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

lable at ScienceDirect

European Journal of Medicinal Chemistry 70 (2013) 380e392

Contents lists avai

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,*

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

a r t i c l e i n f o

Article history:Received 8 April 2013Received in revised form3 October 2013Accepted 7 October 2013Available online 16 October 2013

Keywords:CancerStereoselective synthesisAziridine carbohydrate derivativeSelective cytotoxic activity

* Corresponding authors.E-mail addresses: [email protected] (J.M. Vega-Pérez)

Guerra).

0223-5234/$ e see front matter � 2013 Elsevier Mashttp://dx.doi.org/10.1016/j.ejmech.2013.10.020

a b s t r a c t

A series of new aziridines b-D-galactopyranoside derivatives were synthesized from alkenyl b-D-gal-actopyranosides employing Sharpless conditions. The structures of the compounds were established by1H NMR, 13C NMR, MS, HRMS and elemental analysis. The stereoselectivity of the reaction and thestructural requirements of the alkenyl precursor for improving diastereoisomeric excesses of the directaziridination reaction were also studied.

The new compounds were subjected to a preliminary screening for cytotoxic activity against humanlung 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 againstbreast cancer cells, melanoma cells, and non-malignant cells from the same origin. Its cytotoxic activitywas similar to that of the positive controls, displaying a highly selective cytotoxic activity against bothtypes of cancer cells.

� 2013 Elsevier Masson SAS. All rights reserved.

1. Introduction

Aziridine moiety, a three-membered heterocycle, analogue toepoxide with a nitrogen group replacing the oxygen, is an impor-tant scaffold in organic synthesis [1]. The chemistry of aziridineshas attracted considerable attention over the last few decades, andit is profoundly dependent on their ability to undergo nucleophilicring opening, both stereo- and regioselectively [2]. This allowsthe installation of a wide range of functional groups in a 1, 2-relationship to nitrogen, and provides access to an important poolof nitrogen-containing compounds [3e7]. This makes them versa-tile synthetic intermediates that are used for the synthesis of bio-logically active products [8e16].

Besides their importance as reactive intermediates, manyaziridine-containing compounds have demonstrated to possessbiological activity, essentially due to the presence of the aziridinering. In this sense this functional group is present in different types ofcompounds with antitumoral activity, such as mitomycins [17e23],

, [email protected] (F. Iglesias-

son SAS. All rights reserved.

benzoquinones [24e26], azinomycins [27e30] and epothilones [31]derivatives.

Other natural and/or synthesized aziridine-containing com-pounds, with different structures (lipids, steroids, amino acids, aswell as their peptide derivatives), have also shown to be promisingcandidates for the development of new drugs against several dis-eases, especially neoplasms [32].

The work presented here is included in a research line of ourgroup aimed at the synthesis of new compounds with potentialantitumor activity, possessing different chemical structures.

We recently described the synthesis of new isoprenyl-thioureaand urea derivatives designed to act as farnesyl diphosphate ana-logues, and evaluated their cytotoxic activity, with promising re-sults [33]. General structure 1, Fig. 1.

An important objective in the design of new chemotherapeuticagents is to increase their specificity avoiding the death of healthycells.

In this regard, an usual approach followed in the search ofpromising leading compounds, both with antitumor [34] andantiviral [35] activity, is to attach the biologically active residue todifferent carbohydrate templates, trying to improve physicochem-ical and biological properties (carbohydrate moiety is found in

Delta:1_given name

Delta:1_surname

Delta:1_given name

Delta:1_surname

Delta:1_given name

Delta:1_surname

Delta:1_given name

Delta:1_surname

mailto:[email protected]

mailto:[email protected]

http://crossmark.crossref.org/dialog/?doi=10.1016/j.ejmech.2013.10.020&domain=pdf

www.sciencedirect.com/science/journal/02235234

http://www.elsevier.com/locate/ejmech

http://dx.doi.org/10.1016/j.ejmech.2013.10.020



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

Fig. 2. General backbone for new glycosylglycerol derivatives.

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

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 70 (2013) 380e392 381

many natural anticancer products [36]) and to influence the spec-ificity and consequently to decrease the cytotoxicity.

We have prepared a variety of new glycosylglycerol derivativesand 1-OAcyl-3-O-b-D-glycosyl-sn-glycerol analogues by stereo-selective dihydroxylation of a range of alkenyl b-D-hexopyrano-sides under Donohoe’s conditions, (general structure 2, Fig. 2) andpresented our preliminary results of cytotoxicity and selectivityassays [37]. Among all the tested compounds, the best results forboth antitumor activity and selectivity were those of galacto gly-cosylglycerol derivatives.

The inherent toxic effect of aziridines has promoted intensivestudies aimed at obtaining new derivatives and evaluating theirpharmacological activity and selectivity, to procure substances thatcan be used as chemotherapeutic agents. Our contribution in thisline, presented here, is to combine in a general scaffold (3) theaziridine ring (crucial for the antitumor activity of various com-pounds) and the galacto moiety as the carbohydrate template, inorder to obtain new potentially active compounds and study theiractivityeselectivity profile, Fig. 3.

This paper therefore has a dual purpose. On one hand, thedevelopment of a synthetic methodology for the stereoselectiveazidirination reaction of alkenyl glycosides (galacto derivatives).Interestingly, this is the first time carbohydrates are used to inducechirality in direct aziridination reactions of alkenes. And on theother hand, the evaluation of antitumor activity and analysis of thestructureeactivity relationship of these compounds.

2. Results & discussion

2.1. Chemistry

From a range of alkenyl galactopyranosides previously describedby us [37,38], we proceeded to the aziridination reaction using theconditions described by Sharpless, who uses TsNClNa as a nitrogensource and a bromine-based catalyst system: phenyl-trimethylammonium tribromide, PhNMe3þBr3- (also known as PTAB)[39], and to evaluate the stereoselectivity of the process. Our goalwas to make an initial screening to identify the structural re-quirements that provided greater chemical and stereochemicalyields.

For this we used as precursors a set of different functionalizedalkenes which differ in the substituents of the olefin moiety as wellas 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 satisfac-tory 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 aziridinylb-D-galactopyranosides were divided into two groups according tothe structure of the precursor olefin residue. The first group com-prises those terminal aziridines (compounds 14e16, entries 1e3,Table 1); the second group comprises those not terminal aziridineswith substituted 2-position of the aziridine moiety (compounds17e23, entries 4e10, Table 1). As can be seen in Table 1, compoundsobtained with largest diastereoisomeric excesses were compounds14e16 (derived from terminal olefins), with values between 77%

and 99%. However, the obtained excesses fall drastically (9e31%) forcompounds with any substituents at 2 position of the aziridine, 17,20e23. Note that if the alkenyl residue has a Ph group at 2-positionof the olefin, the reaction does not evolve to the aziridine com-pound, but to intermediate products (compounds 18 and 19, entries5 and 6, Table 1). These intermediate were isolated by columnchromatography and identified by mass spectroscopy. Fig. 4 showsthe proposed structure for these products, according to massspectrometry data.

Analyzing in turn the stereoselectivity differences obtained inthe terminal alkenes, we see that compound 14 obtained in 99% de(R1 ¼ Me) has the sugar hydroxyl groups benzylated, while incompound 16 (R1 ¼ Me) these groups are free. De decreases in thiscase to 77% (compare entry 1 vs entry 3, Table 1). The same happenswith non-terminal aziridines (entry 7 vs entry 4, entry 10 vs entry9). This leads us to think that the protection of positions 2 and 3 ofthe sugar could help increase the stereoselectivity of the process.

Based on these results we decided to address the stereoselectivepreparation of new aziridines with general backbone 24, Fig. 5.

As precursors for the synthesis of the aziridines, we neededterminal olefines with different R groups on their first carbon; toobtain them we started from the alkenyl b-D-galactopiranoside 5and through a three-step synthetic sequence, involving oxidativecleavage of the alkene, Grignard reagents addition and subsequentoxidation of the generated alcohol, we obtained the new de-rivatives with keto function in the aglycon (compounds 31e34,Scheme 2). By subsequent Wittig reaction, we got the precursoralkene.

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 thefollowing signals: the aldehydic proton at 9.67 ppm (compound25), the signal for CH(OH) proton at 3.8e3.6 ppm and the signal forthe hydroxilic proton at 3.0e2.7 ppm (compounds 26e30), both atthe aglycon moiety. 13C NMR spectra show the signals for carbonylcarbon at 201 ppm (compound 25) and at 209 ppm (compounds31e34). In case of compound 28, with R ¼ tBu, the oxidation re-action was not successfully, possibly due to steric problems.

Wittig reactionwas carried out with compounds 31e34 in orderto prepare the appropriate olefins according to the general back-bone above mentioned (Fig. 5). Compounds 35e38 were obtainedin high yields and were used as precursors for the synthesis of the

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.

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 70 (2013) 380e392382

aziridines (Sharpless conditions [39]) to obtain compounds 39e42in high yields (Scheme 3).

The stereoselectivity of this reaction was almost complete sothese compounds were obtained as practically one stereoisomer(Table 2).

The structures of the new azirinide derivatives were confirmedby their NMR analysis (1H and 13C). Table 3 summarizes spectro-scopic data for the aziridine group in compounds 14e17, 20e23 and39e42.

In order to assess how the loss of the aziridine ring affected bothbiological activity (IC50) and selectivity, we subjected two aziridinesto the opening reaction. The chosen aziridines had the generalscaffold but different R; CH3 in one (compound 14) andCH2(CH2)12CH3 in the other one (compound 16) and two differentamines were used as nucleophiles. The obtained products, 43 and44, were also subjected to bioassay (Scheme 4).

2.2. In vitro cytotoxic activity

To examine the cytotoxic activity of our compounds againstcancer cells they were tested in vitro against A549 human lungcancer cells by using the MTT method. To evaluate the selectivity ofour compounds, they were also tested in an MTT assay againstMRC5 human non-malignant lung fibroblasts (for conditions ofthe MTT assay, see the Exptl. Sect.). Data were averaged from atleast three independent experiments and are expressed asmeans � standard error of the means (SEM). Cisplatin was used aspositive control.

Table 1Asymmetric synthesis of aziridine b-D-galactopyranosides derivatives (14e23).

Entry Compound R1 R2 R3 R4 R5 Yielda (%) Deb (%)

1 14 Me H H Bn Bn 67 >992 15 H H H Bn Bn 74 773 16 Me H H H H 65 774 17 H Me Me H H 87 235 18 H H Ph H H Intermediate Intermediate6 19 H H Ph Bn Bn Intermediate Intermediate7 20 H Me Me Bn Bn 67 318 21 H H n-C7H15 H Bn 72 339 22 H H Me H H 59 910 23 H H Me Bn Bn 69 28

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

reaction mixture.

We carried out these early biological tests of the aziridines 14e17, 20e23 and 39e42 and ring-opening compounds 43 and 44.

The viability of human lung cancer cells A549 and human non-malignant lung fibroblasts MRC5 treated for 48 h with severalconcentrations of each compound is shown in Figs. 6e19 (seeSupporting information).

Data (IC50) observed for compounds submitted to antitumoralassay are presented in Table 4.

Analyzing the collected data shown in Figs. 6e19 and in Table 4we can consider three types of profiles for the pair cytotoxic ac-tivity/selectivity of 14e17, 20e23 y 39e42. The best profile wasobserved in compounds 14, 15, 21 and 41. They were not only ourmost active compounds (IC50 73e235 mM, entries 1, 2, 6 and 11,Table 4) but also the most selective, presenting such selectivityfrom low product concentrations (see Figs. 6, 7, 11 and 16).

For the IC50 values of these products, survival percentage ofhealthy cells is in the 90e100% range. The most selective com-pounds were 14 and 41 which at concentrations around 300 mM,achieve a viability of cancer cells about 30e40% with little affectionon the viability of normal cells (Figs. 6 and 16), maintaining thisselectivity even with high concentrations.

The second type of observed behaviour was for compounds16, 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, 9and 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 lowcytotoxic activity.

From the structural point of view, the most active compounds(14, 15 and 41) were terminal aziridines with the sugar moiety di-O-protected with R: Methyl, H and Nonyl respectively at 1-position

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

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


of the aziridine ring. The highest activity was found when R: H, incompound 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 adecrease in the cytotoxic activity, with IC50 increasing almost to600 mM (entries 9 and 10). It’s worth noting that the debenzylatedcompund analogue to 14, compound 16, showed similar activity(IC50 154 mM vs 153 mM, entries 1 vs 3) but a worse selectivityprofile (Fig. 6 vs Fig. 8).

In the first group of aziridines, those showing the best profile, iscompound 21with an IC50 (235 mM) slightly higher than those of itsgroup (compounds 14, 15 and 41) (entry 6 vs entries 1, 2 and 11).This compound is a di-O-protected non-terminal aziridine, with anheptyl group at 2-position of the aziridine moiety. However, forother non-terminal aziridines, compounds 20 and 23, high IC50were observed, with values > 800 mM (entries 5 and 8). Their an-alogues with positions 2 and 3 of the sugar deprotected, com-pounds 17 and 22, were more active, IC50 about 350e380 mM(entries 4 and 7).

Compounds 43 and 44, obtained from the ring opening reactionwith amines, were also subjected to biological assay. They weremore cytotoxic against MRC5 cells than A549 cells (entries 13 and14), and compound 44 stood out for its toxicity.

As a result of this study, we chose compound 14, one of the mostactive but, especially, one of the most selective. We then conducteda preliminary study of its antitumor activity against other tumortypes. To check whether this selectivity against cancer cells wasrepeated in other types of cancer, compound 14 was subjected toin vitro assays using MTT methodology versus breast cancer cells

Scheme 2. Synthesis of new galactopyranoside derivatives (31-34). Reagent and conditions:(ii) Substrate (1 mmol), RMgBr (2 mmol), N2, THF, �78 �C, 12h (iii) Substrate (1 mmol), PC

and melanoma, and their corresponding nonmalignant cell lines(Figs. 20 and 21, Supporting information).

Data (IC50) observed for compound 14 submitted to antitumoralassay against tumoral breast cancer andmelanoma are presented inTable 5.

As shown in the viability graphs (Figs. 20 and 21), compound 14also has a high selectivity for MCF7 breast cancer cells and UACC-62melanoma cells. For breast cancer cells it presents a selectivityprofile similar to that lung cancer cells; at the IC50 value the per-centage of survival of nonmalignant cells is around 80% (Fig. 20). Inthe case of melanoma cells selectivity is better, from the lowestconcentrations tested. At the highest concentration (1.0 mM,Fig. 21) it was not cytotoxic to normal skin cells (VH-10), while theviability of the melanoma cells (UACC-62) was only 10%. Therefore,we can say that this compound was highly selective against mel-anoma cells UACC-62.

From the data collected in Table 5we see that compound 14was,for these tumor cells (breast and melanoma), more active than thepositive control used in each case (cisplatin and 5-fluorouracilrespectively) and clearly more selective than the positive controlagainst cells of breast cancer.

3. Conclusions

Focused on the design of new compoundswith cytotoxic activityand based on the fact that many aziridine-containing compoundshave demonstrated to possess biological activity, essentially due tothe presence of the aziridine ring, our first objective was to preparenew aziridinic compounds derived from sugar. We performeddirect aziridination reaction on alkenes using different alkenyl b-D-galactopyranosides (acting as chiral templates) through an easy andhigh yielded reaction. A range of aziridinyl derivatives differentlysubstituted in positions 1 and 2 of the aziridine ring and with po-sitions 2 and 3 of the sugar either free or di-O-protected weresynthesized. Those terminal aziridines with protected sugar andthe 1-position of the aziridine ring substituted were obtained as asingle diastereoisomer, independently of the nature of thesubstituent.

Our next aim was to assess the cytotoxic activity of these com-pounds, for which they were tested in vitro against human A549lung cancer cells by using the MTT method. To evaluate theirselectivity they were also tested in an MTT assay against MRC5human non-malignant lung fibroblasts.

(i) Substrate (1 mmol), Me3NO (2 mmol), OsO4 catalytic, CH2Cl2. NaIO4 (2 mmol), H2OC (2 mmol), CH2Cl2.

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.

Table 3NMR spectroscopic data (d [ppm]) for the aziridine group in compounds 14e17, 20e23 and 39e42.

Entry Compound 10-H 20-H NSO PhCH 10-C 20-C NSO PhCH


The best compounds (higher activity and selectivity) were ter-minal aziridines with the sugar moiety di-O-protected, with R: H,Methyl and Nonyl at 1-position of aziridine ring, being the activityhigher when R: H. The presence of a Ph or a Propyl groups in theaziridine considerably decreases activity. In general, nonterminalaziridines showed higher IC50 values and yet the activity of theseproducts was higher for unprotected derivatives than for dibenci-lated ones.

Aziridines were submitted to ring opening reaction with N-nucleophiles and the obtained compounds were subjected to bio-logical assays. They showed higher cytotoxicity against non-malignant cells than to human lung cancer cells.

We selected compound 14 (one of the most active against lungcancer cells, and one of the most selective) and subjected it tosimilar tests of antitumor activity against both breast andmelanonacancer cells. The results showed that compound 14 is very activeand selective against these types of cancer.

To sum up, compound 14 has been shown to possess a highselectivity against 3 different types of cancer cells: lung, breast andskin. These are initial results that are still under study, in order tounderstand the mechanism of action of this substance, besidestrying to get other sugar-derived aziridines with antitumor activity.

4. Experimental section

4.1. Chemistry

4.1.1. GeneralAll reagents, solvents, and starting materials were obtained

from commercial suppliers and used without further purification.Evaporations were conducted under reduced pressure. Reactionsweremonitored by thin layer chromatography (TLC) using Kieselgel60 F254 (E. Merck) plates and UV detector for visualization. Flashcolumn chromatographywas performed on Silica Gel 60 (E. Merck).Yields are of purified products. Melting points were obtained on aStuart Melting Point Apparatus SMP 10 and are uncorrected. Opticalrotations were obtained on a Perkin Elmer Polarimeter Model 341at 25 �C. Mass spectra were recorded on a Micromass AUTOSPECQmass spectrometer: EI at 70 eV and CI at 150 eV, HR mass

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

Entry Compound Yielda (%) Deb (%)

1 39 70 >992 40 75 >993 41 72 >994 42 68 >99

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

reaction mixture.

measurements with resolutions of 10,000. NMR spectra wererecorded at 25 �C on a Bruker AMX500 spectrometer and on aBruker AV500 spectrometer at 500MHz for 1H and 125MHz for 13C.The chemical shifts are reported in ppm on the d scale relative toTMS. COSY, DEPT, HSQC, and NOESY experiments were performedto assign the signals in the NMR spectra.

4.1.2. Methodology for the synthesis of alkenyl b-D-galactopyranoside derivatives (35e38)4.1.2.1. 2-Oxoethyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-gal-actopyranoside (25). To a solution of olefin (1.0 mmol) and trime-thylamine-N-oxide (2.0 mmol) in dichloromethane (20 mL), wasadded catalytic OsO4, and the reaction mixture was stirred at roomtemperature for 2 h. After this time sodium bisulphite was addedand stirring for 15 min and washed with water. The organic phasewas concentrated under reduced pressure. To a solution of theresultant diol in ethanol (40 mL) a solution of sodium periodate(2.0 mmol) in distilled water was added and stirring for 2 h. Theethanol was evaporated and the aqueous phase was extracted withdichloromethane and the organic phase was concentrated to dry-ness. The solid was purified by column chromatography usinghexane-ethyl acetate (1:1) as eluent (0.416 g, 85% yield). Mp 122e123 �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, OCH2-COH), 7.8e7.3 (m, 15H, Ph), 5.49 (s, 1H, PhCH), 4.93 (d, 1H,

2 3 2 3

1 14 e 2.50, 2.50 2.36 48.6 38.6 21.52 15 4.29e4.37 3.79e3.90 1.55 49.2 33.2 21.63 16 e 2.54, 2.67 2.41 49.4 38.4 21.54 17 3.23 e 2.41 50.3 49.5 21.55 20 3.23 e 2.26 50.6 51.0 21.36 21 2.93e2.97 2.93e2.97 2.37 48.0 46.6 21.57 22 3.06 2.48 2.38 46.2 43.2 21.88 23 3.00 2.90 2.28 47.0 43.4 21.59 39 e 2.73, 3.04 2.36 53.6 37.5 21.510 40 e 2.45, 2.60 2.35 68.9 38.2 21.511 41 e 2.44, 2.60 2.34 52.4 38.1 21.512 42 e 2.44, 2.60 2.34 52.4 38.1 21.5

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, 2-PhCHAHBO), 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), 4.29e4.20 (m, 3H, H-6e, OCH2CHO), 4.13 (dd,1H, J3,4¼ 3.7 Hz, J4,5¼1.0 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).13C 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 (2-PhCH2O), 74.4 (OCH2CHO), 73.7 (C-4), 72.0 (3-PhCH2O), 69.0 (C-6), 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 tem-perature for 12 h. The reaction mixture was diluted in dichloro-methane and washed successively with an aqueous saturatedsolution of ammonium chloride and with water, dried over MgSO4,filtered and the filtrate was evaporated to dryness under reducedpressure. The resultant crude was purified by columnchromatography.

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 4Cytotoxic activity data (MTT assay).

Entry Compound IC50 (mM) �SEM A549 cells IC50 (mM) �SEM MRC5 cells

1 14 153 � 44 >10002 15 73 � 13 183 � 203 16 154 � 10 312 � 274 17 389 � 16 567 � 125 20 >1000 >10006 21 235 � 118 >10007 22 351 � 63 544 � 328 23 804 � 99 >10009 39 599 � 91 570 � 4610 40 579 � 54 793 � 2011 41 154 � 16 575 � 3112 42 w1000 w100013 43 492 � 41 156 � 8114 44 15 � 4 2 � 015 Cisplatin 13 � 5 139 � 51

obtained in a 1.7:1 ratio (26% de). The pure diastereomeric mixturewas obtained as a solid by column chromatography using hexane-ethyl 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.1H NMR (500 MHz, CDCl3, d ppm): 7.6e7.3 (m, 20H, Ph), 5.51 (s,0.37H, PhCHminor), 5.50 (s, 0.63H, PhCHmajor), 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), 4.10e4.00 [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, OCHAHB-CH(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].13C 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 mi-nor), 78.4 (C-2 major), 78.3 (C-2 minor), 77.1 [OCH2CH(OH)Phmajor], 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 (3-PhCH2O minor), 71.8 (3-PhCH2O major), 69.2 (C-6 major), 69.0 (C-6 minor), 66.7 (C-5 minor), 66.6 (C-5 major). HRMS (FAB): calcd. forC35H36O7Na 591.2359; found, 591.2365 [M þ Na]þ. Anal. Calcd. forC35H36O7: 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)-benzyli-dene-b-D-galactopyranoside (27). Two stereoisomers were ob-tained in a 1.3:1 ratio (13% de). The pure diastereomeric mixturewas obtained as a solid by column chromatography using hexane-ethyl 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. 1HNMR (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, 3-PhCH2O), 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, OCHAHB-

CH(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)CH2CH2CH3major], 3.58 (m, 1H, H-3), 3.46 [dd, 0.45H, Jgem ¼ 10.6 Hz, J¼ 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)CH2CH2CH3major], 2.76 [s, 0.43H, OCH2CH(OH)CH2CH2CH3 minor], 1.51e1.33

Table 5Cytotoxic activity data (MTT assay).

Entry Compound IC50 (mM) �SEMMCF-7 cells

IC50 (mM) �SEMMCF-10 cells

IC50 (mM) �SEMUACC-62 cells

IC50 (mM) �SEMVH-10 cells

1 14 12 � 2 567 � 114 196 � 190 >10002 Cisplatin 25 � 2 23 � 4 e e

3 5-Fluorouracil e e 264 � 66 >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-1major), 104.22 (C-1 minor), 101.30 (PhCHminor), 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 (2-PhCH2O minor), 75.5 (2-PhCH2O major), 75.4 [OCH2CH(OH)CH2CH2CH3 minor], 73.7 (C-4), 71.9 (3-PhCH2O major), 71.8 (3-PhCH2O minor), 70.4 [OCH2CH(OH)CH2CH2CH3 minor], 76.2[OCH2CH(OH)CH2CH2CH3 major], 69.2 (C-6 minor), 69.1 (C-6 ma-jor), 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 stereoisomerswere obtained in a 1.5:1 ratio (20% de). The pure diastereomericmixture was obtained as a syrup by column chromatography usinghexane-ethyl acetate (2.5:1) as eluent (0.411 g, 75% yield). Mp 144e145 �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), 3.93e3.83 [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-5minor), 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)3major], 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 (C-3 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 [OCH2-CH(OH)C(CH3)3 minor], 71.9 (3-PhCH2O major), 71.8 (3-PhCH2Ominor), 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 [OCH2-CH(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)-benzyli-dene-b-D-galactopyranoside (29). Two stereoisomers were ob-tained in a 1.6:1 ratio (23% de). The pure diastereomeric mixturewas obtained as a syrup by column chromatography using hexane-ethyl acetate (2.5:1) as eluent (0.494 g, 80% yield); [a]D ¼ þ12.6 (c1.0, 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, H-6a), 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 mi-nor], 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, OCH2-CH(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-2minor), 78.4 (C-2 major), 76.1 [OCH2CH(OH)CH2(CH2)7CH3 minor],75.6 (2-PhCH2Ominor), 75.5 (2-PhCH2Omajor), 75.4 [OCH2CH(OH)CH2(CH2)7CH3 major], 73.7 (C-4), 71.9 (3-PhCH2O major), 71.8 (3-PhCH2O 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 ma-jor), 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)-benzyli-dene-b-D-galactopyranoside (30). Two stereoisomerswere obtainedin a 1.2:1 ratio (9% de). The pure diastereomeric mixture was ob-tained as a syrup by column chromatography using hexane-ethylacetate (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, dppm): 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, 0.45H, J1,2 ¼ 7.7 Hz, H-1minor), 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)12CH3major, 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-1major),104.2 (C-1minor),101.3 (PhCHminor), 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)12CH3minor], 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-PhCH2Omajor), 71.8 (3-PhCH2O minor), 70.7 [OCH2C(OH)CH2(CH2)12CH3minor], 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 [OCH2-C(OH)CH2(CH2)12CH3 major], 32.9 [OCH2C(OH)CH2(CH2)12CH3 mi-nor], 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 theappropriate 2-hydroxyalkyl derivative (1.0 mmol) in dichloro-methane (20 mL), molecular sieve 4�A and PCC (2.0 mmol) were


added and the mixture was stirred at room temperature overnight.The resultant crude was filtered by silica flash column usingdiethylether as solvent and the resultant crude was purified bycolumn chromatography.

4.1.2.3.1. 2-Oxo-2-phenylethyl 2,3-di-O-benzyl-4,6-O-(S)-benzyli-dene-b-D-galactopyranoside (31). The solid was purified by columnchromatography 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, 2-PhCHAHBO), 4.86 (d, 1H, Jgem ¼ 16.0 Hz, OCHAHBCOPh), 4.79e4.73(m, 3H, 2-PhCHAHBO, 3-PhCH2O), 4.60 (d,1H, J1,2¼ 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). 13CNMR (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 (C-5). 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-b-D-galactopyranoside (32). The solid was purified by column chro-matography 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%) [MþNa]þ. 1H NMR (500MHz, CDCl3, d ppm): 7.6e7.3(m, 15H, Ph), 5.52 (s, 1H, PhCH), 4.98 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 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, 3-PhCHAHBO), 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, OCHAHB-COCH2CH2CH3), 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, OCH2CO-CHAHBCH2CH3), 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 (C-1), 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 C32H36O7Na555.2359; 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-b-D-galactopyranoside (33). The solid was purified by column chro-matography 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/z639 (100%) [MþNa]þ. 1HNMR (500MHz, CDCl3, d ppm): 7.6e7.2 (m,15H, Ph), 5.49 (s, 1H, PhCH), 4.97 (d, 1H, Jgem ¼ 11.0 Hz, 2-PhCHAHBO), 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, 3-PhCHAHBO), 4.43 (d, 1H, J1,2 ¼ 7.7 Hz, H-1), 4.32 [d, 1H,Jgem¼ 16.5Hz, OCHAHBCOCH2(CH2)7CH3], 4.26 (dd,1H, J5,6e¼ 1.5Hz,J6e,6a ¼ 12.4 Hz, H-6e), 4.24 [d, 1H, Jgem ¼ 16.5 Hz, OCHAHB-

COCH2(CH2)7CH3], 4.12 (dd, 1H, J3,4 ¼ 3.7 Hz, J4,5 ¼1.0 Hz, H-4), 4.01(dd,1H, J5,6a¼ 1.7Hz, J6e,6a¼ 12.3Hz, H-6a), 3.92 (dd,1H, J1,2¼7.7Hz,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, OCH2-COCH2(CH2)7CH3]. 13C NMR (125 MHz, CDCl3, d ppm): 209.2[OCH2COCH2(CH2)7CH3], 128.9e126.4 (3Ph), 103.3 (C-1), 101.3

(PhCH), 79.2 (C-3), 78.2 (C-2), 75.3 (2-PhCH2O), 74.1 [OCH2-COCH2(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 [OCH2-COCH2(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)-benzylidene-b-D-galactopyranoside (34). The solid was purified by column chro-matographyusinghexane-ethyl acetate (2.5:1) as eluent (0.470g, 75%yield). Mp 136e137 �C; [a]D ¼þ12.2 (c 1, CH2Cl2); MS (FAB):m/z 709(80%) [Mþ Na]þ. 1H NMR (500MHz, CDCl3, d ppm): 7.6e7.2 (m, 15H,Ph), 5.49 (s,1H, PhCH), 4.97 (d,1H, Jgem¼ 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, 3-PhCHAHBO), 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, OCHAHB-COCH2(CH2)12CH3], 4.26 (dd,1H, J5,6e¼ 1.2 Hz, J6e,6a¼ 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, J1,2¼ 7.7Hz, J2,3¼ 9.7 Hz, H-2), 3.58 (dd,1H, J2,3¼ 9.7 Hz,J3,4 ¼ 3.6 Hz, H-3), 3.32 (s, 1H, H-5), 2.65 [m, 1H, OCH2CO-CHAHB(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, OCH2-COCH2(CH2)12CH3]. 13C NMR (125 MHz, CDCl3, d ppm): 209.3 [OCH2-

COCH2(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 [OCH2-COCH2(CH2)12CH3], 31.9e22.7 [OCH2COCH2(CH2)12CH3], 14.1 [OCH2-

COCH2(CH2)12CH3]. HRMS (FAB): calcd. for C43H58O7Na 709.4080;found, 709.4070 [MþNa]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 (tri-phenyl)phosphonium bromide (1.2 mmol) in dry THF (40 mL) wascooled to �70 �C, then a 2.5 M solution of n-butyllithium in hexane(2.3 mmol) was added dropwise under argon atmosphere, main-taining the temperature at �70 �C. The mixture was stirred until itbecame bright red (ylide formation, w1 h) and allowed to slowlywarm up to �30 �C, the keto derivate (1.0 mmol) was added, andthemixturewas stirred for 1 h at�30 �C and left to stand for 12 h at20 �C. The reaction mixture was concentrated and the resultantcrude was purified by column chromatography.

4.1.2.4.1. 2-Phenylallyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (35). The solid was purified by column chro-matography 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/z587 (20%) [MþNa]þ. 1H NMR (500MHz, 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 (2-PhCH2O), 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-b-D-galactopyranoside (36). The solid was purified by column chro-matography 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):


m/z 553 (20%) [MþNa]þ. 1H NMR (500MHz, 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, 3-PhCH2O), 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,J5,6e¼ 1.5 Hz, J6e,6a¼ 12.4 Hz, H-6e), 4.11 (d,1H, J¼ 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 C33H38O6Na553.2566; 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-b-D-galactopyranoside (37). The solid was purified by column chro-matography 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/z639 (60%) [Mþ 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, 2-PhCHAHBO), 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,6a¼12.3Hz,H-6a), 3.88 (dd,1H, J1,2¼7.7Hz, J2,3¼9.6Hz,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,J¼ 7.40Hz, OCH2C(CH2(CH2)7CH3)]CH2]. 13C NMR (125MHz, 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. forC39H52O6Na 639.3662; found, 639.3644 [M þ Na]þ. Anal. Calcd. forC39H52O6: 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)-benzyli-dene-b-D-galactopyranoside (38). The solid was purified by columnchromatography using hexane-ethyl acetate (3.5:1) as eluent(0.480 g, 77% yield).Mp 123e124 �C; [a]D¼þ28.3 (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, 2-PhCHAHBO), 4.92 [s, 1H, OCH2C(CH2(CH2)12CH3)]CHAHB,], 4.82e4.74 (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,6a¼ 12.4 Hz, H-6e), 4.11 (d, 1H, J3,4¼ 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,J1,2¼7.8Hz, J2,3¼ 9.6 Hz, H-2), 3.58 (dd,1H, J2,3¼ 9.6 Hz, J3,4¼ 3.7Hz,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,J¼ 7.0 Hz, OCH2C(CH2(CH2)12CH3)]CH2]. 13C NMR (125MHz, 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)12CH3)]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 thereaction mixture was vigorously stirred at�20 �C for 12 h. Then themixture was concentrated to dryness and the resultant crude waspurified by column chromatography.

4.1.3.1. 2-Methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (14).Only one stereoisomer was obtained (>99% de). The solid was pu-rified 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, 3-PhCH2O), 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 (125MHz, CDCl3, d ppm): 143.8e126.4 (4Ar), 103.3 (C-1), 101.2 (PhCH), 79.0 (C-3), 78.2 (C-2), 75.1 (2-PhCH2O), 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 C38H41NO8SNa694.2451; 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-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (15). Two ste-reoisomers were obtained in a 7.7:1 ratio (77% de). The major dia-stereoisomer was isolated as a syrup by column chromatographyusing 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. 1HNMR (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, 2-PhCHAHBO, 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 C37H39NO8SNa680.2294; found; 680.2271 [M þ Na]þ.

4.1.3.3. 2-Methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl4,6-O-(S)-benzylidene-b-D-galactopyranoside (16). Two stereoiso-mers were obtained in a 7.6:1 ratio (77% de). The pure diastereo-meric mixture was obtained as a solid by column chromatography


using hexane-ethyl acetate (1:3) as eluent (0.319 g, 65% yield). Mp95e96 �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-1major), 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 (C-2), 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 4,6-O-(S)-benzylidene-b-D-galactopyranoside (17). Two stereoisomerswere obtained in a 1.6:1 ratio (23% de). The pure diastereomericmixture was obtained as a solid by column chromatography usinghexane-ethyl acetate (1:4) as eluent (0.439 g, 87% yield). Mp 85e86 �C; [a]D ¼ �7.8 (c 1.0, CH2Cl2); MS (CI): m/z 506 (20%) [M þ H]þ.1H 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-1minor), 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)2major], 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 mi-nor), 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 [Mþ 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 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (20).Two stereoisomers were obtained in a 1.9:1 ratio (31% de). The purediastereomeric mixture was obtained as syrup by column chro-matography 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, H-4), 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)2major], 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,

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(N-SO2C6H4CH3)C(CH3)2 minor], 2.26 [s, 1.98H, OCH2CH(N-SO2C6H4CH3)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].13C NMR (125 MHz, CDCl3, dppm): 138.6e126.3 (3Ar), 103.5 (C-1major), 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-PhCH2Omajor), 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-5major), 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(N-SO2C6H4CH3)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-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (21). Two stereoiso-mers were obtained in a 2:1 ratio (33% de). The pure diastereomericmixture was obtained as syrup by column chromatography usinghexane-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. 1HNMR (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-1major), 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), 4.03e3.94 [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].13C NMR (125 MHz, CDCl3, d ppm): 129.4e126.3 (3Ar), 103.3 (C-1minor), 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-4major), 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(N-SO2C6H4CH3)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)-ben-zylidene-b-D-galactopyranoside (22). Two stereoisomers were ob-tained in a 1.2:1 ratio (9% de). The pure diastereomeric mixture wasobtained as syrup by column chromatography using hexane-ethylacetate (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, PhCHminor), 5.55(s, 0.55H, PhCH major), 4.36e4.24 [m, 3H, H-1, H-6eOCHAHBCH(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,


OCH2CH(NSO2C6H4CH3)CH(CH3) minor], 1.50 (d,1.35H, J1,2¼ 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-4major), 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(N-SO2C6H4CH3)CH(CH3) minor], 14.3 [OCH2CH(NTs)CH(CH3) major],14.2 [OCH2CH(NTs)CH(CH3) minor]. HRMS (FAB): calcd. forC24H29NO8SNa 514.1512; found, 514.1541 [M þ Na]þ.

4.1.3.8. 2,3-[N-(4-Methylbenzenesulfonyl)imino]butyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (23). Two ste-reoisomers were obtained in a 1.8:1 ratio (28% de). The pure dia-stereomeric mixture was obtained as syrup by columnchromatography 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/z694 (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, PhCHmajor), 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-1major), 101.1 (PhCH major), 101.0 (PhCH minor), 79.1 (2-PhCH2Omajor), 79.0 (2-PhCH2O minor), 78.4 (3-PhCH2O minor), 78.3 (3-PhCH2O 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) mi-nor],,43.4 [OCH2CH(NTs)CH(CH3) major], 21.6 [OCH2CH(N-SO2C6H4CH3)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. forC39H43NO8SNa 694.2562; found; 694.2535 [M þ Na]þ.

4.1.3.9. 2,3-[N-(4-Methylbenzenesulfonyl)imino]-2-phenylpropyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (39).Only one stereoisomer was obtained (>99% de).The solid was pu-rified 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, 3-PhCH2O), 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, H-4), 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 (3-PhCH2O), 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. forC44H45NO8SNa 756.2607; found, 756.2590 [M þ Na]þ. Anal. Calcdfor 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-propylpropyl2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (40).Only one stereoisomer was obtained (>99% de). The syrup waspurified 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, OCH2C(CH2CH2CH3)(NTs)CHAHB], 2.35 [s, 3H, OCH2C(CH2CH2CH3)(N-SO2C6H4CH3)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, OCH2C(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 (C-2), 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(CH2CH2CH3)(NTs)CH2], 38.2 [OCH2C(CH2CH2CH3)(NTs)CH2], 33.4[OCH2C(CH2CH2CH3)(NTs)CH2], 21.5 [OCH2C(CH2CH2CH3)(N-SO2C6H4CH3)CH2], 19.1 [OCH2C(CH2CH2CH3)(NTs)CH2], 14.0[OCH2C(CH2CH2CH3)(NTs)CH2]. HRMS (FAB): calcd. for C40H45NO8SNa 722.2764; found, 722.2750 [M þ Na]þ.

4.1.3.11. 2,3-[N-(4-Methylbenzenesulfonyl)imino]-2-nonylpropyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (41).Only one stereoisomer was obtained (>99% de). The syrup was pu-rified by column chromatography using hexane-ethyl acetate (3.5:1)as eluent (0.563 g, 72% yield); [a]D¼þ12.2 (c 1.0, CH2Cl2); MS (FAB):m/z 806 (30%) [Mþ 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, J1,2¼7.7Hz,H-1), 4.30 (dd,1H, J5,6e¼1.1Hz, J6e,6a¼12.3Hz,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,J2,3¼ 9.6Hz,H-2), 3.53 (dd,1H, J2,3¼ 9.6Hz, J3,4¼3.7Hz,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)7CH3)(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 (125MHz, 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.


4.1.3.12. 2,3-[N-(4-Methylbenzenesulfonyl)imino]-2-tetradecylpropyl2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (42).Only one stereoisomer was obtained (>99% de). The syrup was pu-rified by column chromatography using hexane-ethyl acetate (3:1) aseluent (0.537 g, 68% yield); [a]D¼þ43.2 (c 1.0, CH2Cl2);MS (FAB):m/z876 (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,J1,2¼7.7Hz,H-1), 4.32 (dd,1H, J5,6e¼1.1Hz, J6e,6a¼12.3Hz,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,6a¼ 12.3Hz,H-6a), 3.74 (dd,1H, J1,2¼7.8Hz, J2,3¼ 9.6Hz,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)12CH3)(NTs)CH2].13CNMR (125MHz, CDCl3, dppm): 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 C51H67NO8SNa876.4485; found, 876.4466 [Mþ 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. Afterthe complete disappearance of aziridine ((TLC showed that allthe starting material had reacted), the reaction mixture wascooled at room temperature and concentrated under reducedpressure. The resultant crude was purified by columnchromatography.

4.1.4.1. 3-Dodecylamino-2-(4-methylbenzenesulfonamide)propyl2,3-di-O-benzyl-4,6-O-(S)-benzylidene-b-D-galactopyranoside (43).Only one stereoisomer was obtained (>99% de). The syrup was pu-rified 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/z879 (50%) [MþNa]þ. 1HNMR(500MHz, CDCl3, dppm):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, J3,4¼ 3.7Hz, J4,5¼1.0Hz,H-4), 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, OCH2C(CH3)(NHTs)CHAHB(NHCH2(CH2)10CH3)], 2.47 [m, 2H, OCH2C(CH3)(NHTs)CH2(NHCH2(CH2)10CH3)], 2.26 [s, 3H, OCH2C(CH3)(NH-SO2C6H4CH3)CH2(NHCH2(CH2)10CH3)], 1.43e1.22 [m, 20H, OCH2C(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(NHCH2(CH2)10CH3)], 31.9e22.6 [OCH2C(CH3)(NHTs)CH2(NHCH2(CH2)10CH3)], 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. forC50H68N2O8SNa 879.4594; found, 879.4567 [Mþ Na]þ.

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 stereoisomerwas obtained (>99% de). The syrup was purified by column chro-matography 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(CH2CH2)(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), 2.66e2.40 [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), 62.4e53.2 [OCH2C(CH2(CH2)12CH3)(NHTs)CH2N(CH2CH2)(CH2CH2)NCH2OH)], 59.2 [OCH2C(CH2(CH2)12CH3)(NHTs)CH2N(CH2CH2)(CH2CH2)NCH2OH)], 32.8e22.6 [OCH2C(CH2(CH2)12CH3)(NHTs)CH2N(CH2CH2)(CH2CH2)NCH2OH)], 21.3 [OCH2C(CH2(CH2)12CH3)(NHSO2C6H4CH3)CH2N(CH2CH2)(CH2CH2)NCH2OH)], 14.1 [OCH2C(CH2(CH2)12CH3)(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 conditionsThe human A549 lung cancer cell line, the human lung fibro-

blastic MRC-5 cell line, the human MCF7 breast adenocarcinomacell line, the human VH-10 fibroblastic foreskin cell line and thehuman UACC-62 melanoma cell line were maintained in DMEMsupplemented with 2 mM glutamine, 50 mg/ml penicillin, 50 mg/mlstreptomycin and 10% foetal bovine serum. The human MCF10breast epithelial cell line was maintained in a 1:1 mixture of Dul-becco’s modified Eagle’s medium and Ham’s F12 medium supple-mented with 20 ng/ml epidermal growth factor, 100 ng/ml choleratoxin, 10 mg/ml insulin and 500 ng/ml of hydrocortisone (95%) andhorse serum (5%). Cell lines were cultured at 37 �C in a humidifiedatmosphere containing 5% CO2. Cell culture reagents were obtainedfrom Life Technologies. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] salt, 5-Fluorouracil, cisplatin andwere purchased from Sigma Chemical Co.

4.2.2. Cell proliferation assaysThe MTT assay is a colorimetric technique that allows the

quantitative determination of cell viability. It is based on thecapability of viable cells to transform the MTT salt [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] into aformazan dye. Exponentially growing cells were seeded into 96-well plates and drugs were added 24 h later. Following an incu-bation 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, plateswere incubated for 10 h at 37 �C and optical densities were


measured at 540 nm on a multi-well plate spectrophotometerreader. Cell viability was expressed as a percentage relative tocontrols. All data were averaged from at least three independentexperiments and were expressed as mean � standard error of themeans (SEMs).

Acknowledgements

The authors thank thanks Junta de Andalucía for financial sup-port (PI-0058-2012 and PI 0892-2012). Carlos Palo-Nieto thanksJunta de Andalucía (P09-AGR4597) and Ministerio de AsuntosExteriores y Cooperación (AECID A/023577/09) for financial sup-port. Authors are also grateful to CITIUS (Centro de Investigación,Tecnología e Innovación de la Universidad de Sevilla) by recordingNMR 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, Tetra-

hedron 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.

[20] N. Hirayama, K. Shirahata, Acta Crystallogr. C47 (1991) 409e411.[21] (a) I. Uchida, S. Takase, H. Kayakiri, S. Kiyoto, M. Hashimoto, J. Am. Chem. Soc.

109 (1987) 4108e4109;(b) S. Gruschow, L.C. Chang, Y. Mao, D.H. Sherman, J. Am. Chem. Soc. 129(2007) 6470e6476;(c) M. Tomasz, Chem. Biol. 2 (1995) 575e579;(d) T. Fukuyama, S. Goto, Tetrahedron Lett. 30 (1989) 6491e6494.

[22] (a) T.C. Judd, R.M. Williams, Angew. Chem. Int. Ed. 41 (2002) 4683e4685;(b) T.C. Judd, R.M. Williams, J. Org. Chem. 69 (2004) 2825e2830;(c) M. Suzuki, M. Kambe, H. Tokuyama, T. Fukuyama, Angew. Chem. Int. Ed. 41(2002) 4686e4688;(d) M. Suzuki, M. Kambe, H. Tokuyama, T. Fukuyama, J. Org. Chem. 69 (2004)2831e2843;(e) R. Ducray, M.A. Ciufolini, Angew. Chem. Int. Ed. 41 (2002) 4688e4691.

[23] B.M. Trost, B.M. O’Boyle, Org. Lett. 10 (2008) 1369e1372.[24] S.E. Pierce, L.J. Guziec, F.S. Guziec, J.S. Brodbelt, Chem. Res. Toxicol. 23 (2010)

1097e1104.[25] S.L. Winski, R.H.J. Hargreaves, J. Butler, D. Ross, Clin. Cancer Res. 4 (1998)

3083e3088.[26] D. Hussein, S.V. Holt, K.E. Brookes, T. Klymenko, J.K. Adamski, A. Hogg,

E.J. Estlin, T. Ward, C. Dive, G.W.J. Makin, Br. J. Cancer 101 (2009) 55e63.[27] (a) K. Yokoi, K. Nagaoka, T. Nakashima, Chem. Pharm. Bull. 34 (1986) 4554e

4561;(b) K. Nagaoka, M. Matsumoto, J. Oono, K. Yokoi, S. Ishizeki, T. Nakashima,J. Antibiot. 39 (1986) 1527e1532.

[28] S. Ishizeki, M. Ohtsuka, K. Irinoda, K. Kukita, K. Nagaoka, T. Nakashima,J. Antibiot. 40 (1987) 60e65.

[29] (a) M. Tomasz, R. Lipman, B.F. McGuinness, K. Nakanishi, J. Am. Chem. Soc. 110(1988) 5892e5896;(b) J.W. Lown, K.C. Majumdar, Can. J. Biochem. 55 (1977) 630e635;(c) T. Hata, F. Koga, Y. Sano, K. Kanamori, A. Matsumae, R. Sugawara, T. Hoshi,T. Shimi, S. Ito, S. Tomizawa, J. Antibiot. Ser. A. 7 (1954) 107e112;(d) R.W. Armstrong, M.E. Salvati, M. Nguyen, J. Am. Chem. Soc. 114 (1992)3144e3145;(e) T. Fujiwara, I. Saito, H. Sugiyama, Tetrahedron Lett. 40 (1999) 315e318.

[30] (a) R.S. Coleman, A.J. Carpenter, Tetrahedron 53 (1997) 16313e16326;(b) R.S. Coleman, J.-S. Kon, T.E. Richardson, J. Am. Chem. Soc. 121 (1999)9088e9095.

[31] A. Reguerio-Ren, R.M. Borzilleri, X. Zheng, S.-H. Kim, J.A. Johnson,C.R. Fairchild, F.Y.F. Lee, B.H. Long, G.D. Vite, Org. Lett. 3 (2001) 2693e2696.

[32] F.M.D. Ismail, D.O. Levitsky, V. Dembitsky, E. J. Med. Chem. 44 (2009) 3373e3387.

[33] J.M. Vega-Pérez, I. Periñán, M. Argandoña, M. Vega-Holm, C. Palo-Nieto,E. Burgos-Morón, M. López-Lázaro, C. Vargas, J.J. Nieto, Fernando Iglesias-Guerra, Eur. J. Med. Chem. 58 (2012) 591e612.

[34] (a) J. Godlewska, K. Badowska-Rostonek, J. Ramza, L. Kaczmarek,W. Peczynska-Czoch, A. Opolski, Radiol. Oncol. 38 (2004) 137e144;(b) K. Badowska-Roslonek, L. Kaczmarek, J. Ramza, J. Godlewska, A. Opolski,W. Peczynska-Czoch, Pol. J. Chem. 79 (2005) 369e386.

[35] (a) J.S. Barradas, M.I. Errea, N.B. D’Accorso, C.S. Sepúlveda, E.B. Damonte, Eur. J.Med. Chem. 46 (2011) 259e264;(b) F.C. da Silva, M.C.B.V. de Souza, I.I.P. Frugulhetti, H.C. Castro, S.L. deO. Souza, T.M.L. de Souza, D.Q. Rodrigues, A.M.T. Souza, P.A. Abreu,F. Passamani, C.R. Rodrigues, V.F. Ferreira, J. Med. Chem. 44 (2009) 373e383.

[36] (a) G. Zhang, L. Fang, L. Zhu, J.E. Aimiuwu, J. Shen, H. Cheng, M.T. Muller,G.E. Lee, D. Sun, P.G. Wang, J. Med. Chem. 48 (2005) 5269e5278;(b) C. Marminon, F. Anizon, P. Moreau, S. Léonce, A. Pierre, B. Pfeiffer,P. Renard, M. Prudhomme, J. Med. Chem. 45 (2002) 1330e1339.

[37] J.M. Vega-Pérez, C. Palo-Nieto, I. Periñán, M. Vega-Holm, J.M. Calderón-Mon-taño, M. López-Lázaro, F. Iglesias-Guerra, Eur. J. Org. Chem. (2012) 1237e1252.

[38] J.M. Vega-Pérez, I. Periñán, C. Palo-Nieto, M. Vega-Holm, F. Iglesias-Guerra,Tetrahedron: Asymmetry 21 (2010) 81e95.

[39] J.U. Jeong, B. Tao, I. Sagasser, H. Henniges, K.B. Sharpless, J. Am. Chem. Soc. 120(1998) 6844e6845.



http://refhub.elsevier.com/S0223-5234(13)00661-2/sref1


http://refhub.elsevier.com/S0223-5234(13)00661-2/bib2a


http://refhub.elsevier.com/S0223-5234(13)00661-2/bib2b



http://refhub.elsevier.com/S0223-5234(13)00661-2/bib2c


























































http://refhub.elsevier.com/S0223-5234(13)00661-2/bib21d












http://refhub.elsevier.com/S0223-5234(13)00661-2/bib22e












































































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

Documents

Transcript of Aziridines from alkenyl-β-D-galactopyranoside derivatives: Stereoselective synthesis and in vitro...