4 research outputs found
Catalytic Oxidative 1,2-Shift in 1,1′-Disubstituted Olefins Using Arene(iodo)sulfonic Acid as the Precatalyst and Oxone as the Oxidant
An efficient, catalytic hypervalent iodine-mediated oxidative 1,2-shift of 1,1′-disubstituted olefins is described. This methodology provides concise access to homobenzylic ketones with electron-donating substituents. In the case of cyclic systems, this transformation results in ring-expanded β-benzocycloalkanones, which are useful for further elaboration
Dyotropic Rearrangements of Fused Tricyclic β‑Lactones: Application to the Synthesis of (−)-Curcumanolide A and (−)-Curcumalactone
Dyotropic rearrangements of fused, tricyclic β-lactones
are
described that proceed via unprecedented stereospecific, 1,2-acyl
migrations delivering bridged, spiro-γ-butyrolactones. A unique
example of this dyotropic process involves a fused bis-lactone possessing
both β- and δ-lactone moieties which enabled rapid access
to the core structures of curcumanolide A and curcumalactone. Our
current mechanistic understanding of the latter dyotropic process,
based on computational studies, is also described. Other key transformations
in the described divergent syntheses of (−)-curcumanolide A
and (−)-curcumalactone from a common intermediate (11 and 12
steps from 2-methyl-1,3-cyclopentanedione, respectively), include
a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization
(NCAL) leading to a tricyclic β-lactone, a Baeyer–Villiger
oxidation in the presence of a β-lactone, and highly facial-selective
and stereocomplementary reductions of an intermediate spirocyclic
enoate. The described dyotropic rearrangements significantly alter
the topology of the starting tricyclic β-lactone, providing
access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones
in a single synthetic operation
Dyotropic Rearrangements of Fused Tricyclic β‑Lactones: Application to the Synthesis of (−)-Curcumanolide A and (−)-Curcumalactone
Dyotropic rearrangements of fused, tricyclic β-lactones
are
described that proceed via unprecedented stereospecific, 1,2-acyl
migrations delivering bridged, spiro-γ-butyrolactones. A unique
example of this dyotropic process involves a fused bis-lactone possessing
both β- and δ-lactone moieties which enabled rapid access
to the core structures of curcumanolide A and curcumalactone. Our
current mechanistic understanding of the latter dyotropic process,
based on computational studies, is also described. Other key transformations
in the described divergent syntheses of (−)-curcumanolide A
and (−)-curcumalactone from a common intermediate (11 and 12
steps from 2-methyl-1,3-cyclopentanedione, respectively), include
a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization
(NCAL) leading to a tricyclic β-lactone, a Baeyer–Villiger
oxidation in the presence of a β-lactone, and highly facial-selective
and stereocomplementary reductions of an intermediate spirocyclic
enoate. The described dyotropic rearrangements significantly alter
the topology of the starting tricyclic β-lactone, providing
access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones
in a single synthetic operation
Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440
The
development of a scalable route to TEV-37440, a dual inhibitor
of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK),
is presented. The medicinal chemistry route used to support this target
through nomination is reviewed, along with the early process chemistry
route to support IND (inversigational new drug) enabling activities
within CMC (Chemistry, Manufacturing, and Controls). The identification
and development of an improved route that was performed in the pilot
plant to supply early phase clinical supplies are discussed. Details
surrounding the use of a novel ring expansion, a selective nitration
through a para-blocking group strategy, a single-pot amination–hydrogenation,
a diastereomeric salt resolution, a through-process step to avoid
a hazardous intermediate, and a practical formation of a trihydrochloride
dihydrate salt are disclosed