Enantioselective Total Synthesis of (+)-Stephadiamine through Bioinspired Aza-Benzilic Acid Type Rearrangement

Abstract

We report the first enantioselective total syntheses of the hasubanan alkaloid (−)-metaphanine and the norhasubanan alkaloid (+)-stephadiamine. Key features of these syntheses include diastereoselective oxidative phenolic coupling reaction and subsequent regioselective intramolecular aza-Michael reaction, which efficiently construct the hasubanan skeleton with the all-carbon quaternary stereogenic center at C13. Based on our hypothesis regarding the biosynthetic pathway of (+)-stephadiamine, we found that (−)-metaphanine is easily converted to (+)-stephadiamine via aza-benzilic acid type rearrangement reaction.

Catalytic Enantioselective Synthesis of Morpholinones Enabled by Aza-Benzilic Ester Rearrangement

“…Therefore, the benzilic acid (ester) rearrangement is in this sense unique, as it deals with 1,2-diones . In spite of its synthetic significance, − there is only one report on the enantioselective benzilic ester rearrangement . We began our studies using phenylglyoxal hydrate ( 2a ) and 2-(phenylamino)­ethan-1-ol ( 3a ) as test substrates for optimization of the conditions (Table ).…”

Developments in the Synthesis of Hasubanan Alkaloids

“…These findings were reconceptualized in the most recent works of Odagi and Nagasawa [10,11] (Scheme 22). First, the chirality was induced via benzylic hydroxyl (cf.…”

“…Their polycyclic cage skeleton has inspired several original approaches from different research groups, in particular, groups of Profs. Herzon, [1–3] Reisman, [4] Trauner, [5,6] Castle, [7,8] and very recently Zhu [9] and Nagasawa [10,11] . Origins of such intensive research interest are apparently caused not by bioactivity of hasubanan alkaloids itself, which is scarcely reported, [12] but of their derivatives and more complex structural analogs.…”

“…Another driving factor for research is their obscure biosynthesis [16–18] . The latest works of Nagasawa group are aimed to bring these two branches of the research together in the study of approaches aimed on specification of actual biosynthetic pathways [10,11] …”

“…Herzon, [1][2][3] Reisman, [4] Trauner, [5,6] Castle, [7,8] and very recently Zhu [9] and Nagasawa. [10,11] Origins of such intensive research interest are apparently caused not by bioactivity of hasubanan alkaloids itself, which is scarcely reported, [12] but of their derivatives and more complex structural analogs. In this respect, the report on antiamnesic properties and selective T-cell cytotoxicity of the related alkaloid acutumine, [13] as well as disputed affinity of ent-hasubanans to opioid receptors, [14,15] may have become the triggering factors.…”