Franco Cozzi

Poly(Ethylene Glycol)-Supported Proline: A Versatile Catalyst for the Enantioselective Aldol and Iminoaldol Reactions

(2S,4R)-4-Hydroxyproline has been anchored to the monomethyl ether of poly(ethylene glycol), MW 5000, by means of a succinate spacer to afford a soluble, polymer-supported catalyst (PEG-Pro) for enantioselective aldol and iminoaldol condensation reactions. This organic catalyst can be considered as a minimalistic version of a type I aldolase enzyme, with the polymer chain replacing the enzymes peptide backbone, and the proline residue acting as the enzymes active site. In the presence of PEG-Pro (0.25–0.35 mol equiv.), acetone reacted with enolizable and non-enolizable aldehydes and imines to afford β-ketols and β-aminoketones in good yield and high enantiomeric excess (ee), comparable to those obtained using non-supported proline derivatives as the catalysts. Extension of the PEG-Pro-promoted condensation to hydroxyacetone as the aldol donor opened an access to synthetically relevant anti-α,β-dihydroxyketones and syn-α-hydroxy-β-aminoketones, that were obtained in moderate to good yields, and good to high diastereo- and enantioselectivity. Exploiting its solubility properties, the PEG-Pro catalyst was easily recovered and recycled to promote all of the above-mentioned reactions, that occurred in slowly diminishing yields but virtually unchanged ees.

Enantioselective aldol condensations catalyzed by poly(ethylene glycol)-supported proline

Keywords: aldol reactions; asymmetric catalysis; catalyst immobilization; chiral bases; soluble polymers

Through-space interactions between face-to-face, center-to-edge oriented arenes: importance of polar-π effects

Two series of conformationally restricted polycyclic compounds (1-3 and 4-7) have been synthesized as model systems for studying the through-space interactions between face-to-face, center-to-edge (parallel-offset) oriented arenes. These compounds feature different X substituents on one of the interacting rings. By monitoring the variation of the delta Gz for the rotation around the aryl-aryl bond in 1-7 as a function of X by 2D [1H,1H] EXSY NMR spectroscopy, it was found that the barriers increase on passing from electron-donating to electron-withdrawing substituted derivatives. Quantum mechanical calculations [MP2/DVZ (2d,p)//B3LYP/DVZ(2d,p)] gave barrier values and variations in agreement with the experimental data. The results are consistent with a repulsive arene-arene interaction dominated by electrostatic effects.

Poly(ethylene glycol)‐Supported Chiral Imidazolidin‐4‐one: An Efficient Organic Catalyst for the Enantioselective Diels–Alder Cycloaddition

A tyrosine-derived imidazolidin-4-one was immobilized on a modified poly(ethylene glycol) and converted in situ into a soluble polymer-supported catalyst for the enantioselective Diels–Alder cycloaddition of acrolein to 1,3-cyclohexadiene (up to 92% ee) and 2,3-dimethyl-1,3-butadiene (73% ee). Catalyst recycling (up to four cycles) was accompanied by some loss of the chemical efficiency and marginal erosion of the enantioselectivity.

The S‐Thioester Enolate/Imine Condensation: A Shortcut to β‐Lactams

The condensation between imines and S-thioester metal enolates provides a mild, efficient, and straightforward route to the preparation of β-lactams. The synthetic applications and the stereochemical aspects of this reaction are discussed.

Immobilization of catalysts derived from Cinchona alkaloids on modified poly(ethylene glycol)

Abstract The straightforward immobilization of some derivatives of Cinchona alkaloids on modified poly(ethylene glycol)s is reported. The compounds, obtained by simple reactions exploiting different sites for the attachment of the alkaloids to the polymer, were tested as catalysts in the enantioselective benzylation of the benzophenone imine of glycine t -butyl ester (ee up to 64%) and in the conjugate addition of thiophenol to cyclohexenone (ee 22%). The observed stereoselectivities were compared to those obtained either with the unsupported catalysts or with the catalysts immobilized on different polymeric matrixes. The influence of the poly(ethylene glycol) moieties on the catalytic activity is discussed.

Soluble-polymer-supported synthesis of beta-lactams on a modified poly(ethylene glycol)

A modified poly(ethylene glycol) (PEG) has been developed for the soluble-polymer-supported synthesis of beta-lactams. The monomethylether of PEG (MeOPEG) with an average M(W) of 5000 was used as the support, a 4-(3-propyl)phenyl residue as the spacer, and a 4-oxyphenylamino group as the moiety with the reactive functionality. From this modified PEG representative aromatic, heteroaromatic, unsaturated, and aliphatic imines were obtained in high yields by different procedures. The polymer-supported imines were then employed to prepare several beta-lactams by enolate/imine condensation and ketene/imine cycloaddition. Examples of the control of the absolute stereochemistry during the azetidinone ring formation are also reported. The reactions carried out on the polymer-bound imines showed a remarkable similarity to those performed on nonimmobilized imines, both in terms of yields and stereoselectivities. Removal of the beta-lactams from the polymer has also been accomplished to directly deliver the N-unsubstituted azetidinones.

Highly stereoselective synthesis of optically active masked syn-α,β-dihydroxy aldehydes.

Dihydroquinidine acetate promoted osmylation of acetals of E-α,β- unsaturated aldehydes occurs with up to 40:1 stereoselection to afford the corresponding protected syn-α,β -dihydroxy aldehydes.

1,3-dipolar cycloaddition reactions of azomethine ylides on enantiomerically pure (E)-γ-alkoxy-α,β-unsaturated esters

Abstract Enantiomerically pure (E)-γ-alkoxy-α,β-unsaturated esters were reacted with azomethine ylides obtained from glycine imines in the presence of LiBr and diazabicycloundecene (DBU), to afford tetrasubstituted pyrrolidines with complete regiocontrol and fair to excellent diastereoselectivity (only two diastereoisomers formed in up to 96: 4 diastereoisomeric ratio). The results are compared with those of other 1,3-dipolar cycloadditions, and the origin of stereocontrol is discussed.

Diastereoselective synthesis of 1,2-diphenyl-1,2-diaminoethanes by Yb(OTf)3 accelerated reductive coupling of imines

Abstract New reaction protocols have been established to perform the reductive coupling of N -benzyl benzaldimines to 1,2-diphenyl-1,2-diaminoethanes in mild, stereoselective, and catalytic conditions by the use of SmI 2 and Yb(OTf) 3 .