MAGNETIC RESONANCE IN CHEMISTRYMagn. Reson. Chem. 2001; 39: 283–287

Note

NMR studies of the conformational behaviour andtautomerism of bis- and tris-saccharidoguanidines

Gabor Toth,1∗ Tamas Gati,1 Istvan Pinter,2 Jozsef Kovacs2† and Rainer Haessner3

1 Technical Analytical Research Group of the Hungarian Academy of Sciences, Institute for General and Analytical Chemistry of the Budapest Universityof Technology and Economics, Szent Gellert ter 4, H-1111 Budapest, Hungary2 PROCHEM Research and Development Ltd, P.O.B. 17, H-1525 Budapest, Hungary3 Technische Universitat Munchen, Organisch-Chemisches Institut, D-85747 Garching, Germany

Received 13 September 2000; Revised 14 December 2000; Accepted 3 January 2001

The reaction of an acetyl-protected symmetrical sugar carbodiimide with amines yielded the correspondingtrisubstituted guanidine derivatives 2–6 with two or three sugar units. Their tautomerism, isomerism andconformational behaviour were elucidated by application of one- and two-dimensional 1H and 13C NMRspectroscopy. The rate of tautomerisation was calculated from ROESY exchange measurements. Copyright 2001 John Wiley & Sons, Ltd.

KEYWORDS: NMR; 1H NMR; 13C NMR; guanidino sugars; conformational analysis; tautomerism; ROESY; exchange

INTRODUCTION

Iminophosphoranes (phosphinimines) of sugars,1 easilyaccessible by the Staudinger reaction2 of the correspondingazido compounds, proved to be advantageous synthons forvarious N-containing derivatives.3 Among these, the corre-sponding carbodiimide-linked pseudooligosaccharides1,3c,e

appear as very attractive synthetic intermediates, easilyproviding ureas, thioureas and guanidines, by standardchemical transformations.4,5 Because of the growing interestin the biological6 and synthetic7 application of guanidines,we have focused on the preparation of their glycosyl deriva-tives via the corresponding sugar carbodiimide precursors.

Reaction of N, N0-bis(tetra-O-acetyl-ˇ-D-glucopyranosyl)carbodiimide1 (1) and secondary amines (1.2 equiv.), suchas piperidine, morpholine and N-methylpiperazine, in drydichloromethane afforded the guanidines 2–6 (Scheme 1).The analogous bis(hepta-O-acetyl-ˇ-cellobiosyl)guanidinederivatives have also been synthesized recently.8

Using a special secondary amine component, suchas methyl 4,6-O-benzylidene-2,3-dideoxy-2,3-epimino-˛-D-allopyranoside,9 easily available from the correspondingepiminophosphonium salt,3a the reaction gave the guanidinederivative 6, bearing sugar substituents on all three nitrogenatoms of the central unit. Synthesis of the guanidine6 represents a new access to macromolecules such as

ŁCorrespondence to: G. Toth, Technical and Analytical Group ofthe Hungarian Academy of Sciences, Institute for General andAnalytical Chemistry of the Budapest University of Technologyand Economics, Szent Gellert ter 4, H-1111, Budapest, Hungary.E-mail: g-toth@tki.aak.bme.hu†Present address Gedeon Richter Ltd, P. O. Box 27, H-1475Budapest 10, Hungary.Contract/grant sponsor: Hungarian National Research Foundation;Contract/grant numbers: T026264; T023371.

O

N OCH3

OOPh

R−N=C=N−R

R:

6 :

RN

H R

N

R′

amine

OAcO

AcO

OAC

CH2OAC

13 : morpholyl

4 : N–methyl–piperazinyl

5 : NH3Cl

2 : piperidinyl

R′:

Scheme 1. Synthesis of compounds 2–6.

glycodendrimers10 which are of growing interest owing totheir highly branched but symmetrical structure and to theirability to undergo carbohydrate–protein interactions.

EXPERIMENTAL

Compounds

General methodsTLC was performed on aluminium sheets coated with silica gel60 F254 (Merck); detection was effected using UV radiation andcharring with H2SO4. Column chromatograpy and dry column flashchromatograpy11 were carried out on silica gel 60 (230–400 mesh)(Merck).

N,N’-Bis(2,3,4,6-tetra-O-acetyl-ˇ-D-glucopyranosyl)piperidine-1-carboximidamide (2)To a solution of 1 (703 mg, 1 mmol) in anhydrousdichloromethane (3 ml) was added piperidine (0.10 g, 1.18 mmol)and the mixture was allowed to stand at room temperature.TLC (diethylether) showed no starting carbodiimide (Rf 0.4) after3 h. The product was precipitated by addition of a large excessof n-hexane and triturated several times to yield 2 as a whitepowder (601 mg, 76%); m.p., 93–96 °C; [˛]D,–43.3 (CHCl3, c 1.5).

DOI: 10.1002/mrc.835 Copyright 2001 John Wiley & Sons, Ltd.

284 G. Toth et al.

TLC, Rf 0.3 (9 : 1 EtOAc–EtOH), Rf 0.4 (4:1 EtOAc–EtOH). Anal.Calcd for C34H49N3O18 (787.79): C, 51.84; H, 6.27; N, 5.33. Found: C,52.19; H, 6.48; N, 5.04%.

N,N’-Bis(2,3,4,6-tetra-O-acetyl-ˇ-D-glucopyranosyl)morpholine-4-carboximidamide (3)To a solution of 3 (703 mg, 1 mmol) in anhydrousdichloromethane (3 ml) was added freshly distilled morpho-line (0.10 g, 1.15 mmol) and the mixture was allowed to stand atroom temperature. TLC (diethylether) showed no starting carbodi-imide (Rf 0.4) after 3 h. The product was precipitated and trituratedseveral times with n-hexane as described for 2, to give 3 as asolid (0.75 g, 95%); m.p., 85–87 °C; [˛]D,–43.3 (CHCl3, c 1.6). TLC, Rf0.6 (9 : 1 EtOAc–EtOH), Rf 0.7 (4 : 1 EtOAc–EtOH). Anal. Calcd forC33H47N3O19 (789.76): C, 50.19; H, 6.00; N, 5.32. Found: C, 50.72; H,6.38; N, 5.11%.

N,N’-Bis(2,3,4,6-tetra-O-acetyl-ˇ-D-glucopyranosyl)-(1-methyl-piperazine-4)carboximidamide (4)The reaction of 1 (703 mg, 1 mmol) and freshly distilled N-methylpiperazine (0.12 g, 1.2 mmol) was carried out as describedfor 2. The product (4) was obtained as a white solid (0.74 g,92%); m.p., 97–99 °C; [˛]D,–42.3 (CHCl3, c 1.8). TLC: Rf 0.1 (4 : 1EtOAc–EtOH),Rf 0.3 (7 : 2 : 1 EtOAc–EtOH–water). Anal. Calcd forC34H50N4O18 (802.81): C, 50.87; H, 6.28; N, 6.98. Found: C, 51.18; H,6.48; N, 6.51%.

N,N’-Bis(2,3,4,6-tetra-O-acetyl-ˇ-D-glucopyranosyl-guanidinium chloride (5)To a solution of 1 (0.17 g, 0.24 mmol) in dry DMF (10 ml),ammonium chloride (0.10 g, 1.87 mmol) was added. The suspensionwas stirred at room temperature for 3 days when TLC (1 : 1methylene chloride–tert-butyl methyl ether) revealed no startingcarbodiimide. The excess of NH4Cl was filtered, the filtrate waspartly evaporated and the residue was treated with tert-butyl methylether to precipitate 5 as fine crystals (0.12 g, 66%); m.p., 197–199 °C;[˛]D,–37.5 (DMF–CHCl3, c 0.7). Anal. Calcd for C29H42N3O18(756.13): C, 46.07; H, 5.60; N, 5.56. Found: C, 46.98; H, 5.48; N,5.71%.

Methyl 4,6-O-benzylidene-2,3-dideoxy-2,3-[N-(N’,N’’-bis(2,3,4,6-tetra-O-acetyl-ˇ-D-glucopyranosyl)carboximidamido)epimino]-˛-D-allopyranoside (6)A mixture of methyl 4,6-O-benzylidene-2,3-dideoxy-2,3-epimino-˛-D-allopyranoside 9 (0.66 g, 2.5 mmol) and triphenylphosphineoxide (0.70 g, 2.5 mmol), obtained by alkaline hydrolysis of thecorresponding epimino-phosphonium salt,3a was dissolved in chlo-roform (10 ml) and 1 (1.75 g, 2.49 mmol) was added to the solu-tion. After standing for 24 h at room temperature, TLC (9 : 1Et2O–acetone) showed no starting epimine, but the spots of the prod-uct (6) (Rf 0.6), and that of triphenylphosphine oxide (Rf 0.25). Thereaction mixture was concentrated and the residue (3.2 g) subjectedto dry column flash chromatography11 using Et2O–acetone (9 : 1) aseluent. Eluted first was pure 6 isolated as a white foam; 0.86 g (36%).TLC, Rf 0.6 (9 : 1 Et2O–acetone). Work-up of subsequent fractionsyielded further crops of 6 (1.38 g) contaminated with Ph3O. Anal.Calcd for C43H55N3O22 (965.94): C, 53.47; H, 5.74; N, 4.35. Found: C,53.11; H, 5.42; N, 4.03%.

The salts 3-HC and 4-HC were obtained only in the NMR sampletube by adding three drops of trifluoroacetic acid.

NMR measurementsNMR spectra were recorded in CDCl3 and DMSO-d6

at room temperature using a Bruker Avance DRX-500spectrometer. Chemical shifts were referenced to the solventand are transformed to the TMS scale by υ�CHCl3� D 7.27,υ�CDCl3� D 77.0, υ[�CH3�2SO] D 2.51 and υ[�CD3�2SO] D39.0. In the 1D measurements (1H, 13C, z-filtered TOCSY),64 K data points were acquired. In the 1D TOCSY experiment,the mixing time was varied between 25 and 200 ms.

Pulse programs for the gs-COSY, TOCSY, ROESY,NOESY, gs-HMQC and edited HSQC experiments weretaken from the Bruker software library, and the parameterswere the same as described before.12,13 The parameters for the

phase-sensitive ROESY exchange measurements using TPPIwere as follows: relaxation delay D1 D 2 s, 90° pulse 10.0 µsfor 1H, continuous wave spin-lock for mixing, duration ofspin-lock varied from 10 ms to 1 s, 90° pulse width andtransmitter attenuation 28 µs and 10 dB, 1 K points in t2,sweep width 5 ppm in F2 and F1, 256 experiments in t1, linearprediction to 512 and zero-filling up to 1 K real points in F1,apodization with a �/2-shifted squared sine-bell in the F1

and F2 dimensions.

Calculation of exchange rate of tautomerismThe exchange rate of tautomerism was determined fromROESY exchange cross-peak intensities according to thefollowing equation, neglecting the effect of spin–spincoupling:14

ln(

r C 1r � 1

)D ktm

where r D �IH�1,H�1 C IH�10,H�10 �/�IH�1,H�10 C IH�10,H�1�,IH�1,H�1 and IH�10,H�10 being the intensities of the diagonalpeaks, IH�1,H�10 and IH�10,H�1 are the intensities of the crosspeaks, k the exchange rate constant (s�1) and tm the mixingtime of the ROESY experiment (s).

RESULTS AND DISCUSSION

New guanidino sugars (2–6) were synthesized from 1 byreaction with amines (see Experimental section). In thefollowing we report the spectral assignments and discusstautomerism, isomerism and the conformational analysis ofcompounds of type 2–6.

For the characterization of the guanidine moiety thepropensity for tautomerism and isomerism (Scheme 2)should be considered. Compounds 2–6 exhibit a high degreeof analogy with sugar isourea ethers reported previously.15 Inall the investigated compounds, one glucopyranosyl groupis attached to an NH and the other one to an imine N-atom,i.e. they are non-equivalent. Slow tautomerism on the NMRtime-scale should result in two different signal sets, whilefast exchange would give only one averaged spectrum for theglucopyranosyl units. Considering the inversion of the imineN-atom, in the case of a slow tautomerism, the appearanceof the E/Z isomers might be expected. On the one hand, alow activation energy of inversion leads to the averaging ofeach signal at room temperature. On the other hand, a highenergy barrier of the activation should give two separatesets. A complete 1H and 13C NMR signal assignment wasachieved utilizing HMQC, HSQC and TOCSY experiments.The selective z-filtered 1D TOCSY experiments proved tobe extremely useful in the case of 6, and despite the strongsignal overlapping allowed the separate observation of thespin system of the three different sugar moieties. The 1H and13C chemical shifts and characteristic J(H,H) and 1J(C,H) aresummarized in Table 1.

In the HMQC spectra two different signal sets for theglucopyranosyl moiety were observed (Fig. 1). The protonsignals were rather broad, indicating slow exchange, butby measuring the proton spectrum in acid-free CDCl3 thesignals were sharper, allowing the determination of a value

Copyright 2001 John Wiley & Sons, Ltd. Magn. Reson. Chem. 2001; 39: 283–287

NMR of conformational saccharidoguanidines 285

OAcO

AcO

OAc

H

CH2OAcH

NN

N

H

H

CH2OAcOAc

OAc

AcO

O

1 1′C C

NN

N

H

1 1′C

H

C

NN

N

tautomerism

E/Z isomerism

1

1'

Scheme 2. Tautomerism and isomerism of guanidino sugars.C1 and C10

denote anomeric carbons of sugar units.

of 9.5 Hz for the J(NH,H-1) vicinal coupling constant. Thisvalue indicates a preferred antiperiplanar arrangement of thetwo protons and means that the lifetime of this tautomer islonger than 17 ms [ > �1/2�� ð 9.5].16

The appearance of only one set of signals for theglucopyranosyl substituent of the imine N-atom might mean

NH

NCH2

OCH2

6

423

3

5

5

ppm

ppm

5.0 4.5 4.0 3.5

50

60

70

80

1′

1′

4′

5′

5′

6′

6′

3′2′

4′3′ 2′2,4 1

1

6a 6b

Figure 1. gs-HMQC spectrum of 3.

either a fast N inversion or the presence of a stable Z- orE-isomer.

For the conformational analysis we used the ROESYspectra. Arrows (Scheme 3) indicate the characteristic

Table 1. 1H and 13C NMR chemical shifts (υ, relative to TMS) and coupling constantsa (J, Hz) of 2–6 in CDCl3

2 3 3-H+ 4 4-H+ 5-HCb 6c

Atom No. 1H 13C 1H 13C 1H 13C 1H 13C 1H 13C 1H 13C 1H 13C

1 4.68 85.4 4.70 83.2 4.90 82.3 4.60 83.2 4.94 81.7 5.34 79.1 5.10 79.32 4.98 71.5 4.98 71.3 5.30 70.6 5.00 71.3 5.16 70.7 4.99 69.9 4.69 71.63 5.27 73.1 5.28 72.9 5.39 72.4 5.28 72.9 5.30 72.2 5.19 72.3 4.85 72.24 5.02 68.5 5.00 68.4 5.16 67.6 5.00 68.4 5.05 67.6 5.01 67.4 4.69 67.55 3.74 73.6 3.71 73.6 4.09 74.1 3.75 73.4 4.04 73.8 4.25 73.0 3.16 70.66a 4.22 62.2 4.19 62.3 4.32 62.1 4.22 62.1 4.21 62.3 4.20 61.5 3.74 61.66b 4.11 4.10 4.32 4.11 4.18 4.06 3.5110 4.33 86.5 4.33 86.3 — — 4.36 86.3 — — — — 4.40 86.520 5.08 73.4 5.07 73.1 — — 5.07 72.9 — — — — 5.00 72.230 5.20 73.3 5.19 73.3 — — 5.20 73.2 — — — — 5.26 73.040 5.02 68.8 5.02 68.8 — — 5.00 68.7 — — — — 5.00 68.950 3.85 73.3 3.86 73.1 — — 3.86 72.9 — — — — 3.95 73.56a0 4.17 62.9 4.18 62.8 — — 4.17 62.8 — — — — 4.23 62.76b0 4.17 4.18 — — 4.17 — — — — 4.17NH 5.45 5.56 9.78 5.50 8.70 6.14=CN 159.8 158.9 158.9 158.8 159.3 156.4 158.7NCHaHb 3.28 49.1 3.38 48.6 3.70 49.4 3.39 47.6 3.83/3.83 43.3 — — — —

3.04 3.07 3.15 3.83/4.29 45.9 — — — —NCHcHd — — — — — — 2.40 54.5 3.44/3.64 51.8 — — — —

— — — — — — 2.40 3.64/3.64 52.0 — — — —2 ð CH2 1.55 25.8 — — — — — — — — — — — —CH2 1.56 24.6 — — — — — — — — — — — —OCH2 — — 3.68 66.5 3.89 65.5 — — — — — — — —NCH3 — — — — — — 2.31 46.0 2.97 43.3 — — — —

a 3J�1, 2�¾ 3J�2, 3�¾ 3J�3, 4�¾ 3J�4, 5�¾ 3J�1, NH�¾ 9.5, 3J�5, 6a�¾ 5.5, 3J�5, 6b¾ 2.0, 2J�6a, 6b�¾ 12.0; allopyranosyl unit: 3J�100, 200� D 4.3,3J�200, 300� D 6.7, 3J�300, 400� D 2.6, 3J�400, 500� D 9.0, 3J�500, 6a00� D 10.5, 3J�500, 6b00� D 5.0, 2J�6a00, 6b00� D 10.5.b Solvent: DMSO-d6.c Allopyranosyl unit: 1H chemical shifts H-100 4.97, H-200 3.34, H-300 3.16, H-400 3.85, H-500 4.08, Ha-600 4.26, Hb-600 3.66, H-700 5.51, Ph-700

7.36–7.53, OCH3 3.45. 13C chemical shifts and 1J(C,H) couplings: C-100 95.4 (167), C-200 39.3 (177), C-300 38.6 (181), C-400 77.4 (140), C-500

60.2 (146), C-600 69.1 (157, 141), C-700 103.7 (162), Ph-700 137.0,126.6,129.0, 130.0, OCH3 55.9. 1J(C-1,H-1) = 162, 1J�C-10, H-10� D 150.

Copyright 2001 John Wiley & Sons, Ltd. Magn. Reson. Chem. 2001; 39: 283–287

286 G. Toth et al.

NH

ppm

ppm

5.0 4.5 4.0

4.0

4.5

5.0

5.5

4′3′ 1′ 6′ 5′2′1 53 2,4

6a 6b

Figure 2. NOESY exchange spectrum of 3-HC.(mix D 750 ms).

proton–proton proximities between the two glucopyranosylunits. These data indicate an E configuration of the iminegroup, i.e. the nitrogen heterocycle and the sugar unit areon the opposite sides of the C N double bond. Further-more, a threefold equilibrium of the conformers A, B andC was established. In principle there are further possibleconformers obtained by rotation around the bond betweenthe imino nitrogen and the anomeric carbon. The reason forthe absence of these conformers may be attributed to theunfavorable steric repulsion between the sugar units. Con-sidering the tautomerism and isomerism of the guanidine

b)

k = 18.3 sec−1

0

11

22

33

4

0 0,05 0,1 0,15 0,2

mixing time [sec]

ln[(

r+1)

/(r−

1)]

c)

k = 0.50 sec−1

00,050,1

0,150,2

0,250,3

0,350,4

0 0,2 0,4 0,6 0,8

mixing time[sec]

ln[(

r+1)

/(r−

1)]

a)

k = 64.3 sec−1

0,00,20,40,60,81,01,21,4

0 0,005 0,01 0,015 0,02 0,025

mixing time [sec]

ln[(

r+1)

/(r−

1)]

Figure 3. Calculation of the tautomer exchange rate based onthe volume integration of the ROESY exchange peaks H-1 andH-10. (a) Compound 2; (b) Compound 3; (c) Compound 6.

moiety, we are also interested in the exchange, i.e. in atime-resolved three-dimensional structure.

J(NH,H-1) : 9.5 Hz

E isomer

AB

C

NN

N

H

H

O

O

HO

H

H

H

O

H

CH2OAcH

NN

N

O

HH

180˚

OAcO

AcO AcO

AcOH2c

AcOAcO

AcO

AcO

AcO

AcO

OAc

OAc

OAc

OAc

H

CH2OAc

CH2OAc

CH2OAc

CH2OAc

H

NN

N

H

H

OAc OAc

OAc

OAc

O

Scheme 3. Conformational equilibrium. Arrows indicate characteristic steric proximities obtained from the NOESY experiment.

Copyright 2001 John Wiley & Sons, Ltd. Magn. Reson. Chem. 2001; 39: 283–287

NMR of conformational saccharidoguanidines 287

45

47

49

51

53

ppm

ppm 4.2 4.0 3.8 3.6 3.4

1H 2H 2H

HaHaHb Hb

13C

Figure 4. Section of the gs-HMQC spectrum of the salt 4-HC.

The EXSY spectrum (exchange peaks of the NOESYspectrum) of 3 is shown in Fig. 2. The appearance ofinterglycosidic cross peaks, e.g. H-1/H-10, H-3/H- 30 andH-5/H-50, indicates the existence of tautomerism. Forquantitative evaluation of the tautomerization rate theROESY spectra were also measured. We calculated theexchange rates from the intensity of exchange cross peaksobtained by volume integration of a series of ROESY spectrameasured with different mixing times. In the case of 2 and3 the exchange rates were 64.3 and 18.3 s�1, respectively,whereas for 6 it was 0.5 s�1 (Fig. 3). The faster rates observedfor the piperidine and morpholine derivatives (2 and 3)are in accord with the significantly higher basicity of thesecompounds.

It is well known that imino/amino tautomerism of aguanidine or amidine moiety is acid catalyzed. By addinga trace of trifluoroacetic acid to the CDCl3 solution weobtained immediately only one averaged set of signals forthe two glucopyranosyl units. This observation gives anunambiguous proof of the tautomerism.

To our surprise, we observed doubling of the NCHsignals in the HMQC spectrum of compound 4-HC (Fig. 4).Even the 1 : 3 : 3 : 1 intensity ratio for NCH protons of thepiperazine ring is not trivial. This unusual experience withthe piperazine signals can be explained when we consider

that owing to the protonation at the N-methyl groupthe N atom becomes a pseudo-stereogenic centrum andconsequently the signals of the carbon atoms and the protonsof the piperazine ring are diastereomeric.

AcknowledgmentsWe thank Professor H. Kessler for his kind support. G.T. thanksthe A. von Humbold Foundation for a visiting grant (July 2000, TUMunchen). This project was supported by the Hungarian NationalResearch Foundation (T026264 and T023371).

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Copyright 2001 John Wiley & Sons, Ltd. Magn. Reson. Chem. 2001; 39: 283–287