Diastereoselectivity Switch in the Pd(0)/InI-Mediated Reactions of ß-Lactams with Aldehydes: An Entry into Nonracemic Semiprotected (3E)-2,6-Enediols.

The switch from N-methylimidazole (N-MI) to the Et3N N-ligand efficiently alters diastereoselectivity in Pd(0)/InI-mediated allylations of aldehydes with ß-lactam-derived organoindiums. As a result, (3E)-selective allylations and crotylations of a variety of aliphatic and (hetero)aromatic aldehydes with differently substituted chiral ε-amido-allylindiums were developed. Depending on the relative ß-lactam configuration, the reactions occur under kinetic or thermodynamic control, with effective remote 1,5- or 1,4,5-asymmetric induction to afford a diversity of previously unavailable (3E)-2,5-syn-2,6-anti-, (3E)-2,5-anti-2,6-anti-, and (3E)-2,5-anti-2,6-syn-substituted enediols, amino alcohols, and homoallylic alcohols in modest to high yields and with moderate to excellent diastereoselectivity. The effect of the N-ligand as well as ß-lactam and aldehyde structures on the yield and stereoselectivity was investigated.

Remote 1,5-Stereoselectivity Control by an N-Ligand Switch in the Pd(0)/InI-Promoted Reactions of 4-Ethynyl-ß-lactams with Aldehydes.

Configurationally stable ε-amido-propargylindiums, generated in situ from N-Ts-4-ethynylazetidin-2-ones in the presence of InI, catalytic amounts of Pd(PPh3)4, and N-methylimidazole or pyridine ligand react with unusual regioselectivity with aromatic and aliphatic aldehydes to afford 2,6- syn- or 2,6- anti-allenediols with excellent central-to-axial chirality transfer and useful levels of acyclic remote 1,5-stereocontrol.

Acyclic Remote 1,5- and 1,4,5-Stereocontrol in the Catalytic Stereoselective Reactions of ß-Lactams with Aldehydes: The Effect of the N-Methylimidazole Ligand.

The application of the N-methylimidazole ( N-MI) ligand in the Pd(0)/InI-promoted allylations of aldehydes with ß-lactam-derived organoindiums enables the reaction of azetidin-2-ones with diversely substituted allyl moieties, inert under previously reported conditions. As a result, allylations and crotylations of a variety of aromatic and aliphatic aldehydes with previously unavailable chiral ε-amido-allylindiums bearing α-, ß-, or γ-substituted allyl fragments were developed. The reactions occur under thermodynamic control with a highly efficient remote 1,5- or 1,4,5-stereocontrol to afford a diversity of (3 Z)-2,5- anti-2,6- syn- or (3 Z)-2,5- syn-2,6- anti-substituted enediols, aminoalcohols, and homoallylic alcohols in moderate to high yields and with an excellent diastereoselectivity. A detailed study on the effect of the ß-lactam and aldehyde structures and chirality on the yield and stereochemistry in the products was carried out.

Induction of cell killing and autophagy by amphiphilic pyrrolidine derivatives on human pancreatic cancer cells.

We have synthesized a wide array of structurally related amphiphilic compounds, containing a functionalized pyrrolidine polar group coupled to different ether-linked hydrocarbon chains, to generate novel structures with antitumor activity. These newly synthesized amphiphilic pyrrolidine-derived compounds were classified in three different sub-libraries regarding the number of hydroxyl groups substituting the pyrrolidine moiety at C3 and C4. Pyrrolidine compounds with one or none hydroxyl groups showed a potent cell killing activity against pancreatic cancer cells, but they lacked selectivity for tumor cells. Pyrrolidine compounds with two hydroxyl groups induced cell death in a wide variety of pancreatic cancer cell lines, and they were somewhat less cytotoxic to normal non-tumor cells. Among these latter compounds, the diol-derived pyrrolidine 20 ((2R,3R,4S)-2-{(9Z)-hexadec-9-en-1-yloxy]methyl}pyrrolidine-3,4-diol) induced autophagy and a potent apoptotic response in pancreatic ductal adenocarcinoma cells, which was inhibited by Bcl-XL overexpression and by caspase inhibition, in a way similar to that of the amphiphilic ether lipid edelfosine, with which it was compared. Pharmacological and genetic inhibition of autophagy potentiated 20-mediated apoptosis. These structure-activity relationship studies point out the importance of the diol polar group and aliphatic side chain of 20 in promoting apoptosis against pancreatic cancer cells in a rather controlled way, and some additional subtle modifications were found to be potential modulators of the cytotoxic activity.

Effective 1,5-stereocontrol in Pd(0)/InI promoted reactions of chiral N-Ts-4-vinylazetidin-2-ones with aldehydes. An efficient entry into nonracemic semi-protected (3Z)-2,6-anti-enediols.

ε-Amido-allylindiums generated in situ from N-Ts-4-vinylazetidin-2-ones in the presence of 2 eq. of InI and catalytic amounts of Pd(PPh3)4 react with a number of aromatic and aliphatic aldehydes with effective remote 1,5-stereocontrol to afford (3Z)-2,6-anti-enediols as major products in good yields and with excellent diastereoselectivity.

Amides in one pot from carboxylic acids and amines via sulfinylamides.

An efficient method has been developed for the direct amidification of carboxylic acids via sulfinylamides preformed in situ by the reaction of pure amines with prop-2-ene-1-sulfinyl chloride. The method can be applied to aliphatic acids, including pivalic acid, aromatic acids, and primary and secondary amines. It is compatible with acids bearing unprotected alcohol, phenol, and ketone moieties and applicable to the synthesis of peptides. It does not induce their α-epimerization.

Amide formation in one pot from carboxylic acids and amines via carboxyl and sulfinyl mixed anhydrides.

An efficient method has been developed for the preparation of yet unknown acyclic mixed anhydrides of carboxylic and sulfinic acids. Sterically hindered 2-methylbut-3-ene-2-sulfinyl carboxylates add primary and secondary amines preferentially onto the carbonyl moieties realizing a new method for the one-pot preparation of carboxamides. It uses 1:1 mixtures of carboxylic acids and amines without a base, requires no excess of reagents, and liberates only volatile coproducts. Protected di- and tripeptides have been prepared in solution without epimerization by application of this method.