Intramolecular [4 + 2] cycloaddition of nitroalkenes for construction of vicinal quaternary stereocenters

[chemical reaction: see text]. Nitroalkene (E)-1 has been synthesized to test the feasibility of an intramolecular [4 + 2] cycloaddition in a planned synthesis of daphnilactone B. This nitro olefin contains two unique structural features, a nitromethylene lactone and a pendant diene, that combine under the action of SnCl4 in a highly selective fashion to afford nitronates 2a and 2b. These products represent the correct relationship for the vicinal quaternary stereogenic centers in the core of daphnilactone B.     

Synthesis and Reactions of Trifluoromethyl-Substituted 1,3,5-Triazines

A variety of di- and trifluoromethyl-s-triazines are prepared following straightforward synthetic protocols from simple, commercially available starting materials. Trichloromethyl-substituted triazine electrophiles are obtained in good yield and react with amine nucleophiles to afford aminotriazine products in good to excellent yield. The nucleophilic aromatic substitution reaction is broad in scope and proceeds smoothly with both aromatic and aliphatic (primary, secondary, and branched) amines in the presence of non-participating functional groups including alcohols, carboxylic acids, indoles, and common amine protecting groups. Furthermore, most reactions require only a catalytic amount of 4-DMAP with no stoichiometric base and are complete within two hours at ambient temperature.     

Self-assembly of an Octa-uranate Cage Complex with a Rigid bis-Catechol Ligand

While the terminally protected tripeptide Boc-Phe-Gly-m-ABA-OMe I (m-ABA, meta-amino benzoic acid) is an excellent gelator of aromatic organic solvents, another similar tripeptide Boc-Leu-Gly-m-ABA-OMe II, where the Phe residue of peptide I is replaced by Leu, cannot form gels with the same solvents. The morphology of the gels of peptide I, characterised by the field-emission scanning electron microscopy and high-resolution transmission electron microscopy, reveals the formation of nanofibrous networks which are known to encapsulate solvent molecules to form gels. The wide-angle X-ray scattering studies of the gels suggest the β-sheet-mediated self-assembly of peptide I in the formation of a nanofibrous network, where π-stacking interactions of Phe play an important role in the self-assembly and gel formation. The dried gel of peptide I observed between crossed polarisers after binding with a physiological dye, Congo red, shows a bluish-green birefringence, a characteristic of amyloid fibrils.     

Tandem double-intramolecular [4+2]/[3+2] cycloadditions of nitroalkenes. Studies toward a total synthesis of daphnilactone B: piperidine ring construction

[reaction: see text] Two model studies in support of a total synthesis of the complex polycyclic alkaloid daphnilactone B have been completed. The objectives of the models studies were to demonstrate the use of a tandem double-intramolecular [4+2]/[3+2] nitroalkene cycloaddition for the stereocontrolled construction of four of the rings in the core of the natural product. The first model study established the ability to create a pyrrolidine ring corresponding to ring A of daphnilactone B through a modification of the dipolarophile and subsequent functional group manipulations. The second model study required the modification of the dienophile in the [4+2] cycloaddition to accommodate the formation of a piperidine ring (ring B of daphnilactone B). Nitroalkene 26 containing a diene as the dienophile served well in the tandem cycloaddition to afford the nitroso acetal 38a in 77% yield. Subsequent functional group manipulations allowed for the high-yielding conversion to the core of daphnilactone B.     

Tandem double intramolecular [4+2]/[3+2] cycloadditions of nitroalkenes: construction of the pentacyclic core structure of daphnilactone B

An asymmetric synthesis of the ABCD ring system of daphnilactone B is described. The synthesis features a tandem, double intramolecular, [4+2]/[3+2] cycloaddition of a highly functionalized, enantiomerically enriched nitroalkene to generate a pentacyclic nitroso acetal. The cycloaddition establishes six contiguous stereogenic centers including the critical CD ring junction that bears two quaternary stereogenic centers. Hydrogenolysis of the nitroso acetal followed by amide reduction and cyclization provided the AB rings. The methyl substituent on the A ring was installed in the correct configuration via hydrogenation of an exocyclic olefin in the final step.     

Discovery and SAR Studies of Potent Modulators of BMI-1 Expression

In our efforts to identify molecules that selectively reduce the expression of BMI1, a stem cell gene, we discovered and characterized the first-in-class series of small molecules that modulate the expression of BMI1 protein in cancer cells. Structure–activity and structure–property relationships associated with this series were investigated through medicinal chemistry efforts. These studies revealed important structural features required for achieving anti-tumor activity and acceptable pharmacokinetic properties within this series. The 4-CF₃−Ph at the left-side of the molecule, a proper placement of the N-atom on the six-membered heterocycle in the middle, combined with a properly substituted C(2)-methyl benzimidazole on the right-hand side were required to achieve potency, microsomal stability, and exposure upon oral dosing. A compound (PTC-02) with acceptable pharmacological properties and efficacious in vivo in several tumor animal models was identified.