Silvio Cerrini

Approaches to pseudopeptidic ergopeptines. Synthesis and molecular structure of an α-aza-phenylalanine-containing oxa-cyclol

A synthesis of the tetrahedral adduct (oxa-cyclol)6 structurally related to the peptide portion of ergotamine and possessing an α-aza-phenylalanine residue in place of the central phenylalanine is described. The reaction sequence comprises acylation of cyclo-(-azaPhe-Pro-) with (S)-2-benzyloxypropionyl chloride, followed by chemoselective hydrogenolytic removal of the O-benzyl protecting group. The intermediate N-(α-hydroxyacyl)-cyclo-(-azaPhe-Pro-) undergoes spontaneous ring enlargement leading stereospecifically to the tetrahedral adduct 6 tautomeric with the 9-membered cyclodepsitripeptide cyclo-(-Lac-azaPhe-Pro-)7. The stereochemistry of 6 has been confirmed by an X-ray crystallographic analysis which provides, in addition, detailed information on the structural and conformational features of the newly formed pseudopeptide system.

Synthesis of 2,3:4,6-di-O-isopropylidene derivatives of alkyl α- and β-d-galactopyranosides, and elucidation of structure by n.m.r. and x-ray analysis

Abstract Kinetically controlled reaction of 4.5 equiv. of 2-methoxypropene with some alkyl α- and β- d -galactopyranosides gave the 2,3:4,6-di- O -isopropylidene derivatives in high yields (80–85%). With 2 equiv. of 2-methoxypropene, benzyl β- d -galactopyranoside gave the 4,6- and the 3,4-monoacetals in the ratio 30:1 together with ∼20% of the 2,3:4,6-diacetal. The structures of methyl 2,3:4,6-di- O -isopropylidene-α- and -β- d -galactopyranosides were determined by X-ray analysis. The former crystallised in the orthorhombic system, P 2 1 2 1 2 1 , with a = 5.503, b = 16.105, c = 16.822 A, and Z = 4, the latter in the monoclinic system, P 2 1 , with a = 10.400, b = 13.344, c = 11.647 A, β = 111.50, and Z = 4. The α anomer and the two molecules of the β anomer had the d -galactopyranoside and the 1,3-dioxane rings in twist-chair conformations and the dioxolane ring in a half-chair conformation. N.m.r. spectroscopy suggested the occurrence of similar conformations in solution.

Crystal structure of trisodium β-D-fructofuranose 1,6-diphosphate octahydrate

Abstract Trisodium β- d -fructose 1,6-diphosphate octahydrate crystallises in the monoclinic space group P21 with unit-cell dimensions a = 13.289(2), b = 11.643(3), c = 7.092(1) A, and β = 102.32(2)°. The unit cell contains two symmetry-related molecules. The structure has been determined by direct methods, and refined to an R value of 0.035 and an Rw value of 0.049. The puckering of the furanose ring is C-3-exo, corresponding to an E3 conformation slightly distorted towards 4T3. The sodium atoms are hexaco-ordinated. The crystal packing involves alternating charged layers and a network of hydrogen bonds which links the molecules belonging to the same layer and to adjacent layers.

Transannular cyclisation of isogermacrone-epoxides

Abstract Isogermacrone-epoxide 2 undergoes acid- and base-induced transannular cyclisation yielding the eudesmane derivatives 8 and 12, respectively, while on treatment with Lewis acid isogermacrone-diepoxide 3 is converted into 11. The structure and stereochemistry of the cyclisation products have been elucidated by spectral methods and that of 8 has been determined by X-ray analysis. The mechanism of the cyclisation reactions is discussed briefly.

Endoannular interactions in cysteine-containing cyclotripeptides: one-step synthesis and crystal structure of a tetracyclic aza-cyclol

Mild unmasking of the thiol group of the linear tripeptide N-chloroacetyl-S-t-butylthio-L-cysteinyl-L-phenylalanyl-L-proline p-nitrophenyl ester (8) with tributylphosphine in aqueous solution at room temperature gave, in one step, the tetrahedral adduct (aza-cyclol)(13). The same adduct was obtained starting from (R)-5-oxothiomorpholin-3-ylcarbonyl-L-phenylalanyl-L-proline p-nitrophenyl ester (12). The conformationally rigid polycyclic skeleton stabilizes the structure of the aza-cyclol (13) which is an example of a tetrahedral adduct derived from amide–amide interaction. Relevant conformational details, as revealed by an X-ray crystallographic analysis, are: the proline ring adopts a Cs-Cβendo conformation; the phenylalanine side-chain is extended towards its nitrogen; the proline Hα and hydroxylic hydrogen atom are in the characteristic planar W conformation.

Oxidation of steroid α-diketones by thallium (III) acetate

Abstract Treatment of 2,3-diketo-cholestane ( 1 ) with thallium triacetate in acetic acid afforded mainly 3α-carbomethoxy-A-nor-5α-cholestan-2-one ( 2 ). Under similar conditions, the 3,4-diketo steroids ( 3 and 4 ) underwent extensive rearrangement affording spiro-lactones ( 9 and 10 ), in low yields. The structural assignment of the spiro-cholestane derivative was supported by crystallographic X-ray analysis. This product was the result of A and B-ring contractions followed by acid-catalysed cyclization of an unsaturated carboxy intermediate.

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.

30-Dechloro-30-methoxy-25-O-methyl-N-methylnaphthomycin A

The reaction of naphthomycin A with methyl iodide gives the title compound as the major product. The structure of 30-dechloro-30-methoxy-25-O-methyl-N-methylnaphthomycin A-methanol-water (1/1/1), C 43 H 53 NO 10 .CH 3 OH.H 2 O, is reported and is compared with that of the minor product, the 25-O-methylnaphthomycin A iminomethyl ether, and with that of the analogous actamycin. Despite the chemical differences, the two naphthomycin derivatives have a very similar chair-like molecular shape, which is quite different from that of actamycin

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-).