A new synthetic approach to the lactol moiety of halichoblelide

A stereoselective approach to the γ-lactol moiety of halichoblelide is described starting from commercially available (R)-1-butyn-3-ol. The key step is the hydroboration of a chiral protected 1,2-butadien-3-ol and its addition to furfural

Stereodivergent addition of 4-Silyloxy-1,2-Allenes to aldehydes by hydroboration

We have established a new stereodivergent approach to 2-vinyl-1,3-diols based on a hydroboration of allene/addition of aldehyde tandem process. The stereocenter present next to the allenyl moiety (C1) in the starting allene effectively determines the configuration of the new formed carbinol (C3) whereas the relative configuration of C2 and C3 is determined by the configuration (E/Z) of the transient 2- alkenylborane intermediate. It should be noted that the order of mixing of the reagents and the kind of aldehyde used allowed us to obtain three out of the four possible diastereomers of the 1,3- diol

A Useful allene for the stereoselective synthesis of protected quaternary 2-amino-2-vinyl-1,3-diols

Treatment of readily available allene 1 with Cy2BH followed by addition of an aldehyde led to quaternary protected 2-amino-2-vinyl-1,3-diols in high yield and excellent stereochemical purity. The choice of benzoyl as N-protecting group is critical since the observed N- to O-Bz transfer during the process prevents later undesired isomerizations in the adducts and keeps all heteroatoms protected

Convenient synthesis of C75, an inhibitor of FAS and CPT1

C75 is a synthetic racemic α-methylene-γ-butyrolactone exhibiting anti-tumoral properties in vitro and in vivo as well as inducing hypophagia and weight loss in rodents. These interesting properties are thought to be a consequence of the inhibition of the key enzymes FAS and CPT1 involved in lipid metabolism. The need for larger amounts of this compound for biological evaluation prompted us to develop a convenient and reliable route to multigram quantities of C75 from easily available ethyl penta-3,4-dienoate 6. A recently described protocol for the addition of 6 to a mixture of dicyclohexylborane and nonanal followed by acidic treatment of the crude afforded lactone 8, as a mixture of cis and trans isomers, in good yield. The DBU-catalyzed isomerization of the methyl esters 9 arising from 8 gave a 10:1 trans/cis mixture from which the trans isomer was isolated and easily transformed into C75. The temporary transformation of C75 into a phenylseleno ether derivative makes its purification, manipulation and storage easier

A new synthetic approach to the lactol moiety of halichoblelide

A stereoselective approach to the γ-lactol moiety of halichoblelide is described starting from commercially available (R)-1-butyn-3-ol. The key step is the hydroboration of a chiral protected 1,2-butadien-3-ol and its addition to furfural

Total synthesis of (-)-isoavenaciolide

An enantioselective approach to (-)-isoavenaciolide was achieved starting from 1- undecyn-3-ol. The synthesis relied upon the preparation of a chiral 4-silyloxy-2-alkenylborane by hydroboration of a protected 2,3-allenol and subsequent stereoselective addition to 2- thiophenecarboxaldehyd

A Useful allene for the stereoselective synthesis of protected quaternary 2-amino-2-vinyl-1,3-diols

Treatment of readily available allene 1 with Cy2BH followed by addition of an aldehyde led to quaternary protected 2-amino-2-vinyl-1,3-diols in high yield and excellent stereochemical purity. The choice of benzoyl as N-protecting group is critical since the observed N- to O-Bz transfer during the process prevents later undesired isomerizations in the adducts and keeps all heteroatoms protected

Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.

Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer

Convenient synthesis of C75, an inhibitor of FAS and CPT1

C75 is a synthetic racemic α-methylene-γ-butyrolactone exhibiting anti-tumoral properties in vitro and in vivo as well as inducing hypophagia and weight loss in rodents. These interesting properties are thought to be a consequence of the inhibition of the key enzymes FAS and CPT1 involved in lipid metabolism. The need for larger amounts of this compound for biological evaluation prompted us to develop a convenient and reliable route to multigram quantities of C75 from easily available ethyl penta-3,4-dienoate 6. A recently described protocol for the addition of 6 to a mixture of dicyclohexylborane and nonanal followed by acidic treatment of the crude afforded lactone 8, as a mixture of cis and trans isomers, in good yield. The DBU-catalyzed isomerization of the methyl esters 9 arising from 8 gave a 10:1 trans/cis mixture from which the trans isomer was isolated and easily transformed into C75. The temporary transformation of C75 into a phenylseleno ether derivative makes its purification, manipulation and storage easier