A novel synthesis of cyclic α-amino aldehydes, amino alcohols, and α-amino acid methyl esters from cyclic ketones through sulfinylaziridines

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps in good yields, with N-lithio arylamines gave sulfinylaziridines in high yields. On treatment with N-lithio aniline or N-lithio p-chloroaniline, the sulfinylaziridines gave α-amino aldehydes in high yields. The α-amino aldehydes were converted to amino alcohols and α-amino acid methyl esters in moderate to good yields. This procedure offers an efficient method for synthesis of cyclic α-quaternary α-amino aldehydes, amino alcohols, and α-amino acid derivatives from cyclic ketones.     

A synthesis of optically active α-quaternary α-amino acids and esters by assembling three components, ketones, (R)-chloromethyl p-tolyl sulfoxide, and sodium azide, via sulfinyloxiranes

Treatment of lithium α-sulfinyl carbanion of chloromethyl p-tolyl sulfoxides with ketones at low temperature afforded adducts in almost quantitative yields, which were exposed to t-BuOK to give sulfinyloxiranes in high yields. The sulfinyloxirane was reacted with benzylamine to give α-amino aldehyde, which was oxidized with iodine in methanol to afford α-amino carboxylic ester in moderate yield. The sulfinyloxiranes were treated with sodium azide to afford α-azido aldehydes in good yields. Oxidation with NaClO₂ followed by catalytic hydrogenation of the azido group of the α-azido aldehydes gave α-quaternary α-amino acids in good overall yields. The oxidation of the azido aldehydes with iodine in methanol in the presence of KOH followed by the catalytic hydrogenation resulted in α-quaternary α-amino acid methyl esters in good yields. When these reactions were carried out starting from unsymmetrical ketones and optically pure (R)-chloromethyl p-tolyl sulfoxide, a new method for a synthesis of optically active α-quaternary α-amino acids and esters in good overall yields was realized.     

Highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids by addition of benzylzinc reagents to chiral imines of trifluoropyruvate

An effective and facile method for highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids was developed in good yields with high diastereoselectivity (dr >20:1) via MgCl₂-accelerated addition of benzylzinc reagents (Knochel type organozinc reagents) to (R)-phenylglycinol methyl ether based imines of trifluoropyruvate.     

A novel synthesis, including asymmetric synthesis, of α-quaternary α-amino acid methyl esters from ketones via sulfinyloxiranes

Sulfinyloxiranes were synthesized from ketones and chloromethyl p-tolyl sulfoxide in two steps in almost quantitative yields. The sulfinyloxiranes were treated with NaN₃ in the presence of NH₄Cl to afford α-azido aldehydes, which were oxidized with iodine in the presence of KOH in methanol to give α-azido methyl esters in good overall yields. Catalytic hydrogenation of the α-azido esters afforded α-quaternary α-amino acid methyl esters in quantitative yields. Starting from β-tetralone and optically pure (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of optically pure (R)-(+)-methyl 2-aminotetraline-2-carboxylate was realized in good overall yields.     

A new synthesis of enantiomerically pure α- and β-amino acid derivatives using aziridinyl anions

Optically active sulfinylaziridines having a 4-methoxyphenyl group on their nitrogen atom were synthesized from optically active 1-chloroalkyl p-tolyl sulfoxide and an imine derived from benzaldehyde and p-anisidine stereoselectively in good overall yields. The sulfinylaziridines were treated with ethylmagnesium bromide or tert-butyllithium to afford aziridinylmagnesiums or aziridinyllithiums, respectively, in quantitative yields. Cross-coupling of the aziridinylmagnesiums with iodoalkanes in the presence of Cu(I) iodide gave tri-substituted aziridines in high yields from which enantiomerically pure β,β-disubstituted β-amino acid derivatives were synthesized. A β-amino acid derivative having deuterium at the stereogenic center was also realized by this method. On the other hand, from the aziridinyllithium, enantiomerically pure quaternary phenylalanine and quaternary aspartic acid derivatives were synthesized.     

Synthesis of chiral β-3-amino-2-hydroxyalkanoates and 3-alkyl-3-hydroxy-β-lactams by double asymmetric induction

Reactions of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic, mandelic, and phenyllactic acids, with aliphatic (S_S)- and (S_R)-tert-butylsulfinyl aldimines afforded conformationally restrained C2-disubstituted N,O-orthogonally protected 3-amino-2-hydroxyalkanoates in the form of N-sulfinyl protected 1′-aminodioxolan-4-ones. The product distribution showed that there is significant kinetic selectivity, due to the presence of ‘matched’ and ‘mismatched’ components, between the (S)- or (R)-tert-butylsulfinyl aldimines and the (2S)-enolates of the 1,3-dioxolan-4-ones. Selective methoxide-induced removal of the acetal group of the N-sulfinyl-1′-aminodioxolanones yielded the corresponding N-sulfinyl protected methyl alkanoates. In addition, the selective acid-induced removal of the sulfinyl group of the N-sulfinyl-1′-aminodioxolanones provided the corresponding N-unprotected 1′-aminodioxolanones, whose base-induced cyclization afforded the corresponding β-lactams.     

A convenient approach to an advanced intermediate for (+)-lactacystin synthesis

A fully stereoselective preparation of the advanced intermediate 24 for the synthesis of (+)-lactacystin from known 1,2:5,6-di-O-isopropylidene-α-d-gulofuranose (2), as the source of chirality, has been achieved. The C-5 methyl group was introduced via a Wittig olefination followed by Pd/C-mediated hydrogenation of the conformationally restricted alkene 11 in a highly stereoselective manner. The stereogenic tetrasubstituted carbon centre at C-3, with an amino group, was installed stereoselectively via an Overman rearrangement, which was efficiently controlled by a saccharide environment.     

Unnatural multidentate metal ligating α-amino acids

A family of penta- and hexadentate metal ligating α-amino acids, suitably protected for Fmoc solid-phase chemistry, has been prepared. These residues incorporate the mono-amides of ethanolaminetriacetic acid, ethylenediaminetriacetic acid, and ethylenediaminetetraacetic acid as side chains. Side chains are tethered varying distances (n) from the Cα-carbon to allow metal binding events to occur at distinct distances from the peptide backbone. These residues are designed to allow the facile installation of metal chelates along a peptide backbone.     

anti Ethyl β-thienyl-β-amino-α-hydroxy propionate: a regio and stereoselective ring opening of trans ethyl 2-thienyl-glycidate

anti Ethyl β-thienyl-β-amino-α-hydroxy propionate was obtained regio- and diastereo-selectively in three steps and 45% overall yield, while 95% syn ethyl β-chloro-β-thienyl-α-hydroxy ester was obtained regio-selectively in two steps and 50% overall yield, both from 2-thienyl aldehyde.     

Photocatalytic aerobic cross-coupling reaction of N-substituted anilines with N-aryl glycine esters: Synthesis of α-aryl α-amino esters

A novel photocatalytic cross dehydrogenative coupling reaction of N-aryl glycine esters with N-substituted anilines has been developed. The reaction proceeds effectively using methylene blue as a photocatalyst under visible light irradiation without any metal, chemical oxidant or additive. A variety of α-aryl α-amino derivatives were prepared in moderate to excellent yields with a high para-regioselectivity.     

Synthesis of difluorinated pseudopeptides using chiral α,α-difluoro-β-amino acids in the Ugi reaction

2,2-Difluoro-3-(2-hydroxy-1 R-phenylethylamino)-3 S-phenylpropionic acid 3, obtained by a Reformatsky-type reaction of ethyl bromodifluoroacetate with (4R)-2,4-diphenyloxazolidine, was used as a classical carboxylic acid in the Ugi reaction to prepare various difluorinated pseudopeptides 5a-n. Compounds 5 were then deprotected by hydrogenolysis to furnish difluorinated pseudopeptides 6.     

Stereoselective Mannich-type reaction of chlorotitanium α-phenylseleno esters enolates with aromatic aldimines

The stereoselective Mannich-type reaction of α-phenylseleno chlorotitanium enolates with aromatic aldimines is described. The corresponding α-phenylseleno-β-amino esters were obtained in good yields and with moderate to good diastereoselectivity. A rationale for the predominant syn selectivity based on a chelated cyclic transition state is suggested. The obtained compounds are useful synthetic tools and direct precursors of new α-phenylseleno-β-lactams.     

The first synthesis of N,O-protected β-isoserines bearing two adjacent quaternary stereogenic centers and their corresponding β-lactams

The reaction of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic and mandelic acids, with (S_R)-tert-butyl sulfinyl ketimines, derived from butan-2-one, pentan-2-one, and decan-2-one, afforded conformationally restrained β^2,2,3,3-isoserines bearing two adjacent quaternary stereogenic centers in the form of N-sulfinyl protected 1′-amino-dioxolan-4-ones. The selective acid-induced removal of the sulfinyl protecting group provided the corresponding 1′-aminodioxolanones, whose base-induced cyclization afforded the corresponding chiral tetra-substituted 3-hydroxy-β-lactams. The synthesis of a dipeptide by reaction coupling between the 1′-aminodioxolanone (2S,5R,1′R)-19 and N,N-dimethylglycine was successfully achieved.     

Synthesis of β-chloro α-amino acids: (2S,3R)- and (2S,3S)-3-chloroleucine

The first syntheses of (2S,3R)- and (2S,3S)-3-chloroleucine (3-chloro-d-leucines 1 and 2) have been achieved from d-3-hydroxyleucine and allo-d-3-hydroxyleucine, respectively, through the formation of the corresponding N-Cbz β-lactones, followed by a ring opening promoted by lithium chloride and a debenzylation process.     

A new synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with N-magnesio arylamine as the key reaction

A new synthesis of pipecolic acid and homopipecolic acid derivative was accomplished from 1-chloroalkyl p-tolyl sulfoxides having a 2-aminophenyl group at the ω-position by treatment with i-PrMgCl via the intramolecular reaction of magnesium carbenoid with N-magnesio arylamine. In a similar way, proline and pipecolic acid derivatives were synthesized from 1-chloroalkyl p-tolyl sulfoxides having an arylamino group at the ω-position.     

(R)-4-Hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl acetate: chiral building block for the synthesis of optically active α-substituted α-amino acid derivatives

(R)-4-Hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl acetate was efficiently obtained by lipase-catalyzed asymmetrization of the prochiral diol. (R)-4-Hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl acetate was converted to (R)-2-(hydroxymethyl)glutamic acid and a synthetic intermediate of (−)-deoxydysibetaine.     

Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide

A Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide is described. Asymmetric allylic substitution using acyclic β-keto esters with a nitrogen functional group at the α-carbon as prochiral nucleophiles proceeded in the presence of 5 mol % of Pd catalyst, 10 mol % of chiral diaminophosphine oxide 1j, BSA, and appropriate additives, affording the corresponding quaternary α-amino acid derivatives in excellent yield and in up to 92% ee.     

Synthesis of enantiopure, axially chiral, C-tetrasubstituted α-amino acids with binaphthyl-based crowned side chains and 3D-structural analysis of their peptides

The syntheses of the terminally protected, crowned, C^α-tetrasubstituted α-amino acids with only axial chirality, the two diastereomers Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe and Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, and their respective enantiomers Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe, all derived from 2′,1′:1,2; 1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bip), were performed by bis-alkylation with cyclization of racemic (R+S)-Boc-[HO]₂-Bip-OMe, possessing two phenolic OH groups at the 6,6′-positions of the biphenyl frame of Bip, using (+)-(R)- and (−)-(S)-Binol[(OCH₂CH₂)₂OTs]₂ (2,2′-bis[5-tosyloxy-3-oxa-1-pentyloxy]-1,1′-binaphthyl), respectively, as the alkylating agent followed by chromatographic separation. Two series of terminally protected model peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and i+3 positions of the sequence, combined with either l-Ala or l-Ala/Aib, were synthesized by solution methods. Their 3D-structural analyses by FTIR absorption and NMR suggest that these peptides preferentially adopt folded secondary structures.     

Multicomponent Hantzsch cyclocondensation as a route to highly functionalized 2- and 4-dihydropyridylalanines, 2- and 4-pyridylalanines, and their N-oxides: preparation via a polymer-assisted solution-phase approach

An improved and efficient entry to highly functionalized β-(2-pyridyl)- and β-(4-pyridyl)alanines and the corresponding 1,4-dihydro and N-oxide derivatives has been developed by one-pot thermal Hantzsch-type cyclocondensation of aldehyde-ketoester-enamine systems in which one of the reagents (aldehyde or ketoester) was carrying the unmasked but protected chiral glycinyl moiety. Thus coupling N-Boc-O-benzyl aspartate β-aldehyde, acetoacetate and aminocrotonate esters afforded tetrasubstituted β-(4-dihydropyridyl)alanines (75% yield). One of these products was almost quantitatively transformed into the β-(4-pyridyl)alanine derivative which in turn was oxidized to the corresponding N-oxide. Each of these enantiomerically pure (Mosher's amide analysis) heterocyclic α-amino acids was incorporated into a tripeptide by coupling with (S)-phenylalanine. In a similar way tetrasubstituted β-(2-dihydropyridyl)alanine, β-(2-pyridyl)alanine and β-(1-oxido-2-pyridyl)alanine were prepared via Hantzsch cyclocondensation reaction using benzaldehyde, aminocrotonate, and acetoacetate carrying the N-Boc-O-benzyl glycinate moiety. It was shown that the work up of the reaction mixtures derived from the cyclocondensation and oxidation reactions can be carried out by the use of polymer supported reagents and sequestrants thus allowing the isolation of the products in high purity without any chromatography.     

Diastereoselective synthesis of syn-aminoalcohols via contributing CH-π interaction: simple synthesis of (−)-bestatin

¹H NMR and X-ray crystallography studies revealed that a CH-π and chelation control in aromatic aminoaldehydes (1-6) effects a highly diastereoselective addition to afford optically active syn-aminoalcohols (1a-6a). This methodology was applied to the synthesis of (−)-bestatin.