Amino-esters

Diastereocontrolled conjugate additions of amines to a,B-unsaturated iron acyls where the n -CpFe(CO)(PPh ) moiety directed the addition have been achieved. Addition of the amine occurred away from the bulky phosphine ligand. Oxidative cleavage of the iron moiety allowed preparation of the corresponding esters (and also B-lactams) 

A novel ot-amino-ester synthesis consisted of the reduction of a-hydrazono- (a-azo-) esters, resulting from additions of benzenedia- 

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In the present preparation, ethyl acetoacetate is treated with sufficient nitrous acid to convert half into the a-nitroso (or a-oximino) ester, which is reduced by zinc and acetic acid to the a-amino ester (I). The latter then condenses with... 

The catalytic oxidative carbonylation of allene with PdCb and CuCh in MeOH affords methyl a-methoxymethacrylate (559)[499]. The intramolecular oxidative aminocarbonylation of the 6-aminoallene 560 affords the unsaturated J-amino ester 561. The reaction has been applied to the enantioselective synthesis of pumiliotoxin (562)[500]. A similar intramolecular oxycarbonyla-tion of 6-hydroxyallenes affords 2-(2-tetrahydrofuranyl)acrylates[501]. 

Aqueous ammonia and acryUc esters give tertiary amino esters, which form the corresponding amide upon ammonolysis (34). Modem methods of molecular quantum modelling have been appHed to the reaction pathway and energetics for several nucleophiles in these Michael additions (35,36). 

The intermediates of type (8), wherein G is an electron withdrawing group, which are used in the dyestuffs industry, are usually produced by the user companies themselves and used direcdy. The type (9) amino ester is another product from the SCL range of thiophene derivatives, produced in metric ton quantities for specific outlets. 

The main reaction of this type has been the reductive cyclization of nitropyridine derivatives carrying an o-amino ester or o-aminocarbonyl substituent. These cyclize in situ via the o-diamino derivative to give pyridopyrazines of known constitution, either for establishment of structure of products obtained in the ambiguous Isay synthesis (see Section 2.15.15.6.1), or in the synthesis of aza analogues of biologically active molecules. 

Benzo[b]furan-3-carboxylic acid, 2-amino-esters... 

HONZL RUDINGER Peptide Synthesis Peptide synthesis by coupling ot acyl azides with amino esters... 

In addition, Namazi and coworkers expanded the DHPM core by constructing pyrrolo[3,4-rf pyrimidines via the classical approach. First, DHPM 59 was delivered in 60% yield using the standard Biginelli conditions. 59 was then brominated in high yield to afford 60. Substitution of bromide 60 with methylamine followed by cyclization of the intermediate amino ester furnished pyrrolo[3,4-rf pyrimidine 61 in 53% yield. 

Amino esters (26) have also been shown to yield pyrido[2,3- Z]-pyrimidin-4(3I/)-ones (25, 27) when treated with isocyanates and isothiocyanates. The reactions proceed via intermediate ureido and thioureido derivatives. 

Q, 9/3,9n/3)]-9-(Benzyloxycarbonylamino)-6-oxoperhydropyrido[2,l-Z)][l, 3]thiazine-4-carboxylic acid was obtained from the methyl ester by treatment with 2 N LiOH in MeOH at 0°C for 4.5 h. The carboxyl group was coupled with amino esters. The 9-(benzyloxycarbonylamino) group was deprotected by treatment with a 1 1 mixture of TFA and CH2CI2 at room temperature and the amino group was acylated with an amino acid (97MIP4, 98USP5710129). 

Thus, condensation of isoniazide with acetone at the basic nitrogen gives the corresponding Shiff base (8). Catalytic reduction affords the antidepressant, iproniazid (9). Addition of the same basic nitrogen to methyl acrylate by Michael condensation leads to the 3-amino ester (10). This is converted to the amide, nialamide (11), on heating with benzylamine. 

Carboxylic acid, 161, also serves as starting material for a substituted pyrazine that has proven to be an important diuretic agent. As the first step in the synthesis the acid is converted to the corresponding amide (165). Treatment with a single equivalent of hypobromous acid effects Hoffmann rearrangement of only one of the amide groups. Ethanolysis of the intermediate carbamate leads directly to the amino ester (166). Exposure of the... 

Reduction of the imine with sodium borohydride leads to an intermediate amino-ester that cyclizes spontaneously to the <5-lactam function. Solvolysis of the acetyl group with methoxide followed by acylation of the hydroxyl group thus liberated with trimethoxybenzoyl chloride leads to 38. Bischler-Napieralski cyclodehydration (phosphorus oxychloride) effects closure of the remaining ring. Reduction of the imine thus formed with sodium borohydride gives 39. This, it should be noted, leads to the... 

Hydrogen gas can be replaced by ammonium formate for the reduction of nitro compounds to amines. The ammonium formate method is efficient, and the rapid workup procedure by simple filtratkin makes it widely used for converting the NO to the NH. ° For example, ct-nitro esters are reduced to ct-amino esters in excellent yields on treatment v/ith HCO NH and PdAZ in methanol. ... 

Amides N-bloeked amino aeids Amino esters... 

Likewise, thermolysis of 4-azidophenyl methyl ketone in methanol yields 5-acetyl-2-methoxy-3//-azepine (60%), compared to only an 8% yield from the photolytic reaction.78 119 The thermolysis of phenyl azide in refluxing cyclohexanol yields no 3H-azepine, only diphenyl-diazene (10%) and aniline (30%).74 In contrast, thermolysis of methyl 2-azidobenzoate in cyclohexanol furnishes a mixture of methyl 2-(cyclohexyloxy)-3//-azepine-3-carboxylate (20 % bp 127°C/0.1 Torr) and methyl 2-aminobenzoate (60%). Thermolysis of the azido ester in methanol under nitrogen in an autoclave at 150 C yields a 7 10 mixture (by 1HNMR spectroscopy) of the amino ester and methyl 2-methoxy-3//-azepine-3-carboxylate, which proved to be difficult to separate, and much tar.74 The acidic medium179 is probably responsible for the failure of methyl 2-azidoberjzoate to yield a 3//-azepine when thermolyzed in 3-methoxyphenol aniline (40%) is the major product.74... 

A variety of methods for the asymmetric syntheses of aziridine-2-carboxylates have been developed. They can be generally classified into eight categories based on the key ring-forming transformation and starting materials employed (i) cyclization of hydroxy amino esters, (ii) cyclization of hydroxy azido esters, (iii) cyclization of a-halo- and ot-sulfonyloxy-(3-amino esters, (iv) aziridination of ot, 3-unsaturated esters, (v) aziridination of imines, (vi) aziridination of aldehydes, (vii) 2-carboxylation of aziridines, and (viii) resolution of racemic aziridine-2-carboxylates. 

The earliest method developed for the preparation of nonracemic aziridine-2-car-boxylates was the cyclization of naturally occurring (3-hydroxy-a-amino acid derivatives (serine or threonine) [4]. The (3-hydroxy group is normally activated as a tosyl or mesyl group, which is ideal for an intramolecular SN2 displacement. The cyclization has been developed in both one-pot and stepwise fashion [4—9]. As an example, serine ester 3 (Scheme 3.2) was treated with tosyl chloride in the presence of triethylamine to afford aziridine-2-carboxylate 4 in 71% yield [9]. Cyclization of a-hydroxy- 3-amino esters to aziridine-2-carboxylates under similar conditions has also been described [10]. 

Aziridine-2-carboxylates 12 (Scheme 3.4) have also been prepared from 3-hy-droxy-a-amino esters 9 by treatment with sulfuryl chloride in place of tosyl or mesyl chloride. Treatment of 9 with thionyl chloride in the presence of triethylamine, followed by oxidation of 10 with sodium periodate and a catalytic amount of... 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

Cyclization of a-Halo- and a-Sulfonyloxy- l-amino Esters and Amides... 

Ring-opening of aziridine-2-carboxylates with alcohols has been reported to give (3-alkoxy-a-amino esters [16, 102]. Treatment of as-aziridine 127 (Scheme 3.45) with alcohol in the presence of a catalytic amount of boron trifluoride etherate afforded P-alkoxy-ot-amino esters 128 in 57-100% yields [16,102a], The reaction is both regio- and stereoselective, affording 128 as the only product. 

E)-alkene dipeptide isostere 48, 51, 63 alkenylepoxide 42 alkoxy carbonyl protecting group 32 P-alkoxy-a-amino esters... 

Equiv of the imine 2 is dissolved in the appropriate solvent and 1 cquiv of the silyl ketene acetal 1 is added, the mixture is cooled to —70 °C and 0.1 equiv of TMSTf is added. After 15 h the reaction is quenched with H.O. 10% aq NH40H is added to make the piT basic, and the reaction mixture is extracted with F.tOAc. The crude product (obtained after the usual workup) is subjected to silica gel chromatography (pet. cthcr/Et20) to give the pure /J-amino ester 3. 

The. tytt-selective process [d.r. (syn/anti) >90 10] is rationalized by a C(E,E) type of transition state 5. The diastereofacial selectivity, determined by converting /1-amino esters 3 to /1-lactams 4 and measuring their optical purity, is satisfying (70% ee)29. 

In general, metalated 2-azaallyl anions derived from imines of a-amino esters serve both as Michael donors and as 1,3-dipolar reagents the course of the reaction, as well as the stereochemical outcome depends upon the base and the reaction conditions82,83. 

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