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Synthetic Communications: AnInternational Journal for RapidCommunication of Synthetic OrganicChemistryPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/lsyc20

Simple and Reliable Protocol for Metal-Free Assembling of the Bibrachial SchiffBases and Their Reduced DerivativesBearing Amino Acids or Short PeptideResiduesNataliya E. Borisova a , Tatiana G. Gulevich b , Marina D. Reshetova a

& Valeri A. Knizhnikov ba Department of Chemistry, M. V. Lomonosov Moscow StateUniversity, Moscow, Russiab Institute of Physical Organic Chemistry, National Academy ofSciences of Belarus, Minsk, BelarusAccepted author version posted online: 01 Feb 2012.Version ofrecord first published: 02 Nov 2012.

To cite this article: Nataliya E. Borisova , Tatiana G. Gulevich , Marina D. Reshetova & Valeri A.Knizhnikov (2013): Simple and Reliable Protocol for Metal-Free Assembling of the Bibrachial SchiffBases and Their Reduced Derivatives Bearing Amino Acids or Short Peptide Residues, SyntheticCommunications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,43:3, 345-360

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SIMPLE AND RELIABLE PROTOCOL FOR METAL-FREEASSEMBLING OF THE BIBRACHIAL SCHIFF BASESAND THEIR REDUCED DERIVATIVES BEARING AMINOACIDS OR SHORT PEPTIDE RESIDUES

Nataliya E. Borisova,1 Tatiana G. Gulevich,2

Marina D. Reshetova,1 and Valeri A. Knizhnikov21Department of Chemistry, M. V. Lomonosov Moscow State University,Moscow, Russia2Institute of Physical Organic Chemistry, National Academy of Sciences ofBelarus, Minsk, Belarus

GRAPHICAL ABSTRACT

Abstract A simple and efficient protocol is developed for the preparation of bibrachial chiral

heterodentate ligands bearing two amino acid or peptide side chains on different scaffolds.

Keywords Amino acid; heterodentate ligands; peptides; Schiff base

INTRODUCTION

The Schiff bases as well as reduced Schiff bases bearing chiral amino acid frag-ments on a phenol scaffold are important chiral building blocks for supramoleculararchitectures.[1] The design of reduced Schiff base complexes that contain one aminoacid residue is a fast-growing area of crystal design.[2–6] Moreover, complexes of theSchiff base ligands bearing one amino acid residue show unusual magnetochemis-try[7] and catalytic activity[5,8,9] as well as biological activity[10–12] and high potentialfor DNA cleavage.[13] The creation of various types of three-dimensional (3D) crys-tal architectures requires the amino acid ligand to be obtained in solely pure form

Received May 18, 2011.

Address correspondence to Nataliya E. Borisova, Department of Chemistry, M. V. Lomonosov

Moscow State University, Leninskie Gory, 1=3, 119992, Moscow, Russia. E-mail: Borisova.nataliya@

gmail.com

Synthetic Communications1, 43: 345–360, 2013

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397911.2011.597534

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before the metallation procedure, whereas the complexes for the biological or cata-lytic tests can occasionally be obtained via a template method.[14]

In spite of the wide application area of Schiff bases bearing one amino acid sidegroup and their reduced derivatives, we can observe only scarce examples of bibra-chial Schiff bases and their complexes bearing two amino acid side groups. Only afew works have dealt with Schiff bases from dicarbonyl compounds and aminoacids,[15–18] and there are no data concerning the supramolecular architectures ofthe complexes of their reduction derivatives. To bring within reach a wide range ofbibrachial reduced Schiff bases bearing two amino acid residues or even smallpeptides on any scaffolds, we investigate a simple, mild, and efficient procedure forfurnishing these systems. The usual one-pot procedure for the preparation of thereduced Schiff bases starts from a water solution of the amino acid potassium orsodium salts[9] and leads to corresponding reduced Schiff bases in moderate yields(40–77%). This procedure is not favored for creating bibrachial compounds becauseof its lack of selectivity and because the presence of the unconverted starting com-pound and by-products makes the reaction mixture inseparable. The preparationof the Schiff base by condensation of 2,6-diformyl-4-methylphenol with freeL-histidine in methanol at pH 6.5[18] could not be considered as universal becauseof the high basicity of the imidazole nitrogens, which allow the usual amino acidzwitterion structure to exist as well as a specie with a deprotonated amino group. Sev-eral efforts to prepare bibrachial Schiff bases have also been published by us.[13] Thearticle describes the development of a useful procedure for the creation of reducedSchiff base ligands bearing two amino acid side chains on various scaffolds.

For the preparation of the bibrachial Schiff bases bearing two amino acid resi-dues, we suggest using a multistep procedure (Scheme 1) instead of the one-pot[9]

method. The isolation and purification of the intermediate Schiff base allowby-products to be avoided, so the following reduction of the Schiff bases would leadto bibrachial ligands 4 and 5 of high purity. The use of the amino acid’s methyl esters2 to avoid the formation of zwitterions causes low activity of the ammonium group

Scheme 1. Two principal ways to bibrachial ligands based on amino acids.

346 N. E. BORISOVA ET AL.

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in the Schiff condensation, but this requires two additional steps in the reaction: theinsertion and removal of the methyl ester.

The initial step of the sequence is the preparation of the Schiff bases. Toinvestigate the influence of electronic properties and topography of dicarbonyl com-pounds on the efficacy of Schiff base formation, a series of dicarbonyl derivativeswas examined (Scheme 2, Tables 1 and 2). We selected 2,6-diformyl-4-tert-butylphe-nol 1b as a model dicarbonyl derivative routinely used in obtaining Schiff bases. Wealso chose superaromatic 2,5-pyrroldialdehyde (1a), which is known to form azo-methines in poor yields.

To optimize the procedure of Schiff bases 3 preparation, a broad variety ofconditions was attempted. The best results were obtained when condensations wereperformed by stirring the concentrated methanol solutions at rt for several hours inthe presence of freshly dried 3A molecular sieves together with MgSO4 (Scheme 2,Tables 1 and 2). The solvent has a crucial role, changing the solvent to ethanol toyield ethyl ester of the ligand 3. Yields of the Schiff bases are good irrespective ofthe nature of dicarbonyl 1, so we can expect that the reaction is not sensitive toelectronic effects of the dicarbonyls. The reduction of two azomethine bonds bythreefold excess of sodium borohydryde proceeds smoothly in anhydrous methanolat �30 �C to give the desired bibrachial methyl esters 4 in good yields (Scheme 3,Tables 1 and 2). The target bibrachial acids 5 were obtained by demethylation ofthe methyl esters by treatment of the compound 4 with sodium hydroxide(Scheme 3, Tables 1 and 2).

Further development of the method leads to the simplification of the initialprocedure. We found that the sodium salt of various amino acids 6 (isolated sodiumsalt of salt formed in situ from sodium methylate and amino acid) can react withdicarbonyl compounds to give disodium salts of the corresponding Schiff bases(Scheme 4, Tables 1 and 2).

Scheme 2. Condensation of methyl esters of amino acids with dicarbonyl compounds.

BIBRACHIAL CHIRAL LIGANDS 347

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The electronic effects of dicarbonyls or their topography (1e) show no effect onthe yields of the Schiff bases, which are usually good (Table 1). The obtained sodiumsalts 7 were easily reduced by threefold excess of sodium borohydride to correspond-ing bibrachial ligands 5, which can be isolated as sodium salts 50 or as free targetligands 5 (Scheme 5, Tables 1 and 2). The salts 50 are of high potential so far asthe preparation of coordination supramolecular networks includes in situ generationof salts of the reduced Schiff bases.[2–4,9]

The desired bibrachial reduced Schiff bases 5 are obtained by a two-stage pro-cedure in good overall yields. The final objective of our studies was to demonstratethe possibility of using this method to obtain bibrachial reduced Schiff bases fromsmall peptides and a variety of dialdehydes. We chose simple commercially availablebiologically active dipeptide carnosine for furnishing the desired amines 5 (Scheme 6,Tables 3 and 4).

Yields of the Schiff bases 8 as well as those of their reduction products 9 aregood. There is an influence of the volume of the substituent on reaction direction,probably because of changing the solubility of the Schiff base 8 (see entries b and c

in Table 4). The Schiff base 8b is not soluble in methanol, but more lipophiliccompound 8c is, so reduction of the Schiff base 8c yields corresponding amine9c, but reduction of Schiff base 8b yields partial decomposition of the startingcompound and isolation of the mixture of corresponding reduced Schiff baseand free carnosine.

In summary, we have developed a simple, mild, and efficient protocol for thesynthesis of various bibrachial reduced Schiff bases bearing two amino acid orpeptidic residues on different scaffolds. The key advantages of this approach areits generality, simplicity, and good overall yields. Coupled with the availabilityof starting dicarbonyl compounds and amino acids, it affords additional syntheticbenefits for constructing novel chiral bibrachial polydentate ligands for supramol-ecular architecture.

Table 1. Isolated yields of the pure compounds 3–7

L-Methionine (A) L-Histidine (B)L-Serine (C) L-Valine (D) b-Alanine (E)

Compound

Sodium

salt

Methyl

ester

Sodium

salt

Methyl

ester

sodium

salt

sodium

salt

sodium

salt

1a 7Aa 81%

5Aa 73%

3Aa 75%

4Aa 73%

5Aa 75%

7Ba 78%

5Ba 76%

3Ba 70%a

4Ba 70%

5Ba 70%

7Ca 87%

5Ca 75%

1b 7Ab 85%

5Ab 78%

50Ab 83%

3Ab 75%

4Ab 70%

5Ab 75%

a 7Cb 90%

5Cb 85%

50Cb 85%

1c 7Ac 80%

5Ac 75%

50Ac 76%

a 7Cc 87%

5Cc 80%

50Cc 78%

7Dc 95%

1d 7Ad 80%

5Ad 66%

a 7Cd

5Cd

1e 7Ae 65%

5Ae 75%

7Be 60%

5Be 57%

7Ee 70%

5Ee 60%

aA mixture of intramolecular cyclization products was isolated.

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Table

2.Spectroscopic

data

fortheaminoacidcompounds3–7

Product

Mp(�C)

IR(K

Br)

(cm

�1)

1H

NMR

(400MHz,

CD

3OD=TMS)d

13C

NMR

(100MHz,

CD

3OD)d

Anal.

3Aab

a1631(C

=N);1737(C

O2Me)

2.04(s,6H,2SCH

3),2.1–2.7

(m,8H,

4CH

2),3.70(s,6H,2OCH

3),4.11(t,

J¼6.4Hz,2H,2CH),6.50(s,2H,2CH),

8.06(s,2H,2HC=N)

Calcd.forC18H

27N

3O

4S2:C

52.28;

H6.58;N

10.16.

Found:C

52.41;

H6.75;N

10.03

3Ab

a1737(C

O2Me),1630(C

=N)

2.04(s,6H,2SCH

3),2.1–2.7

(m,8H,

4CH

2),3.70(s,6H,2OCH

3),4.11(t,

J¼6.4Hz,2H,2CH),7.50(s,2H,2CH),

8.06(s,2H,2HC=N)

3Ba

71–73

1629(C

=N),1736(C

O2Me),

3357(N

H)

3.05–3.23(m

,4H,2CH

2),3.72(s,6H,

2OCH

3),4.18–4.37(m

,2H,2CH),6.52(s,

2H,2CH),6.77(s,2H,2CH),7.56(s,2

H,2CH),7.86(s,2H,2HC=N).

Calcd.forC20H

23N

7O

4:C56.46;

H

5.45;N

23.05.Found:C

56.68;

H

5.73;N

22.77

4Aab

b1735(C

O2Me)

1.60–1.95(m

,4H,2CH

2),1.99(s,6H,

2SCH

3),2.5

(s,J¼7.2Hz,4H,CH

2),3.34

(t,J¼6.8Hz,

2H,2CH),3.59(s,4H,

2CH

2N),3.65(s,6H,3OCH

3),5.77(s,2

H,2CH)

Calcd.forC18H

31N

3O

4S2:C

51.77;

H7.48;N

10.11.

Found:C

52.02;

H7.63;N

10.27

4Abb

a1733(C

O2Me)

1.98(s,6H,2SCH

3),2.10–2.35(m

,8H,

4CH

2),2.33(s,3H,CH

3),3.73(t,

J¼6.6Hz,

2H,2CH),3.80(s,6H,

2OCH

3),4.26(s,4H,2CH

2N),7.24(s,2

H,2CH)

4Ba

41–43

1735(C

O2Me)

2.96(d,J¼6.5Hz,

4H,2CH

2),3.64(s,6

H,2OCH

3),3.45–3.90(m

,6H,

2CH

2Nþ2CH),5.85(s,2H,2CH),6.85

(s,2H,2CH),7.69(s,2H,2CH)

Calcd.forC20H

27N

7O

4:C55.93;

H

6.34;N

22.83.Found:C

56.16;

H

6.55;N

22.65

5Aa

176–178

1609(C

O2H)

2.07(s,6H,2CH

3),2.17(t,J¼9.0Hz,

4

H,2CH

2),2.56(t,J¼9.0Hz,4H,2CH

2),

(Continued

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Table

2.Continued

Product

Mp(�C)

IR(K

Br)

(cm

�1)

1H

NMR

(400MHz,

CD

3OD=TMS)d

13C

NMR

(100MHz,

CD

3OD)d

Anal.

3.73(t,J¼7.0Hz,

2H,2CH,),4.26(s,4

H,2CH

2),6.37(s,2H,2CH)

5Ab

150–152

1737(C

O2H)

2.12(s,6H,2SCH

3),2.20(m

,4H,2CH

2),

2.12(s,3H,CH

3),2.68(t,J¼8.6Hz,4H,

2CH

2),3.68(t,J¼5.1Hz,2H,2CH),4.16

(d,J¼�12.9Hz,

2H,CHN,),4.23(d,

J¼�12.9Hz,

2H,CHN),7.17(s,2H,

2CH).

13.9,19.2,28.9,29.0,

46.3,60.2,

119.4,131.7,134.1,

151.0,172.8.

Calcd.forC19H

26N

2O

5S22H

2O:C

49.33;

H6.54;N

6.06.Found:C

49.32;

H6.20;N

5.79

50 Abc

3424(O

H),1609(C

O2�)

2.02(s,6H,2SCH

3),2.06(m

,4H,2CH

2),

2.17(s,3H,CH

3),2.62(t,J¼7.6Hz,4H,

2CH

2),3.59(t,J¼6.1Hz,2H,2CH),4.02

(d,J¼�13.5Hz,

2H,CHN),4.15(d,

J¼�13.5Hz,

2H,CHN),7.07(s,2H,

2CH)

14.0,19.3,29.1,47.5,

53.9,60.5,119.7,

128.9,132.5,155.1,

174.5.

5Ac

3419(O

H),1743(C

O2H)

1.34(s,9H,t-Bu),2.12(s,6H,2SCH

3),

2.24(dt,J¼6.6,7.8Hz,

4H,2CH

2),2.68

(t,J¼7.8Hz,

4H,2CH

2),3.96(t,

J¼6.6Hz,

2H,2CH),4.31(d,J¼�

13.2Hz,

2H,CHN),4.35(d,J¼�

13.2Hz,

2H,CHN),7.51(s,2H,2CH).

13.8,29.2,29.3,30.4,

33.8,46.3,58.9,

119.3,130.7,

144.0,152.9,170.7

Calcd.forC22H

36N

2O

5S2�H

2O:C

53.85;

H7.81;N

5.71.Found:C

53.76;

H7.63;N

5.68

50 Acc

227–229

3426(O

H),1603(C

O2�)

1.29(s,9H,t-Bu),2.10(s,6H,2SCH

3),

2.15(m

,4H,2CH

2),2.66(t,J¼7.09Hz,4

H,2CH

2),3.53(t,J¼5.1Hz,

2H,2CH),

4.02(d,J¼�16.4Hz,

2H,CHN),4.18(d,

J¼�16.4Hz,

2H,CHN),7.23(s,2H,

2CH)

14.0,29.8,30.9,32.4,

33.2,47.3,62.6,

118.3,123.9,126.8,

156.1,181.8.

5Ad

228–230

1690(C

O2H)

1.89(ddd,J¼�14.18,

7.83,6.35Hz,

2H,

2CH),1.95(ddd,2J¼�14.18,3J¼7.83,

6.35Hz,

2H,2CH),2.07(s,6H,2SCH

3),

2.59(t,J¼7.83Hz,

4H,2CH

2),3.19(dd,

13.9,30.4,33.2,53.1,

63.3,120.9,137.4,

159.0,180.3

Calcd.forC17H

27N

3O

4S2:C

50.85;

H6.78;N

10.46.

Found:C

51.04;

H6.95;N

10.22

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J¼6.35,6.51Hz,

2H,2CH),3.75(d,

J¼�13.45Hz,

2H,CHN),3.85(d,J¼�

13.45Hz,

2H,2CHN),7.28(d,

J¼7.58Hz,

2H,CHpy),7.70(t,

J¼7.58Hz,

1H,CHpy)

5Ba

dec.>166

1685(C

=O)

3.19(d,J¼6.48Hz,

4H,2CH

2),3.78(t,

J¼6.48Hz,

2H,2CH),4.18(d,J¼�

14.18Hz,

2H,2CHN),4.24(d,J¼�

14.18Hz,

2H,2CH),6.25(s,2H,2CH),

7.14(s,2H,2CH),8.24(s,2H,2CH)

26.2,42.7,59.9,

112.3,117.2,122.8,

128.8,134.6,172.1

5Bec

170–173

3.17(d,J¼6.2Hz,

4H,2CH

2),3.83(t,

J¼6.7Hz,

2H,2CH),4.05(s,4H,

2CH

2),4.39(br.s,8H,2C5H

4),7.03(s,2

H,2CH),7.76(s,2H,2CH)

Calcd.forC24H

28FeN

6O

4:C55.40;

H5.42;N

16.15.

Found:C

55.59;

H5.71;N

16.00

5Caa

204–206

1696(C

=N)

3.62(t,J¼4.4Hz,

2H,2CH),3.88(d,

J¼1.96Hz,

2H,2CH),3.89(d,

J¼0.61Hz,

2H,2CH)4.26(s,4H,

2CH

2),6.29(s,2H,2CH)

42.3,59.4,62.0,

112.2,122.8,171.3

5Cbc

192–198

1737(C

O2H)

2.18(s,3H,CH

3),3.72(dd,J¼3.7,

5.6Hz,

2H,CH),3.87(dd,J¼5.6,�

12.5Hz,

2H,2CHN),3.94(dd,J¼3.7,�

12.5Hz,

2H,CHN),4.23(s,4H,2CH

2),

7.17(s,2H,2CH).

19.2,46.1,59.3,62.5,

119.4,131.6,133.9,

149.8,171.1.

Calcd.forC15H

18N

2O

7H

2O

MeO

H:C

49.48;

H6.23;N

7.21.

Found:C

49.43;

H5.98;N

7.30

50 Cba

212–214

1604(C

O2�)

2.35s(3H,CH3),3.87t(2H,CH,

J¼5.6Hz),4.02dand4.06d(2H

each,

CHN,J¼�2.2Hz),4.33d(4H,CH2,

J¼5.6Hz),7.28s(2H,CH)

5Cc

dec.158

1739(C

O2H)

1.28s(9H,t-Bu),4.08m

(6H,CH,CH2),

4.43br.s(4H,CH2O

H),7.54s(2H,CH)

Calcd.forC18H

28N

2O

7�2

H2O:C

51.42;

H7.67;N

6.66.Found:C

51.62;

H7.63;N

6.47.

50 Cc

a1603(C

O2�)

1.32s(9H,t-Bu),3.74t(2H,CH,

J¼3.7Hz),4.01m

and4.06d.d

(4H,

CH2,J¼3.7,�12.47Hz),4.35dand4.38

d(2H

each,CH2N,J¼6.1Hz),7.47s

30.6,34.3,47.2,59.8,

62.6,119.3,

128.7,129.7,154.7,

171.3

(Continued

)

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Table

2.Continued

Product

Mp(�C)

IR(K

Br)

(cm

�1)

1H

NMR

(400MHz,

CD

3OD=TMS)d

13C

NMR

(100MHz,

CD

3OD)d

Anal.

(2H,CH)

5Cd

204–206

1633(C

O2H)

3.83(dd,J¼4.15,3.18Hz,

2H,2CH),

3.96(dd,J¼4.15,�11.98Hz,

2H,2CH),

4.08(dd,J¼3.18,�11.98Hz,

2H,2CH),

4.54(s,4H,2CH

2),7.39(d,J¼7.58Hz,2

H,2CHpy),7.85(t,J¼7.58Hz,

1H,

CHpy)

49.8,60.2,

64.6,123.1,139.5,

153.0,172.7

Calcd.forC13H

19N

3O

6:C49.84;

H

6.11;N

13.41.Found:C

49.99;

H

6.27;N

13.33.

5Ee

225–227

2.57t(4H,2CH2,J6.6Hz),3.22t(4H,

2CH2,J6.5Hz),4.15s(4H,2CH2),4.45

br.s(4H,2C5H4),4.51br.s(4H,2C5H4)

Calcd.forC18H

24FeN

2O

4:C55.69;

H6.23;N

7.22.Found:C

55.83;H

6.17;N

6.98.

7Aa

dec.>200

1634(C

=N),1587(C

O2�)

2.07(s,6H,2CH

3),2.09(t,4H,2CH

2,

J¼5.93Hz),2.22(dddd,4H,J¼9.19,

7.12,5.93,�13.65Hz,),2.44–2.56(m

,4H,

2CH

2),3.91(dd,2H,2CH,J¼8.93,

4.52Hz),6.59(s,2H,2CH),8.10(s,2H,

2CH=N)

15.30,31.87,35.23,

49.86,

76.40,116.18,

134.41,154.09,

180.31

Calcd.for

C16H

20N

3Na 3O

4S2�H

2O:C40.93;

H4.72;N

8.95.Found:C

41.30;H

4.72;N

8.69.

7Ab

136–139

3423(O

H),1712(C

=O),1629

(C=N)

2.02(m

,4H,CH2),2.08(s,6H,SCH3),

2.27(s,3H,CH3),2.59(t,4H,CH2,

J¼8.3Hz),4.03(dd,2H,CH,J¼4.6,

3.7Hz),7.38(s,2H,CH),8.36(s,2H,

CH=N)

13.7,30.1,31.5,34.3,

72.2,124.0,137.5,

137.8,155.7,162.9,

179.8.

Calcd.forC19H

24N

2Na2O

5S2:C

48.50;

H5.14;N

5.95.Found:C

48.32;

H5.29;N

5.65

7Ac

dec.>160

3426(O

H),1649(C

O2�),1629

(C=N)

1.33s(9H,t-Bu),2.09s(6H,SCH3),

2.15m

(2H,CHN),2.25m

(2H,CHN),

2.55m

(4H,CH2),4.06t(2H,CH,

J¼4.7Hz),7.63s(2H,CH),8.42s(2H,

CH=N).

13.8,29.9,30.2,33.5,

33.7,71.6,117.3,

128.0,137.4,163.4,

165.5,174.4

7Ad

140–143

1593(C

=N,CO

2�)

2.06s(6H,SCH3),2.2m

(4H,CH2),2.5m

(4H,CH2),4.1

d.d

(2H,CH),7.89m

(3H,

pyridine),8.43s(2H,HC=N)

Calcd.forC17H

21N

3Na2O

4S2:C

46.25;

H4.79;N

9.52.Found:C

46.41;

H5.03;N

9.39

7Ae

216–218

1590(C

=O),1637(C

=N)

2.10s(6H,2SCH3),2.12–2.70m

(8H,

Calcd.forC22H

26FeN

2Na2O

4S2:C

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4CH2),3.85t(2H,2CH,J6.4Hz),4.50

br.s(4H,2C5H4),4.79br.s(4H,2C5H4),

8.16s(2H,2CH=N).

48.18;

H4.78;N

5.11.Found:C

48.33;

H4.91;N

4.90

7Ba

1633(C

=N)

3.04(dd,J¼9.41,�14.43Hz,4H,2CH

2),

3.99(dd,J¼9.11,4.10Hz,

2H,2CH),

6.43(s,2H,2CH),6.73(s,2H,2CH),

7.52(s,2H,2CH),7.78(s,2H,2CH)

33.1,77.7,116.0,

134.3,135.9,135.9,

136.2,153.9,179.9

7Be

155–157

1593(C

=O),1635(C

=N)

3.20d(4H,2CH2,J6.1Hz),3.92t(2H,

2CH,J6.7Hz),4.43br.s(4H,2C5H4),

4.62br.s(4H,2C5H4),6.83s(2H,2CH),

7.56s(2H,2CH),7.92s(2H,2CH=N)

Calcd.forC24H

22FeN

6Na2O

4:C

51.45;

H3.96;N

15.00.

Found:C

51.63;

H4.18;N

14.81

7Cb

122–125

3406(O

H),1629(C

=N,CO

2�)

2.26s(3H,CH3),3.89t(2H,CH,

J¼5.4Hz),4.00d(4H,CH2OH,

J¼5.4Hz),7.35s(2H,CH),8.30s(2H,

CH=N).

Calcd.forC15H

16N

2Na2O

7:C

47.13;

H4.22;N

7.33.Found,%:C

47.45;

H4.41;N

7.77

7Cc

>185withdec.

1633(C

=N,CO

2�)

1.32s(9H,t-Bu),3.86t(2H,CH,

J¼11.3Hz),4.03d(4H,CH2OH,

J¼11.3Hz),7.55s(2H,CH),8.33s(2H,

CH=N)

30.2,33.2,63.8,73.5,

117.9,131.1,

151.7,166.0,178.8.

7Cdb

dec.84–86

1597(C

=NþCO

2�)

3.55(dd,J¼5.05,6.80Hz,

2H,2CH),

3.72(dd,J¼�13.48,6.80Hz,

2H,2CH),

3.75(dd,J¼�13.48,5.04Hz,

2H,2CH),

7.90(m

,3H,3CH),8.26(s,2H,2CH=N)

65.4,78.9,127.2,

140.0,154.4,162.6,

177.9

Calcd.forC13H

13N

3Na2O

6:C

44.20;

H3.71;N

11.90.

Found:C

44.00;

H3.95;N

11.77.

7Dc

dec.223–225

1647(C

O2�),1631(C

=N)

0.98d(6H,CH3,J¼6.61Hz),1.03d(6H,

CH3,

J¼6.36Hz),1.33s(9H,t-Bu),2.30

d.t(2H,CH,J¼6.61,6.36Hz),3.65br.s

(2H,CH),7.57s(2H,CH),8.30s(2H,

CH=N)

17.3,18.6,30.1,31.9,

33.1,79.3,

121.5,135.2,136.4,

148.4,163.1,176.7

7Ee

dec.>100

1563(C=O),1644(C

=N)

2.49t(4H,2CH2,J7.1Hz),3.70t(4H,

2CH2,J7.0Hz),4.45t(4H,2C5H4,J

1.8Hz),4.71t(4H,2C5H4,J1.8Hz),

8.19s(2H,2CH=N)

40.3,59.3,71.0,73.4,

81.9,164.5,180.2

Calcd.forC18H

18FeN

2Na2O

4:C

50.49;

H4.24;N

6.54.Found,%:C

50.67;

H4.48;N

6.27

aOilysubstances.

bSpectrarecorded

inCDCl 3.

c Spectrarecorded

inD

2O.

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Scheme 3. Reduction and subsequent demethylation of the bibrachial Schiff bases.

Scheme 4. Condensation of sodium salts of amino acids with various dicarbonyl compounds.

Scheme 5. General scheme of the preparation of the bibrachial ligands and their sodium salts.

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EXPERIMENTAL

1H and 13C NMR spectra were recorded on a Bruker Avance 400-MHz NMRspectrometer at 24 �C. Infrared (IR) spectra were determined on a Nicolet Fouriertransform (FT–IR) spectrometer.

The starting dicarbonyls were synthesized according to literature methods:1a[19], 1b and c[20], 1d,[21] and 1e[22]. All syntheses were performed in anhydroussolvents under an argon atmosphere.

Synthesis of Schiff Bases 3

To a solution of dialdehyde 1 (10mmol) in MeOH (100ml), freshly preparedamino acid methyl ester (20mmol), MgSO4 (2 g), and 3 A molecular sieves (2 g) wereadded. The mixture was stirred for 7 h, filtered, and evaporated. The residue wasextracted with anhyd Et2O, the extract was filtered and evaporated, hexane(100ml) was added to the residue, and the oily product was separated, washed withhexane, and dried at 40 �C in vacuum to give 3Aa and 3Ba (Tables 1 and 2).

Ethyl Ester of the Ligand 3Ba

Sodium (0.92 g, 40mmol) was dissolved in EtOH (100ml) and then L-histidinemethyl ester dihydrochloride (4.84 g, 20mmol) added with stirring. Dialdehyde 1a

(1.23 g, 10mmol), MgSO4 (2 g), and 3 A molecular sieves (2 g) were added, and themixture was stirred for 7 h and filtered. The filtrate was treated as described to yield3.08 g (68%), brown powder, mp 58–60 �C. IR (KBr): 1628 (C=N), 1733 (C=O) cm�1.1H NMR (400MHz, CD3OD), d¼ 1.23 (t, J¼ 7.1Hz, 6H, CH3), 3.00–3.20 (m, 4H,CH2), 4.15–4.35 (m, 2H, CH), 4.17 (q, J¼ 7.0Hz, 4H, OCH2), 6.52 (s, 2H, CH), 6.79

Scheme 6. General scheme of the synthesis of bibrachial ligands based on short peptides.

BIBRACHIAL CHIRAL LIGANDS 355

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Table

3.Spectroscopic

data

forthecarnosinecompounds8and9

Product

IR(K

Br)

cm�1

1H

NMR

(400MHz,

CD

3OD=TMS)d

13C

NMR

(100MHz,

CD

3OD)d

Anal.

8a

1637(C

=N),

1601(C

O2�)

2.55(t,J¼6.60Hz,

4H)3.00(dd,

J¼7.34,�14.92Hz,

2H)3.16(dd,

J¼4.77,�14.94Hz,

2H)3.76(t,

J¼6.48Hz,

4H)4.48(dd,J¼7.09,

4.65Hz,

2H)6.58(s,2H)6.80(s,2H)

7.41(s,2H)8.12(s,2H)

30.8,38.6,50.0,56.3,57.5,

115.6,120.6,133.8,134.3,

135.9,154.9,173.5,178.5

Calcd.for

C24H

27N

9Na2O

6�3H

2O�E

tOH:C

45.68;

H5.75;N

18.44.Found:C

45.70;H

5.77;

N18.05

8b

2.25(s,3H)2.34(t,J¼6.36Hz,4H)2.60

(t,J¼6.85Hz,

13H)2.84(t,J¼6.48Hz,

4H)2.98(dd,J¼7.46,�15.04Hz,

2H)

3.14(dd,J¼4.77,�15.09Hz,2H)3.82(t,

J¼6.72Hz,

4H)4.50(dd,J¼7.46,

4.77Hz,

2H)6.80(s,2H)6.83(s,3H)

7.53(s,3H)8.56(s,2H)

20.4,30.7,30.8,38.4,39.4,40.2,

56.3,56.9,120.7,133.7,134.9,

135.9,164.5,173.2,178.3

8c

1637(C

=N),

1601(C

O2�)

1.29(s,9H)2.63(t,J¼6.60Hz,4H)2.98

(dd,J¼7.58,�14.67Hz,

2H)3.15(dd,

J¼3.50,�14.60Hz,

2H)3.85(t,

J¼6.60Hz,

4H)4.51(dd,J¼7.50,

3.50Hz,2H)6.81(s,2H)7.46(br.s.,2H)

7.71(s,2H)8.58(s,2H)

30.8,31.8,31.9,35.1,37.9,38.4,

50.0,55.8,56.4,117.9,120.7,

121.8,129.4,131.4,133.8,

135.9,140.7,165.5,168.0,

172.9,178.3

Calcd.for

C30H

36N

8Na 2O

7�2H

2O�2EtO

H:C

51.38;

H6.59;N

14.10.Found:C

51.67;H

6.45;

N14.22

8d

1655(C

=N),

1605(C

O2�)

2.59(ddd,J¼8.57,7.34,�14.19Hz,

2H)

2.72(ddd,J¼6.39,6.37,�14.19Hz,

1H)

2.97(dd,J¼6.25,�14.79Hz,

2H)3.16

(dd,J¼5.55,�14.67Hz,2H)3.92(dddd,

J¼8.57,7.34,6.39,�15.21Hz,

4H)4.51

30.7,38.2,56.3,58.0,126.5,

135.9,140.1,154.6,163.6,

173.8,178.4

Calcd.for

C25H

27N

9Na 2O

6�3H

2O�2EtO

H:C

46.96;

H6.12;N

17.00.Found:C

46.64;H

5.87;

N17.17

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(dd,J¼6.25,5.55Hz,

2H)6.81(s,2H)

7.47(s,2H)7.84(d,J¼7.82Hz,2H)8.00

(t,J¼7.70Hz,

1H)8.41(s,2H)

9aa

1676(C

O2H)

2.64(br.s.,15H)3.06(br.s.,10H)3.18

(br.s.,18H)3.25(br.s.,6H)4.20(br.s.,

16H)4.48(br.s.,8H)6.25(br.s.,9H)

7.15(br.s.,8H)8.30(br.s.,8H)

29.3,32.8,44.1,44.6,56.2,

112.9,118.4,124.8,133.6,

135.3,172.3,177.8

Calcd.forC24H

33N

9O

6�4H

2O�M

eOH:C

44.89;

H7.92;N

16.25.

Found:C44.89;

H

7.95;N

16.59

9ca

1.33(s,28H)2.83(t,J¼6.48Hz,

13H)

3.21(dd,J¼15.28,

8.44Hz,

8H)3.34(t,

J¼6.48Hz,

9H)3.35(dd,J¼5.14,�

15.28Hz,

3H)4.34(s,11H)4.74(dd,

J¼8.44,5.01Hz,

7H)7.43(s,7H)7.59

(s,5H)8.84(s,7H)

27.9,31.9,35.4,44.7,48.4,53.5,

118.6,121.6,131.4,131.9,

135.1,146.1,153.6,172.5,173.9

9da

1680(C

O2H)

2.69(td,J¼5.75,�16.30Hz,

4H)2.83

(td,J¼5.75,�16.36Hz,

3H)3.03(dd,

J¼15.16,

8.80Hz,9H)3.23(dd,J¼5.00,

�15.16Hz,

9H)3.36(t,J¼5.75Hz,

6H)

4.46(br.s.,21H)7.07(s,8H)7.44(d,

J¼7.83Hz,8H)7.92(t,J¼7.83Hz,4H)

8.05(s,8H)

29.5,33.1,45.6,51.6,56.8,

118.7,123.6,134.1,140.4,

152.7,172.7,177.9

Calcd.forC25H

33N

9O

6�6H

2O�M

eOH:C

43.73;

H7.95;N

15.30.

Found:C43.69;

H

8.11;N

14.93

aSpectrarecorded

inD

2O.

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(s, 2H, CH), 7.58 (s, 2H, CH), 7.87 (s, 2H, HC=N). Anal. calcd. for C22H27N7O4: C,58.27; H, 6.00; N, 21.62.Found: C, 58.35; H, 6.12; N, 21.43.

Synthesis of Reduced Schiff Bases Methyl Esters 4

A solution of Schiff base 3 (5mmol) in MeOH (75ml) was cooled to �30 �C,NaBH4 (0.57 g, 15mmol) was added, and the mixture was stirred for 1 h at �30 �Cand for 1 h at room temperature. A solution of acetic acid (0.9 g, 15mmol) in MeOH(10ml) was then added dropwise, the mixture was stirred for 1 h, and the solvent wasremoved. The residue was extracted with Et2O, filtered, and concentrated underreduced pressure, and then 100ml of hexane was added. The oily material was sepa-rated from the hexane solution, washed with hexane, and dried under reduced pressureat 45 �C to give 4Aa and 4Ba (Tables 1 and 2).

Synthesis of Reduced Schiff Bases 5

To a solution of methyl ester 4 in EtOH (50ml), a solution of NaOH (0.48 g,12mmol) in water (50ml) was added. The mixture was stirred for 14 h, treated with3MHCl (4ml) and evaporated. The desired 5was extracted with acetone and concen-trated. To the solution of 5, hexane=Et2O were added. The precipitates of 4were sepa-rated and precipitated again from acetone to give 5Aa, 5Ab, and 5Ba (Tables 1 and 2).

Synthesis of the Schiff Bases Sodium Salts 7

L-Amino acid (10mmol) was added at room temperature to a solution ofNaOEt prepared from sodium (0.23 g, 10mmol) and EtOH (100ml). The mixturewas stirred for 1 h at room temperature. The corresponding dialdehyde (5mmol)and 4 g of 3A molecular sieves were added, and the mixture was stirred for 10 hand filtered. The filtrate was concentrated under reduced pressure and cooled to�30 �C, and the yellow powder was filtered off, washed with Et2O, and dried to give7Aa–7Ae, 7Ba, 7Be, 7Ca–7Cc, and 7Dc, 7Ee (Tables 1 and 2).

Synthesis of Sodium Salts of Reduced Schiff Bases 5’

A solution of Schiff base 7 (5mmol) in MeOH (100ml) was cooled to �30 �C,NaBH4 (0.57 g, 15mmol) was added, and the mixture was stirred for 1 h at �30 �Cand was allowed to warm up to room temperature. A 2N solution of HCl in EtOH(7.5ml) was slowly added dropwise, and the mixture was stirred for 1 h and

Table 4. Furnishing the carbosine-based ligands 8 and 9

Dicarbonyl 1 Schiff base 8 Reduced Schiff base 9

1a 8a 86% 9a 79%

1b 8b 85% —

1c 8c 87% 9c 82%

1d 8d 80% 9d 83%

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evaporated under reduced pressure. The residue was extracted with anhydrousEtOH, the extract was filtered and evaporated, and the residue was treated withEt2O. The precipitate was filtered off, washed with Et2O, and dried to give 50Ab,50Ac, 50Cb, and 50Cc (Tables 1 and 2).

Synthesis of Reduced Schiff Bases 5

A solution of Schiff base sodium salt 7 (5mmol) in MeOH (100ml) was cooledto �30 �C, NaBH4 (0.57 g, 15mmol) was added, and the mixture was stirred for 1 hat �30 �C and allowed to warm up to room temperature. A 2N solution of HCl inEtOH (12.5ml) was slowly added dropwise, and the mixture was stirred for 1 h andevaporated under reduced pressure. The residue was extracted with anhydrousEtOH, the extract was filtered and evaporated, and the residue was treated withEt2O. The precipitate was filtered off, washed with Et2O, and dried to give 5Aa–

5Ad, 5Be, 5Ca–5Cc, and 5Ee (Tables 1 and 2).

Synthesis of Carnosine Schiff Bases 8

Carnosine (2.26 g, 10mmol) was added at room temperature to a solution ofNaOEt prepared from sodium (0.23 g, 10mmol) and EtOH (100ml). After the dissol-ution of peptide, the corresponding dialdehyde (5mmol) and 4 g of 3A molecularsieves were added, and the mixture was stirred for 5 h and filtered. The filtrate wasconcentrated under reduced pressure and cooled to �30 �C, and the powder wasfiltered off, washed with Et2O, and dried to give 8a–d (Tables 2 and 3).

Reduction of Carnosine Schiff Bases

A solution of Schiff base sodium salt 8 (5mmol) in MeOH (100ml) was cooledto �30 �C, NaBH4 (0.57 g, 15mmol) was added, and the mixture was stirred for 1 hat �30 �C and allowed to warm up to room temperature. A 2N solution of HCl inEtOH (12.5ml) was slowly added dropwise, and the mixture was stirred for 1 h andevaporated under reduced pressure. The residue was extracted with anhydrousEtOH, the extract was filtered and evaporated, and the residue was treated withEt2O. The precipitate was filtered off, washed with Et2O, and dried to give 9a, 9c,and 9d (Tables 2 and 3).

ACKNOWLEDGMENTS

This study was performed with financial support by the Byelorussian Foun-dation for Basic Research (Project No. Kh08R-051), the Russian Foundation forBasic Research (Project No. 08-03-90 025), and partly by a grant from the presidentof the Russian Federation (Project No. MK-3588.2008.3).

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