Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino Nitriles as Trianion Synthons

Abstract

Lepadiformine A, B and C were synthesized in enantiomerically pure form using a reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving-groups, and subsequent reductive lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski-Potier reaction as the key step. The synthetic strategy is stereoselective and convergent, and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.

Marine natural products

“…974 A stereoselective and convergent synthesis of lepadiformines A-C (Clavelina lepadiformis and C. moluccensis) 975,976 has been reported, conrming the absolute conguration of lepadiformine B. 977 A thorough investigation of different methods used to determine the absolute conguration of synoxazolidinone natural products (Synoicum pulmonaria) 978,979 has highlighted the value and reliability of VCD. 980 The structures and absolute congurations of the brominated 1,2,3,4-tetrahydro-b-carboline alkaloids eudistomidin G-I (Eudistoma glaucus) 981,982 have been conrmed by synthesis 983 as have those of an iodinated nucleoside 984 originally reported from Diplosoma sp.…”

Trianion Synthon Approach to Spirocyclic Heterocycles

“…5 The assembly of carbocyclic 6,7 and especially, heterocyclic 8 frameworks by double alkylation of α-heteronitriles is an underdeveloped transformation. Nitrile anions are competent nucleophiles that have been applied to the formation of complex molecules using nitrile anion alkylation methodology.…”

“…Nitrile anions are competent nucleophiles that have been applied to the formation of complex molecules using nitrile anion alkylation methodology. 9 Based on the double alkylation/reductive cyclization strategy we developed for the lepadiformine alkaloids, 7 we set out to extend this method to the synthesis of diverse spirocyclic heterocycles.…”

‐Aminonitriles: From Sustainable Preparation to Applications in Natural Product Synthesis

“…The synthetic challenge arising from the fused tricyclic structure of the lepadiformine alkaloids and their potential antiarrhythmic properties has inspired several groups to perform synthetic studies on these intriguing natural products. Rychnovsky's strategy for the synthesis of lepadiformines A, B, and C ( 167 ) envisioned a route where all three rings were introduced in quick succession from similar acyclic dibromides, which were stereoselectively synthesized beforehand. Synthesis of the α‐aminonitrile 162 proceeded through TBS‐protection of 3‐amino‐1‐propanol ( 161 ), cyanomethylation and N ‐Boc‐protection.…”