Total Syntheses of (−)‐Secologanin, (−)‐5‐Carboxystrictosidine, and (−)‐Rubenine

Abstract

The first enantioselective total syntheses of (−)‐secologanin (1), (−)‐5‐carboxystrictosidine (2), and (−)‐rubenine (3) were accomplished in 10, 9, and 14 steps, respectively. The key transformation in the synthesis of 1 was a sequential anti‐selective organocatalytic Michael reaction/Fukuyama reduction/spontaneous cyclization to form an optically active dihydropyran ring. In addition, the secologanin tetraacetate (16), which is a potential key intermediate for the bioinspired divergent syntheses of monoterpenoid indole alkaloids, was prepared in gram‐scale in seven steps. The total syntheses of 2 and 3, which are classified as glycosylated monoterpenoid indole alkaloids, were achieved through bioinspired transformations such as a diastereoselective Pictet–Spengler reaction, a site‐ and stereoselective epoxidation, and a site‐selective epoxide ring‐opening followed by a lactonization reaction.

Total Syntheses of (−)‐Strictosidine and Related Indole Alkaloid Glycosides

“…Our results pertaining to the total synthesis of secologanin tetraacetate ( 7 ) are summarized in Scheme . Thioester derivative 9 , prepared as an E / Z mixture by Knoevenagel condensation with commercially available 3‐trimethylsilylpropynal (81 % yield), was employed in newly developed organocatalytic anti ‐selective Michael reaction.…”

“…With a sufficient quantity of secologanin tetraacetate ( 7 ) in hand, we commenced with our experiments involving diastereoselective Pictet–Spengler cyclization for the synthesis of (−)‐strictosidine ( 1 ). Since moderate diastereoselectivity had been observed earlier when using l ‐tryptophan methyl ester (quantitative yield, 3 S :3 R =2.6:1; Table , entry 1), ( S )‐α‐cyanotryptamine [( S )‐ 8 ], prepared through a three‐step transformation from N ‐Cbz‐ l ‐tryptophan (see details in the Supporting Information), was employed in an initial trial. Secologanin tetraacetate ( 7 ) and ( S )‐ 8 in CH 2 Cl 2 were treated with trifluoroacetic acid (TFA, 5 equiv) in the presence of MS 4 Å at 0 °C.…”

Bioinspired Divergent Oxidative Cyclization from Strictosidine and Vincoside Derivatives: Second‐Generation Total Synthesis of (−)‐Cymoside and Access to an Original Hexacyclic‐Fused Furo[3,2‐b]indoline

“…We significantlyi mproved the synthesis of cymoside (À)-1 that we published earlier this year [5] by startingf rom enantiopure secologanin tetraacetate insteado fi ts racemic aglycon. After the Pictet-Spengler reaction, the key bioinspired oxidative cyclization of strictosidine derivative 15 a between the indole and the C16-C17 enol ether proceeded well in presence of the glucose moiety.C ymoside (À)-1 was synthesized in 4s teps, and 18 %y ield from secologanin tetraacetate 14 which was obtained according to the synthesis by Ishikawa and co-workers, [12] while our first-generation synthesis required 6s teps and resultedi n1 .7 %y ield from racemic secologanin aglycon (AE)-5. In ad ivergent manner,t he oxidation of the vincoside derivative 15 b,t he 3-epimer of 15 a,y ielded an ew fused hexacyclic furo[3,2-b]indoline structure 20 via reaction with the terminal C18-C19 alkene insteado ft he C16-C17 enol ether.I tw as obtained in 4s teps with 25 %y ield from secologanin tetraacetate 14.W hile unexpected, we think that this new skeleton is the more interesting part of our report since it expands the molecular diversity and complexity accessible from the strictosidine/ vincoside skeleton.…”

“…However, at the end of our endeavor,I shikawa and co-workersf illed this important gapa nd reported the first enantioselective synthesis of secologanin (À)-4 (Scheme 3). [12] The authors cleverly took advantage of an organocatalyzed trans-selective Michael addition developed by Hong et al of aldehyde 12 onto1 -thioester acrylate 11. [13] Reductiono ft he thioester,g lycosylation of 13,h ydroboration, and sulfoxidee limination delivered secologanin tetraacetate (À)-14 and then secologanin (À)-4.T herefore, after the completion of our first generation synthesis of cymoside (À)-1,i t appeared evident to us that using enantiopure secologanin tetraacetate (À)-14,p roduced by the Ishikawa enantioselective synthesis, could greatlyi mprovet he efficiency of the enantioselectives ynthesis of cymoside (À)-1 (Scheme 3).…”

Enantioselective Total Synthesis of Cymoside through a Bioinspired Oxidative Cyclization of a Strictosidine Derivative

“…[13,14] Indeed, the latter would arise from the Pictet-Spengler reaction [15] of as ecologanin derivative 8 which would be obtained as described by Tietze three decades ago. [16][17][18] It involved ad omino sequence of aK noevenagel condensation between monoprotected malondialdehyde 9 and 3-formyl-1,1,1-trichloroacetone 10 followed by an inverse-demand hetero Diels-Alder cycloaddition between generated enal 11 and enol ether 12. [16a] Methanolysis, sulfoxide elimination, and release of the aldehyde from the dithiane furnished secologanin aglycon 8.…”