Febrifugine Research Paper

Febrifugine

Febrifugine is a quinazolinone alkaloid first isolated from the Chinese herb Dichroa febrifuga but also found in the garden plant Hydrangea .The isomeric forms of alkaloids (+)-febrifugine (1) and (+)-isofebrifugine (2), are found in the roots and leaves of the Chinese Medicinal plant Dichroa febrifuga (also called Chinese quinine) which belongs to the Saxifragaceae family. For many centuries the roots and leaves of Dichroa febrifuga have been used in East Asia for the treatment of symptoms of fever. Decoctions of Chang Shan, was considered as one of the fundamental herbs in Chinese medicine, this was also been used in the treatment of a variety of ailments including stomach cancer. Its traditional use in the treatment of malaria

Baker’s first reported racemic synthesis, subsequent studies depend on on the diastereoselective reduction of substituted hetero aromatic species.

Baker’s another method to febrifugine was based on a diastereoselective reduction of a mono substituted furan which is followed by elaboration of the products into piperidines .Baker Treated 4 with hydrogen in the presence of Adam’s catalyst (platinum oxide usually represented as platinum (IV)oxide hydrate) and N-benzoylation of the resultant amino tetrahydrofuran gave 5. The melting point of the product (5) was 117 degree Celsius. In contrast, N-benzoyl protection of 4 was made to get 6. Later 6 is hydrogenated with Pd/C led to the isolation

Of 7 which had identical combustion analysis to 5 but possessed a melting point of 156 degree Celsius. Their relative structures cannot be determined due to lack of analytical tools, but both diastereoisomers were subsequently used by Baker to access the structure of

This method is based on two stereoselective carbon–carbon bond forming reactions to introduce the stereogenic centres. The reaction was carried out with a tin (II)-mediated asymmetric aldol condensation between the achiral aldehyde 22and achiral silyl enol ether 23 in the presence of diamine 24. Followed by this reaction, asymmetry was successfully induced and esters 25 and ent-25 were isolated in good enantiomeric and diastereomeric in excess amount. Then by using a modified version of the Barton–McCombie deoxygenation conversion of chiral enantio enriched ester 25 to 26 was carried out, Aldehyde (27) obtained from reduction and subsequent oxidation in 4 steps.The yiled was 55%. This reaction was later used in a three component Mannich type reaction with 2-methoxyaniline (28) and functionalized enol ether (29), which in the presence of ytterbium tri-dodecylsulfate (Yb(DS)3) gave the desired b-aminomethyl ketone adduct (30) in excellent yield. This mixture of diastereoisomers was then carried through the next two steps to get piperidine (31) as the major compound. The synthesis of unnatural (-)-febrifugine (1) continued with an oxidative double deprotection with ceric (IV) ammonium nitrate (CAN) followed by N-tert-butyloxycarbonyl (Boc)