A New Enantioselective Total Synthesis of Natural Vincamineviaan IntramolecularMannichReaction of an Silyl Enol Ether

Abstract

Natural Vincamine (1) has been synthesized in an enantioselective manner starting from the ethylpentenal 7. In the key step a mixture of the diastereoisomeric racemates, 14 and 15, was directly obtained from the silyl enol ether 11 and the dihydro‐β‐carboline 12 by the way of an intramolecular Mannich reaction of the intermediate 13 (Scheme 4). The undesired stereoisomers, 14 and 15b, were recycled to 15a using the related reversible Mannich reaction 18 ⇄ 14 + 15, followed by crystallization of the salt from 15a and (+)malic acid. 15a was converted to natural vincamine (1) in several steps including the known transformation 20→1.

Bioinspired Divergent Oxidative Cyclizations of Geissoschizine: Total Synthesis of (–)‐17‐nor‐Excelsinidine, (+)‐16‐epi‐Pleiocarpamine, (+)‐16‐Hydroxymethyl‐Pleiocarpamine and (+)‐Taberdivarine H

“…We were inspired by the synthesis of vincamine ( 55 ) for which the 6‐membered E ring was formed by the ring contraction of the 7‐membered‐ring α‐ketolactam 54 under the action of sodium methoxide. [ 32 ] Accordingly, our retrosynthesis to obtain pleiocarpamine, implied protonation of the hydroxyl group of 52 and stereoselective addition of a hydride into the more accessible face of the resulting carbocation. 16‐Hydroxy‐pleiocarpamine 52 would, indeed, arise from the ring contraction of keto‐lactam 53 .…”

“…We were unable to obtain 53 by direct oxidation of 59 , [ 38 ] we therefore turned towards a two‐step procedure previously used in the synthesis of vincamine. [ 32a ] Oxidation of lactam 59 with tert ‐butyl nitrite delivered crude α‐ketoxime ester 72 . [ 39 ] Despite several attempts, hydrolysis of the latter into 53 did not meet with success.…”

Aldehyde Intermediates in the Synthesis of Tacamine‐Type Indole Alkaloids: Preparation of (±)‐apotacamine

“…We recently published a synthesis of (f)-vincamine (2) in which the key reaction was the condensation of aldehyde 3 ('Oppolzer's aldehyde') [7] with a glycine ester [8]. For the preparation of (&)-tacamine (1) via the same strategy, we have now investigated the synthesis of aldehyde 4, a structural analogue of 3.…”

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

“…[5] In light of their unique structures and promising biological activities,eburnane alkaloids have been privileged targets of synthetic and medicinal chemists for years. [1,[9][10][11][12][13][14] The Pictet-Spengler reaction between tryptamine (7)a nd dimethyl-4-ethyl-4-formylheptanedioate (8), and the Bischler-Napieralski reaction of lactame 9 followed by reduction as pioneered by Kuehne [9a] and Wenkert, [10a] respectively,are among the most exploited transformations towards this end. An inherent drawback associated with these otherwise very elegant syntheses is the lack of the diastereoselectivity of these reactions (Scheme 1b,c).…”

“…Indeed, the steric difference between an ethyl and amethoxycarbonylethyl group attached to C20 is not significant enough to differentiate the two faces of the neighboring iminium function. Thecontrol of the C20/ C21 relative stereochemistry is in fact an unsolved issue in the synthesis of eburnane alkaloids.O ther approaches,i ncluding Oppolzerssynthesis involving intramolecular Mannich reaction (Scheme 1d) [11] and Qinsr ecent radical-based cascade approach, [12] afforded the desired products with low diastereoselectivities (Scheme 1e). We have recently developed as hort enantioselective synthesis of (À)-5 by way of an integrated sequence involving an oxidative cleavage of the cyclopentene 10 to the corresponding dialdehyde followed by ah ighly diastereoselective cyclization of the hypothetical intermediate A in which C2 was sp 3 hybridized (Scheme 1f).…”