Explorations on the total synthesis of (±)-isoschizogamine using an intramolecular 1,4-dipolar cycloaddition strategy

Abstract

A new strategy for the synthesis of the isoschizozygane alkaloid core has been developed that is based on a 1,4-dipolar cycloaddition reaction of a cross-conjugated heteroaromatic betaine. The required substituted piperidin-2-one needed for the eventual 1,4-dipolar cycloaddition step was prepared using an aza-Claisen rearrangement.

Are Alkyne Reductions Chemo-, Regio-, and Stereoselective Enough To Provide Pure (Z)-Olefins in Polyfunctionalized Bioactive Molecules?

“…In the presence of (dba) 3 Pd 2 ·CHCl 3 (2.5 mol %) and tri- o -tolylphosphine (10 mol %), hydrosilanes, and acetic acid as hydrogen donors in benzene, internal alkynes were quickly (60 s to 20 min) reduced to ( Z )-olefins in good yields (65–95%), without any over-reduction or reduction of other doubles bonds in the molecule. Interestingly, esters, free hydroxyl, nitro, ODMPS, OPMB, and OTBS groups, phenylsulfides, ketone, but also isolated and conjugated double bonds did not interfere with this reduction process. , Diethylphosphonate and amide functions were well tolerated also. However, the high stereospecificity observed is dramatically spoiled, in some cases, by in an situ isomerization of the formed ( Z )-double bond. ,, ( Z )-Vinylsilanes obtained from TMS-alkynes also readily isomerized (moderate yield, Z / E ratio: 1/2 to 1/3.7; prolonged reaction times in comparison with internal alkynes were needed for full conversion).…”

“…Interestingly, esters, free hydroxyl, nitro, ODMPS, OPMB, and OTBS groups, phenylsulfides, ketone, but also isolated and conjugated double bonds did not interfere with this reduction process. 283,286 Diethylphosphonate 287 and amide 288 functions were well tolerated also. However, the high stereospecificity observed is dramatically spoiled, in some cases, by in an situ isomerization of the formed (Z)-double bond.…”

“…However, the high stereospecificity observed is dramatically spoiled, in some cases, by in an situ isomerization of the formed (Z)-double bond. 283,287,288 (Z)-Vinylsilanes obtained from TMS-alkynes also readily isomerized (moderate yield, Z/ E ratio: 1/2 to 1/3.7; prolonged reaction times in comparison with internal alkynes were needed for full conversion).…”

Total Synthesis of (−)-Isoschizogamine

“…The two nitrogen atoms of these heterocycles form an aminal that is adjacent to a quaternary carbon. These fascinating structural features have attracted the attention of synthetic chemists, and one racemic total synthesis by Heathcock and two synthetic studies have been reported to date. Herein we disclose a novel total synthesis of isoschizogamine that features a unique approach to the construction of the carbon framework.…”

Synthesis and Applications of Vinylaziridines and Ethynylaziridines

“…N -Acetylaziridine 346 , which was easily prepared via Wittig reaction of the enantiomerically pure aziridine aldehyde, was stereoselectively converted to the seven-membered lactam 348 by the aza-Claisen rearrangement . Reduction of ester with diisobutylaluminium hydride (DIBAL-H) followed by a formal hetero-Diels–Alder reaction using aniline 349 gave the highly functionalized tetrahydroquinoline derivative 350 , which is an advanced intermediate for the synthesis of isoschizogamine ( 351 ) …”