Gaetano Angelici

Enamine Catalysis with Low Catalyst Loadings - High Efficiency via Kinetic Studies

Kinetic studies on enamine catalysis provided insight into the rate determining step(s) of peptide catalyzed conjugate addition reactions between aldehydes and nitroolefins. They demonstrate that not enamine formation but both the reaction of the enamine with the electrophile and hydrolysis of the resulting imine are rate limiting. These results allowed for reducing the catalyst loading by a factor of 10 to as little as 0.1 mol %. This is the lowest catalyst loading that has been achieved so far in enamine catalysis with low molecular weight catalysts for a broad range of substrates.

Nanofibers from Oxazolidi-2-one Containing Hybrid Foldamers: What is the Right Molecular Size?

A series of oligomers of the type Boc-(L-Phe-D-Oxd)(n)-OBn (Boc = tert-butoxycarbonyl; Oxd = 4-methyl-5-carboxy oxazolidin-2-one; Bn = benzyl) were prepared for n = 2-5. The shortest oligomer, Boc-(L-Phe-D-Oxd)(2)-OBn, aggregates and forms a fiber-like material with an anti-parallel beta-sheet structure in which the oligopeptide units are connected to each other by only one intermolecular hydrogen bond. The longer oligomers exhibit structural heterogeneity. They start to organize into secondary structures by the formation of intramolecular hydrogen bonds at the pentamer level. Microscopy and diffraction of the oligomers indicated a crystalline character for only the shorter ones.

A Fiberlike Peptide Material Stabilized by Single Intermolecular Hydrogen Bonds

Aggregation and disaggregation are central phenomena in nature. In this context, formation of fibers through selfassembly is of particular interest, as protein fibers are involved in intraand extracellular functions. Moreover, several diseases such as Alzheimer s or prion diseases are characterized by extracellular protein depositions. Recently, it was demonstrated that b-sheet layers are the most stable superstructure, although an exact explanation for the existence of this “dead-end” structure cannot yet be given. To understand aggregation phenomena, oligopeptides that interfere with or mimick [9–14] these processes may be designed and prepared. Indeed, the potential applications of such supramolecular assemblies exceed those of synthetic polymers since the building blocks may introduce biological function in addition to mechanical properties. All reported examples show fiber-forming peptides that are stabilized in the solid state by at least two N H···O=C hydrogen bonds. Herein, we present a fiberlike material that is stabilized by only single hydrogen bonds between dipeptide units. Such an assembly represents the absolute borderline case of a sheet structure. The fiberlike material was obtained by aggregation of Boc-l-Phe-d-Oxd-OBn (1; Boc = tert-butoxycarbonyl; Phe = phenylalanine; Oxd = 4-methyl-5-carboxy oxazolidin-2-one; Bn = benzyl), which can be easily synthesized by coupling of Boc-l-Phe-OH with H-d-Oxd-OBn (for details, see the Supporting Information). Compound 1 was purified by flash chromatography using a 1:1 mixture of cyclohexane and ethyl acetate as the eluting solvent. The formation of a fiberlike white solid was detected after evaporation of the mixture overnight. Moreover, a 20– 25 mm solution of 1 in the same solvent mixture forms a gel, which becomes a white solid after slow solvent evaporation (Figure 1a). The molecule also shows good solubility in polar

Synthesis of imidazolidin-2-one-4-carboxylate and of (tetrahydro)pyrimidin-2-one-5-carboxylate via an efficient modification of the Hofmann rearrangement.

A mild and efficient methodology for the rearrangement of protected asparagine and protected glutamine is reported; good results are obtained with a wide selection of protecting groups.

Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: implications of metal heterogeneity for evolution and antibiotic drug design.

The development of resistance to virtually all current antibiotics makes the discovery of new antimicrobial compounds with novel protein targets an urgent challenge. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is an essential metallo-enzyme for growth and proliferation in many bacteria, acting in the desuccinylation of N-succinyl-L,L-diaminopimelic acid (SDAP) in a late stage of the anabolic pathway towards both lysine and a crucial building block of the peptidoglycan cell wall. L-Captopril, which has been shown to exhibit very promising inhibitory activity in vitro against DapE and has attractive drug-like properties, nevertheless does not target DapE in bacteria effectively. Here we show that L-captopril targets only the Zn(2+)-metallo-isoform of the enzyme, whereas the Mn(2+)-enzyme, which is also a physiologically relevant isoform in bacteria, is not inhibited. Our finding provides a rationale for the failure of this promising lead-compound to exhibit any significant antibiotic activity in bacteria and underlines the importance of addressing metallo-isoform heterogeneity in future drug design. Moreover, to our knowledge, this is the first example of metallo-isoform heterogeneity in vivo that provides an evolutionary advantage to bacteria upon drug-challenge.

Atom Economic and Highly Syn‐selective Prolinamide‐Catalyzed Cross‐aldol Addition of Hydroxyacetone to Aromatic Aldehydes

Abstract The highly selective cross‐aldol addition of hydroxyacetone (HA) to p‐nitro and m‐nitrobenzaldehyde is reported; the reaction is catalyzed by three different di‐ or tripeptides all containing D‐Pro in the N‐terminal position and one or two residues of β3‐homophenylglycine (β3‐hPhg): H‐D‐Pro‐(R)‐β3‐hPhg‐OBn, H‐D‐Pro‐(R)‐β3‐hPhg‐(S)‐β3‐hPhg‐OBn and H‐D‐Pro‐[(S)‐β3‐hPhg]2‐OBn. Several reaction conditions have been tested, always in the absence of a protecting group on the HA hydroxyl. This reaction affords the desired compounds with complete regioselectivities being the other regioisomer completely avoided. Furthermore high enantioselectivities and satisfactory diastereoselectivities, always favouring the syn diastereoisomers, were obtained. The stereochemistry of the diols was further confirmed by the analysis of the 1H NMR spectrum of the corresponding carbonates, obtained by reaction of the syn/anti mixtures with triphosgene in presence of dimethylamino‐pyridine (DMAP).

Exploring the Conformation of Mixed Cis–Trans α,β-Oligopeptoids: A Joint Experimental and Computational Study

The synthesis and conformational preferences of a set of new synthetic foldamers that combine both the α,β-peptoid backbone and side chains that alternately promote cis- and trans-amide bond geometries have been achieved and addressed jointly by experiment and molecular modeling. Four sequence patterns were thus designed and referred to as cis-β- trans-α, cis-α- trans-β, trans-β- cis-α, and trans-α- cis-β. α- and β NtBu monomers were used to enforce cis-amide bond geometries and α- and β NPh monomers to promote trans-amides. NOESY and molecular modeling reveal that the trans-α- cis-β and cis-β- trans-α tetramers show a similar pattern of intramolecular weak interactions. The same holds for the cis-α- trans-β and trans-β- cis-α tetramers, but the interactions are different in nature than those identified in the trans-α- cis-β-based oligomers. Interestingly, the trans-α- cis-β peptoid architecture allows establishment of a larger amount of structure-stabilizing intramolecular interactions.

Synthesis and structure analysis of ferrocene‐containing pseudopeptides

Ferrocene with its aromaticity and facile redox properties is an attractive moiety to be incorporated into functional moieties. Medicinal applications of ferrocene are well known and ferrocene itself shows cytotoxic and antianemic properties. In this article, we will describe the synthesis and the structure analysis of two pseudopeptides containing a ferrocene moiety as N‐terminal group. After purification, Fc‐l‐Phe‐d‐Oxd‐OBn [l‐Phel‐phenylalanine; d‐Oxd(4R,5S)‐4‐Methyl‐5‐carboxy‐oxazolidin‐2‐one] appears as bright brown solid that spontaneously forms brown needles. The X‐ray diffraction of the crystals shows the presence of strong π interactions between the ferrocenyl moiety and the phenyl rings, while no NH•••OC hydrogen bonds are formed. This result is confirmed by FT‐IR and 1H NMR analysis. In contrast, both FT‐IR and 1H NMR analysis suggest that Fc‐(l‐Phe‐d‐Oxd)2‐OBn forms a turn conformation stabilized by intramolecular NH•••OC hydrogen bonds in solution. Chiroptical spectroscopies (ECD and VCD) substantially confirmed the absence of a well‐defined folded structure. The presence of the Fc moiety is responsible for specific ECD signals, one of which displayed pronounced temperature dependence and is directly related with the helicity assumed by the Fc core. Solid‐state ECD spectra were recorded and rationalized on the basis of the X‐ray geometry and quantum‐mechanical calculations.