Cesare Gennari

Direct synthesis of Z-unsaturated esters. A useful modification of the horner-emmons olefination.

Abstract New phosphonoester reagents and reaction conditions are described which yield Z-alpha, beta-unsaturated esters stereoselectively and in high yield from aliphatic and aromatic aldehydes.

Asymmetric synthesis of trans- β -lactams through TiCl4-mediated addition to imines.

Abstract TiCl 4 -mediated addition of the chiral silyl ketene acetal (2) to benzylideneaniline proceeds with high stereoselectivity to give, after cyclization, trans- β -lactam (7) in good yield and 95% e.e.

Supramolecular ligand–ligand and ligand–substrate interactions for highly selective transition metal catalysis

The use of non covalent supramolecular ligand-ligand and ligand-substrate interactions in transition metal-catalysed transformations is a new, rapidly emerging area of research. Non-covalent interactions between monodentate ligands such as hydrogen bonding, coordinative bonding, ion pairing, π-π interactions and the formation of inclusion compounds, have been shown to impart higher activity and chemo-, regio-, and stereoselectivity to the corresponding transition metal complexes in a number of catalytic applications. Analogously, supramolecular ligand-substrate interactions, and particularly hydrogen bonding, have been used to direct the regio- and stereochemistry of several metal-catalysed reactions. The catalytic systems relying on supramolecular interactions are generally capable of self-assembling from simpler components in the environment where catalysis is to take place, and are therefore very well-suited for combinatorial catalyst discovery strategies and high-throughput screening.

conformational preferences of peptides containing reverse-turn mimetic bicyclic lactams: inverse γ-turns versus type-ii′ β-turns — insights into β-hairpin stability.

The solid-phase synthesis and characterization of a series of peptides (3–9), containing reverse-turn mimetic bicyclic lactams (1a, 1b), was reported in the preceding paper. The bicyclic lactams (1a, 1b) possess high structural similarity to the two central residues of a β-turn. The conformational preferences of the constrained peptides have been investigated by NMR spectroscopy and IR spectroscopy. Our experimental results have been complemented by computer modelling studies and show that the constrained peptides (3–9) form an inverse γ-turn or a type-II′ β-turn through intramolecular hydrogen bonding, depending on the nature of the reverse-turn mimic. In N-acetylated tetrapeptide mimics incorporating the two different bicyclic lactams (a series and b series), H5 is available for either a γ-turn (7-membered ring with the carbonyl group of the bicyclic lactam) or a β-turn (10-membered ring with the carbonyl group of residue 2), as shown in Figures 7 and 9. The a series incorporating the (5,7)-bicyclic lactam predominantly induces the γ-turn conformation, while the b series incorporating the (5,6)-bicyclic lactam can promote either a γ-turn or a β-turn conformation, with the β-turn usually being preferred and with varying degrees of β-hairpin formation.

Lewis acid mediated aldol condensations using thioester silyl ketene acetals

Abstract BF3-OEt2 mediated thioester silylketene acetal additions to aldehydes are stereoconvergent and give high anti-syn ratios and good chemical yields. An acyclic transition state model was hypothesized in order to account for the observed selectivity. Theoretical methods (MNDO) were used to evaluate the ground-state conformations of thioester silylketene acetals and to model the acyclic transition states. Lewis acid mediated additions of thioester silylketene acetals to 2-phenylpropion-aldehyde (BF3-OEt2), O-benzyl lactic aldehyde (SnCl4), 2,3-0,O-dibenzyl glyceraldehyde (SnCl4), and 3-benzyloxy-2-methylpropionaldehyde (TiCl4) were found to be highly diastereoface selective so that three contiguous stereocenters could be established. With α-, β- , or α,β-alkoxy aldehydes, relative stereoselection (chelation) effectively controls internal stereolection. The ground state conformations of the chiral aldehydes were studied using molecular mechanics (MM2).

Discovery of a New Efficient Chiral Ligand for Copper‐Catalyzed Enantioselective Michael Additions by High‐Throughput Screening of a Parallel Library

A combinatorial library of 125 chiral Schiff base ligands 5 was synthesized with the use of solution-phase parallel synthesis and solid-phase extraction (SPE) techniques to scavenge excess reagents and reaction by-products and avoid chromatography. The synthetic methodology coupled five N-Boc-protected beta-amino sulfonyl chlorides 1a-e with five different amines 2f-j to give 25 N-Boc sulfonamides 3, which were in turn deprotected and coupled with five salicylaldehydes 4p-t to give 125 ligands 5 in good yields and of sufficient purity to be used in ligand-catalyzed reactions. These ligands were tested in the copper-catalyzed conjugate addition of dialkyl zinc to cyclic and acyclic enones. A multisubstrate high-throughput screening of the library was performed with an equimolar mixture of 2-cyclohexenone and 2-cycloheptenone (9 and 10, respectively, 0.2 mmol total), with 5.5 mol% ligand 5 (0.011 mmol) and 5 mol% Cu(OTf)2 (OTf= OSO2CF3) (0.010 mmol) in 1:1 toluene/ hexane at - 20 degrees C. From the screening of the library, 5bhr was identified as the best ligand, which yielded 3-ethylcyclohexanone (12) and 3-ethylcycloheptanone (13) in 82% and 81% ee, respectively, and complete conversions. Under optimized conditions (2.75 mol% 5bhr, 2.5 mol% copper(i) triflate, toluene as reaction solvent), improved results were obtained for 12 (90% ee, 93% yield) and for 13 (91% ee, 95% yield). Selected ligands 5 were also tested in the addition of Me2Zn to 2-cyclohexenone (9, ee up to 79%), of Et2Zn to 2-cyclopentenone (11, ee up to 80%) and to acyclic enones 16 and 17 (ee up to 50%).

Improved enantioselective synthesis of anti α-methyl-β-hydroxyesters through TiCl4-PPh3 mediated aldol condensation

Abstract The complex between TiCl 4 and PPh effectively catalyses the aldol addition of silyl ketene acetals to aldehydes dramatically improving the anti-syn ratios.

Cyclic RGD-Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds as New Potent Integrin Ligands

The synthesis of eight bifunctional diketopiperazine (DKP) scaffolds is described; these were formally derived from 2,3-diaminopropionic acid and aspartic acid (DKP-1-DKP-7) or glutamic acid (DKP-8) and feature an amine and a carboxylic acid functional group. The scaffolds differ in the configuration at the two stereocenters and the substitution at the diketopiperazinic nitrogen atoms. The bifunctional diketopiperazines were introduced into eight cyclic peptidomimetics containing the Arg-Gly-Asp (RGD) sequence. The resulting RGD peptidomimetics were screened for their ability to inhibit biotinylated vitronectin binding to the purified integrins α(v)β(3) and α(v)β(5), which are involved in tumor angiogenesis. Nanomolar IC(50) values were obtained for the RGD peptidomimetics derived from trans DKP scaffolds (DKP-2-DKP-8). Conformational studies of the cyclic RGD peptidomimetics by (1)H NMR spectroscopy experiments (VT-NMR and NOESY spectroscopy) in aqueous solution and Monte Carlo/Stochastic Dynamics (MC/SD) simulations revealed that the highest affinity ligands display well-defined preferred conformations featuring intramolecular hydrogen-bonded turn motifs and an extended arrangement of the RGD sequence [Cβ(Arg)-Cβ(Asp) average distance ≥8.8 Å]. Docking studies were performed, starting from the representative conformations obtained from the MC/SD simulations and taking as a reference model the crystal structure of the extracellular segment of integrin α(v)β(3) complexed with the cyclic pentapeptide, Cilengitide. The highest affinity ligands produced top-ranked poses conserving all the important interactions of the X-ray complex.

Asymmetric synthesis of functionalized α -amino-β-hydroxy acids via chiral norephedrine-derived oxazolidines

Abstract Both anti and syn enantiomerically pure functionalized α -amino-β-hydroxy acids and derivatives were synthesized starting from norephedrine-derived oxazolidine (1). The key-steps of the synthesis were the nucleophilic epoxidation of (1) and the nucleophilic opening of epoxy acid (3) with ammonia, both reactions proved regio- and diastereospecific. High yield preparation of the target anti aldehyde (9) was accomplished using standard procedures. The complementary syn aldehyde (23) was obtained via alkaline isomerization of the cis oxazolidinone (13) to the trans one. The aldehyde function of (9) and (23) provides a useful handle for manipulation to more complex structures, allowing potential access to a range of optically pure α -amino-β-hydroxy acids. The formal total synthesis of the monocyclic β-lactam antibiotic “carumonam” was accomplished using the present methodology.

A new method for the solution and solid phase synthesis of chiral β-sulfonopeptides under mild conditions

Abstract Chiral β-sulfonopeptides were synthesized both in solution and in the solid phase using the sulfonyl chlorides derived from enantiomerically pure 2-substituted taurines under mild coupling conditions [cat. 4-dimethylaminopyridine (DMAP) and excess methyl trimethylsilyl dimethylketene acetal (MTDA) as a proton trap].