Total synthesis of (+)-cylindradine A

Abstract

Cylindradines A and B, members of the polycyclic pyrrole-imidazole alkaloids (PIAs), are the only congeners bearing a 3-carbamoylpyrrole unit among the PIAs. In this communication, we described a total synthesis of (+)-cylindradine A based on intramolecular Friedel-Crafts type cyclization of pyrrole-aldehyde and oxidative cyclization of tricyclic pyrrolopyrrolidine-guanidine with hypervalent iodine to construct the cyclic guanidine structure including the N,N'-aminal moiety.

Cutting-Edge and Time-Honored Strategies for Stereoselective Construction of C–N Bonds in Total Synthesis

“…Similar oxidative formation of the iminium cation mediated by (diacetoxyiodo)benzene was employed by Nagasawa and co-workers for the installation of a 2-aminoimidazolidine ring during the synthesis of cylindradine A. 122 Another oxidative formation of an iminium cation was reported by Rychnovsky for the installation of a nitrile group into the pyrrolidine ring during the synthesis of several Lepadiformine alkaloids (other aspects of this synthesis are discussed in section 13). 123 As reported during the total synthesis of morphine, methyl carbamate is another suitable precursor of the N-acyliminium cation for an intramolecular Mannich reaction (Scheme 12c).…”

“…The latter transformation is known to proceed through the formation of an iminium cation, affording aspidophytine in 39% yield over two steps. Similar oxidative formation of the iminium cation mediated by (diacetoxyiodo)­benzene was employed by Nagasawa and co-workers for the installation of a 2-aminoimidazolidine ring during the synthesis of cylindradine A . Another oxidative formation of an iminium cation was reported by Rychnovsky for the installation of a nitrile group into the pyrrolidine ring during the synthesis of several Lepadiformine alkaloids (other aspects of this synthesis are discussed in section ).…”

Applications of Friedel–Crafts reactions in total synthesis of natural products

“… 202,203 Nagasawa and co-workers in 2014 developed a total synthesis of (+)-cylindradine A through intramolecular FC-type cyclization reaction of pyrrole-aldehyde and oxidative cyclization of tricyclic pyrrolopyrrolidine–guanidine with hypervalent iodine to make the cyclic guanidine structure involving the N , N -aminal scaffold. 204 The total synthesis of cylindradine A was initiated from oroidin 186, which was converted into 187 in several steps. Compound 187 containing aldehyde and 4-carbamoylpyrrole functional substituents gave compound 188 via an intramolecular FC-type reaction.…”

“…Subsequently, (+)-cylindradine A 185 was provided from compound 190a in 58% yield upon several steps ( Scheme 41 ). 204 …”

Recent Advances in Bromination of Aromatic and Heteroaromatic Compounds

“…Aromatic electrophilic bromination using traditional reagents including Br 2 has been exceedingly broadly employed to synthesize a variety of products comprising alkaloids, [95][96][97][98][99][100] physiologically active compounds, [99][100][101][102] nucleoside analogues, 103 and dyes. 104,105 In many instances, successful selective bromination depended on the structure…”