A New Total Synthesis of dl‐Pumiliotoxin‐C via an Indanone

Abstract

dl‐Pumiliotoxin‐C (4) was synthesized in a practical manner from trans‐4‐hexenal (9). The key step 14 → 15 (Scheme 3) involves an intramolecular Diels‐Alder reaction giving mainly the cis‐fused indanols 15a, which were converted to the cis‐fused ketone 16. After Beckmann‐rearrangement of 16 the octahydroquinolinone 7 was transformed to the lactim‐ether 23. (Scheme 7). Reaction of 23 with propylmagnesium bromide followed by hydrogenation furnished dl‐4 in a highly stereoselective fashion.

Stereoselective Total Synthesis of Eburnane‐Type Alkaloids Enabled by Conformation‐Directed Cyclization and Rearrangement

“…The compound (‐)‐ 6 , biogenetically derived from (+)‐ 1 , displays a potent antibacterial activity against P. aeruginosa (MIC=2 μ m ) . In light of their unique structures and promising biological activities, eburnane alkaloids have been privileged targets of synthetic and medicinal chemists for years . The Pictet–Spengler reaction between tryptamine ( 7 ) and dimethyl‐4‐ethyl‐4‐formylheptanedioate ( 8 ), and the Bischler–Napieralski reaction of lactame 9 followed by reduction as pioneered by Kuehne and Wenkert, respectively, are among the most exploited transformations towards this end.…”

“…The control of the C20/C21 relative stereochemistry is in fact an unsolved issue in the synthesis of eburnane alkaloids. Other approaches, including Oppolzer's synthesis involving intramolecular Mannich reaction (Scheme d) and Qin's recent radical‐based cascade approach, afforded the desired products with low diastereoselectivities (Scheme e). We have recently developed a short enantioselective synthesis of (−)‐ 5 by way of an integrated sequence involving an oxidative cleavage of the cyclopentene 10 to the corresponding dialdehyde followed by a highly diastereoselective cyclization of the hypothetical intermediate A in which C2 was sp 3 hybridized (Scheme f) .…”

Intramolecular Diels-Alder Reactions

“…In each case the distribution of products is determined by a balance of forces in the possible transition states. In reactions catalysed by Lewis acids, however, the trans dienophile (10) gave the endo product (11) exclusively, but selectivity with the eis dienophile (13) was not improved.…”

Total Synthesis of (±)‐Pumiliotoxin C: An Electrochemical Approach

“…Finally, the expected stereospecific alkylation-hydride reduction process of the cis-fused aminonitrile 15 established the trans relationship between the propyl group at C-2 and the methyl substituent at C-5. trogen fixation, [7] cycloaddition reactions, [8][9][10][11] Beckmann rearrangement of tetrahydroindenones, [12] [3,3]-sigmatropic rearrangements, [13] addition of Grignard reagents to pyridinium salts, [14] and biomimetic approaches. [15] In addition, several elegant, well-designed enantioselective syntheses of natural (-)-1 have been reported in the last decade.…”