Reactivity of Aziridinomitosene Derivatives Related to FK317 in the Presence of Protic Nucleophiles

Abstract

The syntheses and reactivity of N-TBDPS and N-trityl protected derivatives of an aziridinomitosene corresponding to FK317 are described. New reactivity patterns were observed for these highly sensitive and functionally dense heterocycles under mild nucleophilic conditions approaching the threshold for degradation. Thus, the silyl or trityl protected aziridinomitosene reacted with Cs2CO3/CD3OD to give isomeric products where substitution occurred at C(10) and C(9a) (mitomycin numbering) providing a CD3 ether and a CD3 hemiaminal respectively. These findings show that heterolysis at C(10) is faster than at aziridine C(1), in contrast to the behavior of typical aziridinomitosenes in the mitomycin series. The labile N-TBDPS hemiaminal and the more stable N-trityl hemiaminal resemble the mitomycin K substitution pattern. A reagent consisting of CsF in CF3CH2OH/CH3CN desilylated a simple N-TBDPS aziridine, but caused nucleophilic cleavage at C(1) as well as C(10) without cleavage of the N-TBPDS group in the fully functionalized penultimate aziridinomitosene. The high reactivity of the C(10) carbamate with nucleophiles precludes the use of deprotection methodology that requires N-protonation for fully functionalized aziridinomitosenes in the FK317 series.

cis‐Aziridine Synthon Based Synthetic Investigation for Tamiflu Employing Horner‐Wadsworth‐Emmons Reaction

“…Accordingly, ester functionality of cis-aziridine 3 was reduced into alcohol 28 by using LiAlH 4 as a reducing agent which was then converted to iodide 27 under Mitsunobu reaction condition in 92 % yield. [19] It is important to note that, attempt to get iodide 27 from aziridine-2-alcohol 28 under Appel reaction condition or by mesylation followed by treatment with iodide source ended up in allylic amine formation. [20] Iodide 27 was then alkylated with methyl diethylphosphonoacetate using NaH as a base to obtain alkylated product 26 as a mixture of diastereomers in 83 % yield.…”