Total synthesis of (+)-azimine via diastereoselective aminopalladation

Abstract

Abstract:The aminopalladation of amino allylic alcohol using Cl2Pd(MeCN)2 in CH2Cl2 gave the 2,6-disubstituted piperidine with excellent diastereoselectivity. This compound was successfully converted into (+)-azimine (1) using cross-metathesis and Shiina macrolactonization.

Divergent Synthesis of 2,6-Disubstituted Piperidine Alkaloid, (+)-Spectaline by Palladium-Catalyzed Cyclization

“…Next, Pd(II)-catalyzed cyclization of the precursors 6a, 6b, and 6c were examined ( Table 1). As expected from our previous studies, 10,11 PdCl2 catalyst gave the cis-2,6-disubstituted piperidine backbone as a major product when the unprotected primary alcohol was employed as the precursor (entry 2 to 4), while Pd(0) catalyst [Pd(dba)2] was ineffective (entry 1). THF was found to be a superior solvent for the cyclization reaction (entry 4).…”

“…THF was found to be a superior solvent for the cyclization reaction (entry 4). Use of TBDMS group as a hydroxyl protecting group instead of MOM group, which was used in the previous synthesis of (+)-azimine, 11 improved the yield of the desired cyclized product 3 from 61% to 88%. Relative stereochemistry of the cis-products was confirmed by an NOE experiment.…”

“…Although (+)-spectaline (1), isolated from the leaves of Cassia spectabilis, has been stereo-selectively synthesized by several groups, [6][7][8][9] further refinement would be desirable regarding the overall steps and/or convergence of the synthetic route. In addition, in our previous syntheses of related piperidine derivatives, ()-cassine and (+)-azimine, 10,11 rather long reaction steps were required for the construction of cis-2,6-disubstituted piperidin-3-ol backbone (14 steps, 4.5%). Therefore, we applied Pd(II)-catalyzed cyclization 10,11 to a substrate-controlled diastereoselective cyclization for the convergent synthesis of the spectalines.…”

“…In addition, in our previous syntheses of related piperidine derivatives, ()-cassine and (+)-azimine, 10,11 rather long reaction steps were required for the construction of cis-2,6-disubstituted piperidin-3-ol backbone (14 steps, 4.5%). Therefore, we applied Pd(II)-catalyzed cyclization 10,11 to a substrate-controlled diastereoselective cyclization for the convergent synthesis of the spectalines. …”

Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor

“…The key intermediate 4 is synthesized from a precursor 5 by Pd(II) catalyzed diastereoselective cyclization. 12,13 The selectivity and efficiency have been well established by our previous syntheses of decahydroisoquinolin scaffold 11 and natural products containing piperidine 14 and pyrrolidine 15 scaffolds. As an acyl substituent of an amino group, the 4-bromobenzoyl group was selected owing to the expected additional interactions with SARS 3CL pro , as inhibitors containing 4-halogenated benzoyl substituents exhibited better inhibitory activities than those containing 4-phenyl substituted benzoyl substituents in our previous study.…”