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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
To link to this article: http://dx.doi.org/10.1080/00397911.2011.597534
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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
345
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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.
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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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