Efficient Asymmetric Synthesis of Pumiliotoxin Cvia Intramolecular [4+2] Cycloaddition

Abstract

An efficient asymmetric synthesis in nine steps of natural (À)-pumiliotoxin C (1), a decahydroquinoline alkaloid found in the skin of Central American frog species, is presented. The enantiomerically pure starting material (S)-norvalinol (3), obtained from commercial (S)-norvaline, was cyclized in a one-pot procedure to the tosylated aziridine 5. Ring opening with propargylmagnesium bromide led to the acetylenic sulfonamide tosylamide 6, free of the allenic isomer. Compound 6 was methylated on the acetylenic C-atom, reduced, and deprotected with Na in liquid NH 3 to give the (E)-configured unsaturated amine 8, which was condensed with crotonaldehyde to the imine 9 and N-acylated with isobutanoyl chloride to the key intermediate 2.Intramolecular Diels-Alder reaction furnished a diastereoisomeric mixture of N-protected octahydroquinolines 10. After catalytic hydrogenation and cleavage of the amide, natural 1 was obtained as the main product in 25% overall yield; 3.2% of its isomer 11 with the inverse configurations in position 4a, 5, and 8a was also isolated.

Short and Efficient Synthesis of Optically Active N-Tosyl Aziridines from 2-Amino Alcohols

“…All reagents and solvents from commercial suppliers were used without further purification. All products obtained had physical and spectroscopic properties identical to those reported in the literature [ 3 , 4 , 6 ].…”

“…Although the latter procedure is high yielding, it requires several steps and anhydrous reaction conditions. The first inconvenient has been avoided in two procedures previously described for special intermediates in alkaloid syntheses: (S)-leucinol ( 3 , R = CH 2 iPr) has been transformed in a one-pot procedure to the corresponding N-tosylaziridine 1 using excess of tosyl chloride and triethylamine and catalytic amounts of 4-dimethylaminopyridine in dichloromethane [ 5 ], similarly, the chiral key intermediate 1 (R = nPr) of our Pumiliotoxin C synthesis has been obtained directly from (S)-norvalinol with sodium hydride as base in anhydrous THF [ 6 ]. However, the experimental risks due to the use and destruction of large amounts of hydride and the need for anhydrous reagents and solvents, represented serious limitations for a general application, especially under tropical conditions of extreme humidity, and prompted us to look for less hazardous solvent/base combinations.…”

Total Syntheses of Chelidonine and Norchelidonine via an Enamide–Benzyne–[2 + 2] Cycloaddition Cascade

“…Our laboratory recently unveiled a de novo cascade of pericyclic ring-openings of amidobenzocyclobutanes and N- tethered intramolecular Diels–Alder [IMDA] cycloadditions initiated through an enamide–benzyne–[2 + 2] cycloaddition ( 1 → 2 → 3 → 4 in Scheme ) . This tandem cascade possesses the unique feature of not only linking together the prevailing benzyne chemistry − with enamides that have become a highly versatile and accessible functional group − but also accentuating the less developed thermally driven [2 + 2] cycloaddition reaction manifold − while exploiting the powerful Oppolzer-type N- tethered IMDA strategy. − Accordingly, an application of this cascade in the synthesis of benzophenanthridine alkaloids [see 5 in the box] was pursued. In particular, we have been focusing on (+)-chelidonine 6 and (+)-norchelidonine 7 , which despite being known for well over a century, − remain an excellent proving ground for showcasing synthetic methods. , Our strategy would be based on the above cascade using benzyne precursor 9 and enamide 10 .…”

“…1 This tandem cascade possesses the unique feature of not only linking together the prevailing benzyne chemistry 2-4 with enamides that have become a highly versatile and accessible functional group, 5-7 but also accentuating the less developed thermally driven [2 + 2] cycloaddition reaction manifold, 8-10 while exploiting the powerful Oppolzer-type N -tethered IMDA strategy. 11-15 Accordingly, an application of this cascade in the synthesis of benzophenanthridine alkaloids [see 5 in the box] was pursued. In particular, we have been focusing on (+)-chelidonine 6 and (+)-norchelidonine 7 , which despite being known for well over a century, 16-21 remain an excellent proving ground for showcasing synthetic methods.…”

Oppolzer-Type Intramolecular Diels–Alder Cycloadditions via Isomerizations of Allenamides

“…Although Oppolzer 8,9 had elegantly demonstrated the concept of N -tethered 1-ami do-dienes in intramolecular Diels-Alder cycloadditions [IMDA], 10 relative to the intermolecular pursuit, it has shown limited applications in the last forty years in part due to a lack of efficient synthetic access to these cycloaddition precursors. 10,11 We recently reported 12 that γ–isomerizations of allenamides 1 provide a facileentry to 1-ami do-dienes 3 via a stereoselective 1,3-H shift [Scheme 1].…”