Chemistry of ureido carboxylic and ureylene dicarboxylic acids - Turpion

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dures for the synthesis of ureido carboxylic and ureylene dicar- boxylic acids. Chemical transformations of these compounds are summarised. New fields of ...
Russian Chemical Reviews 75 (3) 191 ± 206 (2006)

# 2006 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2006v075n03ABEH003589

Chemistry of ureido carboxylic and ureylene dicarboxylic acids A N Kravchenko, I E Chikunov

Contents I. Introduction II. Synthesis of ureido carboxylic and ureylene dicarboxylic acids III. Chemical transformations of ureido carboxylic acids

Abstract. The review presents a comparative analysis of procedures for the synthesis of ureido carboxylic and ureylene dicarboxylic acids. Chemical transformations of these compounds are summarised. New fields of application of ureido carboxylic acids in the synthesis of chiral, diastereomeric and enantiomerically pure N-carboxyalkylglycolurils are considered. The bibliography includes 129 references. references.

191 191 197

reaction product, viz., ethyl ester of ureidoacetic acid (N-carbamoylglycine), was not isolated in pure form but was subjected to cyclisation giving rise to hydantoin. O H3N+

Cl7 O

I. Introduction

KOCN

HN

7KCl

II. Synthesis of ureido carboxylic and ureylene dicarboxylic acids Harries 8

First syntheses of ureido acids were performed by in the early twentieth century and were based on the reaction of glycine ethyl ester hydrochloride with potassium cyanate (by analogy with the first synthesis of urea from ammonium isocyanate 9). The A N Kravchenko, I E Chikunov N D Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation. Fax (7-495) 135 53 28, tel. (7-495) 135 88 17, e-mail: [email protected] Received 30 March 2005 Uspekhi Khimii 75 (3) 217 ± 233 (2006); translated by T N Safonova

H+ HN

O OEt

OEt

Procedures for the preparation of ureido carboxylic and ureylene dicarboxylic acids (hereinafter, ureido acids and ureido diacids, respectively) and their chemical transformations are being widely discussed in the literature. These compounds deserve attention because of diverse physiological activities.1 ± 7 For example, the simplest representative of ureido acids, viz., N-carbamoylglycine, exerts sedative, antihypoxic and anticonvulsant effects in mice.2 N-Carbamoyl-b-alanine binds to the PEPT2 protein in Pichia pastoris yeast cells, serves as a peptide transporter in Xenopus laevis oocytes and has antidiabetic properties.3 N-Carbamoyl-gaminobutyric acid shows properties of a weak GABA antagonist (GABA is g-aminobutyric acid).4 N d-Methyl-N d-nitroso-(S)-citrulline was shown 5 to be an antitumor agent. N,N 0 -Carbonylbis(methionine) is used for the design of insulin analogues.6, 7 Besides, ureido (di)acids are promising building blocks in the synthesis of various biologically active heterocyclic compounds. The aim of the present review is to systematise procedures for the synthesis of ureido (di)acids and their chemical transformations. Reactions of achiral, racemic and optically pure ureido acids with a-dicarbonyl compounds and 4,5-dihydroxyimidazolidin-2-ones in the synthesis of potential biologically active glycoluril derivatives containing N-carboxyalkyl groups are considered.

O NH2

NH O

Various procedures have been developed for the synthesis of ureido acids. Let us mention the following three main methods: (1) reactions of amino acids with KOCN (the cyanate method); (2) reactions of amino acids with urea; (3) cleavage of 5-substituted imidazolidine-2,4-diones (hydantoins) and related compounds. Selected representatives of this class were synthesised according to alternative procedures. Methods for the synthesis of ureylene dicarboxylic acids are reviewed in a special section.

1. Cyanate method for the synthesis of ureido carboxylic acids Numerous ureido acids were synthesised by the cyanate method. N-Carbamoylation reactions were carried out with achiral, racemic and optically active S- and R-amino acids (Table 1). The reactions of KOCN with amino acids were carried out in aqueous solutions in the absence of catalysts or in the presence of an alkali or an acid at temperatures from 20 to 100 8C; the reaction time varied from 20 min to 48 h. The yields of ureido acids 1a ± u are 40% ± 67% (see Table 1). O NH2

H2O, H+ or OH7

+ KOCN

HO2C X

HN

NH2

R

HO2C X R 1a ± u R = H, X = (CH2)n: n = 0 (a), 1 (b), 2 (c), 3 (d); R = H, X = CH2NHC(O) (e); X is absent: R = Me (f), Et (g), Prn (h), Pri (i), Bui (j), Bus (k), CH2SH (l), (CH2)2SMe (m), CH2CO2H (n), CH2C(O)NH2 (o), (CH2)2CO2H (p), (CH2)2C(O)NH2 (q), CH(OH)Me (r), Bn (s), CH2C6H4OH-4 (t), (CH2)3NHC(O)NH2 (u).

The reactions of amino acid esters with alkyl isocyanates also afford ureido acid derivatives. In both cases, the reactions proceed by the mechanism 33 analogous to the mechanism of the synthesis of urea from ammonium cyanate.9, 28

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A N Kravchenko, I E Chikunov

carbamates. Calculations and experimental data showed 15 that all reactions are first order with respect to each reagent.

Table 1. Synthesis of ureido acids by the cyanate method. Starting Reaction conditions amino acid

Ureido acid 1

Ref.

Gly

b-Ala GABA

d-APA Gly-Gly N-MeAla Ala

Ala . HCl a-ABA nor-Val Val

Leu Leu . HCl Ile Cys Met Asp Asn Glu Gln Thr Phe Phe . HCl Tyr Cit

a H2O, 100 8C; HCl H2O, KOH a a H2O, D, 20 min; HCl, pH 3 H2O, D, 20 min; HCl, pH 3 b c H2O, 20 8C, 22 h; 6 M AcOH H2O, D, 20 min; HCl, pH 2, c 720 8C, 7 h c H2O, D, 4 h; HCl, pH 2 H2O, D, 20 min; HCl, 7 h d H2O, D, 30 min; HCl, 20 8C, 7 h e f H2O, 40 8C H2O, D f HCl, H2O, D, 20 min, pH 3 f f H2O, 50 8C, 15 h, pH 7.5 H2O, 60 8C, 4 h f g H2O, 20 8C, 60 h H2O, 20 8C, 48 h, pH 2 h i H2O, 50 8C, 15 h, pH 7.5 H2O, 60 8C, 4 h i H2O, 20 8C, 48 h, pH 2 i H2O, 20 8C, 72 h, pH 2 j H2O, 60 8C, 4 h or 50 8C, 18 h; j pH 7.5 H2O k KOH, H2O a l m H2O, D, 30 min 1 M KOH, H2O b n n H2O, D H2O, D c o p KOH, H2O H2O, 20 8C, 40 h; HCl, pH 2, 5 ± 7 h q H2O, 50 8C, pH 8 r H2O, D, 4 h; pH 2 s H2O, 60 8C, 4 h s H2O, 50 8C, 15 h, pH 7 s H2O, D t H2O, D d u

10, 11 12 13, 14 13 ± 15 16 14, 17, 18 19 10, 14, 20 10, 14 21 11, 22 13 15 23 19 19, 24 15 11 19 19 15

Note Hereinafter, d-APA is d-aminopentanoic acid and a-ABA is a-aminobutyric acid, Cit is citrulline; a the reaction was carried out also with the use of NaOCN and NaOH; b fulminic acid was used instead of KOCN; c partial racemisation of amino acid occurs; d the reaction was performed with the use of HNCO.

7

R1

N C O

H2NR2

R1

N C O R2H2N+

R1HN

NHR2 O

The mechanism and kinetics of the reaction of amino acids with cyanate anions have been considered in detail.15 In this study, a kinetic model of N-carbamoylation in the pH range of 2 ± 13 at *40 ± 50 8C was suggested. In aqueous solutions, KOCN forms isocyanic acid, which undergoes to hydrolysis or nucleophilic addition of amines, i.e., several competitive processes occur. It is assumed that the reactions of cyanate ions with water (reactions 1 ± 3), ammonia (reaction 5) and alkylamines (reaction 6) involve the electrophilic (proton) or nucleophilic (OH7) attack on isocyanic acid to form carbamates or urea derivatives (in the case of N-nucleophiles). In addition, the CO2ÿ 3 anion efficiently catalyses hydrolysis of HNCO (reaction 4). Each slow step (the rate constants of these steps are denoted by k1 ± k4) is followed by fast cleavage of carbamates (or carbaminic acid) to give NH3 and CO2. It should be noted that ureas are much more stable than

NH‡ 4 + CO2 (1)

rate-determining

HNCO + H2O

NCO7

+ H2 O

HNCO + CO2ÿ 3 NCO7 + HCOÿ 3 HNCO + NH3 NCO7 + NH‡ 4

+

NCO7 + H3NR

fast

OH

O H2N

NCO7 + H3O

HNCO + HO7

H2 N

k2

k 02 +

HNCO + H2NR 25 26 15 27, 28 27, 28 29, 30 12 31 15 23 23 15 30 32

+OH

k1

HNCO + H3O+

NH3 + CO2

(2)

NH3 + HCOÿ 3

(3)

OH

k3

H2O

O k 03

O7

H2N

k4

H2O

O H2O

k 04

O7

H2N

NH3 + 2 HCOÿ 3 (4)

+ HCOÿ 3

k5

O (5)

k 05

H2N

NH2

k6

O k 06

(6) H2N

NHR

The following optimum conditions of the selective formation of ureido acids were found by studying the reactions of glycine, L-alanine, b-alanine, L-phenylalanine, L-valine, L-leucine, DLmethionine, N e-trifluoroacetyl-L-lysine and L-threonine: pH 7 ± 8, 50 8C, a 1.5 ± 2-fold excess of cyanate and the reaction time of 10 ± 24 h. Under these conditions, the NH3 and CO2 concentrations are low, the formation of carbamates and urea is insignificant, and hydrolysis of ureido acids occurs so slowly that this process can be ignored. Consequently, ureido acids are formed as the major products. The results of kinetic studies were used to synthesise the corresponding ureido acids in preparative yields (40% ± 80%). One of the authors of the present review has made an important contribution to the development of the cyanate method (see Refs 13 and 14). The conditions of the reaction of amino acids with KOCN were optimised taking into account the data 15 on the kinetics of N-carbamoylation. A distinguishing feature of the procedure is that KOCN is added portionwise to an amino acid solution in water or aqueous isopropyl alcohol at 80 ± 90 8C. Then the reaction mixture is heated to boiling followed by storage of the reaction mixture for 20 ± 30 min, which afforded ureido acids 1a ± u in 60% ± 94% yields. In the procedures used earlier, KOCN was added in one portion, and, after 48 h, the reaction products were obtained in yields of only 43% ± 61%.24 In addition, N-carbamoylation performed under the conditions used earlier 24 was accompanied by competitive hydrolysis of cyanate ions. In many investigations,11 ± 15, 17 ± 27, 29, 31, 32 it was reported that the chiral carbon atom was not affected in transformations of optically active amino acids into ureido acids. However, partial racemisation of (R)- and (S)-aspartic acids was observed 30 in the reaction with potassium cyanate in the presence of an alkali. This fact remained unexplained.

2. Reactions of amino acids with urea Some ureido acids were synthesised by the reactions of amino acids with urea (Table 2).

Chemistry of ureido carboxylic and ureylene dicarboxylic acids

193

O O

NH2 HO2C

( )n

R

H2N

HN

HO7

+ NH2

HO2C

NH2

( )n

R 1a,c,f ± j,n,p,s,t,v,w

n = 0: R = (CH2)4NH2 (v), CH2Ind (Ind is indol-3-yl) (w). Table 2. Synthesis of ureido acids by the reaction of amino acids with urea.

3. Cleavage of hydantoins and related compounds

Ureido acid 1

Reaction conditions

Ref.

a

H2O, NaOH, 110 8C, 2 h; 140 8C H2O, Ba(OH)2 110 ± 112 8C, 1 h HCl, H2O, D, 15 h H2O, Ba(OH)2 HCl, H2O, D, 15 h H2O, Ba(OH)2 H2O, Na2CO3 HCl, H2O, D, 15 h H2O, Ba(OH)2 H2O, Ba(OH)2 HCl, H2O, D, 15 h H2O, Ba(OH)2 H2O, Ba(OH)2 H2O, Na2CO3 H2O, Ba(OH)2

34 21, 35 36 19 35 19 35 12 19, 35 37 35 19 35 35 12 38

c f g i j n p s t va wb

reaction products prepared according to both procedures are comparable with those attained by the cyanate method. However, the advantage of the latter is that the product precipitates from the reaction mixture, so that one recrystallisation from an appropriate solvent is sufficient to obtain pure products in individual form. The synthesis of ureido acids 1a,j by the reactions of Gly and Leu, respectively, with nitrourea was also documented.39 On the whole, the procedure for the synthesis of ureido acids involving urea is less popular than the cyanate method.

a Lys was used as the staring amino acid; b Trp was used as the staring amino acid.

The reactions can be carried out according to two procedures: either by prolonged (up to 15 h) refluxing of an acidified aqueous solution of the reagents or by heating in the presence of an alkali at 110 ± 140 8C (see Table 2). In both cases, it is necessary to purify ureido acids by repeated recrystallisations. The yields of the

Virtually all ureido acids can be synthesised by the cleavage of the corresponding 5-substituted hydantoins or related compounds. Both chemical and biochemical processes are suitable for this purpose (Table 3). O

O HN O

NH ( )n

R

2a ± c,f,i ± k,m,n,p ± u

HN

H2O

HO2C

( )n

NH2 R

1a ± c,f,i ± k,m,n,p ± u

Alkaline hydrolysis is the simplest method for the cleavage of heterocycles 2. Under these conditions, ureido acids 1a ± c were prepared from the corresponding achiral compounds, viz., hydantoin (2a),40 dihydrouracil (2b) 42 and [1,3]diazepane-2,4-dione (2c),44 and compounds 1f,m,n,s ± u were synthesised from chiral substrates, viz., 5-methylhydantoin (2f),45 5-[2-(methylthio)ethyl]hydantoin (2m),51 2,6-dioxohexahydropyrimidine-4-carboxylic acid (2n),25 5-benzylhydantoin (2s), 5-(4-hydroxybenzyl)hydantoin (2t) 30 and [3-(2,5-dioxoimidazolidin-4-yl)propyl]urea (2u).32 Generally, hydrolysis is performed with aqueous NaOH or Ba(OH)2 on heating. This approach is suitable only for the synthesis of ureido acids in which the chiral carbon atom retains the configuration of the chiral centre of the starting hydantoin. Biochemical cleavage of cyclic compounds 2 under the action of microorganisms or enzymes is the most common and preparative method.

Table 3. Synthesis of ureido acids by decomposition of hydantoins 2. Com- n pounds 1 and 2

R

a

0

b

Chemical method

Biochemical method

reaction conditions

ref.

reaction conditions

ref.

H

H2O, Ba(OH)2, D

40

Pseudomonas sp. AJ-11220, Tris ± HCl buffer (pH 8.5), 30 8C, 2 h

41

1

H

H2O, NaOH, D

42

the same hydantoinase (dihydropyrimidinase EC 3.5.2.2) P. putida DSM 84

41 43

c

2

H

H2O, NaOH

44

7

f

0

Me

0.6 N KOH, 70 8C, 8 h

45

hydantoin-hydrolysing enzyme, ATP, KCl, MgSO4, 0.1 M Tris ± HCl, 30 8C, 20 h anaerobic bacterium P. anaerobius, 50 8C immobilised cells of Agromyces, Chromobacterium or Cellulomonas, glucose, yeast extract, 30 8C, 20 h DL-hydantoinase from Bacillus stearothermophilus NS1122A, phosphate buffer (pH 7.0), 60 8C, 30 min Pseudomonas sp. AJ-11220, Tris ± HCl buffer (pH 8.5), 30 8C, 2 h D-hydantoinase 1, H2O, 50 8C, 22.8 h, pH 8.5

i

0

Pri

7

Pseudomonas sp. AJ-11220, Tris ± HCl buffer (pH 8.5), 30 8C, 2 h D-hydantoinase 2, H2O, 50 8C, 43.7 h, pH 8.5

Hansenula sp. Tris buffer, 32 8C, 24 h hydantoin-hydrolysing enzyme, ATP, KCl, MgSO4, 0.1 M Tris ± HCl, 30 8C, 20 h Bacillus brevis AJ-12299, 0.1 M Tris ± HCl (pH 7), 30 8C, 24 h

46 47 18 48 41 49 41 49 48, 50 46 46

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A N Kravchenko, I E Chikunov

Table 3 (continued). Com- n pounds 1 and 2 j

k

m

0

0

0

R

Chemical method reaction conditions

Bui

Biochemical method ref.

7

Bus

7

C2H4SMe

NaOH, H2O, 80 ± 120 8C,