Imines glycine-derived

Alkylation of imines, glycine derivatives, and Schiif base derivatives... 

Ma and co-workers extended use of chiral guanidine catalysts to the addition of glycine derivatives to acrylates [121], Addition products were achieved in high yield with modest enantioselectivity (Scheme 67). The ferf-butyl glycinate benzophenone imines generally provided better enantiomeric ratios than the ethyl glycinate benzophenone imines. Based on this observation, the authors hypothesized that an imine-catalyst complex determines the stereochemical outcome of the product. 

Corey employed a cinchona alkaloid-derived ammonium salt 5 for the solid-liquid phase transfer catalyst, and attained 99% ee in the addition of a glycine-derived imine to 2-cyclohexenone (Scheme 6) [13,14]. 

Protected glycine derivatives have been used as the nucleophilic partner in enantioselective syntheses of amino acid derivatives by chiral PTC (Scheme 10.9). Loupy and co-workers have reported the addition of diethyl acetylaminomalonate to chalcone without solvent with enan-tioselectivity up to 82% ee [44]. The recent report from the Corey group, with catalyst 8a used in conjunction with the benzophenone imine of glycine t-butyl ester 35, discussed earlier, results in highly enantioselective reactions (91-99% ee) with various Michael acceptors (2-cyclo-hexenone, methyl acrylate, and ethyl vinyl ketone) to yield products 71-73 [21], Other Michael reactions resulting in amino acid products are noted [45]. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

An important issue is the right choice of substrate 1 which functions as an anion precursor. Successful organocatalytic conversions have been reported with indanones and benzophenone imines of glycine derivatives. The latter compounds are, in particular, useful for the synthesis of optically active a-amino acids. Excellent enantioselectivity has been reported for these conversions. In the following text the main achievements in this field of asymmetric organocatalytic nucleophilic substitutions are summarized [1, 2], The related addition of the anions 2 to Michael-acceptors is covered by chapter 4. 

The use of benzophenone imines of glycine derivatives [19] as substrates in enantioselective organocatalytic alkylation has been developed toward an excellent method for preparation of a wide range of optically active a-amino acids with high enantioselectivity [1, 20],... 

Asymmetric synthesis of ot-amino acids.1 This optically active phase-transfer catalyst (1) can effect enantioselective alkylation of the imine (2) derived from glycine. The highest enantioselectivity obtains with the t-butyl ester the lowest with benzylic type esters. Alkylation of 2 results in a mixture of enantiomers, but crystallization of the mixture removes the racemic product and leaves the highly pure optically active amino ester in solution. 

Bagley MC, Brace C, Dale JW, Ohnesorge M, Phillips NG, Xiong X, Bower J (2002) J Chem Soc [Perkin 1] 1663 Belattar A, Saxton JE (1992) J Chem Soc [Perkin 1] 679 Bernardi L, Gothelf AS, Hazell RG, Jprgensen KA (2003) Catalytic asymmetric Mannich reactions of glycine derivatives with imines. A new approach to optically active alpha,beta-diamino acid derivatives. J Org Chem 68 2583-2591... 

O Donnell, M. J. The Preparation of Optically Active a-Amino Acids from the Benzophenone Imines of Glycine Derivatives, Aldrichim. Acta 2001,34, 3-15. 

A few years ago Cahard reported a series of studies on the use of immobilized cinchona alkaloid derivatives in asymmetric reactions with phase-transfer catalysts [17[. Two types of polymer-supported ammonium salts of cinchona alkaloids (types A and B in Scheme 8.4) were prepared from PS, and their activity was evaluated. The enantioselectivity was found to depend heavily on the alkaloid immobilized, with the type B catalysts usually giving better results than the type A catalysts. By performing the reaction in toluene at -50 °C in the presence of an excess of solid cesium hydroxide and 0.1 mol equiv of catalyst 10, benzylation of the tert-butyl glycinate-derived benzophenone imine afforded the expected (S)-product in 67% yield with 94% ee, a value very close to that observed with the nonsupported catalyst. (Scheme 8.4, Equation b) Unfortunately-and again, inexplicably-the pseudoenantiomer of 10 proved to be much less stereoselective, affording the R)-product in only 23% ee. No mention of catalyst recycling was reported [18]. 

The asymmetric alkylation of glycine derivatives constitutes a general means of accessing a wide range of natural and unnatural oc-amino acids.111 Recently it has been established that the quaternary ammonium salt, (lS,2S,4S,5/ ,l / )-l-anthracen-9-yl)methyl-2-[benzyloxy(quinolin-4-yl)methyl]-5-ethyl-l-azoniabicyclo [2.2.2]octane bromide, is a highly effective catalyst in the asymmetric liquid-liquid phase-transfer alkylation of tert-butyl AI-(diphenylmethylene)glycinate. Subsequent hydrolysis of the imine provides access to a wide range of a-amino acid fcrt-butyl... 

Enantiomerically pure aldehydes 287 were obtained by DIBAL reduction of the corresponding o-alanine methyl esters. Coupling with t-butyl glycinate quantitatively gave the ( )-imines 288 (Scheme 85). Peracid oxidation did not allow the isolation of oxaziridines 289 which spontaneously decomposed to give complex mixtures of products [156]. This was probably due to a deprotonation a to the ester group accompanied by cleavage of the weak N-O bond. Imines 290, derived from aldehydes 287 and P-alanine esters, could be indeed oxidised into stable oxaziridines 291 which were isolated as mixtures of two dia-stereoisomers (Scheme 86) [157]. 

In 1957, Schlogl reported the synthesis and characterization of several ferrocene amino acids, including ferrocenylala-nine (Fer, 14 Scheme 18). Other organometallic amino acids include alanine, phenylalanine (Phe), glycine derivatives, as well as further ferrocene-based amino acids, which are discussed below. The Schlogl paper also describes the reaction of ferrocene carboxylic acid and ferrocene carbaldehyde with amino acids. The chemistry was later picked up in numerous publications, and ferrocene carboxylic acid amides or ferrocene imines with basically all amino acids and many dipeptides were reported. Such conju tes may serve as ligands for other transition metal ions. " Kraatz has prepared ferrocene carboxylic acid conju tes with short peptides that serve as enzyme inhibitors. ... 

Catalytic AFC reactions of indoles have attracted considerable attention, and there has been significant progress in this area since 2009. Catalytic AFC reactions of aromatic and heteroaromatic compounds with a-imino esters provide a direct approach to optically pure aryl and heteroaryl glycines. In 2009, You and co-workers realized the AFC reaction of indoles with ethyl glyoxylate imine with 10 mol% of chiral phosphoric acid (S)-13b, affording (3-indolyl)glycine derivatives 28 in excellent yields (85-93%) with up to 87% ee (Scheme 6.11). ... 

Barbas et al. described highly enantio- and diastereoselective organocatalytic Mannich reactions of the glycine-derived Schiff base 63 with in situ generated aromatic A -Boc-protected imines from 64 (Scheme 5.31) [42]. Several thiourea-... 

For other examples of use of chiral phosphoric acid as catalyst in the synthesis of indole derivatives, see (a) Q. Kang, Z.-A. Zhao, S.-L. You, Tetrahedron 2009, 65, 1603-1607. Enantioselective synthesis of (3-indolyl)glycine derivatives via asymmetric Friedel-Crafts reaction between indoles and glyoxylate imines. (b) M. Terada, K. Machioka, K. Sorimachi, Angew. Chem. Int. Ed. 2009, 48, 2553-2556. Activation of hemiaminal ethers by chiral Brpnsted acids for facile access to enantioselective two-carbon homologation using enecarbamates. 

Various glycine-derived imines of camphor and other chiral ketones or aldehydes have been alkylated in a diastereoselective maimer to give nonracemic a-amino acids after the cleavage of the auxiliary [24]. A more recent concept for the alkylation of a glycinamide-derived enolate developed by Dixon and coworkers links the chiral auxiliary to the a-nitrogen atom under the form the tetrahydropy-ran 35, available from camphor in a three-step protocol. Upon deprotonation with LiHMDS, a cis-configured enolate is assumed to form wherein the metal is chelated by the tetrahydropyranyl oxygen atom. The treatment of the enolate... 

Ethyl (bornylideneamino)acetate (2) and the imines of (-)-(lf ,2, 5 )-2-hydroxy-3-pinanone and glycine, alanine and norvaline methyl esters were particularly successful as Michael donors. The chiral azaallyl anions, derived from these imines by deprotonation with lithium diisopropylamide in THF at — 80 C, add to various a,/i-unsaturated esters with modest to high diastereoselectivity (see Section 1.5.2.4.2.2.5.). Thus, starting with the imine 2, (R1 = CH,) and ethyl ( )-2-butcnoate, the a,/i-dialkylated glutamate derivative 3 is obtained as a single diastercomer in 90% yield91-92. 

Diastereoselective preparation of a-alkyl-a-amino acids is also possible using chiral Schiff base nickel(II) complexes of a-amino acids as Michael donors. The synthetic route to glutamic acid derivatives consists of the addition of the nickel(II) complex of the imine derived from (.S )-,V-[2-(phenylcarbonyl)phenyl]-l-benzyl-2-pyrrolidinecarboxamide and glycine to various activated olefins, i.e., 2-propenal, 3-phenyl-2-propenal and a,(f-unsaturated esters93- A... 

More recently, catalytic asymmetric allylations of imines and imine derivatives in aqueous media have been studied. An /V-spiro C2-symmetrical chiral quaternary ammonium salt (5,5)-I-Br (,S, .S )-()-Np-NAS-Br] has been evaluated in the allylation of glycine tert-Bu ester benzophenone Schiff base [Ph2C=NCH2COOCMe3] for synthesis of both natural and unnatural a-amino acids (Eq. 11,45).76... 

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