Potent CXCR4 antagonists containing amidine type Peptide bond isosteres.

A series of FC131 [cyclo(-d-Tyr-Arg-Arg-Nal-Gly-)] analogues containing amidine type peptide bond isosteres were synthesized as selective CXC chemokine receptor type 4 (CXCR4) antagonists. An isosteric amidine substructure was constructed by a macrocyclization process using nitrile oxide-mediated C-N bond formation. All of the amidine-containing FC131 analogues exhibited potent SDF-1 binding inhibition to CXCR4.

Design and synthesis of amidine-type peptide bond isosteres: application of nitrile oxide derivatives as active ester equivalents in peptide and peptidomimetics synthesis.

Amidine-type peptide bond isosteres were designed based on the substitution of the peptide bond carbonyl (C=O) group with an imino (C=NH) group. The positively-charged property of the isosteric part resembles a reduced amide-type peptidomimetic. The peptidyl amidine units were synthesized by the reduction of a key amidoxime (N-hydroxyamidine) precursor, which was prepared from nitrile oxide components as an aminoacyl or peptidyl equivalent.

Efficient synthesis of trifluoromethyl and related trisubstituted alkene dipeptide isosteres by palladium-catalyzed carbonylation of amino acid derived allylic carbonates.

A novel stereoselective synthetic approach to (Z)-trifluoromethylalkene dipeptide isosteres (CF(3)-ADIs) is described. Starting from readily available N-Boc-L-phenylalanine, Phe-Gly type CF(3)-ADIs were obtained through palladium-catalyzed carbonylation of allylic carbonates under CO. While the reaction of N-Boc derivatives proceeds in excellent yields but lower stereoselectivity (E: Z = 62:38-43:57), the reaction of the N, N-diBoc derivative exclusively affords the desired (Z)-isomer in 61% yield.

Facile synthesis of fluoroalkenes by palladium-catalyzed reductive defluorination of allylic gem-difluorides.

Chemo- and stereoselective synthesis of fluoroalkenes was achieved in excellent yields via Pd-catalyzed C-F bond activation. In this transformation, Et3N plays a crucial role to produce reactive hydride species such as Ph(EtO)SiH2 and Ph(EtO)2SiH by promoting dehydrogenative coupling. The reaction proceeds efficiently at 50 degrees C with a variety of substrates and is also useful for the synthesis of fluoroalkene peptidomimetics.

Synthesis of (Z)-alkene and (E)-fluoroalkene-containing diketopiperazine mimetics utilizing organocopper-mediated reduction-alkylation and diastereoselectivity examination using DFT calculations.

We have carefully examined the organocopper-mediated reduction-alkylation of gamma-acetoxy or gamma,gamma-difluoro-alpha,beta-unsaturated-delta-lactams for the synthesis of (Z)-alkene- or (E)-fluoroalkene-containing diketopiperazine mimetics. Reduction of acetates 2, 12, 14, and difluorolactam 18 with higher-order cuprate reagents (Me3CuLi2 x LiI x 3 LiBr), followed by trapping the resulting metal dienolate with an electrophile in a one-pot procedure gave alpha-alkylated-beta,gamma-unsaturated-delta-lactams in good yields. Because of side-chain steric repulsion, we found that alkylation using relatively large electrophiles such as BnBr gave mostly 3,6-trans isomers by kinetic trapping of metal enolates.

Stereoselective synthesis of 3,6-disubstituted-3,6-dihydropyridin-2-ones as potential diketopiperazine mimetics using organocopper-mediated anti-SN2' reactions and their use in the preparation of low-molecule CXCR4 antagonists.

Organocopper-mediated anti-SN2' reactions of gamma-phosphoryloxy-alpha,beta-unsaturated-delta-lactams were used to prepare highly functionalized diketopiperazine mimetics. The substrate phosphates 24, 32, and 47 were prepared from alpha-amino acid-derived allylic alcohols 10 by a sequence of reactions that included ring-closing metathesis. In the reactions of phosphates with organocopper reagents, the addition of LiCl dramatically improved anti-SN2' selectivity, indicating that an organocopper cluster containing lithium chloride plays an important role in the determination of regioselectivity.