Gianluca Martelli

Synthesis of a conformationally restricted analog of pregabalin by stereoselective alkylation of a chiral pyrrolidin-2-one

Abstract The 4-benzyloxymethyl pyrrolidin-2-one, 5 , was alkylated leading to 3,4- trans -disubstituted pyrrolidin-2-one 6 in good yield and total diastereoselection, as shown by 1 H NMR data and NOE experiments. After reduction of the carbonyl group to give the trans -3,4-disubstituted pyrrolidine 7 , and removal of the chiral auxiliary, followed by protection of the nitrogen with t -Boc group, the corresponding N -protected pyrrolidine, 8 was obtained. The cleavage of the benzyl ether moiety, followed by oxidation of the hydroxy function, gave in good yield the corresponding pyrrolidine carboxylic acid 2 , a restricted analog of pregabalin.

Analogues of both Leu- and Met-enkephalin containing a constrained dipeptide isostere prepared from a Baylis-Hillman adduct.

An efficient route was developed for the synthesis of the Fmoc-protected dipeptide 4, isostere of Gly-Gly containing an α-methylene β-amino acid; the conformationally restricted analogues of Leu-enkephalin, 3a, and Met-enkephalin, 3b, respectively, were prepared by changing 4 for Gly2-Gly3 in the native compounds 3a and 3b whose biological activities were significantly lower than the parent compounds.

Synthesis of a versatile constrained analogue of dipeptide DG (Asp-Gly)

Summary.The synthesis of an orthogonally protected constrained analogue of dipeptide DG (Asp-Gly) is reported exploiting alkylation of a chiral lactam. The versatility of this analogue was proven by removal of t-Boc protecting group, followed by coupling under homogeneous conditions with t-Boc-Arg(Z2)-Gly, to give a conformationally restricted analogue of RGDG tetrapeptide.

Synthesis of a cyclic isostere of α-methyl homoserine by a stereoselective acylation–alkylation sequence of a chiral γ-lactam

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.

Stereoselective alkylation of chiral pyrrolidin-2-ones leading to novel conformationally restricted analogues of 3-methylaspartic acid: a computational investigation

The stereoselectivity of the alkylation of chiral pyrrolidin-2-ones leading to conformationally restricted analogues of 3-methylaspartic acid was investigated using density functional theory calculations. The overall stereocontrol is regulated by the relative stability of the lithium enolate intermediates which are also involved in the rate-determining step leading to the methylaspartic acid derivative. The computed results explain the observed data and the different diastereoselectivity can be ascribed to the nature of the alkylating group.Graphical abstract

Diastereoselective functionalisation of Baylis–Hillman adducts: a convenient approach to α-methyl-α-amino acids

The N-tosyl carbamates 4a–e, easily prepared starting from the Baylis–Hillman adducts 3a–e, underwent cyclization carried out with I2/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 α-methyl-α-amino acids 8a,b and 10 were obtained in good yield as hydrochlorides.

NOVEL NUCLEOSIDE ANALOGS TETHERED ON (3R,4R)-4-(HYDROXYMETHYL) PYRROLIDIN-3-OL

Novel nucleoside analogs were synthesized, in which (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol bears the nucleobase exploiting a 1-oxoethane-1,2-diyl group. Within this synthetic approach, cleavage of the N-phenylethyl group in the starting compound and introduction of the nucleobase-bearing amidic chain were accomplished with a one-pot procedure, simply using bromoacetyl bromide. Moreover, the benzyl carbonate protecting group was used to obtain easy to handle compounds and avoid deprotection of nucleobases occurring under basic conditions. Eventually, directed towards the preparation of short oligonucleotide sequences, both hydroxy functionalities of the iminosugar were orthogonally protected as benzyl carbonate and dimethoxytrityl ether, respectively. Then, exploiting selective orthogonal deprotections and subsequent use of the phosphoramidite method, a dimer phosphite was synthesized, verifying the possibility of building oligomeric structures displaying these novel nucleoside analogs.

Analogues of nucleosides: synthesis of chiral pyrrolidin-2-ones or pyrrolidines-bearing nucleobases

Abstract Novel analogues of nucleosides tethered on a chiral pyrrolidin-2-one were prepared, but the imide functionality was unstable under basic conditions. Thus, the carbonyl group was removed from pyrrolidin-2-one, and nucleoside analogues bearing a pyrrolidine ring were synthesized, which were unaffected under basic conditions. A nucleoside dimer was also obtained, bearing a carbamate linkage between two units.Graphical AbstractGraphics for use in the Table of Contents