Formal Synthesis of Sarain A: Intramolecular Cycloaddition of an Eight‐Membered Cyclic Nitrone to Construct the 2‐Azabicyclo[3.3.1]nonane Framework

Abstract

An enantioselective route to the tetracyclic skeleton of sarain A has been developed. Asymmetric reduction of an ynone introduced a chiral center which was transferred to the contiguous tertiary stereogenic centers through an Ireland-Claisen rearrangement. The 2-azabicyclo[3.3.1]nonane framework was constructed by an unprecedented intramolecular cycloaddition of an eight-membered cyclic nitrone. Using the steric bias of the bicyclic system, the quaternary carbon atom was constructed by a stereoselective aldol reaction. Further ring formations were performed by ring-closing metathesis for the 13-membered ring and an iodoamidation reaction for the pyrrolidine ring. The present synthesis has successfully provided an alternative route to the late-stage intermediate of Overman's synthesis.

Organocatalytic Asymmetric Synthesis of an Advanced Intermediate of (+)‐Sarain A

“…The unprecedented yet challenging structural features render it an attractive synthetic target. Several groups have been engaged in its synthetic studies [4–13] . However, the total synthesis of sarain A turned out to be a formidable challenge as can be seen from the fact that although the first synthetic study toward the total synthesis of sarain A is dated from 1991, [4a] not until 2006 has the first enantioselective total synthesis been accomplished by Overman and co‐workers [6d,e] .…”

“…However, the total synthesis of sarain A turned out to be a formidable challenge as can be seen from the fact that although the first synthetic study toward the total synthesis of sarain A is dated from 1991, [4a] not until 2006 has the first enantioselective total synthesis been accomplished by Overman and co‐workers [6d,e] . This remains the only total synthesis to date, besides a formal one reported in 2015 [12] . Moreover, the lengthy 48‐step total synthesis did not allow the authors to get enough sample to measure the optical rotation of their synthetic product, [6d,e] which caused an error regarding the sense of optical rotation of sarain A [6f] .…”

“…Moreover, the lengthy 48‐step total synthesis did not allow the authors to get enough sample to measure the optical rotation of their synthetic product, [6d,e] which caused an error regarding the sense of optical rotation of sarain A [6f] . On the other hand, among the reported approaches, only four are enantioselective, [6d,e, 10, 12, 13b] and those leading to advanced intermediates bearing elaborate functional groups required at least 29 steps (Figure 2). Among them, only one is based on a catalytic asymmetric reaction [12] …”

“…On the other hand, among the reported approaches, only four are enantioselective, [6d,e, 10, 12, 13b] and those leading to advanced intermediates bearing elaborate functional groups required at least 29 steps (Figure 2). Among them, only one is based on a catalytic asymmetric reaction [12] …”

Synthesis and Formation Mechanism of a Compound with an Unprecedented Skeleton: Dodecahydro-4,10:5,9-diepoxydipyrrolo[3,4-<i>b</i>:3′,4′-<i>f</i>][1,5]diazocine

“…Intramolecular cycloaddition of nitrones containing an alkene moiety is well known, 1) and is frequently employed for the synthesis of nitrogen-containing natural products. [2][3][4][5][6][7] In contrast, the corresponding cycloaddition of nitrones having an alkyne moiety is much less well studied, and the products are often labile and undergo further transformation or rearrangement.…”