Stereodivergent total synthesis of C5/C6-oxygenated angucyclines: stereochemical reassignment and antitumor
Yuting Cheng1,2, Zihao Dai2, Peng Xu2
1Department of Chemistry, University of Science and Technology of China Hefei 230026 P. R. China.
Abstract:
A unified total synthesis of 16 stereochemically defined 5,6-diol-bearing tetrangomycin-type angucyclines, including PD-116740, TAN-1085, himalaquinone G, and their congeners, was achieved. The synthesis features an acid-catalyzed hydration and subsequent retro-Friedel-Crafts-type ring-opening of a strained cyclobutene precursor to rapidly elaborate the angucycline framework. A completely catalyst-controlled reduction via Noyori asymmetric transfer hydrogenation (ATH) was then implemented to elaborate the C5/C6 diol stereocenters, which overrides inherent substrate biases, precisely transforming a racemic α-hydroxy ketone into all four possible C5/C6 diol stereoisomers. Access to this complete stereoisomeric matrix enabled the stereochemical reassignment of himalaquinone G from the originally assigned cis-(5R,6S)-diol to trans-(5R,6R)-diol. Antitumor activity profiling identified the unnatural enantiomer of PD-116740 as a highly potent agent (IC50 = 0.24 µM against A375 melanoma cells), outperforming its natural counterparts.
Related Concept Videos
Diels–Alder Reaction Forming Cyclic Products: Stereochemistry
Stereoisomerism of Cyclic Compounds
Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry
Stereoisomers
Cycloaddition Reactions: Overview
Thermal Electrocyclic Reactions: Stereochemistry
Selection Rules: Thermal Activation
Conjugated systems containing an even number of π-electron pairs undergo a conrotatory ring closure. For example, thermal electrocyclization of (2E,4E)-2,4-hexadiene, a conjugated diene containing two π-electron pairs, gives trans-3,4-dimethylcyclobutene.


![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)