Glycine diastereoselective alkylation

Diastereoselective Alkylation of Glycine Schiff Base with Optically Enriched Alkyl Halides... 

Chiral glycine enolate synthons have been employed in diastereoselective alkylation reactions [15]. A complementary approach to the synthesis of a-amino acids is the electrophilic amination of chiral enolates developed by Evans [16]. Lithium enolates derived from A-acyloxazolidinones 38, reacted readily with DTBAD to produce the hydrazide adducts 39 in excellent yields and diastereoselectivities (Scheme 18). Carboximides 38 were obtained by A-acylation of (S)-4-(phenylmethyl)-2-oxazoli-dinone and the lithium-Z-enolates of 38 were generated at -78 °C in THF under inert atmosphere using a freshly prepared solution of lithium diisopropylamide (LDA, 1.05 equiv.) [17]. 

Scheme 70 Chiral Auxiliaries Used in the Derivatization of Glycine Equivalents and Diastereoselective Alkylation of Chiral A -Alkylidene Amino Acid Derivatives ...

This reaction was first reported by Schollkopf in 1979. It is a synthesis of an unnatural nonproteinogenic amino acid from the lithiated enolate equivalent of a simple amino acid (e.g., glycine, alanine and valine), which involves the diastereoselective alkylation of the lithiated bis-lactim ether of an amino acid with an electrophile or an Aldol Reaction or Michael Addition to an o ,jS-unsaturated molecule and subsequent acidic hydrolysis. Therefore, the intermediate of the bis-lactim ether prepared from corresponding amino acids is generally referred to as the Schollkopf bis-lactim ether, " Schollkopf chiral auxiliary, Schollkopf reagent, or Schollkopf bis-lactim ether chiral auxiliary. Likewise, the Schollkopf bis-lactim ether mediated synthesis of chiral nonproteinogenic amino acid is known as the Schollkopf bis-lactim ether method, Schollkopf bis-lactim method, or Schollkopf methodology. In addition, the reaction between a lithiated Schollkopf bis-lactim ether and an electrophile is termed as the Schollkopf alkylation, while the addition of such lithiated intermediate to an Q ,j8-unsaturated compound is referred to as the Schollkopf-type addition. ... 

Oppolzer s bornane-10,2-sultams have been used by Josien et al. [56] in the synthesis of a series of conformationally restrained arylalanines [for example, (28), Scheme 5.13] as binding probes for the tachykinin NK-1 receptor. Highly diastereoselective alkylation of the chiral glycinate equivalent (29) was followed by sequential acid- and base-catalyzed hydrolysis reaction to yield the unprotected a-amino acid (28). 

In this segment aryl alanines have proven very effective in many cases. The meanwhile classical way to prepare aryl alanines is the diastereoselective alkylation of chiral glycine derivatives e.g. by the methods of Schollkopf [3], Evans [4], Oppolzer [5], Seebach [6] and others. (Fig.4)... 

Schollkopf has developed chiral auxiliaries in order to synthesise ot-amino acids in high enantiopurity via diastereoselective alkylation of masked glycine.Schollkopf reagents 258 are formed by cyclisation of a chiral amino acid 256 with glycine 257 followed by di-O-all lation (Scheme 14.84). 

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... 

Scheme 4 Diastereoselective allylic alkylation with protected glycine...

Chiral a-amino acids The lithium anion of the N-protected glycine amides 3, prepared by reaction of the pyrrolidine with [bis(methylthio)methylene]glycyl pivalic anhydride (DMAP), is alkylated with high diastereoselectivity. The (S)-amino acid (5) is obtained on acid hydrolysis. 

The low reactivity of glycine enolate with unactivated alkyl halides to form a-amino acids could be overcome by stabilizing the nucleophile using m-aminoindanol-derived hippuric acid 53. This key substrate was readily prepared from commercially available azalactone 54 by a one-pot operation (85% yield, 2 steps). The lithium enolate of amide acetonide 53 with a wide range of alkyl halides proceeded in moderate yields (>60%) and excellent diastereoselectivities (>95% de). Assuming that lithium halide would facilitate the dissociation of the amide enolate from the aggregated state and thus enhance its reactivity, 4 equivalents of lithium chloride were used as additive and resulted in a 25% increase in yield (Scheme 24.11). Reactions with secondary halides... 

N-Bis(methylthio)methylene derivatives of amines (iminodithiocarbonates) were first introduced by Hoppe and Beckmann468 for the synthesis of a-amino acids from glycine. The A bis(methylthio)methyleneamines are prepared by reaction of a primary amine with carbon disulfide (HAZARD) in the presence of triethylamine and iodomethane to form a methyl dithiocarbamate derivative, which is then S-alkylated with a second equivalent of iodomethane in the presence of potassium carbonate as the base. Scheme 8,233 illustrates an alternative one pot procedure applied to the synthesis of /erf-butyl N-[bis(methylthio)-methylene]glycinate and its use in diastereoselective conjugate addition under... 

Asymmetric Synthesis of a-Amino Acids. Chiral ketimines prepared from the title ketone and glycinates can be deprotonated and treated with electrophiles, such as alkyl halides (eq 1), or Michael acceptors, to give a-subsdtuted a-amino acids with moderate to excellent levels of diastereoselectivity. 

Alkylation of the Schiff base of glycine with 2-hydroxy-3-pinanone proceeds in an extremely diastereoselective manner. Thus, fluoro-functionalization on the a-carbon of the Schiff base followed by hydrolysis provides fluorinated a-amino acids in a highly enantiomerically enriched form. 2-Fluoroethylation and 2-fluoroallylation of 157 (see Scheme 9.35) and bromodifluoromethylation of 161 (see Scheme 9.36) give the desired adducts 158 and 162, respectively, with excellent diastereoselectivities. Lithium enolate dimer 160 has been proposed as a reactive intermediate for the stereocontrolled alkylation [61]. The adducts 158 and 162 were transformed to 4-fluoro-2-amino acids (>96% ee) 159 [61] and 3,3-difluoroglutamine 164 [62], respectively. 

---