ABSTRACT
Starting from a chiral 4-hydroxymethyl pyrrolidin-2-one, an isostere of α-methyl homoserine tethered on a γ-lactam ring was prepared exploiting a stereoselective acylation-methylation sequence, followed by Curtius rearrangement, and structural assignment was confirmed by n.O.e. experiments. By reverting the sequence, the 3-carboxy-3-methyl derivative having the opposite configuration at C-3 was obtained with total stereoselection, but Curtius rearrangement invariably afforded only inseparable mixtures of decomposition products.
Subject(s)
Homoserine/chemistry , Lactams/chemistry , Peptides, Cyclic/chemical synthesis , Acylation , Alkylation , Homoserine/chemical synthesis , Methylation , Molecular Structure , Peptides, Cyclic/chemistry , StereoisomerismABSTRACT
Chiral imines 1a,b, already synthesized in our laboratory, were converted in good yield by reduction into the corresponding N-benzyl-γ-lactams 2a,b. Desilylation followed by oxidation of the hydroxymethyl functionality gave the N-benzyl-ß-amino acids 5a,b in good yield and high purity. Starting from compound 6a, the corresponding ß-peptoid dimer 8 was prepared, together with its derivatives 9 and 10, these latter displaying conformational restriction about the peptide bond, as evidenced by NMR data.
Subject(s)
Amino Acids/chemistry , Imines/chemistry , Lactams/chemistry , Peptoids/chemical synthesis , Dimerization , Magnetic Resonance Spectroscopy , Molecular Conformation , Oxidation-Reduction , StereoisomerismABSTRACT
The N-tosyl carbamates 4a-e, easily prepared starting from the Baylis-Hillman adducts 3a-e, underwent cyclization carried out with I(2)/NIS in the presence of NaH, to give the corresponding 2-oxo-1,3-oxazolidines 5a-e in good yield and total stereoselection when the substituent at C-5 is Ar. After the removal of tosyl group, followed by the cleavage of the heterocyclic ring, the alpha-methyl-alpha-amino acids 8a,b and 10 were obtained in good yield as hydrochlorides.
Subject(s)
Amino Acids/chemical synthesis , Amino Acids/chemistry , Crystallography, X-Ray , Cyclization , Models, Molecular , Molecular Structure , Oxazolidinones/chemical synthesis , Stereoisomerism , Tosyl Compounds/chemistryABSTRACT
An efficient route was developed for the synthesis of the Fmoc-protected dipeptide 4, isostere of Gly-Gly containing an alpha-methylene beta-amino acid; the conformationally restricted analogues of Leu-enkephalin, 3a, and Met-enkephalin, 3b, respectively, were prepared by changing 4 for Gly(2)-Gly(3) in the native compounds 3a and 3b whose biological activities were significantly lower than the parent compounds.
Subject(s)
Dipeptides/chemistry , Dipeptides/chemical synthesis , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/pharmacology , Enkephalin, Methionine/analogs & derivatives , Enkephalin, Methionine/pharmacology , Neurotransmitter Agents/chemical synthesis , Neurotransmitter Agents/pharmacology , Amino Acid Sequence , Animals , Drug Design , Electric Stimulation , Enkephalin, Leucine/chemistry , Enkephalin, Methionine/chemistry , Glycylglycine/analogs & derivatives , Glycylglycine/chemical synthesis , Glycylglycine/chemistry , Guinea Pigs , Ileum , Male , Mice , Models, Molecular , Molecular Conformation , Molecular Mimicry , Molecular Structure , Myenteric Plexus/drug effects , Myenteric Plexus/physiology , Neurotransmitter Agents/chemistry , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Stereoisomerism , Vas DeferensABSTRACT
Reactions of(4S,5R)-1-(3,4-Dimethyl-2-oxo-5-phenylimidazolidine)carbonyl-isocyanate (4) with appropriate Baylis-Hillman adducts 5 gave the corresponding acyl carbamates 6,7 as equimolar diastereomeric mixtures. These mixtures were treated with DABCO, to afford with moderate diastereoselection easily separable [2-(3",4"-dimethyl-2"-oxo-5"-phenylimidazolidine-1-carboxamido)(aryl)methyl]acrylates 8 and 9.
Subject(s)
Aza Compounds/chemistry , Carbamates/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
Starting from (3S,4R,1'S)-3-amino-2-oxo-1-[1'-(4-methoxyphenylethyl)]pyrrolidine carboxylic acid (2), the first synthesis of a beta-foldamer containing pyrrolidin-2-one rings is described, whose 12-helix conformation is assigned by NMR analysis and confirmed by molecular dynamics (MD) simulations.
Subject(s)
Amino Acids/chemistry , Carboxylic Acids/chemistry , Cyclohexanes/chemistry , Pyrrolidines/chemistry , Pyrrolidinones/chemistry , Benzhydryl Compounds , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Sensitivity and SpecificityABSTRACT
[reaction: see text] A convenient approach to racemic analogues of N-benzoyl-syn-phenylisoserine was realized via the stereoselective iodocyclization of amides obtained from Baylis-Hillman adducts.
Subject(s)
Alkanes/chemistry , Benzene Derivatives/chemical synthesis , Serine/analogs & derivatives , Serine/chemical synthesis , Cyclization , Iodine/chemistry , Molecular Structure , Paclitaxel/chemistry , StereoisomerismABSTRACT
The asymmetric synthesis of 1,2-diamino-4,5-dimethylcyclohexanes was achieved by the zirconium-catalyzed and -promoted reductive cyclization of N,N'-di[(S)-1-phenylethyl]-4(R),5(R)-diamino-1,7-octadiene. The reaction of the diene with 5 equiv of butylmagnesium chloride and 0.1 mol % of bis(cyclopentadienyl)zirconium dichloride in diethyl ether at 0-20 degrees C gave mainly the 1(R),2(R)-diamino-4(S),5(S)-dimethylcyclohexane derivative having C(2) symmetry, but the reaction with 4 equiv of dibutylzirconocene in tetrahydrofuran at -78 to -50 degrees C gave prevalently the diastereomer with the 4(R),5(S) configuration. By reductive cleavage of the auxiliary, followed by sulfonylation reaction, 1(R),2(R)-di(4-toluenesulfonyl)amino)-4(S),5(S)-dimethylcyclohexane was prepared.
