Synthesis of Dihydromotuporamine C via 3‐Azonia‐Cope Rearrangement of 11‐Membered Cyclic α‐Vinylamine

Abstract

A new synthesis of dihydromotuporamine C (dhMotC), a synthetic analogue of cytotoxic marine alkaloid, has been achieved from inexpensive starting materials. The first stage was the preparation of cyclodecanone by sequential [2+2]‐cycloaddition of N‐(1‐cycloocten‐1‐yl)pyrrolidine with methyl propiolate and electrocyclic ring‐opening, followed by basic hydrolysis. Beckmann rearrangement of cyclodecanone oxime and several step manipulations afforded the pivotal intermediate of the N‐benzylated 11‐membered cyclic α‐vinylamine. The final synthesis of dihydromotuporamine C involved tandem nucleophilic addition with ethynyl p‐tolyl sulfone and 3‐azonia‐Cope rearrangement to form the 15‐membered aza‐macrocycle and reductive amination to install the appended spermidine‐like moiety.

Total Synthesis of the Marine Sponge Alkaloid Motuporamine C Using a Ramberg‐Bäcklund Ring Contraction Strategy

“…As shown in Scheme 8, the trifluoroacetic acid‐mediated removal of the Boc group in 18 provided amine 19 as its trifluroacetate salt. Final reductive amination of 19 with di‐Boc‐protected aldehyde 20 [11] using sodium triacetoxyborohydride in methylene chloride furnished di‐Boc‐protected motuporamine 21 in high yield, which was then quantitatively deprotected by treatment with trifluoroacetic acid to produce motuporamine 3 as its TFA salt.…”

“…The intermediacy of a trans-episulfone like I Scheme 2. Synthesis of cyclic sulfide (11). ChemistrySelect should be invoked in the reaction pathway, and elimination of SO 2 from 12 produces E-13.…”

“…[8] Recently, we initiated a project for the synthesis of macrocyclic natural products with rearrangement methodologies. [9,10] Quite recently, we have accomplished the synthesis of dihydromotuporamine C through a 3-azonia-Cope arrangement strategy for assembling the 15-membered aza-macrocycle, [11] and the total synthesis of motuporamines A and B based on an [n + 4] ring-expansion strategy. [12] Although a few innovative synthetic strategies on motuporamine C have been reported, there is still a high demand for developing efficient synthetic methodologies especially in view of the continuous research interests for bioactive evaluation in drug discovery [13,14] and the fact that the more potent synthetic analogue, i. e. dihydromotuporamine C can also easily be obtained by hydrogenation.…”