Chiral Glycine Research Articles

Chiral auxiliary-induced asymmetric synthesis of (R)- and (S)-Garner’s aldehydes

This article describes the synthesis of optically pure four N-Boc and N-Cbz-protected (R)- and (S)-isomers of Garner’s aldehyde. The key step involves TiCl4-catalyzed Evans' aldol reaction of the uncommon chiral synthon “glycine enolate equivalent” of N-(N-Boc/Cbz-glycinyl) oxazolidinone with gaseous formaldehyde. The chromatographically separable Evans and non-Evans adduct formation takes place through the installation of hydroxymethyl functionality on chiral glycine enolate in good yields. The orthogonality of the reaction was maintained via the “reverse addition” in the aldol reaction on Evans chiral auxiliary. This method provides a promising opportunity for the synthesis of expensive (R)-Garner’s aldehyde evading the use of unnatural d-serine. Moreover, asymmetric alkylation of Li-enolate of N-(N-Boc-glycinyl) oxazolidinone is a promising opportunity for the formation of an exclusive single isomer of (R)-Garner’s aldehyde.

Synthesis of Antiepileptic Drug (R)-Lacosamide and Chronic Pain Reliever (S)-Lacosamide from Chiral Glycine Enolate Equivalent.

A short enantioselective and azide-free synthesis of antiepileptic drug (R)-lacosamide and pain reliever (S)-lacosamide on a large scale has been articulated from an uncommon chiral synthon "glycine enolate equivalent of 4-benzyl-N-glycinyl oxazolidinone". Evans' asymmetric alkylation using N-(N-Boc-glycinyl) oxazolidinone was standardized to ensure the stereoselective formation of (Z)-enolate for a diastereofacial selection in the C-alkylation process of chiral glycine enolate equivalent with different alkyl halides such as methyl iodide, methoxymethyl chloride, benzyl bromide, p-NO2C6H4CH2Br, allyl bromide, and p-OCH3C6H4CH2Br in the presence of lithium diisopropyl amide at -78 °C in THF. This optimized asymmetric C-alkylation method with methoxymethyl chloride on lithium-mediated (Z)-enolate of (4S/4R)-4-benzyl-N-glycinyl oxazolidinones was extended following other subsequent reactions to produce the final lacosamides with no racemization in ∼36 to 45% overall yields from commercially available 4-benzyl-2-oxazolidinone and N-Boc-glycine.

In Situ Generated DBU⋅HF Acts as a Fluorinating Agent in a Hexafluoroisobutylation Tandem Reaction: An Effective Route to 5,5,5,5’,5’,5’‐Hexafluoroleucine

AbstractWe report the direct incorporation of the hexafluoroisobutyl group on a chiral glycine Schiff base complex mediated by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). The fluoroalkylation involves 2‐(bromomethyl)‐1,1,1,3,3,3‐hexafluoropropane reagent, which generates in situ hexafluoroisobutylene (HFIB), and reacts then with the enolate through a tandem allylic shift/hydrofluorination process. We showed that the use of neutral organic base DBU generates in situ an original DBU⋅HF salt, which preserves the fluoride nucleophilicity and acts as a fluorinating agent. This fluoride salt promotes the hydrofluorination of the pentafluorinated alkene overcoming the usual fluoride β‐elimination observed with α‐CF3‐vinyl reagents. With alkali metal bases, by contrast, the hydrofluorination is disfavored and the pentafluorinated alkene intermediate is obtained predominantly. This study highlights the critical role of the fluoride counter ion to preserve its nucleophilicity. The protocol is amenable to multidecagram scale synthesis of enantiopure (S)‐ and (R)‐5,5,5,5’,5’,5’‐hexafluoroleucine and their N‐Fmoc or N‐Boc derivatives in good overall yield.

A convenient and highly enantioselective synthesis of (S)-2-pipecolic acid: an efficient access to caine anesthetics

A novel and enantioselective synthesis of (S)-2-pipecolic acid (5) has been achieved from Oppolzer’s sultam (1) and ethyl N-(diphenylmethylene)glycinate (2) as readily available starting materials. The highly stereoselective alkylation of chiral glycine intermediate (3) with 1,4-dibromobutane afforded the key backbone of (S)-2-pipecolic acid (5) in one-step that was utilized into the preparation of the local anesthetics mepivacaine, ropivacaine and bupivacaine.

Asymmetric synthesis of (S)-3-methyleneglutamic acid and its N-Fmoc derivative via Michael addition-elimination reaction of chiral glycine Ni (II) complex with enol tosylates.

The use of chiral Ni (II)-complexes of glycine Schiff bases has recently emerged as a leading methodology for asymmetric synthesis of structurally diverse Tailor-Made Amino Acids™, playing a key role in the design of modern pharmaceuticals. Here, we report first example of enantioselective preparation of (S)-3-methyleneglutamic acid and its N-Fmoc derivative via a new type of Michael addition-elimination reaction between chiral nucleophilic glycine equivalent and enol tosylates. This reaction was found to proceed with excellent yield (91%) and diastereoselectivity (>99/1 de) allowing straightforward asymmetric synthesis of (S)-3-methyleneglutamic acid derivatives and analogues. The observed results bode well for general application of this Ni (II) complex approach for preparation and biological studies of this previously unknown type of Tailor-Made Amino Acids™.

Convenient Asymmetric Synthesis of Fmoc-(S)-6,6,6-Trifluoro-Norleucine

In this work we report a convenient asymmetric synthesis of Fmoc-(S)-6,6,6-trifluoro-norleucine via alkylation reaction of chiral glycine equivalent. The target amino acid of 99% enantiomeric purity was prepared with 82.4% total yield (three steps).

ChemInform Abstract: Synthesis of Tryptophans by Alkylation of Chiral Glycine Enolate Equivalents with Quaternary Gramines.

AbstractA general method for the synthesis of enantiopure tryptophan derivatives with good overall yields is developed.

Synthesis of tryptophans by alkylation of chiral glycine enolate equivalents with quaternary gramines

Quaternary gramines were found to be a suitable source of the 3-methylindole fragment for diastereoselective alkylation. The best yields and stereoselectivity were obtained for the alkylation of a chiral William’s morpholinone enolate. Based on this transformation, a general method for the synthesis of enantiopure, indole ring substituted tryptophan derivatives was developed with good overall yields.

Chiral glycine formation on cold interstellar grains by quantum tunneling hydrogen–deuterium substitution reactions

We report experimental evidence that chiral glycine (NH2CHDCOOH) is formed by the surface reaction of normal glycine (NH2CH2COOH) solid with deuterium (D) atom at 12K under the simulative conditions of interstellar molecular clouds. Chiral glycine formation is most likely initiated by the tunneling abstraction reaction of H atom by D atom followed by the addition of D atom to the glycine radical (NH2CHCOOH). Given that chiral glycine can form in such a primordial low-temperature environment, it might source molecular chirality as molecular clouds evolve into planetary systems.

Asymmetric synthesis of α-(1-oxoisoindolin-3-yl)glycine: synthetic and mechanistic challenges.

We report herein that the NaOMe-catalyzed reactions between the chiral glycine Schiff base (S)-4 with 2-cyanobenzaldehyde 3a provide for a convenient preparation of the novel α-(1-oxoisoindolin-3-yl)glycine 1 of high pharmaceutical potential. The reactions involve at least eight synthetic steps and can mechanistically be realized only with application of Ni(II) complexes described in this study.

Asymmetric synthesis of all four stereoisomers of 1-amino-3-hydroxy-cyclopentane-1-carboxylic acid

An asymmetric synthesis of all four stereoisomers of 1-amino-3-hydroxy-cyclopentane-1-carboxylic acid based on a chiral glycine equivalent, oxazinone derivative is presented. The crucial point of the performed reactions is the alkylation of (S)- and (R)-glycine equivalent with the respective stereoisomers of 4-(2-iodoethyl)-1,3,2-dioxathiolan-2-oxide using phosphazenic base t-BuP4.

An approach to the asymmetric synthesis of 18F-labeled analog of l-threo-3,4-dihydroxyphenylserine (6-l-threo-[18F]FDOPS) — a new radiotracer for visualization of norepinephrine transporters by positron emission tomography

An asymmetric synthesis method has been suggested as a feasible approach for the preparation of fluorine-18-labeled (T1/2 110 min) analog of l-threo-3,4-dihydroxyphenylserine, i.e., 6-l-threo-[18F]FDOPS ((2S,3R)-2-amino-3-(2-[18F]fluoro-4,5-dihydroxyphenyl)-3-hydroxypropionic acid), a new radiotracer for the evluation of norepinephrine transporters by positron emission tomography (PET). The approach is based on the condensation reaction of 2-[18F]fluoro-4,5-bis(methoxymethoxy)benzaldehyde with a chiral nickel(II) complex and glycine (Ni-(R)-BPB-Gly) with subsequent removal of protection from hydroxy groups by acid hydrolysis. The radiochemical synthesis includes three steps and can be easily implemented into modern automated modules for the synthesis of radiopharmaceutical agents for PET.

Novel preparation of chiral α-amino acids using the Mitsunobu–Tsunoda reaction

An efficient synthesis of racemic or optically active α-amino acids by modified-Mitsunobu alkylation of a racemic or chiral glycine template from alcohols was developed. Libraries of amino acids were prepared in moderate to good yield with good to high enantioselectivity. This simple method widens the scope for preparation of structurally diverse amino acids.

Totally diastereoselective addition of aryl Grignard reagents to the nitrone-based chiral glycine equivalent MiPNO

The reaction of the chiral nitrone MiPNO (2-isopropyl-2,3-dimethyl-1-oxy-2,3-dihydro-imidazol-4-one) with Grignard reagents is totally diastereoselective. Using simple and functionalized arylmagnesium reagents, enantiopure hydroxylamines were obtained in fair to good yields, which in turn could be easily transformed into new chiral ketonitrones. The preparation of enantiopure l-phenylglycine derivatives is also described.

3-Triphenylphosphonio-2,5-piperazinediones as new chiral glycine cation equivalents

3-Triphenylphosphonio-2,5-piperazinediones were effectively synthesized from homochiral valine or proline via Boc-Val-Gly-OMe, Boc-Pro-Gly-OMe or Cbz-Pro-Gly-OMe. Retention of configuration of the primary stereogenic center of the valine and proline moieties was observed. Diastereoselective nucleophilic substitution of the triphenylphosphonium group in 2,5-piperazinediones with S-, N-, P- and C-nucleophiles was observed. The configuration of the substitution products was assigned either by their hydrolysis and decarboxylation or based on the analysis of the H–C(3)–N–H coupling constants of 3-substituted-2,5-piperazinediones derived from proline. The trans-stereoselectivity was predominant in reactions of 3-triphenylphosphonio-1,6-trimethylene-2,5-piperazinediones with the nucleophiles investigated. The stereodifferentiating ability of the proline moiety is much stronger than that of the valine unit and allowed nucleophilic α-functionalization of the glycine moiety with good to excellent diastereoselectivity.

ChemInform Abstract: Asymmetric Synthesis of (S)- and (R)-(2-2H1)Glycine via Photolysis of Optically Active Chromium Carbene Complexes: A Comparison of Stereoselectivity Between Chromium Ketene Complexes, Ketenes, and Ester Enolates.

(S)- and (R)-[2- 2 H i ]glycine («chiral glycine») were synthesized in good yield with high deuterium incorporation and ee's of 82-86% by two different routes. Photolysis of optically active oxazolidine carbene chromium complexes and lithiation-deuteration of optically active α-oxazolidinone acetic esters were carried out. The stereoselectivities of the reactions of ketenes and chromium-bound ketenes with methanol-d were compared

ChemInform Abstract: Synthesis and N-Methyl-D-aspartate (NMDA) Antagonist Properties of the Enantiomers of α-Amino-5-(phosphonomethyl)(1,1′-biphenyl)-3- propanoic Acid. Use of a New Chiral Glycine Derivative.

ChemInform Abstract: Synthesis and N-Methyl-D-aspartate (NMDA) Antagonist Properties of the Enantiomers of α-Amino-5-(phosphonomethyl)(1,1′-biphenyl)-3- propanoic Acid. Use of a New Chiral Glycine Derivative.

ChemInform Abstract: Studies on Ristocetin A. A Synthesis of Protected Ristomycinic Acid Using Organomanganese Chemistry.

Abstract Aryl ether formation by reaction of phenoxide nucleophiles with chloroarene-Mn(CO)3 cationic complexes, followed by reaction of the aryloxyarene-Mn(CO)3 complex with chiral glycine enolate equivalents, provides methodology for the synthesis of protected ristomycinic acid derivatives in a state of high optical purity.

ChemInform Abstract: Stereoselective Aldol Addition of a Chiral Glycine Enolate Synthon to Heteroaromatic Aldehydes.

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ChemInform Abstract: Asymmetric Syntheses of Unnatural Amino Acids and Hydroxyethylene Peptide Isosteres

Unnatural and naturally occurring nonproteinogenic α-amino acids have become important building blocks for the synthesis of biologically active peptides and peptidomimetic drug molecules. The asymmetric synthesis of α-amino acids has therefore become quite important as an indispensable research tool in academic, government, and industrial laboratories, and methodologies have been reviewed extensively. The established methods for the asymmetric synthesis of amino acids can be divided into roughly six categories (1). (1) The highly stereoselective hydrogenation of chiral, nonracemic dehydro amino acid derivatives or the asymmetric hydrogenation of prochiral dehydro amino acid derivatives. Chiral glycine equivalents serve as useful α-amino acid templates undergoing homologation via carbon-carbon bond formation at the α-position through nucleophilic carbanion alkylation (2) or electrophilic carbocation substitution (3). In addition both nucleophilic amination (4) and electrophilic amination (5) of optically active carbonyl derivatives has very recently been developed. (6) Enzymatic and whole-cell-based syntheses have recently become more attractive in terms of substrate versatility, cost, and scale. All of these methods have their relative strengths and weaknesses; the optimum method for each individual application must still be considered on a case-by-case basis with respect to functionality, quantity desired, cost, and time. The focus of this chapter will illustrate the utility of chiral, nonracemic glycinates which are commercially available and can be manipulated in a variety of ways to access structurally diverse classes of α-amino acids.