Ring-opening of cycloalkane epoxides and aziridines with aromatic amines : toward the total synthesis of pactamycin
Abstract Ring-opening reactions of epoxides and aziridines have been extensively studied. The influence of different protecting groups on the hydroxyl group in the ring-opening reactions of cis- and trans- 3-hydroxy-1,2-cycloalkane epoxides with aromatic amines was studied. It was shown that Yb(OTf)3 in toluene was a mild catalyst for regioselective ring-opening, to give -anilino cycloalkanols in good yields. Heating the reaction mixture accelerated the rate of the reaction, albeit at the expense of yield. The aniline moiety was regioselectively added at the carbon furthest from the hydroxyl or ether group to yield a single regioisomer. The same trend was also observed with 3-azidocyclohex-1-ene epoxides and the corresponding 3-carbamates. The reaction time became shorter when acetonitrile was used as solvent, possibly due to the homogeneous medium. Ytterbium(III) triflate has also been used as the catalyst for the regioselective ring-opening of unactivated aziridines in cyclohexanes having an azide or benzyl ether substituent. Azide ion or aniline forms the corresponding trans-products giving access to vicinal diamines in good yields. A racemic ω-alkoxy p-methoxy benzyl ether HDAC inhibitor has been prepared in 8 synthetic steps (26% overall yield) from 1-((tert-butyldiphenylsilyl)oxy)hept-6-en-2-ol. This is an improvement over the published method (9 steps, 16% overall yield). The cross-metathesis method proved to be efficient and practical in this strategy, and alkylation using p-methoxybenzyl trichloroacetimidate in the presence of Sc(OTf)3 improved the overall yield of the synthesis.  An amino alcohol that contains all the core carbons, functional groups and the required stereochemistry present in pactamycin was obtained starting from L-threonine over 27 steps. The methodology described in this thesis allows for a synthesis of this key intermediate on a multigram scale.
Epoxide Aziridine Yb(OTf)3 p-methoxybenzyl trichloroacetimidate HDAC inhibitor Pactamycin L-threonine aziridine Yb(OTf)3