Reactive Intermediates in Peptide Synthesis: First Crystal Structures and <i>ab Initio</i> Calculations of 2-Alkoxy-5(4<i>H</i>)-oxazolones from Urethane-Protected Amino Acids

The structures of the 2-alkoxy-5(4H)-oxazolones derived from 2,2,6,6-tetramethyl-4-[(benzyloxycarbonyl)amino]-1-oxypiperidine-4-carboxylic acid and 2,2,6,6-tetramethyl-4-[(9‘-fluorenylmethoxycarbonyl)amino]-1-oxypiperidine-4-carboxylic acid have been solved by single-crystal X-ray diffraction. The overall geometry of their oxazolone ring compares well with that of 2-alkyl-5(4H)-oxazolones. However, the bond distance from C2 to the exocyclic O(2) atom is shorter than expected for a (sp2)C−O single bond, thus suggesting a significant involvement of a O(2) lone pair in the electron delocalization of the CN π-system. These two structures represent the first examples of 2-alkoxy-5(4H)-oxazolones in the crystal state. Ab initio molecular orbital calculations have been performed on (4S)-2-methoxy-4-methyl-5(4H)-oxazolone and (4S)-2,4-dimethyl-5(4H)-oxazolone [as simple models for 2-alkoxy- and 2-alkyl-5(4H)-oxazolones, respectively, derived from the chiral protein amino acid l-Ala] both in the neutral and deprotonated state. The calculated geometries of the 2-alkoxy- and 2-alkyl-5(4H)-oxazolone systems at the MP2/6-31+G(d,p) level agree well with those experimentally determined in the crystal state. The calculated energetics of deprotonation show only modest differences between the two systems. Conversely, a theoretical investigation of the reaction of model oxazolones with ammonia as a nucleophile indicates that for 2-alkoxy-5(4H)-oxazolones the activation energy of the rate-determining step is significantly lower and the overall stabilization energy is larger than for 2-alkyl-5(4H)-oxazolones. The implications of these results with respect to coupling and racemization of urethane-protected amino acids in peptide synthesis are outlined

Reactive Intermediates in Peptide Synthesis: First Crystal Structures and <i>ab Initio</i> Calculations of 2-Alkoxy-5(4<i>H</i>)-oxazolones from Urethane-Protected Amino Acids

The structures of the 2-alkoxy-5(4H)-oxazolones derived from 2,2,6,6-tetramethyl-4-[(benzyloxycarbonyl)amino]-1-oxypiperidine-4-carboxylic acid and 2,2,6,6-tetramethyl-4-[(9‘-fluorenylmethoxycarbonyl)amino]-1-oxypiperidine-4-carboxylic acid have been solved by single-crystal X-ray diffraction. The overall geometry of their oxazolone ring compares well with that of 2-alkyl-5(4H)-oxazolones. However, the bond distance from C2 to the exocyclic O(2) atom is shorter than expected for a (sp2)C−O single bond, thus suggesting a significant involvement of a O(2) lone pair in the electron delocalization of the CN π-system. These two structures represent the first examples of 2-alkoxy-5(4H)-oxazolones in the crystal state. Ab initio molecular orbital calculations have been performed on (4S)-2-methoxy-4-methyl-5(4H)-oxazolone and (4S)-2,4-dimethyl-5(4H)-oxazolone [as simple models for 2-alkoxy- and 2-alkyl-5(4H)-oxazolones, respectively, derived from the chiral protein amino acid l-Ala] both in the neutral and deprotonated state. The calculated geometries of the 2-alkoxy- and 2-alkyl-5(4H)-oxazolone systems at the MP2/6-31+G(d,p) level agree well with those experimentally determined in the crystal state. The calculated energetics of deprotonation show only modest differences between the two systems. Conversely, a theoretical investigation of the reaction of model oxazolones with ammonia as a nucleophile indicates that for 2-alkoxy-5(4H)-oxazolones the activation energy of the rate-determining step is significantly lower and the overall stabilization energy is larger than for 2-alkyl-5(4H)-oxazolones. The implications of these results with respect to coupling and racemization of urethane-protected amino acids in peptide synthesis are outlined

Unexpected Formation of Dienes in the Diels−Alder Reaction of Exocyclic 1-Bromobutadienes of Polycyclic Hydrocarbons

Polycyclic dienes having an exocyclic 1-bromobutadiene moiety react with dienophiles and fullerene-C60 to afford exclusively dienes via a cycloaddition−elimination mechanism. Neither the primary adducts nor the double addition products derived from a second cycloaddition of the dienophile to the diene could be detected. In one case only, i.e. with 4-phenyl-1,2,4-triazoline-3,5-dione, was the double addition product formed. Contrary to expectations, X-ray diffractometric analysis shows that this adduct is formed following a contrasteric approach

Unexpected Formation of Dienes in the Diels−Alder Reaction of Exocyclic 1-Bromobutadienes of Polycyclic Hydrocarbons

Polycyclic dienes having an exocyclic 1-bromobutadiene moiety react with dienophiles and fullerene-C60 to afford exclusively dienes via a cycloaddition−elimination mechanism. Neither the primary adducts nor the double addition products derived from a second cycloaddition of the dienophile to the diene could be detected. In one case only, i.e. with 4-phenyl-1,2,4-triazoline-3,5-dione, was the double addition product formed. Contrary to expectations, X-ray diffractometric analysis shows that this adduct is formed following a contrasteric approach

Synthesis of β-Imino Carbonyl Enolato Complexes by Reaction of Nickel(II), Palladium(II), and Copper(II) Acetates with the Enaminodiones (MeOCO)(RCO)CC(R‘)NH₂ (R = Me, OMe; R‘ = Et, EtOCO)

Nickel(II), palladium(II), and copper(II) acetates undertake exchange reaction with the β-enaminodiones (MeOCO)(RCO)CC(R‘)NH2 (R = Me, OMe; R‘ = Et, EtOCO) in ethanol to give the neutral complexes [M((MeOCO)(RCO)CC(R‘)NH)2] (1−8) [R = Me, R‘ = Et:  M = Ni (1), Pd (2a,b), Cu (3); R = Me, R‘ = EtOCO:  M = Ni (4), Pd (5), Cu (6); R = MeO, R‘ = Et, M = Pd (7a,b); R = MeO, R‘ = EtOCO, M = Pd (8a,b)]. The trifunctional N,O,O ligands act in all cases as bidentate through the imino and one carbonyl group. Complexes 1−8 are all monomers with a square planar geometry. Nickel and palladium complexes show more than one form in the solid state. For example the palladium complex 2 has been synthesized in two forms a and b, which differ in the conformation of the methoxy carbonyl substituent of the chelate ring, while the third isomer or conformer is obtained by thermal treatment at 120 °C. Complexes 7 and 8 also exhibit two forms which differ in the degree of intermolecular hydrogen bonding. Both 7b and 8b crystallize in monoclinic unit cells [7b:  space group P21/n, a = 11.963(2), b = 8.438(1), c = 19.637(2) Å, β = 94.2(1)°. 8b:  P21/c, a = 10.698(2), b = 14.902(2), c = 13.918(2) Å, β = 95.2(1)°] containing four molecules linked by intermolecular hydrogen bonding [N−H···OC, 2.14−2.36 Å]. All complexes are thermally stable and volatile. Their mass spectra exhibit intense molecular ion peaks under EI mass conditions

Synthesis of β-Imino Carbonyl Enolato Complexes by Reaction of Nickel(II), Palladium(II), and Copper(II) Acetates with the Enaminodiones (MeOCO)(RCO)CC(R‘)NH₂ (R = Me, OMe; R‘ = Et, EtOCO)

Nickel(II), palladium(II), and copper(II) acetates undertake exchange reaction with the β-enaminodiones (MeOCO)(RCO)CC(R‘)NH2 (R = Me, OMe; R‘ = Et, EtOCO) in ethanol to give the neutral complexes [M((MeOCO)(RCO)CC(R‘)NH)2] (1−8) [R = Me, R‘ = Et:  M = Ni (1), Pd (2a,b), Cu (3); R = Me, R‘ = EtOCO:  M = Ni (4), Pd (5), Cu (6); R = MeO, R‘ = Et, M = Pd (7a,b); R = MeO, R‘ = EtOCO, M = Pd (8a,b)]. The trifunctional N,O,O ligands act in all cases as bidentate through the imino and one carbonyl group. Complexes 1−8 are all monomers with a square planar geometry. Nickel and palladium complexes show more than one form in the solid state. For example the palladium complex 2 has been synthesized in two forms a and b, which differ in the conformation of the methoxy carbonyl substituent of the chelate ring, while the third isomer or conformer is obtained by thermal treatment at 120 °C. Complexes 7 and 8 also exhibit two forms which differ in the degree of intermolecular hydrogen bonding. Both 7b and 8b crystallize in monoclinic unit cells [7b:  space group P21/n, a = 11.963(2), b = 8.438(1), c = 19.637(2) Å, β = 94.2(1)°. 8b:  P21/c, a = 10.698(2), b = 14.902(2), c = 13.918(2) Å, β = 95.2(1)°] containing four molecules linked by intermolecular hydrogen bonding [N−H···OC, 2.14−2.36 Å]. All complexes are thermally stable and volatile. Their mass spectra exhibit intense molecular ion peaks under EI mass conditions

Synthesis of β-Imino Carbonyl Enolato Complexes by Reaction of Nickel(II), Palladium(II), and Copper(II) Acetates with the Enaminodiones (MeOCO)(RCO)CC(R‘)NH₂ (R = Me, OMe; R‘ = Et, EtOCO)

Nickel(II), palladium(II), and copper(II) acetates undertake exchange reaction with the β-enaminodiones (MeOCO)(RCO)CC(R‘)NH2 (R = Me, OMe; R‘ = Et, EtOCO) in ethanol to give the neutral complexes [M((MeOCO)(RCO)CC(R‘)NH)2] (1−8) [R = Me, R‘ = Et:  M = Ni (1), Pd (2a,b), Cu (3); R = Me, R‘ = EtOCO:  M = Ni (4), Pd (5), Cu (6); R = MeO, R‘ = Et, M = Pd (7a,b); R = MeO, R‘ = EtOCO, M = Pd (8a,b)]. The trifunctional N,O,O ligands act in all cases as bidentate through the imino and one carbonyl group. Complexes 1−8 are all monomers with a square planar geometry. Nickel and palladium complexes show more than one form in the solid state. For example the palladium complex 2 has been synthesized in two forms a and b, which differ in the conformation of the methoxy carbonyl substituent of the chelate ring, while the third isomer or conformer is obtained by thermal treatment at 120 °C. Complexes 7 and 8 also exhibit two forms which differ in the degree of intermolecular hydrogen bonding. Both 7b and 8b crystallize in monoclinic unit cells [7b:  space group P21/n, a = 11.963(2), b = 8.438(1), c = 19.637(2) Å, β = 94.2(1)°. 8b:  P21/c, a = 10.698(2), b = 14.902(2), c = 13.918(2) Å, β = 95.2(1)°] containing four molecules linked by intermolecular hydrogen bonding [N−H···OC, 2.14−2.36 Å]. All complexes are thermally stable and volatile. Their mass spectra exhibit intense molecular ion peaks under EI mass conditions

Heterobimetallic Indenyl Complexes. Synthesis and Carbonylation Reaction of <i>anti</i>-[Cr(CO)₃-μ,η:η-indenyl-Ir(COD)]

The reaction of the anti-[Cr(CO)3-μ,η:η-indenyl-Ir(COD)] (I) complex with an excess of CO in CH2Cl2 at 203 K produces quantitatively the η1-[η6-Cr(CO)3-indenyl]-Ir(COD)(CO)2 intermediate which above 273 K converts into the fully carbonylated complex η1-[η6-Cr(CO)3-indenyl]Ir(CO)4; this in turn is stable up to 313 K. Carbonylation of the anti-[Cr(CO)3-μ,η:η-indenyl-Ir(COE)2] analogue (II) gives the η1-[η6-Cr(CO)3-indenyl]-Ir(CO)4 (VII) species in a single fast step. In contrast to the behavior of the corresponding rhodium complexes, for which η1 intermediates have never been observed and the aromatized substitution product is the stable product, the rearomatization of the cyclopentadienyl ring in iridium complexes to give the “normal” substitution product, viz., anti-[Cr(CO)3-μ,η:η-indenyl-Ir(CO)2] (III) is a difficult process which takes place only on bubbling argon through the solution. The final product III is barely stable in solution. If the carbonylation is carried out using a blanket of CO over the solution of complexes I and II, viz., failing CO, the scarcely soluble iridium dimer [η6-Cr(CO)3-indenyl-η3-Ir(CO)3]2 (IX) stable in the solid state is obtained, probably by dimerization of the unstable intermediate anti-[η6-Cr(CO)3-indenyl-η3-Ir(CO)3] (X)

Reaction of Ketenylidenetriphenylphosphorane (Ph₃PCCO) with Platinum(II) and Palladium(II) Complexes. Synthesis, Characterization, and Molecular Structure of [Pt(η³-C₃H₅){η¹-C(PPh₃)(CO)}(PPh₃)]BF₄

Ketenylidenetriphenylphosphorane, Ph3P CCO, reacts with Pt(II) and Pd(II) η3-allyl complexes (allyl = C3H5, 2-MeC3H4) to give neutral or cationic mononuclear η1-ketenyl derivatives [M(η3-allyl){(η1-C(PPh3)(CO)}L]m+ (L = Cl, m = 0; L = PPh3, m = 1) that have been characterized by elemental analysis, IR, and multinuclear NMR. The X-ray molecular structure determination performed on a single crystal of the air-stable derivative [Pt(η3-C3H5){η1-C(PPh3)(CO)}(PPh3)]BF4 furnishes the first crystallographic evidence of an η1-ketenyl derivative in which the ketene moiety is also involved in an ylide grouping

First Step Toward the Quantitative Identification of Peptide 3₁₀-Helix Conformation with NMR Spectroscopy: NMR and X-ray Diffraction Structural Analysis of a Fully-Developed 3₁₀-Helical Peptide Standard

We have synthesized by solution methods and fully characterized the Nα-blocked heptapeptide methylamide mBrBz-[L-Iva-L-(αMe)Val]2-L-(αMe)Phe-L-(αMe)Val-L-Iva-NHMe, fully based on conformationally constrained Cα-methylated α-amino acids. An X-ray diffraction investigation of the Nα-benzyloxycarbonylated analogue showed that in the crystal state both independent molecules (A and B) in the asymmetric unit of the peptide adopt a fully developed, regular, right-handed 310-helical structure, although molecule A would be slightly distorted at the C-terminal residue. Solution conformational analysis on the mBrBz-blocked peptide was carried out in CDCl3 by means of NMR spectroscopy. For structure determination we performed restrained molecular dynamics simulations in CDCl3 based on a search of the conformational space derived from a simulated annealing strategy. For this peptide the NMR observables can be described by a single backbone conformation, more specifically a rigid 310-helix spanning the amino acid sequence from residue 1 to residue 6. The C-terminal methylamido NH group seems to be involved simultaneously in two H-bonds (with the preceding i − 3 and i − 4 carbonyl groups). Although in this peptide model there are no distinct NOE distances for discriminating 310- versus α-helix conformation, the sum of all NMR-derived restraints clearly results in a 310-helical structure. Convergence from different starting structures (including an α-helix) into a 310-helix was observed