Total synthesis of the tricyclic marine alkaloids (-)-lepadiformine, (+)-cylindricine c, and (-)-fasicularin via a common intermediate formed by formic acid-induced intramolecular conjugate azaspirocyclization.
A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).
Abe
Hideki
H
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Aoyagi
Sakae
S
Kibayashi
Chihiro
C
D000470:Alkaloids / Q000138:chemical synthesis*; D000818:Animals; D003500:Cyclization; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis*; D015363:Quinolones / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013861:Thiocyanates / Q000138:chemical synthesis*; D014561:Urochordata / Q000737:chemistry
D000470:Alkaloids; D006575:Heterocyclic Compounds, 3-Ring; D015363:Quinolones; D013861:Thiocyanates; C448329:fasicularin; C431548:lepadiformine; C485391:cylindricine C