Chiral Glycine Research Articles

Asymmetric Synthesis with 6‐tert‐Butyl‐5‐methoxy‐6‐methyl‐3,6‐dihydro‐2H‐1,4‐oxazin‐2‐one as a New Chiral Glycine Equivalent: Preparation of Enantiomerically Pure α‐Tertiary and α‐Quaternary α‐Amino Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric synthesis of (2S,3R)-capreomycidine and the total synthesis of capreomycin IB.

A 27 step total synthesis of the tuberculostatic macrocyclic peptide antibiotic capreomycin IB has been accomplished. The synthesis features the use of an enolate-aldimine condensation between a chiral glycine aluminum enolate and the benzyl imine of 3-tert-butyldimethylsiloxy-propanal as a means of preparing the cyclic guanidine amino acid (2S,3R)-capreomycidine. Additionally, a Hofmann rearrangement was exacted on a late-stage pentapeptide in order to transform an asparagine residue into a diaminopropanoic acid residue.

Synthesis of the Four Stereoisomers of 1‐Amino‐2‐(hydroxymethyl)cyclobutanecarboxylic Acid and Their Biological Evaluation as Ligands for the Glycine Binding Site of the NMDA Receptor

AbstractA synthesis of all four stereoisomers [(1S,2S)‐, (1R,2R)‐, (1S,2R)‐, (1R,2S)‐] of 1‐amino‐2‐(hydroxymethyl)cyclobutanecarboxyclic acid is presented. The synthesis is based on the chiral glycine equivalent 1, employed in both enantiomeric forms. The key step involves the cyclization of the silyl‐protected iodohydrins 5a−d to the corresponding spiro derivatives 6a−d with the aid of the phosphazenic base tBu‐P4. The final compounds were found to display moderate potency as ligands for the glycine binding site of the NMDA receptor. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

A 2,3‐Butanedione Protected Chiral Glycine Equivalent — A New Building Block for the Stereoselective Synthesis of Enantiopure N‐Protected α‐Amino Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

New Approaches to Stereoselective Synthesis of Fluorinated Amino Acids

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chiral Glycine Cation Equivalents: N‐Acyliminium Species Derived from Diketopiperazines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric Synthesis with 6‐tert‐Butyl‐5‐methoxy‐6‐methyl‐3,6‐dihydro‐2H‐1,4‐oxazin‐2‐one as a New Chiral Glycine Equivalent: Preparation of Enantiomerically Pure α‐Tertiary and α‐Quaternary α‐Amino Acids

AbstractThe chiral oxazinone 2 has been developed as a new chiral glycine equivalent for the asymmetric synthesis of mono‐ and disubstituted α‐amino acids. It is derived from the α‐hydroxycarboxylic acid 1, which serves as a chiral auxiliary, and is easily accessible in enantiomerically pure form by optical resolution of the racemic compound (RS)‐1. For alkylation reactions, 2 was deprotonated with sBuLi or phosphazenic base. Subsequent treatment with alkyl halides yielded the monosubstituted compounds 13/14a−c, e, f, (ent)‐13d, (ent)‐14d, while a second alkylation step, via the corresponding enolates, provided the disubstituted compounds 17/18a−d. Both alkylation steps proceeded with good yields and excellent diastereoselectivities (up to 99% de) and even less reactive electrophiles such as isopropyl iodide could be used. The results obtained in this reaction supported the assumption that the enolate of 2, as well as those of the monosubstituted derivatives of 2, have less tendency to form the aggregates that hamper alkylation reactions with other systems with higher oxygen content. From the major diastereomers of both the mono‐ and the disubstituted derivatives of 2 the corresponding α‐amino acids 33a−c and 34a−d were obtained in high enantiomeric purity by hydrolytic cleavage of the oxazinone ring, accomplished either in two steps with aqueous TFA and aqueous NaOH or in one with either aqueous NaOH or 3 N HBr. Alkylation of the enolate ions of (S)‐2 or (R)‐2 with epichlorohydrins as bifunctional electrophiles provided the hydroxymethylenecyclopropyl derivatives 21 and 22. Hydrolysis of 21 and 22 afforded the free amino acids 35 and (ent)‐35. Reductive amination with aniline after oxidation of 21 and 22 to the corresponding aldehydes 24 and 26 provided the compounds 25 and 27, whereas Mitsunobu treatment of 21 and 22 with 1‐phenyl‐3‐(trifluoroacetyl)urea (28) afforded the urea derivatives 29 and 31. Hydrolysis of these compounds yielded the corresponding 1‐aminocylopropanecarboxylic acid derivatives 36/(ent)‐36 and (ent)‐37. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Synthesis of Tag Introducible (3‐Trifluoromethyl)phenyldiazirine Based Photoreactive Phenylalanine.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A 2,3-butanedione protected chiral glycine equivalent—a new building block for the stereoselective synthesis of enantiopure N-protected α-amino acids

A new chiral glycine equivalent 7 has been synthesised from glycidol using a chiral memory protocol, and its use in the synthesis of N-Z protected alpha-amino acids was demonstrated in a series of diasteroselective lithium enolate alkylation reactions and subsequent acid hydrolyses.

From α‐Amino Acids to Peptides: All You Need for the Journey.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Convenient Syntheses of 2‐, 5‐ and 6‐Fluoro‐ and 2,6‐Difluoro‐L‐DOPA.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chiral glycine cation equivalents: N-acyliminium species derived from diketopiperazines

Studies towards a N,N′-bis(p-methoxybenzyl)diketopiperazine asymmetric glycine cation equivalent for the synthesis of homochiral α-amino acids are described. The oxidation of enolate 3 with molecular oxygen provides either a mixture of hydroxylated diketopiperazines 7 and 8 or trione 10 depending upon the reaction conditions. The nucleophilic reduction of trione 10 and the reaction of acetoxy N-acyliminium ion precursors 5 and 6, derived from 7 and 8, with allyltrimethylsilane and boron trifluoride etherate is examined and a model for the stereoselectivity observed in these additions is presented.

Synthesis of C-Linked Glycopyranosyl Serines via a Chiral Glycine Enolate Equivalent

[formula: see text] The stereoselective preparation of C-linked D-gluco- and D-galactopyranosyl L-serines in their alpha and beta forms is herein reported. The syntheses require the conversion of the allyl C-glycopyranosides into their iodoethyl derivatives, which then undergo substitution with the Williams' chiral glycine enolate equivalent. Deprotection and acetylation affords Boc-protected amino acids for peptide synthesis.

Stereoselective route to 15N-labeled-β-deuterated amino acids: synthesis of (2 S,3 R)-[3- 2H, 15N]-phenylalanine

(2 S,3 R)-[3- 2H, 15N]-Phenylalanine hydrochloride was synthesized utilizing 15N-labeled 8-phenylmenthylhippurate as a chiral glycine equivalent. The key step in the synthesis was the alkylation of the glycine template with ( S)-(+)-benzyl-α-d-mesylate. The doubly labeled alkylation product was obtained in 89% yield with 92% de at the α-carbon and 74% de at the β-carbon. The nature of the electrophile employed in the alkylation step significantly affects the stereochemical outcome at the β-carbon. Hydrolysis of the alkylation product under acidic conditions followed by recrystallization from isopropanol yielded the title compound as the hydrochloride salt. Analysis of the (−)-camphanamide derivative of the final product by NMR spectroscopy and HPLC revealed a 76% de at the α-carbon and a 72% de at the β-carbon. The synthetic strategy described represents a simple yet versatile route to chirally deuterated β-methylene unit containing amino acids.

Synthesis of tag introducible (3-Trifluoromethyl)phenyldiazirine based photoreactive phenylalanine

An efficient synthesis of tag introducible (3-trifluoromethyl)phenyldiazirine based phenylalanine derivatives is described. Alkylation of a chiral glycine equivalent with a spacer containing (3-trifluoromethyl)phenyldiazirinyl bromides enables us to create photoreactive l-phenylalanine derivatives. After introduction of biotin at the spacer, the biotinylated and photoreactive amino acid was applied for l-amino acid oxidase and incorporated into a substrate binding site. These compounds will be powerful tools not only for photoaffinity labeling to elucidate properties of bioactive peptides but also as trifunctional photophors to introduce a ligand skeleton.

Metal complex amino acid synthons: syntheses, structures and stereoselective reactions of (iminoacetato)cobalt(iii) complexes

Amino acid anions (AAO−) chelated to cobalt(III) in [(en)2Co(AAO)](O3SCF3)2 (AA = Gly, Sar, Ala and Glu) were selectively oxidized to their imine derivatives by a new general procedure utilizing PBr3 and N-bromosuccinimide in dmf. The new iminoacetato complexes, Λ- and Δ-[(en)2Co(O2CCHNH)](O3SCF3)2, constitute chiral glycine equivalents which can serve as synthons for stereoselective α-amino acid synthesis. In alkaline EtOH, quantitative addition of CH2(COMe)2, CH2(CO2Et)2 or MeCOCH2CO2Et to the imine of the iminoacetate ligand initially produced both diastereomers of the product α-amino acid cobalt(III) complexes. However, subsequent crystallization-induced asymmetric transformations in the heterogeneous reaction mixtures led to better than 90% excess of a single diastereomer after five days, and the diastereopure product triflate salts were obtained after recrystallization. Both enantiomers of isotopically substituted (3-13C, 98%)aspartic acid were produced by facile synthesis from Δ-[(en)2Co(O2CCHNH)](O3SCF3)2 and diethyl (2-13C)malonate. The new N-methyliminoacetato complex, rac-[(en)2Co(O2CCHNMe)](O3SCF3)2, also yielded to imine addition reactions providing a route to the α-N-methylamino acid subclass. The molecular structures of the new imine complexes, Λ-(+)578-[(en)2Co(O2CCHNH)]Br2·H2O and rac-[(en)2Co(O2CCHNMe)]S2O6·1.5H2O, and the diethyl carboxy-aspartate addition product, (ΛS,ΔR)-[(en)2Co{O2CCH(CH(CO2Et)2)NH2}](ClO4)2, were determined by X-ray crystallography.

Convenient syntheses of 2-, 5- and 6-fluoro- and 2,6-difluoro- l-DOPA

Alkylation under phase transfer conditions of the chiral glycine synthon 2 (prepared from the commercially available Oppolzer chiral sultam) with fluorinated analogues of 3,4-dimethoxybenzyl chloride proceeded with high diastereoselectivity. Hydrolysis of the Schiff base, removal of the chiral auxiliary and HBr demethylation produced 2-, 5-, 6-fluoro- and 2,6-difluoro- l-DOPA in e.e. of >99%.

Stereoselective synthesis of L‐[2,3,4,5‐D4] ornithine

AbstractSynthesis of L‐[2,3,4,5‐D4]ornithine in which all of the diastereotopic hydrogens were stereoselectively labeled with deuterium was investigated. The chirally deuterated 3‐aminopropanal derivative, a key intermediate in this synthesis, was prepared by a catalytic deuteration of an unsaturated γ‐lactone derived for L‐glutamic acid followed by several functional group interconversions. Condensation of the obtained deuterium‐labeled 3‐aminopropanal derivative with a chiral glycine template afforded unsaturated ornithine. The dehydroornithine was then subjected to a catalytic deuteration followed by deprotection to give the L‐[2,3,4,5‐D4]ornithine. Copyright © 2002 John Wiley & Sons, Ltd.

Syntheses of four unusual amino acids, constituents of cyclomarin A

The stereoselective syntheses of four unusual amino acids, constituents of cyclomarin A, are described. The protected N-methylhydroxyleucine 2 was synthesized using Evans’ asymmetric azide-transfer reaction. The unusual amino acid 3 was prepared via diastereoselective methylation of the l-aspartic acid derived lactone 13 . The stereoselective formation of threo-β-methoxyphenylalanine 4 was performed via aldol reaction using Schöllkopf's chiral glycine enolate. The synthesis of N-reverse prenylated tryptophane 5 was achieved by the AQN ligand-promoted Sharpless regioreversed asymmetric aminohydroxylation protocol.

The first asymmetric synthesis of (2 S)- and (2 R)-amino-3,3-dimethoxypropanoic acid

The first asymmetric synthesis of (2 S)-, and (2 R)-amino-3,3-dimethoxypropanoic acid (α-formylglycine dimethylacetal) has been achieved in two steps and 91% overall yield. The key step involved the quenching of a chiral glycine titanium enolate with trimethyl orthoformate.