1-(4-Nitrophenoxycarbonyl)-7-pyridin-4-yl indolizine:a new versatile fluorescent building block. Application to the

synthesis of a series of fluorescent b-cyclodextrins

Francois Delattre, Patrice Woisel,* Gheorghe Surpateanu, Francine Cazier and Philippe Blach

Laboratoire de Synthese Organique et Environnement, EA2599, Universite du Littoral Cote d’Opale, 145, avenue Maurice Schumann,

59140 Dunkerque, France

Received 17 November 2004; revised 11 February 2005; accepted 22 February 2005

Abstract—The synthesis of a series of new fluorescent building blocks 1a–d incorporating a pyridinoindolizine unit and two potentiallyreactive sites is described. The reaction of 1a–d with the mono-6-amino-6-deoxy-b-cyclodextrin provides the corresponding fluorescentwater soluble hosts 2a–d in good yield. The sensor properties of 2a–d in the presence of 1-adamantanol is described.q 2005 Elsevier Ltd. All rights reserved.

1. Introduction

Designing functionalisable fluorescent organic compoundswhich can be used as building blocks for the synthesis ofnew chromogenic derivatives with distinctly differentphysical and/or chemical properties is a great interest tobiologists1 and organic materials chemists.2 Such reactivefluorophores are, for example, widely employed asfluorescent labels in the study of complex biologicalsystems (DNA hybridisation)3 and in analytical HPLCderivatisation reactions4 in order to overcome the problemof low detection limits. It has been shown that the presenceof a functionality on the fluorescent backbone could alsooffer the opportunity to modify their solubility by introdu-cing long chain or ionic moieties with the aim to improvingthe solubility in organic solvents and water, respectively.5

The attachment of fluorophores to synthetic receptors hasalso received considerable interest over the last few years, inendeavours to furnish new fluorescent sensors.6 In particu-lar, fluorescent cyclodextrins have generated considerableinterest from the synthetic community as witnessed byrecent articles dealing with their synthesis and emphasizingtheir sensory,7 but also their biochemical8 and photoelec-tronic9 properties. On the other hand, indolizinic derivativesare of interest as biologically active products and are wellknown to exhibit a variety of pharmacological effectsincluding cardiovascular,10 anti-inflammatory activities11

0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2005.02.063

Keywords: b-Cyclodextrins; Fluorophores; Indolizinic derivatives.* Corresponding author. Tel.: C33 32865 8246; fax: C33 32865 8260;

e-mail: woisel@univ-littoral.fr

but also antioxidant properties.12 In addition to exhibiting aspectrum of pharmacological effects, synthetic indolizinicderivatives are also well known for their fluorescenceproperties and some of them have already been used asdyes13 and biological markers.14

Considering the well known fluorescence properties ofindolizine derivatives, the incessant need for new reactivefluorophores and the increasing importance of fluorescencespectroscopy in both biological and supramolecular recog-nition fields, we were interested on the synthesis on newfluorescent building blocks including an indolizinic unitbearing two potential different reactive functions, e.a a4-nitrophenoxycarbonyl leaving group (site A) and a freepyridinic moiety (site B), as sites for further structuralmodifications (Fig. 1).

Herein, we describe the convenient synthesis and thecharacterisation of the new type fluorescent building block1 and its successful incorporation into the primary face ofthe b-cyclodextrin through the reactivity of the nitrophenyl-ester group (site A). Fluorescence properties of graftcompounds 2a–d are also described through, notably, theevaluation of their sensitivity factors in the presence of1-adamantanol.

2. Results and discussion

2.1. Synthesis and characterisation

Scheme 1 displays the strategy involved for the preparation

Tetrahedron 61 (2005) 3939–3945

Figure 1. The new fluorescent building block 1 and its corresponding b-cyclodextrin fluorescent sensor 2.

Scheme 1. Synthesis of 1a–e.

F. Delattre et al. / Tetrahedron 61 (2005) 3939–39453940

of the new reactive fluorophore 1. The literature offersseveral methods for the construction of the indolizinicunit.15 Among them, due to the easy access of 1,3 dipolesderived from cycloimmonium salts and the wide range ofdipolarophiles commercially available, the 1,3-dipolarcycloaddition of pyridinium ylide derivatives with activateddouble or triple bonds has been shown to be a highlyeffective and powerful strategy to build this pentatomicframework.16

Thus, the salt method17 has been applied in order to obtainthe bipyridinium ylides 6. Quaternization of the bipyridine 3at room temperature in dry acetone with the commerciallyavailable 4-substituted u-bromoacetophenones 4a–d gavethe corresponding monosalts 5a–d in high yields. Next thesesalts in the presence of triethylamine (TEA) form themonosusbstituted carbanions ylides 6a–d ‘in situ’ whichundergo a 1,3-dipolar cycloaddition reaction with the

electron-deficient compound 7 to give primary cycloadducts8a–d which spontaneously furnish, after rearomatisation,finals compounds 1a–d, in good yields (Table 1). It shouldbe noted, that, to the best of our knowledge, thedipolarophile 7 was used for the first time in this type ofchemical transformation. Moreover the presence of theleaving group (4-NO2PhO–) in its structure does not affectthe yield compared to other dipolarophiles previouslyused.16b,k Thus, this activated dipolarophile could offervarious applications with the aim to functionalising otherheterocyclic frameworks. The structure of 1a–d werededuced from their spectroscopic data. IR spectra of 1a–dshowed three characteristic absorption bands at z1610,1725, 1520 cmK1 ascribed to n (C]O), n (O–C]O) and n(NO2), respectively. The C13 spectra exhibited two signalsz185 and 160 ppm for 1a–d, which confirm the presence ofa ketone and a carboxylic acid derivative, respectively.Examination of the crude reaction mixture by 400 MHz 1H

Table 1. Emission variations of 2a–d, measured in phosphate buffer (pHZ7.0, 25 8C) with [2a–d]0Z0.01 mM and [1-adamantanol]Z0.1 mM

Compound Yield (%) DI/I0 lexc (nm) Kb (MK1)

1a 49 — — —1b 53 — — —1c 57 — — —1d 46 — — —2a 52 0.449 274 79,5002b 54 0.306 273 91,2002c 58 0.094 275 192,0002d 38 0.321 276 127,600

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NMR spectroscopy revealed the formation of 1a–d as asingle regioisomer. The assignments of most of the protonsignals were performed using 1D NMR experiment (seeSection 4) and the complete structure elucidation, includingthe determination of the relative regiochemistry, weresecured through two-dimensional techniques (COSY-LRand NOE). The absence in the COSY-LR spectra and inNOESY experiments of crossed signals between H 0

5 andH 0

6 allowed the unambiguous assignment of the regio-chemistry of 1a–d.

The mono-6-amino-6-deoxy-b-cylodextrin 9 was synthe-sised via a three step process involving a preliminaryregioselective tosylation into the primary face of bCD,18

following, by the displacement of the tosyl leaving groupwith NaN3

19 and the reduction of the azido group via theStaudinger reaction.20 (Scheme 2) Then, the mono-6-amino-6-deoxy-b-cylodextrin 9 was treated with 1a–d inNMP (N-Methylpyrrolidone) at 50 8C to give the corre-sponding fluorescent b-CD. Crude 2a–d were isolated byprecipitation from acetone and then successively purifiedusing Sephadex CM25 and G15 chromatography, respect-ively. Analysis of 2a–d by FTIR, NMR, ESIMS andelemental analysis are in agreement with the proposedstructures and with the literature data. The NMR spectra of2a–d display the characteristic signal of the amide protonaround 8.2 ppm and the 13C spectra show clearly twochemical shift values near 164 and 180 ppm belonging tothe CONH and the COAr groups, respectively. To obtainfurther evidence about the initial geometry, 2D-ROESYexperiments have been performed in D2O for all fluorescent

Scheme 2. Preparation of the fluorescent b-cyclodextrins 2a–d.

compounds 2a–d. All Roesy spectra do not display NOEcross peaks between the H-3 and H-5 protons ofthecyclodextrin part and aromatics protons of the pyridino-indolizinic moiety, which indicate distinctly that thefluorophore arm is located outside the cavity. In a previouspaper,21 we described for the first time the reactivity ofcycloimmonium ylides with the electroactive propinamido-bCD. This new tool for the functionalisation of the primaryface of the b-cyclodextrin has resulted in the synthesis of2a–d. Here, the new proposed method offers two majoradvantages, as it furnish significant higher yields (20–30%higher) and because it offers the possibility to graft directlythis new fluorescent arm into another molecular scaffoldswith the aim to obtain new fluorescent artificial receptors.

2.2. Fluorescence study

The purpose here is to check if the new fluorescent moietyappended to the b-cyclodextrin can induce change influorescence emission upon addition of a guest such1-adamantanol in aqueous solution. 1-Adamantanol waschosen for its ability to strongly bind to b-CD and also dueto its non-fluorescent nature, which will not interfere withsubsequent fluorescence measurements.

Figure 2 shows the fluorescence spectra of 2a (2b–d displaythe same fluorescent behaviour in studied concentrations)alone, and in the presence of various concentrations of1-adamantanol in aqueous solution (phosphate buffer, pHZ7.0), respectively. Upon addition of 1-adamantanol to anaqueous solution of 2a, a decrease in the fluorescence

Figure 2. Emission spectra in phosphate buffer (pHZ7.0, 25 8C) of 2a(0.01 mM) at various concentrations of 1-adamantanol (0–1.8 mM).

F. Delattre et al. / Tetrahedron 61 (2005) 3939–39453942

intensity with a shift toward shorter wavelength wereobserved. The result obtained suggests that the pyridino-indolizine linker, which is attached onto the primary face ofthe b-cyclodextrin, is displaced into a more polar environ-ment when the 1-adamantanol is added. To calculate themolecular recognition abilities of 2a–d, the DI/I0 value wasused as the sensitive factor, where DIZI0KI; I and I0 arethe emission intensities in the presence and the absence of1-adamantanol, respectively. Table 1 shows the DI/I0 valuesobtained with 1-adamantanol at 0.1 mM. 2a,b and 2d showa significant sensitivity factors when recorded in thepresence of 1-adamantanol. Compared to the well knowndansyl appended b-cyclodextrin derivative (DI/I0Z0.390 inPhosphate Buffer, pHZ7.0),22 2a displays a comparablesensitivity factor (DI/I0Z0.449) in the presence of 1-ada-mantanol. On the other hand, 2c shows a surprisingly verylow sensitivity. So in order to examine the possiblecorrelation between the fluorescence variation and thebindings ability of the hosts, the binding constants havebeen calculated. The guest-induced fluorescence variationwas employed to calculate the binding constants of thedifferent hosts using the previously method reported byUeno.23 The results are shown in Table 1. While 2a, 2b and2d display almost the same binding behaviour, which isconsistent with the corresponding sensitivity factorsobtained, 2c (RZOCH3) has the strongest binding affinityand the lowest sensitivity factor. This means that thesensitivity value given for 2c is relative, and not an absolute,measure of its sensory ability.

3. Conclusion

We have described in this paper the synthesis and thecharacterisation of a series of new functionalisable fluoro-phores. For their preparation, a new efficient activateddipolarophile was developed. The different fluorescencearms were connected to the primary face of theb-cyclodextrin leading corresponding fluorescent macro-cycles in good yields. Fluorescent sensor properties werealso proved through the variation of the fluorescenceemission of 2a–d upon addition of 1-adamantanol. Thepreparation, using the second reactive site B, of polymericsupramolecular systems bearing this new fluorescent moiety(with and without the cylodextrin moiety) is underway.

4. Experimental

4.1. General

1H and 13C NMR spectra were recorded with a Bruker AM400 spectrometer with tetramethylsilane as internal stan-dard. The abbreviations used are: s (singlet), d (doublet), t(triplet) and m (multiplet). Mass spectra were measuredusing a Platform II Micromass Apparatus. IR spectra wererecorded using a Perkin–Elmer instrument. Melting pointswere obtained with a Reichert Thermopan apparatus and areuncorrected. Fluorescence spectra were recorded using aPerkin–Elmer LS50B spectrometer. Chromatographic sepa-rations were carried out on Aldrich G25 and G15. Allreagents were used as purchased unless otherwise stated.Solvents were dried according to standard procedures.24

All reactions were performed under N2. The reagents weretransferred by syringe

4.1.1. General procedure for the synthesis of 1-substi-tuted-[4,4 0] bipyridium bromides 5a–d. The u-brom-acetophenone compounds 4a–d are commercially available.A solution of u-bromacetophenone 4a–d (8.8 mmol) inacetone (200 mL) was added at room temperature to asolution of bipyridine 3 (1.37 g, 8.8 mmol) in acetone(100 mL). The solution was warmed to 40 8C for 10 h. Thecrude product precipitated, filtered off and washed withacetone to give colourless solids.

1H and C13 spectra of compound 5a, 5c were consistent withliterature data.25

4.1.2. 1-(4-Methylbenzoylmethyl)-[4,4 0]bipyridiniumbromide (5b). Mp 350 8C. 1H NMR (DMSO/TMS): dZ2.46 (s, 3 H, CH3), 6.54 (s, 2 H, CH2NC), 7.51 (d, JZ8.1 Hz, 2H, Hmeta/CO), 8.01 (d, JZ8.1 Hz, 2H, Hortho/CO),8.10 (d, JZ5.8 Hz, 2H, Hmeta/N), 8.78 (d, JZ6.6 Hz, 2H,Hmeta/NC), 8.91 (d, JZ5.8 Hz, 2H, Hortho/N), 9.18 (d, JZ6.6 Hz, 2H, Hortho/NC); 13C NMR (DMSO/TMS): dZ22.2,66.6, 122.9, 126.0, 129.3, 130.6, 131.9, 141.7, 146.4, 147.7,151.9, 153.8, 191.0; IR (KBr): ~nZ3024 cmK1, 2949, 1678,1643, 1602, 1410, 804; MS (ESC, cone 10); m/z (%): 289(100) [MKBr]; C19H17BrN2O: Calcd C 61.80, H 4.64, N7.59; found C 62.02, H 4.72, N 7.46.

4.1.3. 1-(4-Chlorobenzoylmethyl)-[4,4 0]bipyridiniumbromide (5d). Mp 350 8C. 1H NMR (DMSO/TMS): dZ6.51 (s, 2 H, CH2NC), 7.78 (dd, JZ8.6 Hz, 2H, Hmeta/CO),8.10 (m, 4H, Hortho/COCHmeta/N), 8.77 (d, JZ6.9 Hz, 2H,Hmeta/NC), 8.91 (d, JZ4.5 Hz, 2H, Hortho/N), 9.14 (d, JZ6.9 Hz, 2H, Hortho/NC); 13C NMR (DMSO/TMS): dZ66.0,122.2, 125.3, 129.5, 130.3, 132.5, 140.0, 141.0, 147.0,151.2, 153.3, 190.0; IR (KBr): ~nZ3018 cmK1, 2927, 1693,1642, 1588, 1495, 795; MS (ESC, cone 10); m/z (%):309(100) [MKBrK2], 311 (100) [MKBr]; C18H14BrClN2O:Calcd C 55.48, H 3.62, N 7.19; found C 55.62, H 3.73, N7.05.

4.2. General procedure for the synthesis 3-(4-substi-tutedbenzoyl)-1-(4-nitrophenylcarbonyl)-7-pyridin-4-ylindolizines 1a–d

A solution of freshly distilled Et3N (2.7 mmol) was added to

F. Delattre et al. / Tetrahedron 61 (2005) 3939–3945 3943

a stirred solution of 5a–e (2.4 mmol) and 4-nitrophenylpro-piolate 726 (2.4 mmol) in dry NMP at 0 8C under N2, in theabsence of light. The reaction mixture was maintained at0 8C over 2 days. The crude product precipitated, filteredand washed with a large amount of methanol.

4.2.1. 3-(Benzoyl)-1-(4-nitrophenoxycarbonyl)-7-pyri-din-4-ylindolizine 1a. Mp 288–289 8C; 1H NMR(DMSOC5% CF3COOD/TMS): dZ7.60–7.74 (m, 5H,Hmeta/NO2CHmeta/COCHpara/CO), 7.90 (d, JZ6.6 Hz,2H, Hortho/CO), 8.00–7.85 (m, 2H, H 0

3CH 06), 8.37 (d, JZ

9.0 Hz, 2 H, Hortho/NO2), 8.60 (d, JZ6.7 Hz, 2H, H 02), 8.90

(s, 1H, H 05), 9.08 (d, J Z6.7 Hz, 2H, H 0

1), 9.94 (d, JZ7.9 Hz, 1H, H 0

4); 13C NMR (DMSOC5% CF3COOD/TMS): dZ105.7, 114.5, 118.3, 123.4, 123.6, 124.5, 125.3,128.6, 128.7, 128.9, 129.8, 132.4, 134.0, 138.7, 138.8,143.0, 145.1, 152.5, 155.4, 160.6, 185.2; IR (KBr): ~nZ3060 cmK1, 1727, 1611, 1523, 1478, 1347, 861; MS (ESC,cone 60); m/z (%): 464 (100) [MCH], 486 (40) [MCNa];C27H17N3O5: Calcd C 69.97, H 3.70, N 9.07; found C 70.08,H 3.74, N 8.98.

4.2.2. 3-(4-Methylbenzoyl)-1-(4-nitrophenoxycarbonyl)-7-pyridin-4-ylindolizine 1b. Mp 260–261 8C; 1H NMR(DMSOC5% CF3COOD/TMS): dZ2.43 (s, 3H, CH3), 7.42(d, JZ8.1 Hz, 2H, Hmeta/CO), 7.63 (d, JZ9.1 Hz, 2H,Hmeta/NO2), 7.80 (d, JZ8.1 Hz, 2H, Hortho/CO), 7.95 (d,JZ7.3 Hz, 1H, H 0

3), 7.97 (s, 1H, H 06), 8.35 (d, JZ9.1 Hz,

2H, Hortho/NO2), 8.59 (d, JZ6.8 Hz, 2H, H 02), 8.87 (s, 1H,

H 05), 9.08 (d, JZ6.8 Hz, 2 H, H 0

1), 9.96 (d, JZ7.3 Hz, 1H,H 0

4); 13C NMR (DMSOC5% CF3COOD/TMS): dZ21.4,105.4, 114.4, 118.1, 123.4, 123.6, 124.1, 125.3, 128.5,129.1, 129.3, 129.7, 134.1, 135.9, 138.7, 142.7, 143.6,145.0, 151.7, 155.3, 184.8; IR (KBr): ~nZ3072 cmK1, 1725,1600, 1522, 1464, 1345, 861; MS (ESC, cone 60); m/z (%):478 (100) [MCH], 500 (25) [MCNa]; C28H19N3O5: CalcdC 70.43, H 4.01, N 8.80; found C 70.87, H 4.14, N 8.71.

4.2.3. 3-(4-Methoxybenzoyl)-1-(4-nitrophenoxycarbo-nyl)-7-pyridin-4-ylindolizine 1c. Mp 272–273 8C; 1HNMR (DMSO C5% CF3COOD/TMS): dZ3.84 (s, 3H,CH3), 7.15 (d, JZ8.6 Hz, 2H, Hmeta/CO), 7.64 (d, JZ9.1 Hz, 2H, Hmeta/NO2), 7.87–7.94 (m, 3H, H 0

3CHortho/CO), 7.95 (s, 1H, H 0

6), 8.36 (d, JZ9.1 Hz, 2H, Hortho/NO2),8.59 (d, JZ6.7 Hz, 2H, H 0

2), 8.86 (s, 1H, H 05), 9.07 (d, JZ

6.7 Hz, 2H, H 01), 9.90 (d, JZ7.6 Hz, 1H, H 0

4); 13C NMR(DMSOC5% CF3COOD/TMS): dZ55.6, 105.6, 114.5,118.4, 123.4, 123.9, 124.5, 125.4, 127.9, 129.9, 131.0,131.6, 133.7, 138.6, 142.9, 142.7, 145.2, 152.3, 154.8,155.2, 160.7, 184.4; IR (KBr): ~nZ3078 cmK1, 1723, 1597,1520, 1478, 1345, 799; MS (ESC, cone 60); m/z (%): 494(100) [MCH], 516 (40) [MCNa]; C28H19N3O6: Calcd C68.15, H 3.88, N 8.52; found C 68.23, H 3.92, N 8.43.

4.2.4. 3-(4-Chlorobenzoyl)-1-(4-nitrophenoxycarbonyl)-7-pyridin-4-ylindolizine 1d. Mp 255–256 8C; 1H NMR(DMSOC5% CF3COOD/TMS): dZ7.74 (m, 4H, Hmeta/NO2CHmeta/CO), 7.90 (d, JZ8.3 Hz, 2H, Hortho/CO), 7.96(s, 1H, H 0

3), 7.96 (s, 1H, H 06), 8.35 (d, JZ8.9 Hz, 2H,

Hortho/NO2), 8.57 (d, JZ6.0 Hz, 2H, H 02), 8.86 (s, 1H, H 0

5),9.06 (d, JZ6.0 Hz, 2H, H 0

1), 9.94 (d, JZ7.0 Hz, 1H, H 04);

13C NMR (DMSOC5% CF3COOD/TMS): dZ105.7,114.6, 118.1, 123.4, 123.6, 124.2, 125.3, 128.5, 128.9,

129.8, 130.9, 134.6, 137.2, 139.0, 143.5, 145.1, 151.8,155.3, 160.5, 183.9; IR (KBr): ~nZ3069 cmK1, 1728, 1616,1591, 1469, 1344, 798; MS (ESC, cone 60); m/z (%): 498(100) [MCH], 500 (32) [MCHC2], 520 (31) [MCNa],522 (10) [MCNaC2]; C27H16ClN3O5: Calcd C 65.13, H3.24, N 8.44; found C 65.23, H 3.11, N 8.51.

4.3. General procedure for the synthesis of N-(6A-deoxy-b-cyclodextrin-6a-yl)-1-amido-3-(4-substitutedbenzo-yl)-1-(4-nitrophenylcarbonyl)-7-pyridin-4-ylindolizines2a–d.21

A solution of 1a–d (1 mmol) in dry NMP (10 mL) wasadded dropwise to a stirred solution of 9 (1 mmol) in dryDMF (30 mL) at 50 8C under N2. The reaction mixture wasmaintained at 50 8C over 24 h. The yellow solution was thenpoured in acetone (300 mL) and the crude compoundcollected by filtration. The latter was dissolved in water andthe unreacted starting material 1a–d was removed byfiltration and the filtrate was poured again in acetone(300 mL). The resultant precipitate was passed through aCM-25 column by eluting with water. The fractionscontaining the fluorescent b-cyclodextrin were combined,concentrated in vacuum. Finally, the mixture was applied togel filtration using Sephadex G-15 to give 2a–d as fineyellow powders.

4.3.1. N-(6A-Deoxy-b-cyclodextrin-6A-yl)-1-amido-3-benzoyl-7-pyridin-4-ylindolizine 2a. 1H NMR (DMSO/TMS): 3.25–3.90 (m, 42H, H-2, H-4, H-3, H-5, H-6A,B),4.28–4.58 (m, 6H, –OH6), 4.84–5.01 (m, 7H, H-1), 5.63–6.08 (m, 14H, –OH2, –OH3), 7.52–7.76 (m, 4H, H 0

3, H meta/CO, H para/CO), 7.92 (d, JZ8.3 Hz, 2H, H ortho/CO), 7.94(d, JZ5.9 Hz, 2H, H 0

2), 8.21 (s, 1H, H 06), 8.39 (m, 1H, NH),

8.73 (d, JZ5.9 Hz, 2H, H 01), 9.02 (s, 1H, H 0

5), 9.92 (d, JZ7.3 Hz, 1H, H 0

4); 13C NMR (DMSO-d6, d): 60.8, 60.9, 71.0,72.8, 73.2, 74.0, 81.9, 82.3, 82.5, 82.7, 85.1, 102.7, 103.1,113.8, 117.3, 121.2, 126.4, 128.7, 128.8, 129.3, 131.8,150.8, 164.2, 185.4; m/z (%): 1481 (MCNa, 100), 1459(MC1, 15); C63H83N3O36$5H2O: Calcd C 48.87, H 6.05, N2.71; found C 48.98, H 6.13, N 3.02.

4.3.2. N-(6A-Deoxy-b-cyclodextrin-6A-yl)-1-amido-3-(4-methylbenzo yl)-7-pyridin-4-ylindolizine 2b. 1H NMR(DMSO/TMS): 2.44 (s, 3H, –CH3), 3.13–3.84 (m, 42H, H-2,H-3, H-4, H-5, H-6A,B), 4.38–4.58 (m, 6H, –OH6), 4.78–4.97 (m, 7H, H-1), 5.58–6.01 (m, 14H, -OH2, OH3), 7.14 (d,JZ8.8 Hz, 2H, H meta/CO), 7.76 (dd, JZ1.9, 7.4 Hz,1H,H 0

3), 7.85 (d, JZ5.8 Hz, 2H, H 02), 7.89 (d, JZ8.8 Hz, 2H, H

ortho/CO), 8.15 (s, 1H, H 06), 8.34 (m, 1H, NH), 8.73 (d, JZ

5.7 Hz, 2H, H 01), 8.95 (s, 1H, H 0

5), 9.84 (d, JZ7.4 Hz, 1H,H 0

4); 13C NMR (DMSO): 21.9, 60.6, 60.9, 71.2, 73.2, 73.3,73.9, 74.0, 82.1, 82.5 (2!), 85.0, 102.7, 102.7, 103.1,114.6, 117.8, 121.6, 126.7, 129.3, 130.1, 151.5, 164.3,185.2; m/z (%): 1495 (MCNa, 100); 1473 (MC1, 18);C64H85N3O36$5H2O: Calcd C 49.20, H 6.13, N 2.69; foundC 49.28, H 6.10, N 2.73.

4.3.3. N-(6A-Deoxy-b-cyclodextrin-6A-yl)-1-amido-3-(4-methoxybenzoyl)-7-pyridin-4-ylindolizine 2c. 1H NMR(DMSO/TMS): 3.03–3.88 (m, 42H, H-2, H-3, H-4, H-5,H-6A,B), 3.95 (s, 3H, –OCH3), 4.33–4.59 (m, 6H, –OH6),4.78–4.97 (m, 7H, HK1), 5.54–6.07 (m, 14H, –OH2, OH3),

F. Delattre et al. / Tetrahedron 61 (2005) 3939–39453944

7.14 (d, JZ8.7 Hz, 2H, H meta/CO), 7.73 (d, JZ7.4 Hz,1H, H 0

3), 7.89 (d, JZ8.7 Hz, 2H, H ortho/CO), 8.21 (s, 1H,H 0

6), 8.23 (d, JZ6.1 Hz, 2H, H 02), 8.40 (m, 1H, NH), 8.88

(d, JZ6.1 Hz, 2H, H 01), 9.03 (s, 1H, H 0

5), 9.82 (d, JZ7.38 Hz, 1H, H 0

4); 13C NMR (DMSO): 56.4, 60.5, 60.8,60.9, 71.0, 72.2–74.34, 82.0–82.7, 85.0, 102.6, 102.8, 103.0,113.8, 114.8, 119.4, 123.4, 126.2, 129.3, 132.3, 146.5,163.2, 184.5; m/z (%): 1511 (MCNa, 100), 1489 (MCH,20); C64H85N3O37$6H2O: Calcd C 48.15, H 6.12, N 2.63;found C 48.23, H 6.30, N, 2.82.

4.3.4. N-(6A-Deoxy-b-cyclodextrin-6A-yl)-1-amido-3-(4-chlorobenzoy-l)-7-pyridin-4-ylindolizine 2d. 1H NMR(DMSO/TMS): 3.23–3.90 (m, 42H, H-2, H-4 H-3, H-5,H-6A,B), 4.20–4.57 (m, 6H, –OH6), 4.76–4.94 (m, 7H, H-1),5.51–5.99 (m, 14H, –OH2, OH3), 7.64 (d, JZ8.5 Hz, 2H, Hmeta/CO), 7.70 (dd, JZ2.4, 7.4 Hz, 1H, H 0

3), 7.81 (d, JZ8.5 Hz, 2H, H ortho/CO), 7.83 (d, JZ6.1 Hz, 2H, H 0

2), 8.15(s, 1H, H 0

6), 8.26 (m, 1H, NH), 8.7 (d, JZ6.1 Hz, 2H, H 01),

8.94 (s, 1H, H 05), 9.87 (d, JZ7.5 Hz 1H, H 0

4); 13C NMR(DMSO): 60.4, 60.5, 60.8, 71.1, 72.76–74.04, 81.9, 82.0,82.1, 82.5, 82.6, 82.9, 85.1, 102.7, 102.9, 103.1, 114.4,117.9, 121.7, 127.1, 129.4, 129.5, 131.7, 151.5, 164.2,184.2; m/z (%): 1516 (MCNa, 32), 1514 (MCNaK2);C63H82ClN3O36$5H2O: Calcd C 47.81, H 5.86, N 2.65;found C 47.98, H 6.00, N 2.75.

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