Design of a nonreductive method for chemoselective cleavage of hydrazines in the presence of unsaturations: application to a stereoconvergent three-component synthesis of (-)-methyl palustramate.

A chemoselective hydrazine (N-N) cleavage methodology that preserves the integrity of alkenes was developed based on a mild acid-promoted fragmentation of tetrasubstituted 1-(trimethylsilylmethyl)-1-benzylhydrazines. This strategy was applied to a concise asymmetric synthesis of (-)-methyl palustramate (4), which featured a convergent stereo- and regioselective sequential three-component aza[4+2]cycloaddition/allylboration/retro-sulfinyl-ene rearrangement between diene 1f, dienophile 2b, and propionaldehyde to afford cis-2-carboxy-6-hydroxyalkylpiperidine 25. The acid-promoted hydrazinolysis of 25 cleanly afforded key intermediate 31, and the latter led to target 4 in four steps after a series of functional group transformations.

A three-component reaction for diversity-oriented synthesis of polysubstituted piperidines: solution and solid-phase optimization of the first tandem aza[4+2]/allylboration.

This article describes the design and optimization of a simple three-component aza[4+2]/allylboration reaction to access polysubstituted alpha-hydroxyalkyl piperidines in a highly diastereocontrolled fashion from maleimides, 4-boronohydrazonodienes, and aldehydes. The aldehyde component does not interfere with the first aza[4+2] step, and it was found that this tandem reaction provides better yields of piperidine products 5 when carried out in one-pot. The required 4-borono-hydrazonodienes 1 are synthesized efficiently from the condensation of 3-boronoacrolein pinacol ester (4) with hydrazines. Overall, the three-component process using N-substituted maleimides as dienophiles produces four stereogenic centers and is quite general. It tolerates the use of a wide variety of aldehydes and hydrazine precursors with different electronic and steric characteristics. By allowing such a wide substrate scope and up to four elements of diversity, this reaction process is particularly well adapted towards applications in diversity-oriented synthesis of polysubstituted piperidine derivatives. The suitability of the aza[4+2]/allylboration reaction for use in solid-phase chemistry was also demonstrated using a N-arylmaleidobenzoic acid functionalized resin. This novel multicomponent reaction thus offers a high level of stereocontrol and versatility in the preparation of densely functionalized nitrogen heterocycles.