An Easy and Fast Conversion of N2-[(tert-Butoxy)carbonyl]-L-amino Acids to Corresponding Amino-aldehydes

A new method for the preparation of N²-[(tert-butoxy)carbonyl]-L -amino-aldehydes from N²-[(tert-butoxy)carbonyl]-L -amino acids based on reduction of mixed anhydrides with LiAl(t-BuO)₃H is described.     

Synthesis and Properties of a 2-Diazohistidine Derivative: A New Photoactivatable Aromatic Amino-Acid Analog

N^α[(tert-Butoxy)carbonyl]-2-diazo-L -histidine methyl ester 1 was synthesized starting from the corresponding L-histidine derivative. The physico-chemical properties of this new photoactivatable amino-acid derivative were established. The synthetic precursor of 1 , 2-amino-L -histidine derivative 3 , was best isolated and characterized as 2-amino-N^α-[(tert-butoxy)carbonyl]-N^τ-tosyl-L -histidine methyl ester ( 4 ). Selective deprotections of 4 (N^α-Boc, N^α-Tos, COOMe) were achieved, thus allowing the use of the corresponding products in peptide synthesis. The optically active dipeptides 8 and 9 were synthesized by coupling 2-amino-N^τ-tosyl-L -histidine methyl ester ( 5 ) with N-[(tert-butoxy)carbonyl]-L -alanine and N^α-[(tert-butoxy)carbonyl]-N^τ-tosyl-L -histidine ( 6 ) with L-alanine methyl ester, respectively. The question of selective diazotization of a 2-aminohistidine residue in a synthetic peptide was studied using competitive diazotizations between 2-amino-1H-imidazole and several amino-acid derivatives susceptible to undergo nitrosylation. The results show that synthetic photoactivatable peptides incorporating a 2-diazohistidine residue might become useful photoaffinity probes.     

Enantioselective Syntheses of α-Amino Acids from 10-(Aminosulfonyl)-2-bornyl Esters and Di(tert-butyl) Azodicarboxylate. Preliminary Communication

Succesive treatment of chiral esters 1 with LiN(i-Pr)₂/Me₃SiCl and di(tert-butyl) azodicarboxylate/TiCl₄/Ti(i-PrO)₄ gave N,N′ -di[(tert-butoxy)carbonyl]hydrazino esters 9 which on deacylation, hydrogenolysis, transesterification, and acidic hydrolysis furnished (2S)-α-amino acids 6 in high enantiomeric purity with efficient recovery of the auxiliary alcohol 7 .     

Regioselective Deprotection and Acylation of Penta-N-Protected Thermopentamine

The synthesis of the penta-N-protected polyamide 1 (tert-butyl N-{9-allyl-16-azido-13-(trifluoroacetyl)-4-[2-(trimethylsilyl)ethylsulfonyl]-4,9,13-triazahexadecyl]carbamate=tert-butyl N-{3-{{4-{allyl{3-[(3-azidopropyl)(trifluoroacetyl)aminopropyl}amino}butyl}{[2-(trimethylsilyl)ethyl]sulfonyl}amino}propyl}carbamate) is described, a derivative of thermopentamine (PA 3433) containing five independently removable amino-protecting groups. The selective deprotection of the five protecting groups used, i.e., of allyl, azido, (tert-butoxy)carbonyl (Boc), trifluoroacetyl, and [2-(trimethylsilyl)ethyl]sulfonyl (SES), as well as the rapid transamidation reaction of the trifluoroacetyl group yielding secondary amides is discussed. Subsequent acylation with 4-methoxycinnamoyl chloride at each N-atom of the pentamine backbone is achieved. For the acylation of the terminal N-atom the azido group is replaced by a (2,2,2-trichloro-1,1-dimethylethoxy)carbonyl (Tcboc) group.     

Versatile Stereoselective Synthesis of Completely Protected Trifunctional α-Methylated α-Amino Acids Starting from Alanine

A new route to completely protected α-methylated α-amino acids starting from alanine is described (see Scheme). These derivatives, which are obtained via base-catalyzed opening of the oxazolidinones (2S,4R)- and (2R,4S)- 2 , can be directly employed in peptide synthesis. The synthesis of both enantiomers of Z-protected α-methylaspartic acid β-(tert-butyl)ester (O⁴-(tert-butyl) hydrogen 2-methylaspartates (R) or (S)- 4a ), α-methyl-glutamic acid γ-(tert-butyl) ester (O⁵-(tert-butyl) hydrogen 2-methylglutamate (R)- or (S)- 4b ), and of N^ε-bis-Boc-protected α-methyllysine (N⁶,N⁶-bis[(tert-butyloxy)carbonyl]-2-methyllysine (R)- or (S)- 4c ) is described in full detail.     

Synthesis of a S-(Carboxymethyl)cysteine Analog of (L-2-Amino-6-adipyl)-L-cysteinyl-D-valine and its Cell Free Biosynthetic Conversion into 6-[2-(D-2-Amino-2-carboxyethyl)thio) acetamido]penicillanic Acid

A new tripeptide (dimer), bis[(L -cysteine-S-acetyl)-L -hemicystinyl(S² → S²)-D -valine] ( 6 ) was synthesized by coupling N-(tert-butoxycarbonyl)-S-carboxymethyl-L -cysteine benzyl ester ( 1 ) with S-trityl-L -cysteinyl-D -valine benzyl ester and subsequent removal of the protecting groups. After reduction of the disulfide, the free tripeptide Cys (CH₂CO-Cys-D -Val) ( Ib ) was used as a substrate of isopenicillin-N synthetase in a cell-free conversion to 6-[2-((D -2-amino-2-carboxyethyl)thio)acetamido]penicillanic acid ( IIa ).     

Regioselective hydrolysis of ketenimines derived from NH-acids and acetylenic esters in the presence of tert -butyl isocyanide under neutral conditions

The regioselective hydrolysis of ketenimines derived from NH-acids, such as 2,2,2-trichloro-N-phenylacetamide or ethyl-2-anilino-2-oxoacetates and acetylenic esters in the presence of tert-butyl isocyanide in a THF/H₂O system (1/1) without any catalysis leads to a diastereomeric mixture of dialkyl 2-[(tert-butylamino)carbonyl]-3-[(2,2,2-trichloroacetyl)anilino]succinates and dialkyl 2-[(tert-butylamino)carbonyl]-3-[2-ethoxy-2-oxoacetyl)anilino]-succinates in good yields. Dynamic NMR effects were observed in the ¹³C NMR spectra of diethyl 2-[(tert-butylamino)carbonyl]-3-[(2,2,2-trichloroacetyl)anilino]succinate as a result of restricted rotation around the N-aryl single bond. The free energy of activation (ΔG ^#) for this process is 37.9 kJ mol⁻¹ which leads to an observable atropisomerism.     

Regioselective hydrolysis of ketenimines derived from NH-acids and acetylenic esters in the presence of <Emphasis Type="Italic">tert</Emphasis>-butyl isocyanide under neutral conditions

The regioselective hydrolysis of ketenimines derived from NH-acids, such as 2,2,2-trichloro-N-phenylacetamide or ethyl-2-anilino-2-oxoacetates and acetylenic esters in the presence of tert-butyl isocyanide in a THF/H₂O system (1/1) without any catalysis leads to a diastereomeric mixture of dialkyl 2-[(tert-butylamino)carbonyl]-3-[(2,2,2-trichloroacetyl)anilino]succinates and dialkyl 2-[(tert-butylamino)carbonyl]-3-[2-ethoxy-2-oxoacetyl)anilino]-succinates in good yields. Dynamic NMR effects were observed in the ¹³C NMR spectra of diethyl 2-[(tert-butylamino)carbonyl]-3-[(2,2,2-trichloroacetyl)anilino]succinate as a result of restricted rotation around the N-aryl single bond. The free energy of activation (ΔG ^#) for this process is 37.9 kJ mol⁻¹ which leads to an observable atropisomerism. Correspondence: Dr. Farough Nasiri PhD, Department of Chemistry, Faculty of Sciences, University of Kurdistan, P.O. Box 66315-416, Sanandaj, Iran.     

A Novel Amination Reaction with Diphenyl Phosphorazidate: Synthesis of α-amino-acid derivatives

The reaction of enolates of α-unsubstituted carboxamides 3 with diphenyl phosphorazidate (DPPA) and di(tert-butyl) dicarbonate (‘Boc anhydride’) in THF at ?78° yielded 2-{[(tert-butoxy)carbonyl]amino}carboxamides 5 (Scheme 2) which are derivatives of α-amino acids. In this reaction, DPPA acts as an electrophilic amination reagent. A reaction mechanism is proposed in Scheme 3.     

N-Acylureas in Peptide Synthesis: An X-Ray Diffraction and IR-Absorption Study

An X-ray diffraction analysts of two N-acyl derivatives of symmetrical dialkylureas, N-[N^α-(benzyloxycarbonyl)-L -valyl] -N, N′-diisopropylurea ( 1 ) and N-{Nα(tert-butyloxy)carbonyl -L -valyl}-N-N′-dicyclohexylurea ( 2 ), and one N-acyl derivative of an unsymmetrical N-N′-dialkylurea, N-[N^α-(benzyloxycarbonyl)-L -valyl] -N′-(tert-butyl)-N-ethylurea ( 3 ), has been performed. It was established that it is the least hindered O-acylisourca N-atom that attacks intramolecularly the carbonyl group of the N^α-protected amino acid activated by the unsymmetrical carbodiimide to form the major rearrangement product. The occurrence and nature of intra- and intermolecularly H? bonded forms of the N-acylureas in the crystal state were also assessed. It was also shown that soluble N-acylureas may compete with intermolecular (peptide)N? H…O?C(peptide) H-bonds in CH₂Cl₂.     

Collagen cross-links: a convenient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl)butanoate

An efficient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl) butanoate (5), the key intermediate for preparation of collagen cross-links (+)-pyridinoline (Pyd, 1) and (+)-deoxypyridinoline (Dpd, 2) was described from (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (6) in six steps. Also, an improved synthesis of iodide (2S)-(−)-4b was presented.     

Synthesis of a New,Highly Fluorescent Amino Acid Derivative: N‐[(tert‐Butoxy)carbonyl]‐3‐[2‐(1H‐indol‐3‐yl)benzoxazol‐5‐yl]‐L‐alanine Methyl Ester

A simple method of synthesis of a new, highly fluorescent amino acid derivative from the simple and generally available substrates 3‐nitro‐L ‐tyrosine and 1H‐indole‐3‐carbaldehyde is described. The obtained compound, N‐[(tert‐butoxy)carbonyl]‐3‐[2‐(1H‐indol‐3‐yl)benzoxazol‐5‐yl]‐L ‐alanine methyl ester ( 4 ), possesses a high fluorescence quantum yield. The described method illustrates a new possibility of synthesis of amino acid derivatives possessing desirable photophysical properties.     

First asymmetric synthesis of a C2-symmetric 2-endo,6-endo-disubstituted bispidine

The enantioselective synthesis of a C₂-symmetric 2-endo,6-endo-disubstituted bispidine (3,7-diazabicyclo[3.3.1]nonane) has been accomplished for the first time. The key step was a Michael addition of the protected β-amino ester methyl (R)-3-{N-benzyl-N-[(S)-1-phenylethyl]amino}-3-phenylpropionate to its α-methylene derivative delivering an anti,anti-configured α,α′-methylene-bridged bis(β-amino ester) as the major diastereomer. Deprotection, reduction and cyclisation furnished (1R,2R,5R,6R)-2,6-diphenyl-3,7-bis((S)-1-phenylethyl)-3,7-diazabicyclo[3.3.1]nonane in six steps and 15% overall yield.     

Enantioselective Syntheses of Conformationally Rigid,Highly Lipophilic Mesityl‐Substituted Amino Acids

Three N‐Boc‐protected amino acids substituted with a mesityl (=2,4,6‐trimethylphenyl) group were synthesized in enantiomerically pure form, either by asymmetric epoxidation or by aminohydroxylation as the source of chirality. The 3‐mesityloxirane‐2‐methanol 7 , easily available in high enantiomer purity by Sharpless epoxidation, was converted into 3‐{[(tert‐butoxy)carbonyl]amino}‐3‐mesitylpropane‐1,2‐diol 9 by a regio‐ and stereoselective ring opening with an ammonia equivalent (sodium azide or benzhydrylamine), followed by hydrogenation and in situ treatment with (Boc)₂O (Boc=[(tert‐butoxy)carbonyl]) (Scheme 3). Oxidative cleavage of the diol fragment in 9 afforded N‐[(tert‐butoxy)carbonyl]‐α‐mesitylglycine 1 of >99% ee. This amino acid was also prepared in enantiomerically pure form starting from 2,4,6‐trimethylstyrene ( 11 ) by a regioselective Sharpless asymmetric aminohydroxylation, followed by a 2,2,6,6‐tetramethylpiperidin‐1‐yloxyl (TEMPO)‐catalyzed oxidation (Scheme 4). On the other hand, 1‐[(tert‐butoxy)carbonyl]‐2‐{{[(tert‐butyl)dimethylsilyl]oxy}methyl}‐3‐mesitylaziridine 14 was prepared from 9 by a sequence involving selective protection of the primary alcohol (as a silyl ether), activation of the secondary alcohol as a mesylate, and base‐induced (NaH) cyclization (Scheme 5). The reductive cleavage of the aziridine ring (H₂, Pd/C), followed by alcohol deprotection (Bu₄NF/THF) and oxidation (pyridinium dichromate (PDC)/DMF or (TEMPO)/NaClO) provided, in high yield and enantiomeric purity, N‐[(tert‐butoxy)carbonyl]‐β‐mesitylalanine 2 . Alternatively, the regioselective ring opening of the aziridine ring of 14 with lithium dimethylcuprate, followed by silyl‐ether cleavage and oxidation lead to N‐[(tert‐butoxy)carbonyl]‐β‐mesityl‐β‐methylalanine 3 . A conformational study of the methyl esters of the N‐Boc‐protected amino acids 1 and 3 carried out by variable‐temperature ¹H‐NMR and semi‐empirical (AM1) calculations shows the strong rotational restriction imposed by the mesityl group.     

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.     

Novel synthesis of 1,4-thiazin-2-one O-(tert-butyl) oximes and benzo[b][1,4]thiazin-2-one O-(tert-butyl) oximes in the presence of K2CO3/SiO2

A simple and efficient method was developed for the synthesis of 1,4-thiazin-2-one O-(tert-butyl) oximes and benzo[b][1,4]thiazin-2-one O-(tert-butyl) oximes from N-tert-butoxy acyl imidoyl bromides and 2-aminothiols in the presence of K₂CO₃/SiO₂. Twenty five novel compounds were readily synthesized in excellent yields using this procedure. The products possessed Z-stereochemistry with regard to the CN double bond. The reaction proceeded with initial substitution of bromine in the N-tert-butoxy acyl imidoyl bromides by mercapto groups in the presence of K₂CO₃/SiO₂, and subsequent intramolecular Schiff base formation.     

Four oxoindole‐linked α‐alkoxy‐β‐amino acid derivatives

Four structures of oxoindolyl α‐hydroxy‐β‐amino acid derivatives, namely, methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐methoxy‐2‐phenylacetate, C₂₄H₂₈N₂O₆, (I), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐ethoxy‐2‐phenylacetate, C₂₅H₃₀N₂O₆, (II), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐[(4‐methoxybenzyl)oxy]‐2‐phenylacetate, C₃₁H₃₄N₂O₇, (III), and methyl 2‐[(anthracen‐9‐yl)methoxy]‐2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐phenylacetate, C₃₈H₃₆N₂O₆, (IV), have been determined. The diastereoselectivity of the chemical reaction involving α‐diazoesters and isatin imines in the presence of benzyl alcohol is confirmed through the relative configuration of the two stereogenic centres. In esters (I) and (III), the amide group adopts an anti conformation, whereas the conformation is syn in esters (II) and (IV). Nevertheless, the amide group forms intramolecular N—H...O hydrogen bonds with the ester and ether O atoms in all four structures. The ether‐linked substituents are in the extended conformation in all four structures. Ester (II) is dominated by intermolecular N—H...O hydrogen‐bond interactions. In contrast, the remaining three structures are sustained by C—H...O hydrogen‐bond interactions.     

2,5-Chinonmethide des 1,6-Methano[10]annulens mit S,N- und N,N-Acylketenacetal Struktur

2,5-Quinonemethides of 1,6-Methano[10]annulene with the Structures of S,N- and N,N-Acylketene Acetals Investigation on the chemical reactivities of 2-(tert -butoxy)-1,6-methano[10]annulene and the syntheses of the compounds 2, 4, 6–8, 11, 13–22 are described; the results of ¹H- and ¹³C-NMR-spectroscopic measurements are reported.     

A Convenient Synthesis of Vinyl Sulfides

tert-Alkyl sulfides, with an α-(1H-benzotriazol-1-yl) group 6 and 13 , are readily prepared from N-[(aryl-thio)methyl]-1H-benzotriazoles 3 and N-( 11 ), respectively, by reaction with BuLi and then with the appropriate electrophile. The tert-alkyl sulfides 6 and 13 are smoothly converted by BF₃. OEt₂ into vinyl sulfides 5, 7 or 12 , respectively, in satisfactory yields.     

Convenient preparation of highly active phase-transfer catalyst for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

A highly active phase-transfer catalyst was conveniently prepared from the known, easily available (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyldicarboxylic acid. This catalyst exhibited the high catalytic performance (0.01-1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer catalysts, thereby allowing to realize a general and useful procedure for highly practical enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids.