Anion-accelerated asymmetric Nazarov cyclization: access to vicinal all-carbon quaternary stereocenters.

We have developed a catalytic asymmetric Nazarov cyclization that results in the formation of two contiguous all-carbon quaternary stereocenters in high yield with excellent levels of asymmetric induction. This method requires no catalyst recognition elements in the starting materials that are simple diketoesters. Geometrically pure E or Z isomers of the starting material lead to diastereomerically pure products with high enantioselectivity because the species that undergoes cyclization is a rhodium enolate that is configurationally stable.

Natural product preferentially targets redox and metabolic adaptations and aberrantly active STAT3 to inhibit breast tumor growth in vivo.

Dysregulated gene expression programs and redox and metabolic adaptations allow cancer cells to survive under high oxidative burden. These mechanisms also represent therapeutic vulnerabilities. Using triple-negative breast cancer (TNBC) as a model, we show that compared to normal human breast epithelial cells, the TNBC cells, MDA-MB-231 and MDA-MB-468 that harbor constitutively active STAT3 also express higher glucose-6-phosphate dehydrogenase (G6PD), thioredoxin reductase (TrxR)1, NADPH, and GSH levels for survival. Present studies discover that the natural product, R001, targets these adaptation mechanisms. Treatment of TNBC cells with R001 inhibited constitutively active STAT3, STAT3-regulated gene expression, and the functions of G6PD and TrxR1. Consequently, in the TNBC, but not normal cells, R001 suppressed GSH levels, but raised NADPH levels, reflective of a loss of mitochondrial respiration and which led to reactive oxygen species (ROS) induction, all of which led to loss of viable cells and inhibition of anchorage-dependent and independent growth. R001 treatment further led to early pyroptosis and late DNA damage, cell cycle arrest, and apoptosis only in the TNBC cells. Oral administration of 5 mg/kg R001 inhibited MDA-MB-468 xenografts growth in mice, with reduced pY705-STAT3, G6PD, TrxR1, and GSH levels. R001 serves as a therapeutic entity that targets the vulnerabilities of TNBC cells to inhibit tumor growth in vivo.

Fluorine on fluorenes.

A practical synthesis of 1,8-difluorofluorenone and of its (2,7)-dibromo and (2,4,5,7)-tetrabromo derivatives has been developed. Fluorinated fluorenones are the starting materials for polyhalogenated dibenzochrysenes as well as for geodesic hydrocarbons. 2,7-Dibromo-1,8-difluoro-9H-fluoren-9-one was converted to 3,14-dibromo-4,13-difluorodibenzo[g,p]chrysene through a novel strategy.

Modular Synthesis of a Semibuckminsterfullerene.

A convergent synthesis of dibenzochrysenes and diindenochrysenes that proceeds from difluorofluorenes and acetoxyenone 15 has been used to prepare 5,6,11,12-tetrabromosemibuckminsterfullerene (31). The synthesis is highly modular and is distinguished by proceeding through an unsymmetrical intermediate. Our work will enable the straightforward preparation of semibuckminsterfullerenes from diindenochrysenes that lack bilateral symmetry using common reagents and nonpyrolytic conditions.

Synthesis of Fluorenes and Dibenzo[g,p]chrysenes through an Oxidative Cascade.

We have developed robust, operationally simple syntheses of fluorenes and of dibenzo[g,p]chrysenes through oxidative cascade processes. These structures that are commonly encountered in optoelectronic materials, dyes, and pharmaceutical products are accessible from 1,4-dioxaspiro[4.5]decan-8-one. The reactions are conducted open to air with inexpensive, safe CuBr2 or CuCl2.