Ph.D Thesis

Ph.D StudentSinha Santosh
SubjectTandem Oxidative Polycyclization Reaction of
Hydroxypolyenes with Rhenium (VII) Oxide
DepartmentDepartment of Chemistry
Supervisor PROFESSOR EMERITUS Ehud Keinan


The tandem oxidative poly-cyclization reaction with rhenium(VII) oxide reagents, was first reported in 1995. The reaction is highly stereoselective producing either cis or trans tetrahydrofuran (THF) rings. Rhenium(VII) oxide cyclization is a powerful tool by which poly bis-homoallylic alcohols can be transformed into poly-THF products in a single step.

Based on the first reports on monocyclization it was generally accepted that the rhenium(VII) oxide-mediated oxidative cyclization reactions always produce trans-THF rings. The results presented in this work indicate that this is not always true. The stereoselectivity and the relative stereochemistry of the produced THF rings depend on the rhenium(VII) reagents used as well as on the substrate itself.

These conclusions are based on triple oxidative cyclization experiments with trans-trans-trans-4,8,12-trienol using trifluoroacetylperrhenate (CF3CO2ReO3) in the presence of trifluoroacetic anhydride. The tris-THF product obtained from the triple oxidative cyclization was found to have a trans-threo-cis-threo-cis-threo -stereochemistry rather than the expected trans-threo-trans-threo-trans-threo structure.

To understand the stereochemical rules of this reaction, four dienols (trans-trans, trans-cis, cis-cis, cis-trans) were prepared and subjected to the tandem oxidative bis-cyclization reaction with trifluoroacetyl perrhenate (CF3CO2ReO3). The proof of stereochemistry was provided by 19F NMR spectral data of Mosher ester derivatives, 2D 1H-1H COSY, TOCSY and ROESY experiments, and by independent synthesis of authentic reference compounds. Based on these results, a set of rules was deduced to predict product configurations in the single-step tandem bis-cyclization reactions with trifluoroacetylperrhenate. In summary, the stereochemistry of the first THF ring is always trans while that of the subsequent ones depends on the stereochemistry of the two vicinal oxygen functions formed in the first cyclization. When these vicinal oxygen functions have a threo relationship, the next cyclization step produces a cis-THF ring and when they have an erythro relationship, the next cyclization produces a trans-THF ring.

The very high regio- and diastereoselectivity of this reaction makes it a powerful tool for the synthesis of polyoxygenated carbon skeltons containing many stereogenic centers, and for the Annonaceous acetogenins in particular. Many of the acetogenins, which were isolated from the Annonaceae plants, have shown remarkable cytotoxic, antitumor, antimalarial, immunosuppressive, pesticidal and antifeedant activities. The biological activities have led to an increasing interest in the synthesis of these compounds.

The synthesis of natural Annonaceous acetogenins has been achived using the oxidative cyclization reaction using rhenium(VII) oxide as well as various asymmetric methodologies, including the enantioselective and regioselective functionalization of a "naked carbon skeletons" that possess one or more double bonds. Specefically, the Sharpless asymmetric dihydroxylation (AD), asymmetric epoxidation (AE), Mitsunobu, and Williumson’s etherification reaction were used. The combination of these methods with the tandem oxidative cyclization reaction using rhenium(VII) oxide provide easy access to most of the naturally occurring acetogenins. The compounds synthesized via these methods include mucocin, trilobin, squamotacin, asimicin and bullatacin.