Preparation of Protected β2‐ and β3‐Homocysteine, β2‐ and β3‐Homohistidine,and β2‐Homoserine for Solid‐Phase Syntheses

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β‐peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β³‐homoamino acid derivatives were obtained by Arndt–Eistert methodology from Boc‐His(Ts)‐OH and Fmoc‐Cys(PMB)‐OH (Schemes 2–4), with the side‐chain functional groups' reactivities requiring special precautions. The β²‐homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti‐enolates to formaldehyde (generated in situ from trioxane) and subsequent functional‐group manipulations. These include OH→O^tBu etherification (for β²hSer; Schemes 5 and 6), OH→STrt replacement (for β²hCys; Scheme 7), and CH₂OH→CH₂N₃→CH₂NH₂ transformations (for β²hHis; Schemes 9–11). Including protection/deprotection/re‐protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t_R), melting points, optical rotations, HPLC on chiral columns, IR, ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X‐ray crystal‐structure analysis.     

Photochemische Reaktionen 111. Mitteilung [1] Zur Photochemie α, β-ungesättigter γ, δ-Epoxyester I: Singulett- versus Triplettreaktivität

On triplet excitation (E)- 2 isomerizes to (Z)- 2 and reacts by cleavage of the C(γ), O-bond to isomeric δ-ketoester compounds ( 3 and 4 ) and 2,5-dihydrofuran compounds ( 5 and 19 , s. Scheme 1). - On singulet excitation (E)- 2 gives mainly isomers formed by cleavage of the C(γ), C(δ)-bond ( 6–14 , s. Scheme 1). However, the products 3–5 of the triplet induced cleavage of the C(γ), O-bond are obtained in small amounts, too. The conversion of (E)- 2 to an intermediate ketonium-ylide b (s. Scheme 5) is proven by the isolation of its cyclization product 13 and of the acetals 16 and 17 , the products of solvent addition to b . - Excitation (λ = 254 nm) of the enol ether (E/Z)- 6 yields the isomeric α, β-unsaturated ε-ketoesters (E/Z)- 8 and 9 , which undergo photodeconjugation to give the isomeric γ, δ-unsaturated ε-ketoesters (E/Z)- 10 . - On treatment with BF₃O(C₂H₅)₂ (E)- 2 isomerizes by cleavage of the C(δ), O-bond to the γ-ketoester (E)- 20 (s. Scheme 2). Conversion of (Z)- 2 with FeCl₃ gives the isomeric furan compound 21 exclusively.     

Kinetics of the reactions of cyclopropane derivatives. V. The gas-phase unimolecular reactions of 1 α-chloro-2α,3α-dimethylcyclopropane and 1α-chloro-2α,3β-dimethylcyclopropane

Thermolysis of the “all-cis” compound 1α-chloro-2α,3α-dimethylcyclopropane (A) at 550–607 K and 6–115 torr is a first-order homogeneous non-radical-chain process giving penta-1,3-diene (PD) and HCl as products. The Arrhenius parameters are log₁₀A(sec^?1) = 13.92 ± 0.08 and E = 199.6 ± 0.9 kJ/mol. The isomer with trans-methyl groups, 1α-chloro-2α,3β-dimethylcyclopropane (B) reacts by two parallel first-order processes giving as observed products trans-4-chloropent-2-ene (4CP) and PD + HCl, with log₁₀A(sec^?1) = 14.6 and 13.8, respectively, and E = 199.5 and 190.2 kJ/mol, respectively. The 4CP undergoes secondary decomposition to PD + HCl (as investigated previously). Comparison of the results for compounds (A) and (B) with those for other gas-phase and solution reactions leads to the conclusion that the gas-phase thermolyses proceed by rate-determining ring opening to form olefins which may decompose further by thermal or chemically activated reactions, and that the ring opening is a semiionic electrocyclic reaction in which alkyl groups in the 2,3-positions trans to the migrating chlorine semianion move apart, with appropriate consequences for the rate of reaction and the stereochemistry of the products.     

Phosphoryl group differentiating α‐amino acids from β‐ and γ‐amino acids in prebiotic peptide formation

In recent years β‐amino acids have increased their importance enormously in defining secondary structures of β‐peptides. Interest in β‐amino acids raises the question: Why and how did nature choose α‐amino acids for the central role in life? In this article we present experimental results of MS and ³¹P NMR methods on the chemical behavior of N‐phosphorylated α‐alanine, β‐alanine, and γ‐amino butyric acid in different solvents. N‐Phosphoryl α‐alanine can self‐assemble to N‐phosphopeptides either in water or in organic solvents, while no assembly was observed for β‐ or γ‐amino acids. An intramolecular carboxylic–phosphoric mixed anhydride (IMCPA) is the key structure responsible for their chemical behaviors. Relative energies and solvent effects of three isomers of IMCPA derived from α‐alanine (2a–c), with five‐membered ring, and five isomers of IMCPA derived from β‐alanine (4a–e), with six‐membered ring, were calculated with density functional theory at the B3LYP/6‐31G** level. The lower relative energy (3.2 kcal/mol in water) of 2b and lower energy barrier for its formation (16.7 kcal/mol in water) are responsible for the peptide formation from N‐phosphoryl α‐alanine. Both experimental and theoretical studies indicate that the structural difference among α‐, β‐, and γ‐amino acids can be recognized by formation of IMCPA after N‐phosphorylation. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 232–241, 2003     

Synthesis and antioxidant activities of novel N‐aryl (and N‐alkyl) γ‐ and δ‐imino esters and ketimines

Novel N‐aryl (and N‐alkyl) γ‐ and δ‐imino esters 2a–g ( 3a–g ) and N‐aryl (and N‐alkyl) ketimines 2h–j ( 3h–j ) were synthesized in high yields (80–99%) from their corresponding γ‐ and δ‐keto esters and ketones in this study. The structures of the synthesized compounds were clarified by Fourier transform infrared (FT‐IR), NMR (¹H and ¹³C), mass spectrometry, and elemental analyses. Isomerizations [E/Z] were also determined by their ¹H NMR spectra. The free‐radical scavenging activity of imines was evaluated using the 1,1‐diphenyl‐2‐picryl‐hydrazyl (DPPH) method. The relationships between the structure and antioxidant activity of these compounds are discussed. Among these compounds, 2a–c (at the concentration 1000 μg/mL) exhibit high antioxidant activity similar to those of the standards (butylated hydroxyanisole [ BHA], butylated hydroxytoluene [ BHT], and ascorbic acid).     

Poly(β-Amino acids). V. Synthesis and conformation of oligomeric α-isobutyl-L-aspartate

α-Isobutyl-L -aspartate oligomers, Z-(α-i-Bu-Asp)_2n–OEt (n = 1–5), where Z = benzyloxycarbonyl and OEt = ethyl ester, were prepared stepwise, and their conformation in solution was investigated by optical rotation, circular dichroism (CD), and NMR spectroscopy. The oligomers up to hexamer existed only in a disordered form. An ordered structure began to appear at octamer and decamer in chloroform and 2,2,2-trifluoroethanol. The ordered structure was more favorable for N-unprotected oligomers, H-(α-i-Bu-Asp)_2n–OEt, in comparison with the corresponding Z-(α-i-Bu-Asp)_2n–OEt. The effects of oligomer concentration and temperature on the structure were slightly observed. The most likely ordered structure was a β form caused by intramolecular association.     

Lipophilic Functionalized Cobyrinic-Acid Derivatives. Part 1. Cobester α-monoacids (α,α,α,β,β,β-hexamethyl α-hydrogen Coα, Coβ-dicyanocobyrinates)

The four α,α,α, β,β,β,-hexamethyl α-hydrogen Coα, Coβ-dicyanocobyrinates 2b, d–f , with a free b-, d-, e-, and f-propionic-acid function, respectively, were prepared by partial hydrolysis of heptamethyl Coα, Coβ-dicyanocobyrinate (cobester; 1 ) in aqueous sulfuric acid. The cobester monoacids 2b, d–f were obtained as a ca. 1:1:1:1 mixture which was separated. The monoacids were purified by chromatography and isolated in crystalline form. The position of the free propionic-acid function was determined by an extensive analysis of 2b, d–f using 2D-NMR techniques; an analysis of the C,H-coupling network topology resulted in an alternative assignment strategy for cobyrinic-acid derivatives, based on pattern recognition. Additional information on the structure of the most polar of the four hexamethyl cobyrinates, of the b-isomer 2b , was also obtained in the solid state from a single-crystal X-ray analysis. Earlier structural assignments based on 1D-NMR spectra of the corresponding regioisomeric monoamides 3b, d–f (obtained from crystalline samples of the monoacids 2b, d–f ) were confirmed by the present investigations.     

(E)‐,(Z)‐Parallel Preparative Methods for Stereodefined β,β‐Diaryl‐ and α,β‐Diaryl‐α,β‐unsaturated Esters: Application to the Stereocomplementary Concise Synthesis of Zimelidine

Parallel and practical methods for the preparation of both (E)‐ and (Z)‐β‐aryl¹‐β‐aryl²‐α,β‐unsaturated esters 1 and (E)‐ and (Z)‐α‐aryl¹‐β‐aryl²‐α,β‐unsaturated esters 2 are described. These methods involve accessible, robust, stereocomplementary N‐methylimidazole (NMI)‐mediated enol tosylations (14 examples, 70–99 % yield), as well as stereoretentive Suzuki–Miyaura cross‐couplings (36 examples, 64–99 % yield). The highlighted feature of the present protocol is the use of parallel and stereocomplementary approaches to obtain highly (E)‐ and (Z)‐pure products 1 and 2 by utilizing sequential enol tosylations and cross‐coupling reactions. An expeditious and parallel synthesis of (E)‐ and (Z)‐zimelidine ( 3 ), which is a highly representative selective serotonin reuptake inhibitor (SSRI), was performed by utilizing the present methods.     

Radical‐initiated polymerization of β‐methyl‐α‐methylene‐γ‐butyrolactone

β‐Methyl‐α‐methylene‐γ‐butyrolactone (MMBL) was synthesized and then was polymerized in an N,N‐dimethylformamide (DMF) solution with 2,2‐azobisisobutyronitrile (AIBN) initiation. The homopolymer of MMBL was soluble in DMF and acetonitrile. MMBL was homopolymerized without competing depolymerization from 50 to 70 °C. The rate of polymerization (R_p) for MMBL followed the kinetic expression R_p = [AIBN]^0.54[MMBL]^1.04. The overall activation energy was calculated to be 86.9 kJ/mol, k_p/k_t^1/2 was equal to 0.050 (where k_p is the rate constant for propagation and k_t is the rate constant for termination), and the rate of initiation was 2.17 × 10^?8 mol L^?1 s^?1. The free energy of activation, the activation enthalpy, and the activation entropy were 106.0, 84.1, and 0.0658 kJ mol^?1, respectively, for homopolymerization. The initiation efficiency was approximately 1. Styrene and MMBL were copolymerized in DMF solutions at 60 °C with AIBN as the initiator. The reactivity ratios (r₁ = 0.22 and r₂ = 0.73) for this copolymerization were calculated with the Kelen–Tudos method. The general reactivity parameter Q and the polarity parameter e for MMBL were calculated to be 1.54 and 0.55, respectively. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1759–1777, 2003     

The Enantioselective Synthesis of β-Amino Acids,their α-hydroxy derivatives,and the N-terminal components of bestatin and microginin

L -Aspartic acid by tosylation, anhydride formation, and reduction with NaBH₄ was converted into (3S)-3-(tosylamino)butan-4-olide ( 8 ; Scheme 1). Tretment of 8 with ethanolic trimethylsilyl iodide gave the N-protected deoxy-iodo-β-homoserine ethyl ester 9 . The latter, on successive nucleophilic displacement with lithium dialkyl-cuprates ( → 10a–e ), alkaline hydrolysis ( → 11a–e ), and reductive removal of the tosyl group, produced the corresponding 4-substituted (3R)-3-aminobutanoic acids 12a–e (ee > 99%). Electrophilic hydroxylation of 8 ( → 19 ; Scheme 3), subsequent iodo-esterification ( → 21 ; Scheme 4), and nucleophilic alkylation and phenylation afforded, after saponification and deprotection, a series of 4-substituted (2S, 3R)-3-amino-2-hydroxybutanoic acids 24 including the N-terminal acids 24e ( = 3 ) and 24f ( = 4 ) of bestatin and microginin (de > 95%), respectively.     

Thermische Lactonisierung von Estern γ-Brom-α, β-ungesättigter Carbonsäuren zu Δα-Butenoliden. Direkte γ-Bromierung von α, β-ungesättigten Säuren

By heating with iron powder at 120–150° some γ-bromo-α, β-unsaturated carboxylic methyl esters, and, less smothly, the corresponding acids, were lactonized to Δ^7alpha;-butenolides with elimination of methyl bromide. The following conversions have thus been made: methyl γ-bromocrotonate ( 1c ) and the corresponding acid ( 1d ) to Δ^α-butenolide ( 8a ), methyl γ-bromotiglate ( 3c ) and the corresponding acid ( 3d ) to α-methyl-Δ^α-butenolide ( 8b ), a mixture of methyl trans- and cis-γ-bromosenecioate ( 7c and 7e ) and a mixture of the corresponding acids ( 7d and 7f ) to β-methyl-Δ^α-butenolide ( 8c ). The procedure did not work with methyl trans-γ-bromo-Δ^α-pentenoate ( 5c ) nor with its acid ( 5d ). Most of the γ-bromo-α, β-unsaturated carboxylic esters ( 1c, 7c, 7e and 5c ) are available by direct N-bromosuccinimide bromination of the α, β-unsaturated esters 1a, 7a and 5a ; methyl γ-bromotiglate ( 3c ) is obtained from both methyl tiglate ( 3a ) and methyl angelate ( 4a ), but has to be separated from a structural isomer. The γ-bromo-α, β-unsaturated esters are shown by NMR. to have the indicated configurations which are independent of the configuration of the α, β-unsaturated esters used; the bromination always leads to the more stable configuration, usually the one with the bromine-carrying carbon anti to the carboxylic ester group; an exception is methyl γ-bromo-senecioate, for which the two isomers (cis, 7e , and trans, 7d ) have about the same stability. The N-bromosuccinimide bromination of the α,β-unsaturated carboxylic acids 1b , 3b , 4b , 5b and 7b is shown to give results entirely analogous to those with the corresponding esters. In this way γ-bromocrotonic acid ( 1 d ), γ-bromotiglic acid ( 3 d ), trans- and cis-γ-bromosenecioic acid ( 7d and 7f ) as well as trans-γ-bromo-Δ^α-pentenoic acid ( 5d ) have been prepared. Iron powder seems to catalyze the lactonization by facilitating both the elimination of methyl bromide (or, less smoothly, hydrogen bromide) and the rotation about the double bond. α-Methyl-Δ^α-butenolide ( 8b ) was converted to 1-benzyl-( 9a ), 1-cyclohexyl-( 9b ), and 1-(4′-picoly1)-3-methyl-Δ^α-pyrrolin-2-one ( 9 c ) by heating at 180° with benzylamine, cyclohexylamine, and 4-picolylamine. The butenolide 8b showed cytostatic and even cytocidal activity; in preliminary tests, no carcinogenicity was observed. Both 8b and 9c exhibited little toxicity.     

5β,6β‐Epoxy‐17‐oxoandrostan‐3β‐yl acetate and 5β,6β‐epoxy‐20‐oxopregnan‐3β‐yl acetate

In the title compounds, C₂₁H₃₀O₄, (I), and C₂₃H₃₄O₄, (II), respectively, which are valuable intermediates in the synthesis of important steroid derivatives, rings A and B are cis‐(5β,10β)‐fused. The two molecules have similar conformations of rings A, B and C. The presence of the 5β,6β‐epoxide group induces a significant twist of the steroid nucleus and a strong flattening of the B ring. The different C17 substituents result in different conformations for ring D. Cohesion of the molecular packing is achieved in both compounds only by weak intermolecular interactions. The geometries of the molecules in the crystalline environment are compared with those of the free molecules as given by ab initio Roothan Hartree–Fock calculations. We show in this work that quantum mechanical ab initio methods reproduce well the details of the conformation of these molecules, including a large twist of the steroid nucleus. The calculated twist values are comparable, but are larger than the observed values, indicating a possible small effect of the crystal packing on the twist angles.     

Electrospun poly(ε‐caprolactone)‐based composites using synthesized β‐tricalcium phosphate

Non‐woven hybrid membranes based on poly(ε‐caprolactone) (PCL) and as‐synthesized β‐tricalcium phosphate (β‐TCP) were obtained by the electrospinning technique. A wide range of composition was investigated, the filler content spanning between 2 and 60 wt%. The synthesis of the β‐TCP powder was accomplished by titration of calcium hydroxide with phosphoric acid followed by calcination of the resulting precipitate at 1100°C. The as‐dried calcium phosphate was characterized by Inductive Coupled Plasma (AES‐ICP), thermal analysis (TG‐DTA), Fourier Transform Infrared Spectroscopy (FT‐IR), Scanning Electron Microscopy (SEM), and high temperature X‐ray diffraction analysis (HT‐XRD). The specific surface area (SSA) was evaluated by N₂ adsorption. Microstructure of PCL/TCP membranes was investigated by SEM, energy dispersion spectroscopy (EDS), XRD analysis, and SSA measurements. The average fiber diameter ranged between 1 and 2 µm, the porosity was 80–90%, and the SSA 16 m²/g. Mechanical properties were determined by uniaxial tensile test. A remarkable enhancement of the tensile modulus was observed for composites containing up to 4 wt% β‐TCP. The ultimate tensile strength ranged between 2 and 3 MPa for samples loaded up to 8 wt%. For most of the samples, the elongation at break was in the range 100–150%. Copyright © 2010 John Wiley & Sons, Ltd.     

Multichain copoly(α-amino acid). II. Preparation and properties of multi-Nϵ-poly(γ-benzyl-L-glutamyl)copoly(L-lysine γ-methyl-L-glutamate)

A number of multi-N^?-poly(γ-benzyl-L -glutamyl)copoly(L -lysine γ-methyl-L -glutamate)s with branches having various degrees of polymerization and with various intervals of the grafting sites in the core molecule were prepared in N,N-dimethylformamide containing dimethyl sulfoxide by the reaction of N-carboxy anhydride of γ-benzyl L -glutamate with random copoly(L -lysine γ-methyl-L -glutamate)s of different composition with various anhydride-initiator ratios. The relationship between the intrinsic viscosity measured in a coil solvent, dichloroacetic acid (DCA), and the number-average molecular weight determined by osmometry was found to be expressed by the Mark–Houwink–Sakurada equation for the multichain copoly(α-amino acid)s which were made from the same polymeric initiator. The observed α values of the multichain copoly(α-amino acid)s in the equation were lower than that of linear poly(γ-benzyl-L -glutamate). The solvent induced helix–coil transition of the multichain copolymer was investigated in the chloroform?DCA system by the ORD technique. Two kinds of transition regions were clearly distinguished: The α-helices of the core molecules underwent the transition at lower DCA concentration and those of the branch chains at higher DCA concentration. The reduced viscosity of the multichain copoly-(α-amino acid) increased slightly between the two transition regions, in contrast to the large decrease in the reduced viscosity of linear poly(γ-benzyl-L -glutamate) during the helix–coil transition.     

Kinetic and ESR studies on the radical polymerization of α‐n‐(α′‐methylbenzyl) β‐ethyl itaconamates derived from racemic and (s)‐α‐methylbenzylamines

The polymerization of α‐N‐(α′‐methylbenzyl) β‐ethyl itaconamate derived from racemic α‐methylbenzylamine (RS‐MBEI) by initiation with dimethyl 2,2′‐azobisisobutyrate (MAIB) was studied in methanol kinetically and with ESR spectroscopy. The overall activation energy of polymerization was calculated to be 47 kJ/mol, a very low value. The polymerization rate (R_p ) at 60 °C was expressed by R_p = k[MAIB]^0.5±0.05[RS‐MBEI]^2.9±0.1. The rate constants of propagation (k_p ) and termination (k_t ) were determined by ESR. k_p was very low, ranging from 0.3 to 0.8 L/mol s, and increased with the monomer concentration, whereas k_t (4–17 × l0⁴ L/mol s) decreased with the monomer concentration. Such behaviors of k_p and k_t were responsible for the high dependence of R_p on the monomer concentration. R_p depended considerably on the solvent used. S‐MBEI, derived from (S)‐α‐methylbenzylamine, showed somewhat lower homopolymerizability than RS‐MBEI. The k_p value of RS‐MBEI at 60 °C in benzene was 1.5 times that of S‐MBEI. This was explicable in terms of the different molecular associations of RS‐MBEI and S‐MBEI, as analyzed by ¹H NMR. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4137–4146, 2000     

Synthesis of β3‐Peptides and Mixed α/β3‐Peptides by Thioligation

Five β‐peptide thioesters ( 1 – 5 , containing 3, 4, 10 residues) were prepared by manual solid‐phase synthesis and purified by reverse‐phase preparative HPLC. A β‐undecapeptide ( 6 ) and an α‐undecapeptide ( 7 ) with N‐terminal β³‐HCys and Cys residues were prepared by manual and machine synthesis, respectively. Coupling of the thioesters with the cysteine derivatives in the presence of PhSH (Scheme and Fig. 1) in aqueous solution occurred smoothly and quantitatively. Pentadeca‐ and heneicosapeptides ( 8 – 10 ) were isolated, after preparative RP‐HPLC purification, in yields of up to 60%. Thus, the so‐called native chemical ligation works well with β‐peptides, producing larger β³‐ and α/β³‐mixed peptides. Compounds 1 – 10 were characterized by high‐resolution mass spectrometry (HR‐MS) and by CD spectroscopy, including temperature and concentration dependence. β‐Peptide 9 with 21 residues shows an intense negative Cotton effect near 210 nm but no zero‐crossing above 190 nm, (Figs. 2–4), which is characteristic of β‐peptidic 3₁₄‐helical structures. Comparison of the CD spectra of the mixed α/β‐pentadecapeptide ( 10 ) and a helical α‐peptide (Fig. 5) indicate the presence of an α‐peptidic 3.6₁₃ helix.     

Photochemische Reaktionen. 121. Mitteilung. Zur Photochemie von ε,ζ-Methano-α,γ-dienonen und 7,8-Methano-1,3,5-trienen

Photochemistry of ε,ζ-Methano-α,γ-dienones and 7,8-Methano-1,3,5-trienes Irradiation of the δ-cyclopropyl-dienone (E)- 6 (λ ≥ 347 nm) gives (Z)- 6, 10 (1,5-sigmatropic H-shift), (E/Z)- 9 (electrocyclic process involving C(ε), C(ζ)-cleavage) and 11 (ring opening). The corresponding 6-cyclopropyl-triene (E)- 7 gives on singlet excitation (δ > 280 nm) 14 (1,5-sigmatropic H-shift) and, to a smaller extent, the bicyclo [3.2.0] heptenyl-dienes (E/Z)- 13 . However, on triplet excitation (λ ≥ 347 nm, benzophenone) (E)- 7 gives (E/Z)- 13 as the main products. On both ¹π,π*- and ³π,π*-excitation, (Z)- 7 and 15 are formed in small amounts.     

Chemoselectivity Control in the Asymmetric Hydrogenation of γ‐ and δ‐Keto Esters into Hydroxy Esters or Diols

The asymmetric hydrogenation of aromatic γ‐ and δ‐keto esters into optically active hydroxy esters or diols under the catalysis of a novel DIPSkewphos/3‐AMIQ–Ru^II complex was studied. Under the optimized conditions (8 atm H₂ , Ru complex/t‐C₄H₉OK=1:3.5, 25 °C) the γ‐ and δ‐hydroxy esters (including γ‐lactones) were obtained quantitatively with 97–99 % ee. When the reaction was conducted under somewhat harsh conditions (20 atm H₂ , [t‐C₄H₉OK]=50 mm , 40 °C), the 1,4‐ and 1,5‐diols were obtained predominantly with 95–99 % ee. The reactivity of the ester group was notably dependent on the length of the carbon spacer between the two carbonyl moieties of the substrate. The reaction of β‐ and ?‐keto esters selectively afforded the hydroxy esters regardless of the reaction conditions. This catalyst system was applied to the enantioselective and regioselective (for one of the two ester groups) hydrogenation of a γ‐?‐diketo diester into a trihydroxy ester.     

Preparation of (S,S)‐Fmoc‐β2hIle‐OH, (S)‐Fmoc‐β2hMet‐OH,and (S)‐Fmoc‐β2hTyr(tBu)‐OH for Solid‐Phase Syntheses of β2‐ and β2/β3‐Peptides

The preparation of three new N‐Fmoc‐protected (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) β²‐homoamino acids with proteinogenic side chains (from Ile, Tyr, and Met) is described, the key step being a diastereoselective amidomethylation of the corresponding Ti‐enolates of 3‐acyl‐4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐ones with CbzNHCH₂OMe/TiCl₄ (Cbz=(benzyloxy)carbonyl) in yields of 60–70% and with diastereoselectivities of >90%. Removal of the chiral auxiliary with LiOH or NaOH gives the N‐Cbz‐protected β‐amino acids, which were subjected to an N‐Cbz/N‐Fmoc (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) protective‐group exchange. The method is suitable for large‐scale preparation of Fmoc‐β²hXaa‐OH for solid‐phase syntheses of β‐peptides. The Fmoc‐amino acids and all compounds leading to them have been fully characterized by melting points, optical rotations, IR, ¹H‐ and ¹³C‐NMR, and mass spectra, as well as by elemental analyses.     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.