Amino ester derivatives

The addition of phosgene to amino esters, silylated at the nitrogen atom, gives the expected isocyanate derivative [1409]  

In the presence of at least an equimolar amount of NEtj, this reaction was extended to the preparation of Ai-carbonyl-a-amino acid esters derived from a wide variety of amino acids [460], 

The Al,0-silyl derivative shown below is converted into an anhydride on treatment with phosgene [1409]  

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It was first observed that reactions of imines with ketene silyl acetals proceeded smoothly in the presence of 5mol.% Yb(OTf)3 to afford the corresponding /3-amino ester derivatives in moderate yields.50 However, Sc(OTf)3 was found to be a more active catalyst in this reaction. Benzoylhy-drazones also react with ketene silyl acetals in the presence of a catalytic amount of Sc(OTf)3 to afford the corresponding adducts in high yields (Scheme 11).51 In contrast, catalytic activation of benzoylhydrazones by use of a typical Lewis acid such as TiCl4, SnCl4, or BF3-OEt2, etc. is not effective. 

Only limited precedent exists for the stereoselective enolization and subsequent condensation of a-heteroatom-substituted esters 48a and 48b (eq. [29]). Ireland has examined the enolization process for a-amino ester derivatives where the Claisen rearrangement (chair-preferred transition states) was employed to ascertain enolate geometry (Scheme 10) (43). These results imply that 48a [X = N(CH2Ph)2 ] exhibits only modest selectivity for ( )-enoIate formation under the... 

The fourth method also involves a tandem bond-forming strategy of N1-C2 and N4—C5, in which simultaneous formation of both amide bonds of a 2,5-DKP occurs in a one-pot reaction from an a-amino ester derivative. ... 

DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone) conveniently oxidizes ketene silyl acetal (15) to give a-alkoxycarbonyl iminium salt (16)63 Subsequent reaction with nucleophiles gives amino ester derivatives, Nu-CH(NBn2)-C02R. Grignards... 

It was first observed that reactions of imines with ketene silyl acetals proceeded smoothly in the presence of 5 mol % Yb(OTf)3 (a representative lanthanide triflate) to afford the corresponding /3-amino ester derivative in a moderate yield. The yield was improved when Sc(OTf)3, rather than Yb(OTf)3, was used as catalyst (Eq. 3) [10]. Not only silyl enolates derived from esters, but also one derived from a thioester worked well to give the desired /3-amino esters and thioester in high yield. In the reactions of the silyl enolate derived from benzyl propionate, anti adducts were obtained with good selectivity. In addition, the catalyst could be recovered when the reaction was complete, and could be re-used. 

The position, by way of the hydroxy group, has been modified in an attempt to increase the water solubility of benzodiazepines, which are generally highly lipophilic compounds. For example, the amino ester derivative (32) of lorazepam had excellent water sol-... 

The palladium(TI) chloride catalyzed cyclopropanation of racemic /5,y-unsaturated a-amino ester derivative with diazomethane is completely unselective with respect to the exocyclic stereogenic center. One of the diastereomers can be separated and converted into ( )-a-(methylenecyclopropyl)glycine49. 

Mannich-type Reactions. The reactions of imines with ketene silyl acetals proceed smoothly in the presence of Sc(OTf)3 to afford the corresponding /3-amino ester derivative in moderate yield (eq 6). Sc(OTf)3 shows higher activity than Yb(OTf>3 does in this case. The catalyst can be recovered after the reaction is complete and reused. A Mannich-type reaction of IV-(/3-aminoalkyl)benzotriazoles with sUyl enolates has also been developed. Mannich-type reactions of polymer-supported sUyl enol ethers with imines or of polymer-supported a-iminoaceta-tes with silyl enolates are also catalyzed by Sc(OTf)3. 

The 0-protection of A -protected amino acids 55 was achieved by decarboxylative esterification in solvent-free conditions by Colacino et al. (Scheme 4.13). It was found that the use of planetary ball mill was more effective than vibratory mill [8], Commonly used 0-activation reagents (diaUcyl dicarbonate (B0C2O), carbonate (A, A -disuccinimidyl carbonate, DSC), and alkyl chloroformates (ROCOCl, R=Bn, Et, allyl)) were employed in combination with DMAP as base. Reaction parameters had to be optimized for each individual reagent to achieve acceptable yields (selection of results. Table 4.3). Due to high reactivity of benzyloxy chloroformate (Z-Cl), the two-step cycled milling was executed by addition of Z-Cl in 2equiv. portions, so as to consume the chloroformate and reduce the formation of the undesired byproducts. Acidic workup with 10% aqueous citric acid of ether extracts eliminates DMAP and affords the A-protected amino ester derivatives 56 in good yields. 

Jere D, Arote R, Cho MH, Cho CS, Biodegradable poly (/3-amino ester) derivatives for gene and siRNA delivery. In Gustafasson WB (ed.). New Gene Therapy and Cancer Research, Nova Science Publishers Inc., pp. 249-278. 

A few examples of Pd"-catalyzed carboamination reactions between alkyne-tethered amines and aryl halides have also been reported [28d, 47]. For example, treatment of amino ester derivative 50 with Phi in the presence of K2CO3 using Pd(PPh3)4 as catalyst led to the formation of 51 in 80% yield with complete retention of enantiomeric purity (Eq. (1.23)) [28d]. In contrast to the Pd"-catalyzed carboamination... 

Strategy to produce alkyl substituted aminoalkanoic acids, but used p-amino-ester derivatives as precursors. When 5.105 was treated with two equivalents of lithium... 

Genet, Darses, and coworkers reported an interesting enantioselective rhodium-catalyzed 1,4-addition of organotin reagents to electron-deficient a,a -disubstituted alkenes, to afford amino ester derivatives (Scheme 5.18). Indeed, it appeared that their optimized conditions, involving BINAP as the ligand for rhodium and guaiacol, as the proton source worked well for dehydroamino ester derivatives [61]. 

Y. Yu, X. Zhang, and L. Qiu, The anti-tumor efficacy of curcumin when delivered by size/ charge-changing multistage polymeric micelles based on amphiphilic poly(beta-amino ester) derivates. Biomaterials, 35 (10), 3467-79,2014. 

N-phenylazetidinirrm ions react with nudeophilic reagents such as carboxylate anions to form the corresponding amino-ester derivatives. This reaction has been used extensively by the group of Tezuka to produce a large variety of cydic and polycydic polymer stmctures by the so-called dectrostatic sdf assembly - covalent fixation method." ... 

Davis and coworkers have exploited the reactions of chiral JV-sulfinyl-amines in the synthesis of numerous alkaloids. Their route to (—)-epimyr-tine (1098) began with the diastereoselective addition of the enolate anion of methyl acetate to the (Ss)-(4-)-sulfmimine (+)-1128, from which the (Ss,S)-p-amino ester derivative (- -)-1129 was obtained in better than 97% de (Scheme 144). After Claisen condensation of 1129 with ierf-butyl acetate, the sulfmyl group was removed from the resulting P-keto ester (4-)-1130 by treatment with acid, the desuhinylated product then undergoing Mannich cyclization with acetaldehyde. The relative stereochemistry of the sole product, 2,6-a5-disubstituted piperidine (4-)-1131, was corroborated by nOe experiments, which indicated that no epimerization at the stereogenic centers had occurred. After hydrolysis and decarboxylation of... 

Cinchona alkaloids with a thiourea group have also been applied for the asymmetric preparation of amino acid derivatives. Recent examples include an asymmetric Mannich reaction leading to P-amino ester derivatives with a benzoxazole moiety [77] and the formation of P-amino esters with a benzothiazole group [78]. The latter reaction was catalyzed efficiently by a C9 thiourea derivative (26) with a 2,6-dichloro-4-(trifluoromethyl)phenyl group connected to the thiourea group as shown in Scheme 6.34. 

Scheme 11.13 Enantioselective synthesis of a-amino ester derivatives by 50.

Compound 14b catalyzed the aziridination of aliphatic and aromatic a,P-unsaturated aldehydes with similar results to catalyst 14a [15]. Worse results were achieved by using catalyst 14c in the synthesis of terminal N-tosylaziridines [16]. The further oxidation of products 15 allowed the synthesis of chiral p-amino esters derivatives [14—16], whereas their reduction permitted the synthesis of chiral protected amino alcohols [16]. 

The same strategy has been employed successfully for the KR of mono-2- or mono-3-substituted indolines [214] and 2,3-disubstituted indolines [215] using CAL-A or CAL-B (Figure 9.30). Similarly, cyclic a-amino esters derived from the 2,3-dihydroindole and octahydroindole cores have also been resolved successfully using allyl carbonates and CAL-A, attaining excellent selectivity and conversion values [216]. Although less explored, complementary hydrolytic processes have also been reported, as, for instance, Ostaszewski and coworkers used "homemade" animal liver acetone powders for the KR of 2-acetyl-4-phenyl-l,4-dihy-dro-2H-isoquinolin-3-one [217]. 

Davies pioneered a versatile method to prepare chiral /S-amino ester derivatives through diastereoselective conjugate additions of chiral amines onto unsaturated esters [33, 101]. Conjugate addition of lithium amide 103 to acceptor 102 thus afforded an adduct in 82 % yield, and after hydrogenolytic cleavage of the N-benzyl group this provided -amino ester 104 in >98% ee [102]. Such asymmetric amide additions have been demonstrated to have wide substrate scope with respect to the substituents that may be employed on the a,y5-unsaturated esters [33]. 

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