Asymmetric Organocatalytic Mannich Reaction in the Synthesis of Hybrid Isoindolinone-Pyrazole and Isoindolinone-Aminal from Functionalized α-Amidosulfone.

The investigation of the reactivity of an α-amido sulfone derived from 2-formyl benzoate under organocatalytic conditions in the presence of acetylacetone allowed the synthesis of a new heterocyclic hybrid isoindolinone-pyrazole with high enantiomeric excess. Dibenzylamine was also used as a nucleophile to afford an isoindolinone with aminal substituent in 3-position in suitable selectivity. The use of Takemoto's bifunctional organocatalyst not only led to observed enantioselectivity but was also important in accomplishing the cyclization step in both cases. Notably, this catalytic system proved to be particularly effective in comparison to widely used phase transfer catalysts.

Asymmetric Cascade Aza-Henry/Lactamization Reaction in the Highly Enantioselective Organocatalytic Synthesis of 3-(Nitromethyl)isoindolin-1-ones from α-Amido Sulfones.

The asymmetric synthesis of novel 3-substituted isoindolinones is herein reported. A new cascade reaction was developed that consisted of the asymmetric nitro-Mannich reaction of suitable α-amido sulfones designed from 2-formyl benzoates, followed by the in situ cyclization of the adducts. Very high enantioselectivities, up to 98% ee, and very good yields were obtained in the presence of the readily available neutral bifunctional organocatalyst derived from trans-1,2-diaminocyclohexane, which is known as Takemoto's catalyst. The investigation of the reactivity of the obtained products allowed either the selective Boc-deprotection or reduction of the nitro group, leading to further functionalized 3-substituted isoindolinones without affecting the enantiomeric purity.

Scalable (Enantioselective) Syntheses of Novel 3-Methylated Analogs of Pazinaclone, (S)-PD172938 and Related Biologically Relevant Isoindolinones.

Herein, we report the application of an efficient and practical K2CO3 promoted cascade reaction of 2-acetylbenzonitrile in the synthesis of novel 3-methylated analogs of Pazinaclone and PD172938, belonging to isoindolinones heterocyclic class bearing a tetrasubstituted stereocenter. Organocatalytic asymmetric synthesis of the key intermediate and its transformation into highly enantioenriched 3-methylated analog of (S)-PD172938 was also developed. These achievements can be of particular interest also for medicinal chemistry, since the methyl group is a very useful structural modification in the rational design of new and more effective bioactive compounds.

The First Highly Enantioselective Synthesis of 3-Sulfinyl-Substituted Isoindolinones Having Adjacent Carbon and Sulfur Stereocenters.

A highly stereoselective access to 3-sulfinyl-substituted isoindolinones has been achieved by a tandem organocatalytic addition/cyclization reaction of 2-carbobenzyloxy-N-tosylbenzylidenimine with thiols and succeeding diastereoselective oxidation with MCPBA. First, enantioenriched isoindolinone N,S-acetals have been obtained through a dynamic kinetic asymmetric transformation induced by a bifunctional chiral thiourea organocatalyst. In turn, the newly created carbon stereocenter enabled a high diastereocontrol in the subsequent sulfoxidation. Based on DFT calculations, a theoretical rationale for the stereoselectivity of the oxidation reaction is also provided.

Synthesis of ß-sulfinyl cyclobutane carboxylic amides via a formal α to ß sulphoxide migration process.

An original tandem reaction consisting of a thermal elimination-addition process was developed. Highly substituted ß-sulfinyl cyclobutane carboxylic acid derivatives were obtained from isomeric α-sulfinyl derivatives in a single operation in good to high yields and with high trans diastereoselectivity.

A facile access to 1-substituted and unsubstituted 3-isoquinolinones via Mannich or Sn2 initiated cascade reactions under catalyst-free conditions.

Herein we report new cascade processes for the easy access to 1-substituted and C-unsubstituted 3-isoquinolinones. The Mannich initiated cascade reaction led to the synthesis of novel 1-substituted 3-isoquinolinones under catalyst-free conditions in the presence of nitromethane and dimethylmalonate as nucleophiles without the use of any solvent. The optimization of the synthesis of the starting material in a more environmentally benign manner, allowed the identification of a common intermediate useful for the synthesis of C-unsubstituted 3-isoquinolinones as well. The synthetic utility of 1-substituted 3-isoquinolinones was also demonstrated.

Stereoselective Syntheses of Masked ß-Amino Acid Containing Phthalides.

We herein report a protocol for the asymmetric aldol-initiated cascade addition of isoxazolidin-5-ones to ortho-cyanobenzaldehydes by using Takemoto's bifunctional organocatalyst. This approach allows for the synthesis of various novel ß2,2-amino acid-phthalide conjugates with good enantio- and diastereoselectivities in reasonable yields and the further ring-opening of these compounds to acyclic carboxylic acid derivatives was demonstrated too.

Tandem Wittig Reaction-Ring Contraction of Cyclobutanes: A Route to Functionalized Cyclopropanecarbaldehydes.

An original tandem reaction consisting of a Wittig reaction-ring contraction process between α-hydroxycyclobutanone and phosphonium ylides has been developed. Highly functionalized cyclopropanecarbaldehydes are obtained in good to high yield.

Investigating the Anticancer Activity of Isatin/Dihydropyrazole Hybrids.

A series of isatin-dihydropyrazole hybrids have been synthesized in order to assess their potential as anticancer agents. In particular, 12 compounds were evaluated for their antiproliferative activity toward A549, IGR39, U87, MDA-MB-231, MCF-7, BT474, BxPC-3, SKOV-3, and H1299 cell lines, and human foreskin fibroblasts. Four compounds exhibited interesting antiproliferative activity and were further examined to determine their EC50 values toward a panel of selected tumor cell lines. The best compounds were then investigated for their induced mechanism of cell death. Preliminary structure-activity relationship indicates that the presence of a substituent such as a chlorine atom or a methyl moiety in position 5 of the isatin nucleus is beneficial for the antitumor activity. EMAC4001 proved the most promising compound within the studied series with EC50 values ranging from 0.01 to 0.38 µM.