Total Synthesis of the Tricyclic Marine Alkaloids (−)-Lepadiformine, (+)-Cylindricine C, and (−)-Fasicularin via a Common Intermediate Formed by Formic Acid-Induced Intramolecular Conjugate Azaspirocyclization

Abstract

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).

Divergent Total Synthesis of the Tricyclic Marine Alkaloids Lepadiformine, Fasicularin, and Isomers of Polycitorols by Reagent‐Controlled Diastereoselective Reductive Amination

“…Preference for the formation of 28 could be rationalized by Stevens' stereoelectronic principle, [25] The spectroscopic data for compound 28 synthesized by this route were identical to those previously reported. [24] The remaining steps to complete the synthesis were accomplished by employing the same reac- tion conditions as those previously described in the literature. [24] Because the C-2 epimer of 28 could be converted to lepadiformine A in a single step, attempts were made to invert the diastereoselectivity to develop a new selective route to lepadiformine A.…”

“…[24] The remaining steps to complete the synthesis were accomplished by employing the same reac- tion conditions as those previously described in the literature. [24] Because the C-2 epimer of 28 could be converted to lepadiformine A in a single step, attempts were made to invert the diastereoselectivity to develop a new selective route to lepadiformine A. We envisioned that a bulky reducing agent would invert the selectivity because the reduction of iminium ion 27 by a bulky reducing agent could occur through a twisted-boat conformation (equatorial attack) to avoid the severe 1,3-diaxial interactions between the bridge carbon atom (C-11) and the incoming agent.…”

“…The spectroscopic data for compound 60 synthesized by this route were identical to those previously reported. [24] Completion of the synthesis was accomplished by employing the same reaction conditions as those previously described in the literature. [24] The spectral and optical rotation data for synthetic (À)-fasicularin (4) were in good agreement with the reported values.…”

Development of New Synthetic Methods and Its Application to Total Synthesis of Nitrogen-Containing Bioactive Natural Products

“…We have achieved the first total synthesis of racemic fasicularin and lepadiformine, the latter of which led to a revision of the proposed structure 58 of lepadiformine to 59. 62,63) We also have achieved the enantioselective synthesis of (Ϫ)-lepadiformine 64,65) that allowed us to assign the 3S,5R,7aS,11aS configuration for the natural product. 66,67) …”

“…Interestingly, the HCl salt of synthetic racemic 59 is crystalline, whereas natural lepadiformine (also the hydrochloride) is an oil. 64,65) After the above establishment of the relative stereochemistry of lepadiformine, two syntheses of racemic lepadiformine were reported by Weinreb 78) and Funk 79) based on spirocyclization of an allylsilane-N-acyliminium ion and amidoacrolein-derived Diels-Alder reaction, respectively. However, because the natural product is not crystalline and its crystalline derivatives could not be prepared, efforts to obtain an X-ray structure of natural lepadiformine for the determination of the absolute configuration have so far been unsuccessful.…”