 1H, Jgem ¼ 12.0 Hz, 3-PhCHAHBO), 4.74 (d, 1H, Jgem ¼ 12.0 Hz, 3-PhCHAHBO), 4.42 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.34 (d, 1H, Jgem ¼ 16.5 Hz, OCHAHBC(CH2(CH2)7CH3)]CH2, 4.29 (dd, 1H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e), 4.11 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.06 [d, 1H, Jgem ¼ 16.5 Hz, OCHAHBC(CH2(CH2)7CH3)]CH2], 4.00 (dd, 1H, J5,6a ¼ 1.7 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.88 (dd,1H, J1,2 ¼ 7.7 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.56 (m, 1H, H-3), 3.30 (s, 1H, H-5), 2.08 [m, 2H, OCH2C(CH2(CH2)7CH3)] CH2], 1.32 [m, 14H, OCH2C(CH2(CH2)7CH3)]CH2], 0.89 [t, 3H, J ¼ 7.40 Hz, OCH2C(CH2(CH2)7CH3)]CH2]. 13C NMR (125 MHz, CDCl3, d ppm): 145.6 [OCH2C(CH2(CH2)7CH3)]CH2], 125.9e122.4 (3Ph), 111.7 [OCH2C(CH2(CH2)7CH3)]CH2], 102.2 (C-1), 101.3 (PhCH), 79.4 (C-3), 78.4 (C-2), 75.3 (2-PhCH2O), 74.0 (C-4), 72.0 (3-PhCH2O), 71.6 [OCH2C(CH2(CH2)7CH3)]CH2], 69.2 (C-6), 66.4 (C-5), 33.1 [OCH2C(CH2(CH2)7CH3)]CH2], 31.9e22.6 [OCH2C(CH2(CH2)7CH3)] CH2], 14.1 [OCH2C(CH2(CH2)7CH3)]CH2]. HRMS (FAB): calcd. for C39H52O6Na 639.3662; found, 639.3644 [M þ Na]þ. Anal. Calcd. for C39H52O6: C, 76.19; H, 8.20. Found: C, 76.12; H, 8.20. 4.1.2.4.4. 2-Tetradecylallyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (38). The solid was purified by column chromatography using hexane-ethyl acetate (3.5:1) as eluent (0.480 g, 77% yield). Mp 123e124  C; [a]D ¼ þ28.3 (c 0.5, CH2Cl2); MS (FAB): m/z 707 (20%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H, Ph), 5.51 (s, 1H, PhCH), 5.10 [s, 1H, OCH2C(CH2(CH2)12CH3)]CHAHB], 4.97 (d, 1H, Jgem ¼ 10.8 Hz, 2PhCHAHBO), 4.92 [s, 1H, OCH2C(CH2(CH2)12CH3)]CHAHB,], 4.82e 4.74 (m, 3H, 2-PhCHAHBO, 3-PhCH2O), 4.43 (d, 1H, J1,2 ¼ 7.8 Hz, H-1), 4.38 [d, 1H, Jgem ¼ 12.6 Hz, OCHAHBC(CH2(CH2)12CH3)]CH2], 4.32 (dd, 1H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e), 4.11 (d, 1H, J3,4 ¼ 3.7 Hz, H-4), 4.09 [d, 1H, Jgem ¼ 12.6 Hz, OCHAHBC(CH2(CH2)12CH3)]CH2], 4.02 (dd, 1H, J5,6a ¼ 1.7 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.89 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.58 (dd, 1H, J2,3 ¼ 9.6 Hz, J3,4 ¼ 3.7 Hz, H-3), 3.31 (s, 1H, H-5), 2.10 [m, 2H, OCH2C(CH2(CH2)12CH3)]CH2], 1.5e1.2 [m, 24H, OCH2C(CH2(CH2)12CH3)]CH2], 0.90 [t, 3H, J ¼ 7.0 Hz, OCH2C(CH2(CH2)12CH3)]CH2]. 13C NMR (125 MHz, CDCl3, d ppm): 145.6 [OCH2C(CH2(CH2)12CH3)]CH2], 138.8e126.5 (3Ph),

111.7 [OCH2C(CH2(CH2)12CH3)]CH2], 102.2 (C-1), 101.3 (PhCH), 79.4 (C-3), 78.4 (C-2), 75.3 (2-PhCH2O), 74.0 (C-4), 72.0 (3-PhCH2O), 71.7 [OCH2C(CH2(CH2)12CH3)]CH2], 69.2 (C-6), 66.4 (C-5), 33.1 [OCH2C(CH2(CH2)12CH3)]CH2], 31.9e22.7 [OCH2C(CH2(CH2)12 CH3)]CH2], 14.1 [OCH2C(CH2(CH2)12CH3)]CH2]. HRMS (FAB): calcd. for C44H60O6Na 707.4288; found, 707.4268 [M þ Na]þ. Anal. Calcd. for C44H60O6: C, 77.16; H, 8.83. Found: C, 77.11; H, 8.69. 4.1.3. Aziridination reaction (14e17, 20e23, 39e42) To a mixture of the olefin (1.0 mmol) and Chloramine-T$3H2O (1.5 mmol) in CH3CN (15 mL), PTAB (0.1 mmol) was added, and the reaction mixture was vigorously stirred at 20  C for 12 h. Then the mixture was concentrated to dryness and the resultant crude was purified by column chromatography. 4.1.3.1. 2-Methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (14). Only one stereoisomer was obtained (>99% de). The solid was purified by column chromatography using hexane-ethyl acetate (2:1) as eluent (0.450 g, 67% yield). Mp 67e68  C; [a]D ¼ þ52.3 (c 1.0, CH2Cl2); MS (FAB): m/z 694 (50%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.2 (m, 19H, Ar), 5.49 (s, 1H, PhCH), 4.75 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 4.7e4.6 (m, 3H, 2-PhCHAHBO, 3PhCH2O), 4.41 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.29 (dd, 1H, J5,6e ¼ 1.1 Hz, J6e,6a ¼ 12.3 Hz, H-6e), 4.11 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.06 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH3)(NTs) CH2], 4.01 (dd, 1H, J5,6a ¼ 1.5 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.77 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.62 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH3)(NTs)CH2], 3.53 (m, 1H, H-3), 3.31 (s, 1H, H-5), 2.59 [s, 1H, OCH2C(CH3)(NTs)CHAHB], 2.50 [s, 1H, OCH2C(CH3)(NTs)CHAHB], 2.36 [s, 3H, OCH2C(CH3)(NSO2C6H4CH3)CH2], 1.71 [s, 3H, OCHAHBC(CH3)(NTs)CH2]. 13C NMR (125 MHz, CDCl3, d ppm): 143.8e 126.4 (4Ar), 103.3 (C-1), 101.2 (PhCH), 79.0 (C-3), 78.2 (C-2), 75.1 (2PhCH2O), 73.8 (C-4), 71.9 (3-PhCH2O), 71.8 [OCH2C(CH3)(NTs)CH2], 69.1 (C-6), 66.5 (C-5), 48.6 [OCH2C(CH3)(NTs)CH2], 38.6 [OCH2C(CH3)(NTs)CH2], 21.5 [OCH2C(CH3)(NSO2C6H4CH3)CH2], 16.4 [OCH2C(CH3)(NTs)CH2]. HRMS (FAB)): calcd. for C38H41NO8SNa 694.2451; found, 694.2454 [M þ Na]þ. Anal. Calcd. for C38H42NO8S: C, 67.84; H, 6.29; N, 2.08; S, 4.77. Found: C, 67.97; H, 6.07; N, 2.01; S, 4.41. 4.1.3.2. 2,3-[N-(4-Methylbenzenesulfonyl)imino]propyl 2,3-di-Obenzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (15). Two stereoisomers were obtained in a 7.7:1 ratio (77% de). The major diastereoisomer was isolated as a syrup by column chromatography using hexane-ethyl acetate (1.5:1) as eluent (0.486 g, 74% yield); [a]D ¼ þ24.6 (c 0.5, CH2Cl2); MS (FAB): m/z 680 (1%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.2 (m, 19H, Ar), 5.50 (s, 1H, PhCH), 4.98 (d, 1H, Jgem ¼ 10.8 Hz, 2-PhCHAHBO), 4.8e4.7 (m, 3H, 2PhCHAHBO, 3-PhCH2O), 4.48 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.37e4.25 [m, 3H, H-6e, OCHAHBCH(NTs)CH2], 4.12 (m, 1H, H-4), 4.02 (m, 1H, H-6a), 3.95 [m, 1H OCHAHBCH(NTs)CH2], 3.90e3.79 [m, 3H, H-2, OCH2CH(NTs)CH2], 3.58 (m, 1H, H-3), 3.34 (m, 1H, H-5), 1.55 [s, 3H, OCH2CH(NSO2C6H4CH3)CH2]. 13C NMR (125 MHz, CDCl3, d ppm): 143.6e126.4 (Ar), 103.8, 103.7 (C-1), 101.3 (PhCH), 79.3, 79.2 (C-3), 78.3, 78.2 (C-2), 75.4 (2-PhCH2O), 73.8 (C-4), 72.1 (3-PhCH2O), 70.9, 70.5 [OCH2CH(NTs)CH2], 69.1 (C-6), 66.6 (C-5), 49.2, 49.1 [OCH2CH(NTs)CH2], 34.2, 33.2 [OCH2CH(NTs)CH2], 21.6 [OCH2CH(NSO2C6H4CH3)CH2]. HRMS (FAB): calcd. for C37H39NO8SNa 680.2294; found; 680.2271 [M þ Na]þ. 4.1.3.3. 2-Methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 4,6-O-(S)-benzylidene-b-D-galactopyranoside (16). Two stereoisomers were obtained in a 7.6:1 ratio (77% de). The pure diastereomeric mixture was obtained as a solid by column chromatography

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using hexane-ethyl acetate (1:3) as eluent (0.319 g, 65% yield). Mp 95e96  C; [a]D ¼ þ4.1 (c 1.0, CH2Cl2); MS (CI): m/z 492 (20%) [M þ H]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.3 (m, 9H, Ar), 5.56 (s, 0.11H, PhCH minor), 5.55 (s, 0.89H, PhCH major), 4.41 (d, 0.11H, J1,2 ¼ 7.6 Hz, H-1 minor), 4.37(d, 0.89H, J1,2 ¼ 7.6 Hz, H-1 major), 4.32 (dd, 1H, J5,6e ¼ 1.5 Hz, J6e,6a ¼ 12.4 Hz, H-6e), 4.27 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 1.0 Hz, H-4), 4.13e4.06 [m, 2H, H-6a, OCHAHBC(CH3)(NTs)CH2], 3.81 [d, 1H, Jgem ¼ 11.4 Hz, OCHAHBC(CH3)(NTs)CH2], 3.77 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 9.6 Hz, H-2), 3.69 (m, 1H, H-3), 3.50 (s, 1H, H-5), 2.67 [s, 1H, OCH2C(CH3)(NTs) CHAHB], 2.54 [s, 1H, OCH2C(CH3)(NTs)CHAHB], 2.41 [s, 3H, OCH2C(CH3)(NSO2C6H4CH3)CH2], 1.73 [s, 0.33H, OCH2C(CH3)(NTs) CH2 minor], 1.73 [s, 2.67H, OCH2C(CH3)(NTs)CH2 major]. 13C NMR (125 MHz, CDCl3, d ppm): 129.6e126.4 (2Ar), 103.2 (C-1), 101.3 (PhCH), 75.1 (C-4), 72.7 [OCH2C(CH3)(NTs)CH2], 71.3 (C-3), 70.4 (C2), 69.1 (C-6), 66.8 (C-5), 49.4 [OCH2C(CH3)(NTs)CH2], 38.4 [OCH2C(CH3)(NTs)CH2], 21.5 [OCH2C(CH3)(NSO2C6H4CH3)CH2], 17.1 [OCH2C(CH3)(NTs)CH2]. HRMS (CI): calcd. for C24H30NO8S 492.169; 2 found, 492.1699 [M þ H]þ. Anal. Calcd. for C24H29NO8S: C, 58.64; H, 5.95; N, 2.85; S, 6.52. Found: C, 58.70; H, 5.93; N, 2.89; S, 6.32. 4.1.3.4. 3-Methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]butyl 4,6O-(S)-benzylidene-b-D-galactopyranoside (17). Two stereoisomers were obtained in a 1.6:1 ratio (23% de). The pure diastereomeric mixture was obtained as a solid by column chromatography using hexane-ethyl acetate (1:4) as eluent (0.439 g, 87% yield). Mp 85e 86  C; [a]D ¼ 7.8 (c 1.0, CH2Cl2); MS (CI): m/z 506 (20%) [M þ H]þ. 1 H NMR (500 MHz, CDCl3, d ppm): 7.9e7.3 (m, 9H, Ar), 5.58 (s, 1H, PhCH), 4.35e4.31 (m, 1.62H, H-1 major, H-6e), 4.23 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.19 (d, 0.38H, J1,2 ¼ 7.6 Hz, H-1 minor), 4.16e4.13 [m, 1.62H, H-6a, OCHAHBCH(NTs)C(CH3)2 major], 3.90 [dd, 0.38H, Jgem ¼ 11.5 Hz, OCHAHBCH(NTs)C(CH3)2 minor], 3.72e3.69 [m, 1.38H, H-2, OCHAHBCH(NTs)C(CH3)2 minor], 3.64 (m, 1H, H-3), 3.43 [d, 0.62H, Jgem ¼ 11.3 Hz, OCHAHBCH(NTs)C(CH3)2 major], 3.41 (s, 1H, H-5), 3.23 [m, 1H, OCH2CH(NTs)C(CH3)2], 2.43 [s, 1.86H, OCH2C(CH3)(NSO2C6H4CH3)C(CH3)2 major], 2.41 [s, 1.14H, OCH2C(CH3)(NSO2C6H4CH3)C(CH3)2 minor], 1.77, 1.34 [2s, 3.72H, OCH2CH(NTs)C(CH3)2 major], 1.75, 1.35 [2s, 2.28H, OCH2CH(NTs) C(CH3)2 minor]. 13C NMR (125 MHz, CDCl3, d ppm): 129.4e126.3 (2Ar), 102.9 (C-1 major), 102.6 (C-1 minor), 101.4 (PhCH), 75.1 (C-4), 72.6 (C-2 minor), 72.4 (C-2 major), 71.6 (C-3 major), 71.4 (C-3 minor), 69.0 (C-6), 67.5 (C-5), 66.7 [OCH2CH(NTs)C(CH3)2 major], 66.6 [OCH2CH(NTs)C(CH3)2 minor], 50.8 [OCH2CH(NTs)C(CH3)2 minor], 50.3 [OCH2CH(NTs)C(CH3)2 major], 49.5 [OCH2CH(NTs)C(CH3)2], 21.5 [OCH2C(CH3)(NSO2C6H4CH3)C(CH3)2], 21.3, 21.0 [OCH2CH(NTs) C(CH3)2]. HRMS (CI): calcd. for C25H32NO8S 506.1849; found, 506.1803 [M þ H]þ. Anal. Calcd for C25H31NO8S: C, 59.39; H, 6.18; N, 2.77; S, 6.34. Found: C, 59.07; H, 6.27; N, 2.60; S, 6.17. 4.1.3.5. 3-Methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]butyl 2,3di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (20). Two stereoisomers were obtained in a 1.9:1 ratio (31% de). The pure diastereomeric mixture was obtained as syrup by column chromatography using hexane-ethyl acetate (2:1) as eluent (0.458 g, 67% yield); [a]D ¼ þ19.0 (c 1.0, CH2Cl2); MS (FAB): m/z 708 (50%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.1 (m, 19H, Ar), 5.49 (s, 0.66H, PhCH major), 5.48 (s, 0.34H, PhCH minor), 4.82 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 4.74e4.60 (m, 3H, 2-PhCHAHBO, 3-PhCH2O), 4.34 (d, 0.34H, J1,2 ¼ 7.7 Hz, H-1 minor), 4.28e4.24 (m, 1.66H, H-1 major, H-6e), 4.08 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H4), 4.01e3.93 [m, 1.34H, H-6a, OCHAHBCH(NTs)C(CH3)2 minor], 3.85 [dd, 0.66H, Jgem ¼ 11.7 Hz, J ¼ 6.6 Hz, OCHAHBCH(NTs)C(CH3)2 major], 3.78e3.70 (m, 1H, H-2), 3.62 [dd, 0.66H, Jgem ¼ 11.7 Hz, J ¼ 6.6 Hz, OCHAHBCH(NTs)C(CH3)2 major], 3.52 [dd, 0.34H, Jgem ¼ 11.7 Hz, J ¼ 3.7 Hz, OCHAHBCH(NTs)C(CH3)2 minor], 3.47 (m,

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1H, H-3), 3.28 (s, 0.34H, H-5 minor), 3.23 [m, 1H, OCH2CH(NTs) C(CH3)2], 3.18 (s, 0.66H, H-5 major), 2.34 [s, 1.02H, OCH2CH(NSO2C6H4CH3)C(CH3)2 minor], 2.26 [s, 1.98H, OCH2CH(NSO2C6H4CH3)C(CH3)2 major], 1.73, 1.30 [2s, 2.04H, OCH2CH(NTs) C(CH3)2 minor], 1.70, 1.31 [2s, 3.96H, OCH2CH(NTs)C(CH3)2 major]. 13 C NMR (125 MHz, CDCl3, dppm): 138.6e126.3 (3Ar), 103.5 (C-1 major), 103.2 (C-1 minor), 101.1 (PhCH minor), 101.0 (PhCH major), 79.0 (2-PhCH2O minor), 78.8 (2-PhCH2O major), 78.3 (3-PhCH2O major), 78.3 (3-PhCH2O minor), 75.2 (C-4 minor), 75.0 (C-4 major), 73.6 (C-2), 71.9 (C-3 minor), 71.8 (C-3 major), 69.0 (C-6), 67.1 (C-5 major), 67.0 (C-5 minor),66.4 [OCH2CH(NTs)C(CH3)2 minor], 66.3 [OCH2CH(NTs)C(CH3)2 major], 51.0 [OCH2CH(NTs)C(CH3)2], 50.6 [OCH2CH(NTs)C(CH3)2 major], 50.0 [OCH2CH(NTs)C(CH3)2 minor], 21.4 [OCH2CH(NSO2C6H4CH3)C(CH3)2 minor], 21.3 [OCH2CH(NSO2C6H4CH3)C(CH3)2 major], 21.2, 21.1 [OCH2CH(NTs)C(CH3)2]. HRMS (FAB): calcd. for C39H43NO8SNa 708.2607; found, 708.2651 [M þ Na]þ. 4.1.3.6. 2,3-[N-(4-Methylbenzenesulfonyl)imino]decyl 3-O-benzyl4,6-O-(S)-benzylidene-b-D-galactopyranoside (21). Two stereoisomers were obtained in a 2:1 ratio (33% de). The pure diastereomeric mixture was obtained as syrup by column chromatography using hexane-ethyl acetate (2.5:1) as eluent (0.479 g, 72% yield); [a]D ¼ þ9.8 (c 1.0, CH2Cl2); MS (FAB): m/z 688 (60%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.2 (m, 14H, Ar), 5.46 (s, 1H, PhCH), 4.84e4.76 (m, 2H, PhCH2O), 4.34 (d, 0.67H, J1,2 ¼ 7.6 Hz, H-1 major), 4.38e4.27 [m, 2.33H, H-1 minor, H-6e, OCHAHBCH(NTs) CH(CH2)6CH3], 4.11 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.03e 3.94 [m, 2.67H, H-2, H-6a, OCHAHBCH(NTs)CH(CH2)6CH3 major], 3.78 [dd, 0.33H, Jgem ¼ 10.7 Hz, J ¼ 8.4 Hz, OCHAHBCH(NTs) CH(CH2)6CH3 minor], 3.49 (m, 1H, H-3), 3.34 (s, 0.67H, H-5 major), 3.33 (s, 0.33H, H-5 minor), 3.05e3.01 [m, 0.33H, OCH2CH(NTs) CH(CH2)6CH3 minor], 2.97e2.93 [m, 1.34H, OCH2CH(NTs) CH(CH2)6CH3 major], 2.76e2.73 [m, 0.33H, OCH2CH(NTs) CH(CH2)6CH3 minor], 2.39 [s, 0.99H, OCH2CH(NSO2C6H4CH3) CH(CH2)6CH3 minor], 2.37 [s, 2.01H, OCH2CH(NSO2C6H4CH3) CH(CH2)6CH3 major], 1.71e1.18 [m, 12H, OCH2CH(NTs) CH(CH2)6CH3], 0.91 [t, 3H, J ¼ 7.0 Hz, OCH2CH(NTs)CH(CH2)6CH3]. 13 C NMR (125 MHz, CDCl3, d ppm): 129.4e126.3 (3Ar), 103.3 (C-1 minor), 102.9 (C-1 major), 101.1 (PhCH minor), 101.0 (PhCH major), 78.8 (C-3 major), 78.7 (C-3 minor), 73.7 (C-4 minor), 73.4 (C-4 major), 71.9 (PhCH2O minor), 71.8 (PhCH2O major), 70.3 [OCH2CH(NTs)CH(CH2)6CH3 minor], 70.0 [OCH2CH(NTs) CH(CH2)6CH3 major], 69.2 (C-2 minor), 68.1 (C-2 major), 66.8 (C-6), 65.7 (C-5), 48.2 [OCH2CH(NTs)CH(CH2)6CH3 minor], 48.0 [OCH2CH(NTs)CH(CH2)6CH3 major], 46.9 [OCH2CH(NTs) CH(CH2)6CH3 minor], 46.6 [OCH2CH(NTs)CH(CH2)6CH3 major], 31.6e25.1 [OCH2CH(NTs)CH(CH2)6CH3], 21.5 OCH2CH(NSO2C6H4CH3)CH(CH2)6CH3], 14.0 [OCH2CH(NTs)CH(CH2)6CH3]. HRMS (FAB): calcd. for C37H47NO8S 688.2920; found, 688.2950 [M þ Na]þ. 4.1.3.7. 2,3-[N-(4-Methylbenzenesulfonyl)imino]butyl 4,6-O-(S)-benzylidene-b-D-galactopyranoside (22). Two stereoisomers were obtained in a 1.2:1 ratio (9% de). The pure diastereomeric mixture was obtained as syrup by column chromatography using hexane-ethyl acetate (1:4) as eluent (0.314 g, 64% yield); [a]D ¼ þ2.8 (c 1.0, CH2Cl2); MS (FAB): m/z 514 (100%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.2 (m, 9H, Ar), 5.56 (s, 0.45H, PhCH minor), 5.55 (s, 0.55H, PhCH major), 4.36e4.24 [m, 3H, H-1, H-6e OCHAHBCH(NTs)CH(CH3)], 4.22e4.06 [m, 3H, H-4, H-6a, OCHAHBCH(NTs)CH(CH3)], 3.70 (m, 1H, H-2), 3.60 (m, 1H, H-3), 3.46 (s, 0.55H, H-5 major), 3.44 (s, 0.45H, H-5 minor), 3.06 [m, 1H, OCH2CH(NTs)CH(CH3)], 2.48 [m, 1H, OCH2CH(NTs)CH(CH3)], 2.41 [s, 1.65H, OCH2CH(NSO2C6H4CH3)CH(CH3) major], 2.38 [s, 1.35H,

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OCH2CH(NSO2C6H4CH3)CH(CH3) minor], 1.50 (d, 1.35H, J1,2 ¼ 5.8 Hz, OCH2CH(NTs)CH(CH3) minor], 1.48 (d, 1.65H, J1,2 ¼ 5.8 Hz, OCH2CH(NTs)CH(CH3) major]. 13C NMR (125 MHz, CDCl3, d ppm): 129.8e126.3 (2Ar), 103.6 (C-1 minor), 103.4 (C-1 major), 101.3 (PhCH major), 101.1 (PhCH minor), 75.3 (C-4 minor), 75.1 (C-4 major), 73.4 (C-2), 71.6 (C-3), 69.5 (C-6 major), 69.0 (C-6 minor), 67.4 (C-5), 66.1 [OCH2CH(NTs)CH(CH3)], 46.5 [OCH2CH(NTs) CH(CH3) minor], 46.2 [OCH2CH(NTs)CH(CH3) major], 43.3 [OCH2CH(NTs)CH(CH3) minor], 43.2 [OCH2CH(NTs)CH(CH3) major], 21.8 [OCH2CH(NSO2C6H4CH3)CH(CH3) major], 21.6 [OCH2CH(NSO2C6H4CH3)CH(CH3) minor], 14.3 [OCH2CH(NTs)CH(CH3) major], 14.2 [OCH2CH(NTs)CH(CH3) minor]. HRMS (FAB): calcd. for C24H29NO8SNa 514.1512; found, 514.1541 [M þ Na]þ. 4.1.3.8. 2,3-[N-(4-Methylbenzenesulfonyl)imino]butyl 2,3-di-Obenzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (23). Two stereoisomers were obtained in a 1.8:1 ratio (28% de). The pure diastereomeric mixture was obtained as syrup by column chromatography using hexane-ethyl acetate (2:1) as eluent (0.523 g, 68% yield); [a]D ¼ þ32.6 (c 1.0, CH2Cl2); MS (FAB): m/z 694 (60%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.1 (m, 19H, Ar), 5.49 (s, 0.36H, PhCH minor), 5.48 (s, 0.64H, PhCH major), 4.82 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 4.74e4.60 (m, 3H, 2-PhCHAHBO, 3-PhCH2O), 4.34 (d, 0.64H, J1,2 ¼ 7.7 Hz, H-1 major), 4.32 (d, 0.36H, J1,2 ¼ 7.7 Hz, H-1 minor), 4.29e4.23 (m, 1H, H-6e), 4.17 [dd, 0.64H, OCHAHBCH(NTs)CH(CH3) major], 4.09 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.07e3.93 [m, 1.36H, H-6a, OCHAHBCH(NTs)CH(CH3) minor], 3.76e3.72 (m, 1H, H-2), 3.32 (m, 1H, H-3), 3.26 (s, 0.64H, H-5 major), 3.24 (s, 0.36H, H-5 minor), 3.08 [m, 0.36H, OCH2CH(NTs)CH(CH3) minor], 3.00 [m, 0.64H, OCH2CH(NTs)CH(CH3) major], 2.90 [m, 0.64H, OCH2CH(NTs) CH(CH3) major], 2.78 [m, 0.36H, OCH2CH(NTs)CH(CH3) minor], 2.35 [s, 1.92H, OCH2CH(NSO2C6H4CH3)CH(CH3) major], 2.28 [s, 1.08H, OCH2CH(NSO2C6H4CH3)CH(CH3) minor], 1.57 (d, 1.08H, J1,2 ¼ 5.8 Hz, OCH2CH(NTs)CH(CH3) minor], 1.54 (d, 1.92H, J1,2 ¼ 5.8 Hz, OCH2CH(NTs)CH(CH3) major]. 13C NMR (125 MHz, CDCl3, d ppm): 129.8e126.3 (4Ar), 103.7 (C-1 minor), 103.6 (C-1 major), 101.1 (PhCH major), 101.0 (PhCH minor), 79.1 (2-PhCH2O major), 79.0 (2-PhCH2O minor), 78.4 (3-PhCH2O minor), 78.3 (3PhCH2O major), 75.3 (C-4 minor), 75.2 (C-4 major), 73.7 (C-2), 71.9 (C-3), 69.2 (C-6 major), 69.0 (C-6 minor), 67.3 (C-5), 66.4 [OCH2CH(NTs)CH(CH3)], 47.5 [OCH2CH(NTs)CH(CH3) minor], 47.0 [OCH2CH(NTs)CH(CH3) major], 43.7 [OCH2CH(NTs)CH(CH3) minor],,43.4 [OCH2CH(NTs)CH(CH3) major], 21.6 [OCH2CH(NSO2C6H4CH3)CH(CH3) major], 21.5 [OCH2CH(NSO2C6H4CH3) CH(CH3) minor], 14.4 [OCH2CH(NTs)CH(CH3) major], 14.3 [OCH2CH(NTs)CH(CH3) minor]. HRMS (FAB): calcd. for C39H43NO8SNa 694.2562; found; 694.2535 [M þ Na]þ. 4.1.3.9. 2,3-[N-(4-Methylbenzenesulfonyl)imino]-2-phenylpropyl 2,3di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (39). Only one stereoisomer was obtained (>99% de).The solid was purified by column chromatography using hexane-ethyl acetate (2:1) as eluent (0.511 g, 70% yield). Mp 92e93  C; [a]D ¼ þ22.3 (c 1.0, CH2Cl2); MS (FAB): m/z 756 (60%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.1 (m, 24H, Ar), 5.50 (s, 1H, PhCH), 4.72 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 4.63 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(Ph)(NTs)CH2], 4.52e4.45 (m, 3H, 2-PhCHAHBO, 3PhCH2O), 4.43 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.30 (dd, 1H, J5,6e ¼ 1.1 Hz, J6e,6a ¼ 12.3 Hz, H-6e), 4.19 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(Ph)(NTs)CH2], 4.11 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H4), 4.00 (dd, 1H, J5,6a ¼ 1.5 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.68 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.51 (m, 1H, H-3), 3.30 (s, 1H, H-5), 3.04 [s, 1H, OCH2C(Ph)(NTs)CHAHB], 2.73 [s, 1H, OCH2C(Ph)(NTs) CHAHB], 2.36 [s, 3H, OCH2C(Ph)(NSO2C6H4CH3)CH2]. 13C NMR

(125 MHz, CDCl3, d ppm): 142.4e125.2 (5Ar), 103.5 (C-1), 101.0 (PhCH), 79.0 (C-3), 78.1 (C-2), 74.8 (2-PhCH2O), 73.8 (C-4), 71.9 (3PhCH2O), 69.8 [OCH2C(Ph)(NTs)CH2], 69.1 (C-6), 66.5 (C-5), 53.6 [OCH2C(Ph)(NTs)CH2], 37.5 [OCH2C(Ph)(NTs)CH2], 21.5 [OCH2C(Ph)(NSO2C6H4CH3)CH2]. HRMS (FAB): calcd. for C44H45NO8SNa 756.2607; found, 756.2590 [M þ Na]þ. Anal. Calcd for C44H45NO8S: C, 70.66; H, 6.06; N, 1.87; S, 4.38. Found: C, 70.44; H, 5.82; N, 1.88; S, 4.30. 4.1.3.10. 2,3-[N-(4-Methylbenzenesulfonyl)imino]-2-propylpropyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (40). Only one stereoisomer was obtained (>99% de). The syrup was purified by column chromatography using hexane-ethyl acetate (2.5:1) as eluent (0.524 g, 75% yield). Mp 106e107  C; [a]D ¼ þ32.0 (c 1.0, CH2Cl2); MS (FAB): m/z 722 (40%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.2 (m, 19H, Ar), 5.50 (s, 1H, PhCH), 4.77e4.67 (m, 4H, 2PhCH2O), 4.66 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH2CH2CH3)(NTs)CH2], 4.41 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.31 (dd, 1H, J5,6e ¼ 1.1 Hz, J6e,6a ¼ 12.3 Hz, H-6e), 4.25 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH2CH2CH3)(NTs)CH2], 4.11 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.00 (dd, 1H, J5,6a ¼ 1.5 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.74 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.54 (dd, 1H, J2,3 ¼ 9.6 Hz, J3,4 ¼ 3.7 Hz, H-3), 3.32 (s, 1H, H-5), 2.60 [s, 1H, OCH2C(CH2CH2CH3)(NTs)CHAHB], 2.45 [s, 1H, OCH2 C(CH2CH2CH3)(NTs)CHAHB], 2.35 [s, 3H, OCH2C(CH2CH2CH3)(NSO2C6H4CH3)CH2], 1.94 [m, 1H, OCH2C(CHAHBCH2CH3)(NTs)CH2], 1.77 [m, 1H, OCH2C(CHAHBCH2CH3)(NTs)CH2], 1.50 [m, 2H, OCH2C(CH2CH2CH3)(NTs)CH2], 0.92 [t, 3H, J ¼ 7.0 Hz, OCH2 C(CH2CH2CH3)(NTs)CH2]. 13C NMR (125 MHz, CDCl3, d ppm): 138.7.4e126.4 (4Ar), 103.4 (C-1), 101.0 (PhCH), 79.2 (C-3), 78.3 (C2), 75.0 (2-PhCH2O), 73.9 (C-4), 71.9 (3-PhCH2O), 69.2 (C-6), 68.9 [OCH2C(CH2CH2CH3)(NTs)CH2], 66.5 (C-5), 52.3 [OCH2C(CH2 CH2CH3)(NTs)CH2], 38.2 [OCH2C(CH2CH2CH3)(NTs)CH2], 33.4 [OCH2C(CH2CH2CH3)(NTs)CH2], 21.5 [OCH2C(CH2CH2CH3)(NSO2C6H4CH3)CH2], 19.1 [OCH2C(CH2CH2CH3)(NTs)CH2], 14.0 [OCH2C(CH2CH2CH3)(NTs)CH2]. HRMS (FAB): calcd. for C40H45 NO8SNa 722.2764; found, 722.2750 [M þ Na]þ. 4.1.3.11. 2,3-[N-(4-Methylbenzenesulfonyl)imino]-2-nonylpropyl 2,3di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (41). Only one stereoisomer was obtained (>99% de). The syrup was purified by column chromatography using hexane-ethyl acetate (3.5:1) as eluent (0.563 g, 72% yield); [a]D ¼ þ12.2 (c 1.0, CH2Cl2); MS (FAB): m/z 806 (30%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.9e7.2 (m,19H, 4Ar), 5.50 (s,1H, PhCH), 4.73e4.64 (m, 4H, 2PhCH2O), 4.41 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.30 (dd,1H, J5,6e ¼ 1.1 Hz, J6e,6a ¼ 12.3 Hz, H-6e), 4.26 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH2(CH2)7CH3)(NTs)CH2], 4.12 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.01 (dd, 1H, J5,6a ¼ 1.5 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.81 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH2(CH2)7CH3)(NTs)CH2], 3.74 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.53 (dd,1H, J2,3 ¼ 9.6 Hz, J3,4 ¼ 3.7 Hz, H-3), 3.32 (s, 1H, H-5), 2.60 [s, 1H, OCH2C(CH2(CH2)7CH3)(NTs)CHAHB], 2.44 [s, 1H, OCH2C(CH2(CH2)7CH3)(NTs)CHAHB], 2.34 [s, 3H, OCH2C(CH2(CH2)7 CH3)(NSO2C6H4CH3)CH2], 2.00 [m, 1H, OCH2C(CHAHB(CH2)7CH3) (NTs)CH2], 1.78 [m, 1H, OCH2C(CHAHB(CH2)7CH3)(NTs)CH2], 1.32 [m, 14H, OCH2C(CH2(CH2)7CH3)(NTs)CH2], 0.90 [t, 3H, J ¼ 7.0 Hz, OCH2C(CH2(CH2)7CH3)(NTs)CH2]. 13C NMR (125 MHz, CDCl3, d ppm): 138.7e126.4 (4Ar), 103.4 (C-1), 101.0 (PhCH), 79.2 (C-3), 78.3 (C-2), 75.0 (2-PhCH2O), 73.9 (C-4), 72.0 (3-PhCH2O), 69.2 (C-6), 68.9 [OCH2C(CH2(CH2)7CH3)(NTs)CH2], 66.5 (C-5), 52.4 [OCH2C(CH2 (CH2)7CH3)(NTs)CH2], 38.1 [OCH2C(CH2(CH2)7CH3)(NTs)CH2], 31.4 [OCH2C(CH2(CH2)7CH3)(NTs)CH2], 29.5e22.6 [m, OCH2C(CH2 (CH2)7CH3)(NTs)CH2], 21.5 [OCH2C(CH2(CH2)7CH3)(NSO2C6H4CH3) CH2], 14.0 [OCH2C(CH2(CH2)7CH3)(NTs)CH2]. HRMS (FAB): calcd. for C46H57NO8SNa 806.3703; found, 806.3724 [M þ Na]þ.

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 70 (2013) 380e392

4.1.3.12. 2,3-[N-(4-Methylbenzenesulfonyl)imino]-2-tetradecylpropyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (42). Only one stereoisomer was obtained (>99% de). The syrup was purified by column chromatography using hexane-ethyl acetate (3:1) as eluent (0.537 g, 68% yield); [a]D ¼ þ43.2 (c 1.0, CH2Cl2); MS (FAB): m/z 876 (30%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.8e7.2 (m, 19H, Ar), 5.50 (s, 1H, PhCH), 4.76e4.70 (m, 4H, 2PhCH2O), 4.65 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH2(CH2)12CH3)(NTs)CH2], 4.41 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.32 (dd,1H, J5,6e ¼ 1.1 Hz, J6e,6a ¼ 12.3 Hz, H-6e), 4.29 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH2(CH2)12CH3)(NTs)CH2], 4.12 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.00 (dd, 1H, J5,6a ¼ 1.5 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.74 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.51 (m, 1H, H-3), 3.31 (s, 1H, H-5), 2.60 [s, 1H, OCH2C(CH2 (CH2)12CH3)(NTs)CHAHB], 2.44 [s, 1H, OCH2C(CH2(CH2)12CH3)(NTs) CHAHB], 2.34 [s, 3H, OCH2C(CH2(CH2)12CH3)(NSO2C6H4CH3)CH2], 2.00 [m, 1H, OCH2C(CHAHB(CH2)12CH3)(NTs)CH2], 1.81e1.73 [m, 1H, OCH2C(CHAHB(CH2)12CH3)(NTs)CH2], 1.34 [m, 24H, OCH2C(CH2 (CH2)12CH3)(NTs)CH2], 0.91 [t, 3H, J ¼ 7.0 Hz, OCH2C(CH2(CH2)12 CH3)(NTs)CH2]. 13C NMR (125 MHz, CDCl3, d ppm): 144.4e123.6 (4Ar), 103.5 (C-1), 101.1 (PhCH), 79.2 (C-3), 78.3 (C-2), 75.0 (2-PhCH2O), 73.9 (C-4), 71.9 (3-PhCH2O), 69.2 (C-6), 68.9 [OCH2C(CH2(CH2)12CH3)(NTs) CH2], 66.5 (C-5), 52.4 [OCH2C(CH2(CH2)12CH3)(NTs)CH2], 38.1 [OCH2C(CH2(CH2)12CH3)(NTs)CH2], 31.3 [OCH2C(CH2(CH2)12CH3) (NTs)CH2], 29.5e25.9 [OCH2C(CH2(CH2)12CH3)(NTs)CH2], 21.5 [OCH2C(CH2(CH2)12CH3)(NSO2C6H4CH3)CH2], 14.1 [OCH2C(CH2 (CH2)12CH3)(NTs)CH2]. HRMS (FAB): calcd. for C51H67NO8SNa 876.4485; found, 876.4466 [M þ Na]þ. 4.1.4. Aziridine ring opening with nitrogen nucleophiles (43, 44) A solution of the aziridine (1.0 mmol) and the amine (2.0 mmol) in acetonitrile (25 mL) was heated at reflux. After the complete disappearance of aziridine ((TLC showed that all the starting material had reacted), the reaction mixture was cooled at room temperature and concentrated under reduced pressure. The resultant crude was purified by column chromatography. 4.1.4.1. 3-Dodecylamino-2-(4-methylbenzenesulfonamide)propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (43). Only one stereoisomer was obtained (>99% de). The syrup was purified by column chromatography using dichloromethane-methanol (20:1) as eluent (0.665 g, 78% yield); [a]D ¼ þ50.3 (c 1.0, MeOH); MS (FAB): m/z 879 (50%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.8e7.0 (m, 19H, Ar), 5.52 (s, 1H, PhCH), 4.82e4.73 (m, 4H, 2PhCH2O), 4.41e4.38 (m, 2H, H-1, H-6e), 4.14 (dd,1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H4), 4.03 (dd, 1H, J5,6a ¼ 1.5 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.90 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH3)(NHTs)CH2(NHCH2(CH2)10CH3)], 3.78 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.58 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH3)(NHTs)CH2(NHCH2(CH2)10CH3)], 3.56 (m, 1H, H-3), 3.38 (s, 1H, H-5), 2.71 [d, 1H, Jgem ¼ 11.9 Hz, OCH2C(CH3)(NHTs) CHAHB(NHCH2(CH2)10CH3)], 2.60 [d, 1H, Jgem ¼ 11.9 Hz, OCH2 C(CH3)(NHTs)CHAHB(NHCH2(CH2)10CH3)], 2.47 [m, 2H, OCH2C(CH3) (NHTs)CH2(NHCH2(CH2)10CH3)], 2.26 [s, 3H, OCH2C(CH3)(NHSO2C6H4CH3)CH2(NHCH2(CH2)10CH3)], 1.43e1.22 [m, 20H, OCH2 C(CH3)(NHTs)CH2(NHCH2(CH2)10CH3)], 1.03 [s, 3H, OCH2C(CH3) (NHTs)CH2(NHCH2(CH2)10CH3)], 0.88 [t, 3H, J ¼ 7.0 Hz, OCH2C(CH3) (NHTs)CH2(NHCH2(CH2)10CH3)]. 13C NMR (125 MHz, CDCl3, d ppm): 129.2e126.4 (4Ar), 103.0 (C-1), 101.1 (PhCH), 79.3 (C-3), 78.2 (C-2), 76.5 [OCH2C(CH3)(NHTs)CH2(NHCH2(CH2)10CH3)], 75.2 (2-PhCH2O), 73.7 (C-4), 72.0 (3-PhCH2O), 69.1 (C-6), 66.5 (C-5), 58.2 [OCH2C(CH3)(NHTs)CH2(NHCH2(CH2)10CH3)], 56.0 [OCH2C(CH3) (NHTs)CH2(NHCH2(CH2)10CH3)], 50.2 [OCH2C(CH3)(NHTs)CH2(NH CH2(CH2)10CH3)], 31.9e22.6 [OCH2C(CH3)(NHTs)CH2(NHCH2(CH2)10 CH3)], 21.3 [OCH2C(CH3)(NHSO2C6H4CH3)CH2(NHCH2(CH2)10CH3)], 20.2 [OCH2C(CH3)(NHTs)CH2(NHCH2(CH2)10CH3)], 14.1 [OCH2C(CH3)

(NHTs)CH2(NHCH2(CH2)10CH3)]. HRMS (FAB): calcd. C50H68N2O8SNa 879.4594; found, 879.4567 [M þ Na]þ.

391

for

4 .1. 4 . 2 . 3 - ( 4 - H y d r o x y e t h y l p i p e r a z i l m e t h y l ) - 2 - ( 4 methylbenzenesulfonamide)hexadecyl 2,3-di-O-benzyl-4,6-O-(S)benzylidene-b-D-galactopyranoside (44). Only one stereoisomer was obtained (>99% de). The syrup was purified by column chromatography using dichloromethane-methanol (10:1) as eluent (0.798 g, 81% yield); [a]D ¼ þ7.2 (c 1.0, MeOH); MS (FAB): m/z 1008 (30%) [M þ Na]þ. 1H NMR (500 MHz, CDCl3, d ppm): 7.8e7.2 (m, 19H, Ar), 5.70 (s, 1H, NH), 5.50 (s, 1H, PhCH), 4.83e4.75 (m, 4H, 2PhCH2O), 4.38 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.33 (dd, 1H, J5,6e ¼ 1.1 Hz, J6e,6a ¼ 12.3 Hz, H-6e), 4.13 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼ 1.0 Hz, H-4), 4.01 (dd, 1H, J5,6a ¼ 1.5 Hz, J6e,6a ¼ 12.3 Hz, H-6a), 3.92 [d, 1H, Jgem ¼ 10.8 Hz, OCHAHBC(CH2(CH2)12CH3)(NHTs)CH2N(CH2 CH2)(CH2CH2)NCH2OH)], 3.78 (dd, 1H, J1,2 ¼ 7.8 Hz, J2,3 ¼ 9.6 Hz, H-2), 3.59e3.54 [m, 4H, H-3, OCHAHBC(CH2(CH2)12CH3) (NHTs)CH2N(CH2CH2)(CH2CH2)NCH2OH), 3.35 (s, 1H, H-5), 2.66e 2.40 [m, 8H, OCH2C(CH2(CH2)12CH3)(NHTs)CH2N(CH2CH2)(CH2CH2) NCH2OH)], 2.32 [s, 3H, OCH2C(CH2(CH2)12CH3)(NSO2C6H4CH3) CH2N(CH2CH2)(CH2CH2)NCH2OH)], 1.31e0.92 [m, 26H, OCH2C(CH2 (CH2)12CH3)(NHTs)CH2N(CH2CH2)(CH2CH2)NCH2OH)], 0.90 [t, 3H, J ¼ 7.0 Hz, OCH2C(CH2(CH2)12CH3)(NHTs)CH2N(CH2CH2)(CH2CH2) NCH2OH)]. 13C NMR (125 MHz, CDCl3, d ppm): 142.4e126.4 (4Ar), 102.9 (C-1), 101.0 (PhCH), 79.4 (C-3), 77.9 (C-2), 75.2 (2-PhCH2O), 73.6 (C-4), 72.0 (3-PhCH2O), 71.9 [OCH2C(CH2(CH2)12CH3)(NHTs) CH2N(CH2CH2)(CH2CH2)NCH2OH)], 69.1 (C-6), 66.5 (C-5), 62.4e 53.2 [OCH2C(CH2(CH2)12CH3)(NHTs)CH2N(CH2CH2)(CH2CH2)NCH2 OH)], 59.2 [OCH2C(CH2(CH2)12CH3)(NHTs)CH2N(CH2CH2)(CH2CH2) NCH2OH)], 32.8e22.6 [OCH2C(CH2(CH2)12CH3)(NHTs)CH2N(CH2 CH2)(CH2CH2)NCH2OH)], 21.3 [OCH2C(CH2(CH2)12CH3)(NHSO2C6H4 CH3)CH2N(CH2CH2)(CH2CH2)NCH2OH)], 14.1 [OCH2C(CH2(CH2)12 CH3)(NHTs)CH2N(CH2CH2)(CH2CH2)NCH2OH)]. HRMS (FAB): calcd. for C57H83N3O9SNa 1008.5748; found, 1008.5726 [M þ Na]þ. 4.2. Cytotoxicity assays 4.2.1. Materials and cell culture conditions The human A549 lung cancer cell line, the human lung fibroblastic MRC-5 cell line, the human MCF7 breast adenocarcinoma cell line, the human VH-10 fibroblastic foreskin cell line and the human UACC-62 melanoma cell line were maintained in DMEM supplemented with 2 mM glutamine, 50 mg/ml penicillin, 50 mg/ml streptomycin and 10% foetal bovine serum. The human MCF10 breast epithelial cell line was maintained in a 1:1 mixture of Dulbecco’s modified Eagle’s medium and Ham’s F12 medium supplemented with 20 ng/ml epidermal growth factor, 100 ng/ml cholera toxin, 10 mg/ml insulin and 500 ng/ml of hydrocortisone (95%) and horse serum (5%). Cell lines were cultured at 37  C in a humidified atmosphere containing 5% CO2. Cell culture reagents were obtained from Life Technologies. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide] salt, 5-Fluorouracil, cisplatin and were purchased from Sigma Chemical Co. 4.2.2. Cell proliferation assays The MTT assay is a colorimetric technique that allows the quantitative determination of cell viability. It is based on the capability of viable cells to transform the MTT salt [3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] into a formazan dye. Exponentially growing cells were seeded into 96well plates and drugs were added 24 h later. Following an incubation period of 48 h, the medium was removed and MTT (125 mL, 1 mg/mL in medium) was added to each well for 5 h. Then 20% sodium dodecyl sulphate (80 mL) in 0.02 m HCl was added, plates were incubated for 10 h at 37  C and optical densities were

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measured at 540 nm on a multi-well plate spectrophotometer reader. Cell viability was expressed as a percentage relative to controls. All data were averaged from at least three independent experiments and were expressed as mean  standard error of the means (SEMs). Acknowledgements The authors thank thanks Junta de Andalucía for financial support (PI-0058-2012 and PI 0892-2012). Carlos Palo-Nieto thanks Junta de Andalucía (P09-AGR4597) and Ministerio de Asuntos Exteriores y Cooperación (AECID A/023577/09) for financial support. Authors are also grateful to CITIUS (Centro de Investigación, Tecnología e Innovación de la Universidad de Sevilla) by recording NMR and Mass spectra. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ejmech.2013.10.020. References [1] A.K. Yudin, Aziridines and Epoxides in Organic Synthesis, Wiley-VCH GmbH & and Co. KGaA, Weinheim, 2006. [2] (a) P. Lu, Tetrahedron 66 (2010) 2549e2560; (b) F. Grellepois, J. Nonnenmacher, F. Lachaud, C. Portella, Org. Biomol. Chem. 9 (2011) 1160e1168; (c) B. Das, V.S. Reddy, M. Krishnaiah, Y.K. Rao, J. Mol. Catal. Chem. 270 (2007) 89e92. [3] A.B. Pulipaka, S.C. Bergmeier, Synthesis 9 (2008) 1420e1430. [4] B.K. Lee, M.S. Kim, H.S. Hahm, D.S. Kim, W.K. Lee, H.-J. Ha, Tetrahedron 62 (2006) 8393e8397. [5] E.K. Dolence, J.B. Roylance, Tetrahedron: Asymmetry 15 (2004) 3307e3322. [6] W. Medjahed, A.T. Zatla, J.K. Mulengi, F.Z. Baba Ahmed, H. Merzouk, Tetrahedron Lett. 45 (2004) 1211e1213. [7] C. Cimarelli, D. Fratoni, G. Palmieri, Tetrahedron: Asymmetry 20 (2009) 2234e 2239. [8] A.E. Wroblewski, J. Drozd, Tetrahedron: Asymmetry 20 (2009) 2240e2246. [9] D.D. Dhavale, K.S. Ajish Kumar, V.D. Chaudhari, T. Sharma, S.G. Sabharwal, J. PrakashaReddy, Org. Biomol. Chem. 3 (2005) 3720e3726. [10] R. Celia, H.A. Stefani, Tetrahedron 65 (2009) 2619e2641. [11] J.B. Sweeney, Chem. Soc. Rev. 31 (2002) 247e258. [12] B. Smith, A.C. Doran, S. Mclean, F.D. Tingley, B.T. Neill, S.M. Kajiji, J. Pharmacol. Exp. Ther. 298 (2001) 1252e1259. [13] M. Naito, Y. Matsuba, S. Sato, H. Hirata, T. Tsuruo, Clin. Cancer Res. 8 (2002) 582e588. [14] G.A. Prosser, A.V. Patterson, D.F. Ackereley, J. Biotechnol. 150 (2010) 190e194. [15] J.E. Aaseng, S. Melnes, G. Reian, O.R. Gautun, Tetrahedron 66 (2010) 9790e 9797. [16] J.A. Groeper, J.B. Eagles, S.R. Hitchcock, Tetrahedron: Asymmetry 20 (2009) 1969e1974. [17] M.M.L. Fiallo, E. Deydier, M. Bracci, A. Garnier-Suillerot, K. Halvorsen, J. Med. Chem. 46 (2003) 1683e1689. [18] P.J. Keller, U. Hornemann, J. Nat. Prod. 46 (1983) 569e571. [19] (a) N.V. Kaminskaia, G.M. Ullmann, D.B. Fulton, N.M. Kostic, Inorg. Chem. 39 (2000) 5004e5013; (b) M. Kono, Y. Saitoh, K. Shirahata, Y. Arai, S. Ishii, J. Am. Chem. Soc. 109 (1987) 7224e7225.

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Aziridines from alkenyl-β-D-galactopyranoside derivatives: Stereoselective synthesis and in vitro selective anticancer activity.

A series of new aziridines β-D-galactopyranoside derivatives were synthesized from alkenyl β-D-galactopyranosides employing Sharpless conditions. The ...
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