Optisch aktive 3-Amino-2H-azirine als Bausteine für enantiomerenreine α,α-disubstituierte α-Aminosäuren: Synthese des α-Methylphenylalanin-Synthons and Einbau in Modell-Peptide

Optically Active 3-Amino-2H-azirines as Synthons for Enantiomerically Pure αα-Disubstituted α-Amino Acids: Synthesis of the α-Methylphenylalanine Synthons and Some Model Peptides The synthesis of a novel 2-benzyl-2-methyl-3-amino-2H-azirine derivative with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers 9a and 9b (Scheme 4) which are the D - and L -2-methylphenylalanine ((α-Me)Phe) synthons, respectively. The reaction of 9a and 9b with thiobenzoic acid and with Z-leucine yielded the monothiodiamides 10a and 10b (Scheme 5) and the dipeptide derivatives 11a and 11b (Scheme 6), respectively. Methanolysis of 11b yielded 12b . The absolute configuration of 10a was established by X-ray crystallography. The absolute configuration of (α-Me)Phe in 12b has been deduced from the known configuration of L -leucine.     

A New 2H‐Azirin‐3‐amine as a Synthon for 2‐Methylaspartate

The synthesis of a novel 2,2‐disubstituted 2H‐azirin‐3‐amine 3a as a building block for racemic Asp(2Me) is described. This synthon contains an ester group in the side chain. The reaction of 3a with thiobenzoic acid and the amino acid Z‐Val‐OH yielded the racemic monothiodiamide 10a and the dipeptide 11 as a mixture of diastereoisomers, respectively (Scheme 2). In 11 , each of the protecting groups was removed selectively (Scheme 3). First attempts toward the preparation of enantiomerically pure synthons for Asp(2Me) with a chiral auxiliary group in the side chain are described. Synthons 3b with a 1‐(naphthalen‐1‐yl)ethyl ester group and 3c with a menthyl ester group were prepared and reacted with thiobenzoic acid to form monothiodiamides 10b and 10c (Scheme 2). However, the diastereoisomers of the synthons 3b and 3c could not be separated by chromatography.     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines

The synthesis of novel 2,2‐disubstituted 2H‐azirin‐3‐amines with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers (1′R,2R)‐ 4a – e and (1′R,2S)‐ 4a – e (Scheme 1, Table 1), which are synthons for the (R)‐ and (S)‐isomers of isovaline, 2‐methylvaline, 2‐cyclopentylalanine, 2‐methylleucine, and 2‐(methyl)phenylalanine, respectively. The configuration at C(2) of the synthons was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group. The reaction of 4 with thiobenzoic acid, benzoic acid, and the dipeptide Z‐Leu‐Aib‐OH ( 12 ) yielded the monothiodiamides 10 , the diamides 11 (Scheme 2, Table 3), and the tripeptides 13 (Scheme 3, Table 4), respectively.     

Synthese cyclischer Depsipeptide durch direkte Amid-Cyclisierung: 12gliedrige Depsipeptide mit alternierender Sequenz von α-Hydroxy- und α-Aminosäuren

Synthesis of Cyclic Depsipeptides via Direct Amide Cyclization: Cyclic Depsipeptides with 12-Ring Atoms and Alternating Sequence of α-Hydroxy and α-Amino Adds The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine (1; R¹ = R² = R³ = R⁴ = Me) with α-hydroxy-carboxylic acids, followed by selective hydrolysis of the terminal dimethylamide group yields the dipeptide analogues 15a and 18b (Schemes 3 and 4). After protection of the OH group (→ 16a and 19 , resp.), coupling with the C-terminus-protected derivatives 14 and 18a , respectively, by a modified 1,1′-carbonyldiimidazole procedure followed by hydrolysis gives the linear depsipeptides 17c and 20 , respectively. Treatment with HCl gas in toluene at 100° leads to the cyclic depsipeptides 21 and 22 in very good yield. The two model reactions show that the ‘azirine/oxazolone-method’, combined with the ‘direct amide cyclization’, is a versatile procedure for the synthesis of cyclic depsipeptides containing α,α-disubstituted α-amino acids.     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines: Synthesis of Synthons for Tyr(2Me) and Dopa(2Me), and Their Incorporation into Dipeptides

The synthesis of novel unsymmetrically 2,2‐disubstituted 2H‐azirin‐3‐amines with chiral auxiliary amino groups is described. Chromatographic separation of the mixture of diastereoisomers yielded (1′R,2S)‐ 2a , b and (1′R,2R)‐ 2a , b (c.f. Scheme 1 and Table 1), which are synthons for (S)‐ and (R)‐2‐methyltyrosine and 2‐methyl‐3′,4′‐dihydroxyphenylalanine. Another new synthon 2c , i.e., a synthon for 2‐(azidomethyl)alanine, was prepared but could not be separated into its pure diastereoisomers. The reaction of 2 with thiobenzoic acid, benzoic acid, and the amino acid Fmoc‐Val‐OH yielded the monothiodiamides 11 , the diamides 12 (cf. Scheme 3 and Table 3), and the dipeptides 13 (cf. Scheme 4 and Table 4), respectively. From 13 , each protecting group was removed selectively under standard conditions (cf. Schemes 5–7 and Tables 5–6). The configuration at C(2) of the amino acid derivatives (1R,1′R)‐ 11a , (1R,1′R)‐ 11b , (1S,1′R)‐ 12b , and (1R,1′R)‐ 12b was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group.     

Synthese von diastereo- und enantio-selektiv deuterierten β,ε-, β,β-, β,γ- und γ,γ-Carotinen

Synthesis of Diastereo- and Enantioselectively Deuterated β,ε-, β,β-, β,γ- and γ,γ-Carotenes We describe the synthesis of (1′R, 6′S)-[16′, 16′, 16′-²H₃]-β, εcarotene, (1R, 1′R)-[16, 16, 16, 16′, 16′, 16′-²H₆]-β, β-carotene, (1′R, 6′S)-[16′, 16′, 16′-²H₃]-γ, γ-carotene and (1R, 1′R, 6S, 6′S)-[16, 16, 16, 16′, 16′, 16′-²H₆]-γ, γ-carotene by a multistep degradation of (4R, 5S, 10S)-[18, 18, 18-²H₃]-didehydroabietane to optically active deuterated β-, ε- and γ-C₁₁-endgroups and subsequent building up according to schemes \documentclass{article}\pagestyle{empty}\begin{document}${\rm C}_{11} \to {\rm C}_{14}^{C_{\mathop {26}\limits_ \to }} \to {\rm C}_{40} $\end{document} and C₁₁ → C₁₄; C₁₄+C₁₂+C₁₄→C₄₀. NMR.- and chiroptical data allow the identification of the geminal methyl groups in all these compounds. The optical activity of all-(E)-[²H₆]-β,β-carotene, which is solely due to the isotopically different substituent not directly attached to the chiral centres, is demonstrated by a significant CD.-effect at low temperature. Therefore, if an enzymatic cyclization of [17, 17, 17, 17′, 17′, 17′-²H₆]lycopine can be achieved, the steric course of the cyclization step would be derivable from NMR.- and CD.-spectra with very small samples of the isolated cyclic carotenes. A general scheme for the possible course of the cyclization steps is presented.     

Synthesis and Use of 2H‐Azirin‐3‐amines as Dipeptide Synthons

The synthesis of the new 2H‐azirin‐3‐amines (‘3‐amino‐2H‐azirines') 11, 20, 28 , and 33 as dipeptide synthons is described. The reactions of the starting amides with Lawesson reagent gave the corresponding thioamides, and consecutive treatment with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ led to the desired products. It is shown that these 2H‐azirin‐3‐amines can conveniently be used as building blocks of the dipeptides Aib‐(Me)Axx (Axx=alanine, valine), Aib‐Homoproline, and Iva‐Pro in the synthesis of several model peptides. However, some limitations apply for the synthesis of such 2H‐azirin‐3‐amines. The starting material for the azirine synthesis, the corresponding thioamides, cannot generally be synthesized, and the 2H‐azirin‐3‐amines could not be obtained in all cases from the thioamides prepared.     

Solid‐state conformations of linear depsipeptide amides with an alternating sequence of α,α‐disubstituted α‐amino acid and α‐hydroxy acid

Depsipeptides and cyclodepsipeptides are analogues of the corresponding peptides in which one or more amide groups are replaced by ester functions. Reports of crystal structures of linear depsipeptides are rare. The crystal structures and conformational analyses of four depsipeptides with an alternating sequence of an α,α‐disubstituted α‐amino acid and an α‐hydroxy acid are reported. The molecules in the linear hexadepsipeptide amide in (S)‐Pms‐Acp‐(S)‐Pms‐Acp‐(S)‐Pms‐Acp‐NMe₂ acetonitrile solvate, C₄₇H₅₈N₄O₉·C₂H₃N, ( 3b ), as well as in the related linear tetradepsipeptide amide (S)‐Pms‐Aib‐(S)‐Pms‐Aib‐NMe₂, C₂₈H₃₇N₃O₆, ( 5a ), the diastereoisomeric mixture (S,R)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂/(R,S)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂ (1:1), C₃₂H₄₁N₃O₆, ( 5b ), and (R,S)‐Mns‐Acp‐(S,R)‐Mns‐Acp‐NMe₂, C₃₀H₃₇N₃O₆, ( 5c ) (Pms is phenyllactic acid, Acp is 1‐aminocyclopentanecarboxylic acid and Mns is mandelic acid), generally adopt a β‐turn conformation in the solid state, which is stabilized by intramolecular N—H…O hydrogen bonds. Whereas β‐turns of type I (or I′) are formed in the cases of ( 3b ), ( 5a ) and ( 5b ), which contain phenyllactic acid, the torsion angles for ( 5c ), which incorporates mandelic acid, indicate a β‐turn in between type I and type III. Intermolecular N—H…O and O—H…O hydrogen bonds link the molecules of ( 3a ) and ( 5b ) into extended chains, and those of ( 5a ) and ( 5c ) into two‐dimensional networks.     

A Reinvestigation of the α-Alkylation of 4-Monosubstituted 2-phenyloxazol-5(4H)-ones (‘azlactones’): A general entry into highly functionalized α,α-disubstituted α-amino acids

Novel, more reliable and general reaction conditions for the α-alkylation of 4-monosubstituted 2-phenyloxazol-5(4H)-ones ( = 4-monosubstituted 2-phenyl-azlactones) rac- 2 to 4,4-disubstituted 2-phenyloxazol-5(4H)-ones rac- 1 were found (Scheme 2). Thus, a whole range of highly functionalized rac- 1 were prepared in medium-to-good overall yields (40-90%, see Table). Azlactones rac- 1 are ideal precursors for the synthesis of optically pure α,α -disubstituted (R)- and (S)-α-amino acids.     

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 and transformations of (±)-trans-4aβ(H), saα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one

Hydrogenation of 4,7-dimethylcoumarin ( 1 ) in alkaline medium has been shown to furnish a mixture of (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one ( 2 ), (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 3 ) and (±)-cis-4aα(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 4 ) in 40:25:35:ratio, respectively. The stereochemistry of the major hydrogenation product 2 , has been established by transforming it to p-menthane derivatives e.g. (±)-2 (R)-[2′(R)hydroxy-4′(R) methylcyclohex-(1′S)-yl]propan-1-ol ( 20 ) and (±)-trans-3α,6β-dimethyl-3aβ(H),7aα(H)-octahydrobenzofuran ( 12 ). Starting from a mixture of lactones 2, 3 and 4 , lactone 3 has been obtained in pure state employing a sequence of reactions.     

L-Phenylalanine Cyclohexylamide: A simple and convenient auxiliary for the synthesis of optically pure α,α-disubstituted (R)- and (S)-amino acids

This work describes L -phenylalanine cyclohexylamide ( 5c ) as a simple, cheap, and powerful chiral auxiliary for the synthesis of a series of optically pure α,α-disubstituted (R)- and (S)-amino acids of type 1 , such as (R)- and (S)-2-methyl-phenylalanine ( 1a ), (R)- and (S)-2-methyl-2-phenylglycine ( 1b ), and (R)- and (S)-2-methylvaline ( 1c ; Scheme 3). These amino acids were efficiently transformed into the suitably protected and activated amino acid building blocks (R)- and (S)- 12b and (R)- and (S)- 12c (Scheme 4) which are ready for incorporation into peptides by solution or solid-phase techniques. Based on the crystal structures of 6b, 6c , and 7a belonging to the diastereoisomeric peptides series 6 and 7 , the absolute configurations of each member of the series were determined. β-Turn geometries of type II′ and I were observed for 6b and 7a , respectively, whereas 6c crystallized in an extended conformation. The impacts of side-chain variation on conformation and crystal packing of these triamides are discussed.     

Silicon-Directed Regio- and Enantioselective Synthesis of α-Hydroxy-ketones Preliminary Communication

α-Silylated ketones (S)? 2 (ee ≥ 98%), easily available through silylation or silylation/alkylation from ketones 1 using the (?)-(S)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)?/(+)-(R)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP)-hydrazone method, are oxidized to give α-hydroxy-ketones (R)? 5 of high enantiomeric purity (ee ≥ 98%) and in good overall yields (51-70%). The key step of the procedure is the silicon-directed diastereoselective oxidation of the corresponding silyl enol ethers of (S)? 2 , with m-chloroperbenzoic acid or 3-phenyl-2-(phenylsulfonyl)oxaziridine, followed by flash chromatography and desilylation.     

On Triazoles. XXXII. The reaction of 5-amino-1 H-1,2,4-triazolylcarbothiohydrazides with β- and γ-oxo-esters

5-Amino-lH-1,2,4-triazolylcarbothiohydrazides gave β and γ-oxo-esters in boiling ethanol [1,2,4]triazolo- [1,5-d][1,2,4,6]tetrazepine-5-thiones 3 . Analogously ethyl 2-oxocyclohexanecarboxylate provided a mixture of two diastereomeric spiro derivatives 5 and 6 . At 130°, 2-acetonyl-5-methyl-4,5-dihydro-1,3,4-oxadiazole-5-thione ( 8 ) was formed. Ring closure of 3e (R¹ = CH₃, R² = CH₂CH₂COOEt, Q = morpholino) lead to the isomeric pyrrolo[2,1-g][1,2,4]triazolo[1,5-d][1,2,4,6]tetrazepin-8(11H)-one ( 12 ) and pyrrolo[1,2-f][1,2,4]triazolo-[1,5-d][1,2,4,6]tetrazepin-10(7H)-one ( 13 ) derivatives representing two new ring systems.     

Totalsynthese von natürlichem α-Tocopherol. 2. Mitteilung. Aufbau der Seitenkette aus (−)-(S)-3-Methyl-γ-butyrolacton

Total Synthesis of Natural α-Tocopherol A short and efficient route to optically pure (+)-(3 R, 7 R)-trimethyldodecanol ( 14 ) is demonstrated, 14 serving as side chain unit in the preparation of natural vitamin E. The synthesis of 14 is based on the concept of using a single optically active C₅-synthon of suitable configuration and functionalization to introduce both asymmetric centres in 14 . (?)-(S)-3-Methyl-γ-butyrolacton ( 1 ) and ethyl (?)-(S)-4-bromo-3-methylbutyrate ( 2 ), respectively, is used in a sequence of either two Grignard C,C-coupling reactions 5 → 8 and 12 → 13 or two Wittig reactions 17a → 18 and 20 → 21 to achieve this goal. 14 is converted to (2 R, 4′R, 8′R)-α-tocopherol (= vitamin E) by coupling with a chroman unit in known manner. Optical purity of products and intermediates is established.     

Reduction of α,β unsaturated carbonyl compounds by Ni–BH4

The reduction of α,β unsaturated carbonyl compounds by sodiumborohydride is catalysed by Ni(bpy)Cl₂ (bpy=2,2′-bipyridine). Various carbonyl compounds having the general formula R₁CH=CHCRO [where R₁, R=C₆H₅, H; p-MeO---C₆H₄---,C₆H₄; p-CH₃---C₆H₄, C₆H₅; (m-OMe---)(p-OMe---)C₆H₃, C₆H₅; C₆H₅, (CH₃)₂CH---; CH₃, H; m-Br---C₆H₄---, C₆H₅] are reduced to corresponding allylicalcohol [R₁CH=CHCRHOH] at 25°C within half an hour. During these reductions the double bond is partially reduced to give saturated alcohols as minor products having the molecular formula R₁CH₂CH₂CRHOH. The reduction of trans-3-phenyl-2-propenal with NaBH₄ and catalytic amounts of Ni(bpy)Cl₂ in solvents containing active deuterium (D₂O, CD₃OD), leads to the partial incorporation of deuterium at the α and γ positions to give C---D bonded alcohols.     

Highly stereocontrolled boron-mediated synthesis of β-hydroxy-α-amino acids and dipeptides. Part 2

The chiral synthons 1(a–d) were submitted to boron-mediated asymmetric aldol condensation with acetaldehyde and benzaldehyde providing, in high diastereomeric excess (>95%), R,R-configured aldols 2(a–f) which are useful intermediates to enantiomerically pure β-hydroxy-α-amino acids.     

Novel Heterospirocyclic 3-Amino-2H-azirines as Synthons for Heterocyclic α-Amino Acids

The heterospirocyclic N-methyl-N-phenyl-2H-azirin-3-amines (3-(N-methyl-N-phenylamino)-2H-azirines) 1a - d with a tetrahydro-2H-thiopyran, tetrahydro-2H-thiopyran, and a N-protected piperidine ring, respectively, were synthesized from the corresponding heterocyclic 4-carboxamides 2 by consecutive treatment with lithium diisopropylamide (LDA), diphenyl phosphorochloridate (DPPCI), and sodium azide (Scheme 4). The reaction of these aminoazirines with thiobenzoic acid in CH₂Cl₂ at room temperature gave the thiocarbamoyl-substituted benzamides 13a - d in high yield. The azirines 1a-d were used as synthons for heterocyclic α-amino acids in the preparation of tripeptides of the type Z-Aib-Xaa-Aib-N(Ph)Me ( 18 ) by following the protocol of the ‘azirine/oxazolone method’: treatment of Z-Aib with 1 to give the dipeptide amide 15 , followed by selective hydrolysis to the corresponding acid 16 and coupling with the 2,2-dimethyl-2H-azirin-3-amine 17 gave 18 , again in high yield (Scheme 5). With some selected examples of 18 , the selective deprotection of the amino and the carboxy group, respectively, was demonstrated (Scheme 6). The solid-state conformations of the protected tripeptides 18a - d , as well as that of the corresponding carbocyclic analogue 18e , were determined by X-ray crystallography (Figs. 1-3 and Tables 1-3). All five tripeptides adopt a β-turn conformation of type III or III′. The solvent dependence of the chemical shifts of the NH resonances (Fig. 6) suggests that there is an intramolecular H-bond between H-N(4) and O(11) in all cases, which is an indication that a relatively rigid β-turn structure also persists in solution. Surprisingly, the tripeptide acid 20a shows no intramolecular H-bond in the crystalline state (Fig. 7); O(11) is involved in an intermolecular H-bond with the OH group of the carboxy function.     

Nonreductive Enantioselective Ring Opening of N-(Methylsulfonyl)dicarboximides with Diisopropoxytitanium α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5-dimethanolate

The bicyclic and tricyclic meso-N-(methylsulfonyl)dicarboximides 1a–f are converted enantioselectively to isopropyl [(sulfonamido)carbonyl]-carboxylates 2a–f by diisopropoxytitanium TADDOLate (75–92% yield; see Scheme 3). The enantiomer ratios of the products are between 86:14 and 97:3, and recrystallization from CH₂Cl₂/hexane leads to enantiomerically pure sulfonamido esters 2 (Scheme 3). The enantioselectivity shows a linear relationship with the enantiomer excess of the TADDOL employed (Fig.3). Reduction of the ester and carboxamide groups (LiAlH₄) and additional reductive cleavage of the sulfonamido group (Red-Al) in the products 2 of imide-ring opening gives hydroxy-sulfonamides 3 and amino alcohols 4 , respectively (Scheme 4). The absolute configuration of the sulfonamido esters 2 is determined by chemical correlation (with 2a,b ; Scheme 6), by the X-ray analysis of the camphanate of 3e (Fig. 1), and by comparative ¹⁹F-NMR analysis of the Mosher esters of the hydroxy-sulfonamides 3 (Table 1). A general proposal for the assignment of the absolute configuration of primary alcohols and amines of Formula HXCH₂CHR¹R², X = O, NH, is suggested (see 11 in Table 1). It follows from the assignment of configuration of 2 that the Re carbonyl group of the original imide 1 is converted to an isopropyl ester group. This result is compatible with a rule previously put forward for the stereochemical course of reactions involving titanium TADDOLate activated chelating electrophiles ( 12 in Scheme 7). A tentative mechanistic model is proposed ( 13 and 14 in Scheme 7).     

Brominations of Cyclic Acetals from α-Amino Acids and α- or β-Hydroxy Acids with N-Bromosucinimide

The preparation of novel electrophilic building blocks for the synthesis of enantiomerically pure compounds (EPC) is described. Thus, the 2-(tert-butyl)dioxolanones, -oxazolidinones, -imidazolidinones, and -dioxanones obtained by acetalization of pivalaldehyde with 2-hydroxy-, 3-hydroxy-, or 2-amino-carboxylic acids are treated with N-bromosuccinimide under typical radical-chain reaction conditions (azoisobuytyronitril/CCl₄/reflux). Products of bromination in the α-position of the carbonyl group of the five-membered-ring acetals are isolated or identified ( 2, 5 , and 8 ; Scheme 1). The dioxanones are converted to 2H, 4H-dioxinones under these conditions ( 12 , 14 , 15 , 21 , and 22 ; Schemes 2 and 3). The products can be converted to chiral derivatives of pyruvic acid (methylidene derivatives 3 and 6 ) or of 3-oxo-butanoic and -pentanoic acid ( 16 and 23 ). The mechanism of the brominations is interpreted. The conversion of serine to enactiomcrically pure dioxanones 26–28 (Scheme 4) is also discussed.