Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids

A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield.     

Asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to the requisite (E)-α,β-unsaturated ester followed by in situ enolate oxidation with (?)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti-α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO₃-mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn-α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti-α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.     

Synergistic Cu/Pd-Catalyzed Asymmetric Allenylic Alkylation of Azomethine Ylides for the Construction of α-Allene-Substituted Nonproteinogenic α-Amino Acids

An unprecedented asymmetric allenylic alkylation of readily available imine esters, which was enabled by a synergistic Cu/Pd catalysis, has been developed. This dual catalytic system possesses good substrate compatibility, delivering a diverse array of nonproteinogenic α-allenylic α-mono- or α,α-disubstituted α-amino acids (α-AAs) with high yields and generally excellent enantioselectivities. Furthermore, the scalability and practicability of the current synthetic protocol were proven by performing gram-scale reactions and by the first catalytic asymmetric synthesis of naturally occurring (S)-γ-allenic α-amino acid, respectively.     

N-Boc-Protected α-Amino Acids by 1,3-Migratory Nitrene C(sp3)−H Insertion

N-Boc-protected α-amino acids are synthesized in two steps from linear or branched carboxylic acid feedstocks. In the first step, the carboxylic acid is coupled with tert-butyl aminocarbonate (BocNHOH) to generate azanyl ester (acyloxycarbamate) RCO₂NHBoc. In the second step, this azanyl ester undergoes a stereocontrolled iron-catalyzed 1,3-nitrogen migration to generate the N-Boc-protected non-racemic α-amino acid. This straightforward protocol is applicable to the catalytic asymmetric synthesis of α-monosubstituted α-amino acids with aryl, alkenyl, and alkyl side chains. Furthermore, α,α-disubstituted α-amino acids are accessible in an enantioconvergent fashion from racemic carboxylic acids. The new method is also advantageous for the synthesis of α-deuterated α-amino acids. N-Boc-protected α-amino acids synthesized using this two-step protocol are ready-to-use building blocks.     

Nucleophile Ringöffnung von α-Nitrocyclopropancarbonsäure-arylestern mit sterisch geschützter,aber elektronisch wirksamer Carbonyl- und Nitro-Gruppe. Ein neues Prinzip der α-Aminosäure-Synthese (2-Aminobutansäure-a4-Synthon)

Nucleophilic Ring Opening of Aryl α-Nitrocyclopropanecarboxylates with Sterically Protected but Electronically Effective Carbonyl and Nitro Group. A New Principle of α-Amino Acid Synthesis (2-Aminobutanoic Acid a⁴-Synthon) The readily available 2,4,6-tri(tert-butyl)-and 2,6-di(tert-butyl)-4-methoxypahenol esters 2 of α-nitrocyclo-propanecarboxaylic acid ring opening with C-, N-, O-, and S-nucleophiles (cyanide, malonate, azide, anilines, alkoxides, phenoxides, thiolates) in DMF or alcohol solvents (80–95% yield). The products 6 – 14 are 2-nitrobutanoates with the newly introduced substituent in the 4-position. Reduction of the NO₂ group with Zn/AcOH/Ac₂O gives N-acetyl-α-amino acid esters 16 – 22 (40–90% yield). Subsequent oxidative cleavage (H₂O₂/HCOOH) of The p-methoxy-phenyl esters 18 and 20 produces free amino acids (65% 23 and 67% 24 , respectively). Thus, the nitro ester 2 corresponds to a 2-aminobutanoic-acid a⁴-synthon, it is a ‘homo-Michael acceptor’ producing γ-substituted α-amino acids.     

Asymmetric synthesis of α- and β-amino acids by diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)imines

The diastereoselective addition of triorganozincates to (R)-N-(tert-butanesulfinyl)imines has been used as a key step to achieve the synthesis of highly enantiomerically enriched N-protected α- and β-amino acids. Desulfinylation of the addition products followed by benzoylation of the nitrogen atom of the obtained primary amines and oxidation of one of the substituents on the carbon atom connected to the nitrogen complete the sequence. Using the same configuration in the sulfinyl chiral auxiliary, α-amino acids with the (R) or the (S) configuration can be prepared by choosing the proper combination of imine and organozincate. α,α-Disubstituted α-amino esters with high enantiomeric purity can also be prepared when α-imino esters are the starting substrates.     

Application of the addition of triorganozincates to N-(tert-butanesulfinyl)imines to the enantioselective synthesis of α-amino acids

Highly enantiomerically enriched N-protected α-amino acids can be easily prepared from optically pure N-(tert-butanesulfinyl)imines by a four-step sequence involving: diastereoselective addition of a triorganozincate to the imine, removal of the sulfinyl group, benzoylation of the nitrogen atom of the obtained primary amine and oxidation of one of the substituents on the carbon atom α to the nitrogen. Using the same configuration in the sulfinyl chiral auxiliary, amino acids with the (R) or the (S) configuration can be prepared by choosing the proper combination of imine and organozincate. α,α-Disubstituted α-amino esters with high optical purity can also be prepared by the diastereoselective addition of trialkylzincates to α-imino esters.     

Trading N and O. Part 2: Exploiting aziridinium intermediates for the synthesis of β-hydroxy-α-amino acids

The β-hydroxy-α-amino acids (S,S)-allo-threonine, (S,S)-β-hydroxyleucine and a range of aryl substituted (S,S)-β-hydroxyphenylalanines were prepared from the corresponding enantiopure anti-α-hydroxy-β-amino esters via a rearrangement protocol, which proceeds via the intermediacy of the corresponding aziridinium ions. The starting anti-α-hydroxy-β-amino esters were prepared in >99:1 dr using our diastereoselective aminohydroxylation procedure, whereby conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester is followed by oxidation of the resultant enolate with (−)-camphorsulfonyloxaziridine. Subsequent activation of the hydroxyl group within the anti-α-hydroxy-β-amino esters promoted aziridinium ion formation [which proceeds with inversion of configuration at C(2)], and regioselective ring-opening of the intermediate aziridinium ions with H₂O [which proceeds with inversion of configuration at C(3)] gave the corresponding anti-β-hydroxy-α-amino esters as single diastereoisomers (>99:1 dr). Deprotection of these substrates via sequential hydrogenolysis and ester hydrolysis gave the corresponding β-hydroxy-α-amino acids in good yield and high diastereoisomeric and enantiomeric purity.     

3-Amino-2H-Azirines. Synthons for α,α-Disubstituted α-Amino Acids in Heterocycle and Peptide Synthesis [New Analytical Methods (43)]

The recent upswing in peptide chemistry has been accompanied by an increasing interest in nonproteinogenic amino acids. These include the α,α-disubstituted glycines, the best known of which is Aib (2-aminoisobutyric acid, 2-methylalanine). These α-amino acids occur in natural oligopeptides such as the peptaibols, a class of membrane-active ionophores that has been isolated from fungal cultures. The twofold substitution at the α-C atom of the amino acids severely restricts the conformational freedom of the peptides and causes particular secondary structures to be favored; thus, α, α-disubstituted α-amino acids induce the formation of β turns or helices. 3-Amino-2H-azirines are ideal synthons for the construction of oligopeptides, cyclic peptides and depsipeptides (peptolides) containing such α,α-disubstituted α-amino acids. The presence of the ring strain in these molecules means that they can be used in peptide coupling without the need for additional activating reagents. Using 3-amino-2H-azirines a large array of heterocycles containing α, α-disubstituted α-amino acids as structural elements within their skeleton can be synthesized. The driving force in these reactions is the release of the strain on the three-membered ring, which usually takes place in a ring-expansion reaction. The mechanistic elucidation of these reactions, which can be quite complex, contains some surprises.     

2-Benzoyl-2-ethoxycarbonylvinyl-1 and 2-benzoylamino-2-methoxy-carbonylvinyl-1 as N-protecting groups in peptide synthesis. Their application in the synthesis of dehydropeptide derivatives containing N-terminal 3-heteroarylamino-2,3-dehydroalanine

Ethyl 2-benzoyl-3-dimethylaminopropenoate ( 6 ) and methyl 2-benzoylamino-3-dimethylaminopropenoate ( 46 ) were used as reagents for the protection of the amino group with 2-benzoyl-2-ethoxycarbonylvinyl-1 and 2-benzoylamino-2-methoxycarbonylvinyl groups in the peptide synthesis. Reactions of ethyl 2-benzoyl-3-dimethylaminopropenoate (6) with α-amino acids gave N-(2-benzoyl-2-ethoxycarbonylvinyl-1)-α-amino acids 13–19. These were coupled with various amino acid esters to form N-(2-benzoyl-2-ethoxycar-bonylvinyl-1)-protected dipeptide esters 20–31. The removal of 2-benzoyl-2-ethoxycarbonylvinyl-1 group, which was achieved by hydrazine monohydrochloride or hydroxylamine hydrochloride, afforded hydrochlo-rides of dipeptide esters 32–41 in high yields. Similarly, the substitution of the dimethylamino group in methyl 2-benzoylamino-3-dimethylaminopropenoate ( 46 ) by glycine gave N-(2-benzoylamino-2-methoxycar-bonylvinyl-1)glycine ( 47 ), which was coupled with glycine ethyl ester to give N-[N-(2-benzoylamino-2-methoxycarbonylvinyl-1)glycyl]glycine ethyl ester ( 48 ). Treatment of 48 with 2-arnino-4,6-dirnethylpyrimi-dine afforded N-[glycyl]glycine ethyl ester hydrochloride (34) in high yield. Amino acid esters and dipeptide esters were employed in the preparation of tri- 58-70, tetra- 71–82, and pentapeptide esters 83–85 containing N-terminal 3-heteroarylamino-2,3-dehydroalanine. 2-Chloro-4,6-dimethoxy-1,3,5-triazine was employed as a coupling reagent for the preparation of peptides 58–85.     

A concise synthesis of glycosyl-α-amino acid derivatives via homologation of dialdoses into bromo uronic acids and esters

The synthesis of the compounds of the title involves three steps from dialdoses. The reaction between potassium dibromoacetonitrile carbanion and protected dialdoses provides corresponding β-bromo-α-ketonitriles that are easily transformed into α-bromo esters by treatment with methanol or isopropanol or α-bromo acids by treatment with t-BuOH. Substitution of the bromine by sodium azide onto these last compounds and subsequent catalytic hydrogenation of the azide group afford the targeted glycosyl-α-amino acid derivatives. This methodology represents the most rapid access to the key α-amino acid moiety of polyoxins.     

α-Amino Acids: An Emerging Versatile Synthon in Visible Light-Driven Decarboxylative Transformations

α-Amino acids have been widely recognized as environmental-benign and non-fossil carbon sources both in biological and synthetic chemistry. In recent years, with the remarkable development of visible-light photocatalysis in organic synthesis, α-amino acid and its derivatives have received tremendous attention as radical precursors via photocatalyzed decarboxylation, thus realizing diverse aminoalkylated transformations or constructions of novel N-bearing heterocyclic motifs by taking advantage of N-atoms from α-amino acid. This review aims to provide a comprehensive update on the recent exploitation of α-amino acids in visible light photocatalysis, with particular emphasis on the types of α-amino acids employed and their distinct mechanisms applied wherein.     

α-Alkylation of Amino Acids without Racemization. Preparation of Either (S)- or (R)-α-Methyldopa from (S)-Alanine

Enantiomerically pure cis- and trans-5-alkyl-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin-4-ones ( 1, 2, 11, 15, 16 ) and trans-2-(tert-butyl)-3-methyl-5-phenylimidazolidin-4-one ( 20 ), readily available from (S)-alanine, (S)-valine, (S)-methionine, and (R)-phenylglycine are deprotonated to chiral enolates (cf. 3, 4, 12, 21 ). Diastereoselective alkylation of these enolates to 5,5-dialkyl- or 5-alkyl-5-arylimidazolidinones ( 5, 6, 9, 10, 13a-d, 17, 18, 22 ) and hydrolysis give α-alkyl-α-amino acids such as (R)- and (S)-α-methyldopa ( 7 and 8a , resp.), (S)-α-methylvaline ( 14 ), and (R)-α-methyl-methionine ( 19 ). The configuration of the products is proved by chemical correlation and by NOE ¹H-NMR measurements (see 23, 24 ). In the overall process, a simple, enantiomerically pure α-amino acid can be α-alkylated with retention or with inversion of configuration through pivaladehyde acetal derivatives. Since no chiral auxiliary is required, the process is coined ‘self-reproduction of a center of chirality’. The method is compared with other α-alkylations of amino acids occurring without racemization. The importance of enantiomerically pure, α-branched α-amino acids as synthetic intermediates and for the preparation of biologically active compounds is discussed.     

Design of Chiral β-Double Helices from γ-Peptide Foldamers

Chirality is ubiquitous in nature, and homochirality is manifested in many biomolecules. Although β-double helices are rare in peptides and proteins, they consist of alternating L- and D-amino acids. No peptide double helices with homochiral amino acids have been observed. Here, we report chiral β-double helices constructed from γ-peptides consisting of alternating achiral (E)-α,β-unsaturated 4,4-dimethyl γ-amino acids and chiral (E)-α,β-unsaturated γ-amino acids in both single crystals and in solution. The two independent strands of the same peptide intertwine to form a β-double helix structure, and it is stabilized by inter-strand hydrogen bonds. The peptides with chiral (E)-α,β-unsaturated γ-amino acids derived from α-L-amino acids adopt a (P)-β-double helix, whereas peptides consisting of (E)-α,β-unsaturated γ-amino acids derived from α-D-amino acids adopt an (M)-β-double helix conformation. The circular dichroism (CD) signature of the (P) and (M)-β-double helices and the stability of these peptides at higher temperatures were examined. Furthermore, ion transport studies suggested that these peptides transport ions across membranes. Even though the structural analogy suggests that these new β-double helices are structurally different from those of the α-peptide β-double helices, they retain ion transport activity. The results reported here may open new avenues in the design of functional foldamers.     

Oxidations of some α-amino acids under mitsunobu reaction conditions

Reactions of α-amino acids with azodicarboxylates and Ph₃P results in oxidation at the α-carbon. N-acyl or carbamoyl amino acid esters give azodicarobxylate adducts, whereas free α-amino acid esters are converted to the corresponding α-keto esters.     

A new method for the preparation of functionalized unnatural α-H-α-amino acid derivatives

A new method for the preparation of α-H-α-amino acids is reported based on the α-alkylation of iminoacetic acid esters or amides. These imines are readily available by the reaction of glyoxylic acid esters with branched primary amines. The subsequent reaction with methanolic ammonia gave the corresponding iminoacetic acid amides. α-Alkylation of these imines with various electrophiles under basic conditions, followed by an acidic hydrolysis, gave α-amino acids, esters, or amides in up to 93% yield. α-Alkylation under chiral PTC conditions resulted in mono-alkylated amino acids with 90% ee.     

HBTU Mediated Synthesis of α,β-Unsaturated γ-Lactams from E-α,β-Unsaturated γ-Amino Acids

The α,β-unsaturated γ-lactams have been found in many biologically active peptide natural products. Due to their biological activities, extensive efforts have been made in the literature to synthesize the α,β-unsaturated γ-lactams. Here, we are reporting the spontaneous transformation of E-α,β-unsaturated γ-amino acids into α,β-unsaturated γ-lactam through in-situ activation of free carboxylic acid using peptide coupling reagent HBTU and base DIPEA at room temperature. The transformation also involves the E→Z isomerization of α,β-unsaturated γ-amino acids. The reaction is also compatible with the peptides consisting of E-α,β-unsaturated amino acids at the C-terminus. The α,β-unsaturated γ-lactams were isolated in very good yields. Even though the reaction required very mild conditions, the products were isolated in the form of a racemic mixture. However, the products can be separated under a chiral environment. No α,β-unsaturated γ-lactams were observed if the reaction was performed in the presence of free amines. In addition, no racemization was observed during the peptide synthesis. The analysis of the reactions of various substrates revealed that amide NH and γ-CH are important for lactamization. No α,β-unsaturated γ-lactams or E→Z isomerization products were observed in the case of N-Me-(E)-α,β-unsaturated γ-amino acids, whereas in the case of E-α,β-unsaturated γ,γ-dimethyl amino acid α,β-unsaturated γ-lactam was isolated, however, with low yield.     

Enantioselective synthesis of α-fluoro-β(3)-amino esters: synthesis of enantiopure, orthogonally protected α-fluoro-β(3)-lysine

The scope of a tandem conjugate addition-fluorination sequence performed on α,β-unsaturated esters using the enantiopure lithium amide derived from (S)-N-benzyl-N-(α-methylbenzyl)amine, and the electrophilic fluorinating agent N-fluorobenzenesulfonimide has been investigated. Using this method, α-fluoro-β(3)-amino esters can be obtained in up to quantitative yield and 80:20 to >99:1 dr. This simple methodology does not rely on the use of α-amino acids from the chiral pool and thus provides the potential for the preparation of enantiopure α-fluoro-β(3)-amino acids with a wide variety of side chains. Its utility was demonstrated through the synthesis of orthogonally protected (2S,3S)-α-fluoro-β(3)-lysine.     

N-Hydroxymethyl derivatives of α-amino aldehydes used for the stereoselective syntheses of β-amino-α-hydroxy acids

The N-hydroxymethyl derivatives of α-amino aldehydes 1 were utilized for the effective synthesis of several β-amino-α-hydroxy acid derivatives in a one-pot process starting from the corresponding α-amino aldehydes. Properly protected methyl esters 3 were prepared in 65–79% yields from α-amino aldehyde derivatives 1 with more than 20:1 stereoselectivity. The application of suitably protected β-amino-α-hydroxy esters was shown by an efficient synthesis of the bioactive peptide, bestatin, and its more potent analogue, AHPBA-Val, in high yields from ent-3a.