Diastereoselective synthesis glycinates

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

Scheme 16 Diastereoselective synthesis of 2,3-diamino esters and alcohols by the addition of achiral glycine iminoester enolates to chiral M-sulfinylimines...

Ashton, W.T., Dong, H., Sisco, R.M., Doss, G.A., Leiting, B., Patel, R.A., Wu, J.K., Marsilio, F., Thornberry, N.A. and Weber, A.E. (2004) Diastereoselective synthesis and configuration-dependent activity of (3-substituted-cycloalkyl) glycine pyrrolidides and fhiazolidides as dipeptidyl peptidase IV inhibitors. Bioorganic at Medicinal Chemistry Letters, 14, 859-863. 

A diastereoselective synthesis of pyranothiazoles 66 was achieved in a one-pot reaction of the three components glycine, acetic anhydride, and 5-arylidenerhoda-nines 64 by employing MWI under solvent-free conditions. The yields of 66 were 73-86%, compared to 35 3% obtained from conventional heating. The formation of pyranothiazoles 66 occurred through the cyclization of Michael adducts 65... 

Asymmetric synthesis, either enantioselective or diastereoselective, has seldom been performed by photochemical reactions. One of the first examples that may be classified as a photochemical asymmetric synthesis is the photoalkylation of the most simple amino acid, glycine. Elad and Sperling 220) demonstrated that, if glycine is part of a polypeptide chain, there is good control (up to 40 % e.e.) in the creation of the new chiral center. A radical mechanism operates after the first step of photoinitiation of the process. 

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]. 

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. 

Homochiral dihydroimidazoM-one 635 was efficiently oxidized to 2-/< t/-butyl-3-methyl-2,3-dihydroimidazol-4-one A -oxide 636 which adds to functionalized olefins to afford the adducts 637 with high diastereoselectivity (Scheme 151) <20040L1653>. This is an efficient method for the synthesis of chiral glycine analogues 638. 

Other chiral glycine cation equivalents useful for the synthesis of enantiomerically pure a-amino acids are (174) and (175). However, acid-catalyzed reactions of these A/-acyliminium precursors with alkenes or alkynes have not been reported yet. The BF3 Et20-mediated electrophilic aromatic substitution of (175) onto anisole in 98% diastereoselectivity deserves mention here. ... 

Intermediate (5)-l is simply yV-benzyl-4-fluorophenylglycine that has been capped with an ethylene unit. The original synthesis in which 4-fluorophenylacetic acid was transformed to the corresponding chiral oxazolidinone 6 is depicted in Scheme 2. Masked a-azido acid 7 was formed diastereoselectively from this intermediate. Hydrolysis and azide reduction afforded enantiomerically pure (5)-4-fluorophenyl glycine (8). Reductive amination with benzaldehyde introduced the V-benzyl unit and subsequent A, 0-dialkylation with ethylene dibromide provided chiral oxazinone 1. 

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). 

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