Walter Fedeli

N-oxides and related compounds. Part XL. Chemical and X-ray crystallographic investigation of the oxidation products of α-diketone bisacylhydrazones

Oxidation of the title compounds yields O-acyl imidic acids derived from 1-amino-1,2,3-triazoles. This structure best explains the chemical and spectroscopic data and is confirmed by an X-ray crystallographic study of 1-(α-benzoyloxybenzylideneamino)-4,5-dimethyl-1,2,3-triazole (10). Crystals are monoclinic, space group P21/c with Z= 4 in a unit cell of dimensions: a= 5·94 ± 0·03, b= 10·76 ± 0·05, c= 27·31 ± 0·14 A, β= 100·8°± 0·3°. The structure was solved by direct methods and refined to R 0·094.

Peptidic cyclols. Synthesis, and crystal and molecular structure of a tricyclic thia-cyclol

By following a three-step procedure, the linear peptide [(RS)-2-tritylthiopropionyl]-L-phenylalanyl-L-proline (6) has been converted into the cyclic derivative (9). On the basis of spectroscopic data and X-ray crystallographic analysis, compound (9) is shown to be a this-cyclol whose tricyclic system is related to the peptidic portion of the ergot alkaloids. Properties of the new compound are compared to those of previously studied peptidic aza- and oxa-cyclols. The thiazolidinono ring of (9) adopts in the crystal an approximate envelope conformation, whereas the pyrrolidine ring assumes a half-chair conformation. The benzylic side chain of the phenylalanine residue adopts in the crystal a folded conformation which seems to be preferred even in chloroform solution.

Peptidic thiacyclols. Synthesis and structural studies

Deprotection with tri-n-butylphosphine in aqueous medium of 2-t-butyldithiopropionyl-L-phenylalanyl-L-proline p-nitrophenyl ester gives stable thiacyclols. These compounds are isomeric with nine-membered peptidic thiolactones and possess the same stereochemistry at the phenylalanine and proline chiral centres as found in natural oxacyclols (ergot alkaloids). Spectroscopic properties and an X-ray crystallographic analysis are reported. Crystals of the thiacyclol (14) are orthorhombic with a= 16.462(7), b= 15.763(7), c= 6.487(4)A, Z= 4, space group P212121.

Peptide cyclols. Crystal structure and molecular conformation of the oxacyclol derived from L-2-hydroxyisovaleryl-L-phenylalanyl-L-proline

Cyclization of L-2-hydroxyisovaleryl-L-phenylalanyl-L-proline p-nitrophenyl ester gives the corresponding tricyclic oxacyclol. The X-ray crystallographic analysis of the oxa-cyclol is reported; crystals are monoclinic, space group P21, a= 6.794, b= 14.379, c= 9.260 A, β= 92.75°, Z= 2. The final R and Rw values are 0.039 and 0.054, respectively, for 1 890 independent reflections. The conformation of the rings, the torsion angles, and several conformational details found in the solid state for the oxa-cyclol are discussed and compared with those found for natural ergot alkaloids and related synthetic compounds. A comparison between the conformation of the oxacyclol in the crystal with that found in solution by means of 1H n.m.r. spectroscopy, is also reported.

Structural studies of azacyclols derived from linear tripeptides

N-Benzyloxycarbonyl-L-alanyl-L-phenylalanyl-L-proline p-nitrophenyl ester (4) and its N-p-bromobenzyloxycarbonyl analogue (2) each cyclize in alkaline aqueous medium to give a tricyclic system containing a free hydroxy-group derived from intramolecular addition of NH to amide carbonyl. Both the five-membered rings of the tricyclic system assume an envelope conformation. In the six-membered ring only the carbon atom bearing the cyclolic hydroxy-group is out of the plane of the other ring atoms. The benzylic side-chain of the phenylalanine residue adopts an extended conformation in both azacyclols. The crystal and molecular structures and spectral data for the tricyclic compounds (3) and (5) are reported.

Cyclodepsitripeptides. Synthesis, crystal structures and molecular conformations of cyclo(-L-2-hydroxyisovaleryl-L-prolyl-L-prolyl-) and cyclo(-D-2-hydroxyisovaleryl-L-prolyl-L-prolyl-)

The molecular and crystal structures of two diastereoisomeric nine-membered-ring heterodetic cyclotripeptides have been studied by X-ray analysis and compared with those of homodetic ring systems. cyclo(-Hylv-Pro-Pro-)(LLL) and cyclo(-D-Hylv-Pro-Pro-)(DLL) have been synthesized, through lactone-bond formation, starting from the corresponding linear precursors. The prolyl residues possess approximate C2 symmetry in LLL and CS symmetry in DLL. All peptide bonds adopt the cis-conformation and the two lactone bonds the trans-conformation. The most pronounced deviation from planarity is shown by the Pro-Pro bond in LLL (ω2=+22.6°) and by the lactone bond in DLL (ω3=–153.6°). An unusual value of the (θ–φ) parameter (36.8°) was found for Pro3 in LLL; this has been related to the pyramidality of N3. The C2 pseudosymmetry assigned to the backbone conformations of LLL and DLL is discussed and compared with that of cyclo(-Pro2-D-Pro-).

A study on the structures of 3-methoxycarbonylrifamycins by X-ray crystallography and 1H nuclear magnetic resonance spectroscopy

The structures of 3-methoxycarbonylrifamycins were studied by X-ray crystallography and 1H n.m.r. spectroscopy. The results obtained by the two different methods are consistent. The comparison with the conformations of some ansamycins in the solid state shows that in this and in other active compounds the central part of the ansa-chain, directly involved in the inhibitory interaction with the bacterial enzyme DNA-dependent RNA polymerase, remains in general the same, while large conformational changes may occur at the junctions of the ansa-chain with the chromophore-rings, thus generating four kinds of conformers. Therefore the 3-methoxycarbonyl substituent does not seem to exert any influence on the conformation of the ansa-chain which can be related to the decrease of the antibacterial activity of 3-methoxycarbonylrifamycin S.

Synthesis of peptides containing 1,2,3,4-tetrahydroquinoline-2-carboxylic acid. Part 2. Crystal and molecular structure of a 1H,3H,5H-oxazolo[3,4-a]quinolin-3-one derivative obtained from a linear tripeptide

Treatment of N-benzyloxycarbonyl-(S)-alanyl-(S)-phenylalanyl-(R)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (1a) with acetic anhydride–sodium acetate gives a cyclization product (4a) containing the 1H,3H,5H-oxazolo[3,4-a]quinoline system. The structure of the bromo-derivative (4b) was examined by crystallographic and spectroscopic methods. Crystals are monoclinic, space group P21, a= 9.835, b= 26.018, c= 10.856 A, β= 93.78°, Z= 4. The structure has been refined to R 0.08 for 3 615 reflections. The two molecules found in the asymmetric unit assume slight different conformations. Some spectroscopic data for the new peptide are described in relation to the conformations found in the crystals. The mechanism of the cyclization is discussed and related to the Dakin–West reaction.

Crystal and molecular structure of the major products from the benzylation of 1-ethyl-4-phenylpiperidine and 1-isopropyl-4-phenylpiperidine

The structures of the major isomers of 1-benzyl-1-ethyl-(1) and of 1-benzyl-1-isopropyl-4-phenylpiperidinium chloride (2), as determined by X-ray analysis, indicate that N-benzylation of piperidines normally occurs by preferential equatorial attack. Crystals of (1) are orthorhombic, space group Pbca, with Z= 8 in a unit-cell of dimensions: a= 9·41(3), b= 17·94(6), c= 20·47(6)A. Crystals of (2) are monoclinic, space group C2/c, with Z= 8 in a unit-cell of dimensions a= 27·778(19), b= 9·483(7), c= 19·911(12)A, β= 133·05(2)°. The structures were solved by the symbolic addition procedure and refined by block-diagonal least-squares methods to R 0·13 [(1), 2036 photographic data] and 0·048 [(2), 2089 diffractometer data].