Total synthesis and establishment of the absolute stereochemistry of (+)-mostueine. Addition of chiral nucleophiles to 3,4-dihydro-2-methyl-9-(p-toluenesulfonyl)-β-carbolinium iodide

Abstract

A highly convergent synthesis of the pentacyclic indole alkaloid (+)-mostueine (1) is described. The key step involved the coupling of the dianion derived from (1′S)-3-(1′-hydroxyethyl)-4-methylpyridine (4) with the iminium salt 3,4-dihydro-2-methyl-9-(p-toluenesulfonyl)-β-carbolinium iodide (3). Low asymmetric induction (15% de) at the C-1 position of the β-carboline ring system (C-3 of mostueine) was obtained. The nonfermenting baker's yeast-mediated reduction of 3-acetyl-4-methylpyridine provided the hydroxyethylpyridine component in acceptable yield (67%) and high optical purity (99.0% ee). This synthesis of 1 has established that the absolute stereochemistry of mostueine is (3S, 19R).

Proline-Catalyzed Asymmetric Addition Reaction of 9-Tosyl-3,4-dihydro-β-carboline with Ketones

“…At first, 3,4-dihydro-β-carboline ( 2 ) was allowed to react with acetone in the presence of ( S )-proline, and it was found that the substrate decomposed to a complicated mixture. Thus, 9-tosyl-3,4-dihydro-β-carboline ( 1 ) was selected as the next substrate.…”

Stereodivergent Complexity-to-Diversity Strategy en Route to the Synthesis of Nature-Inspired Skeleta

“…To expand the collection with compounds bearing additional chiral centers, the same reaction was performed between the enantiopure octahydroindolo[2,3-a]quinolizine 3h and the 2,3-dihydroxybenzoic acid (34) to afford enantiomerically pure product 35f in good yield. The stereochemistry of compound 35f was confirmed from its 1D and 2D NMR spectra (pages S89−S92 of the Supporting Information).…”

“…Diastereoselective Synthesis of Benzoxazepinone Fused to Octahydroindolo[2,3-a]quinolizine Scaffolds. To expand the scope of this reaction, the 2,3-dihydroxybenzoic acid (34) was replaced with 2,3-dihydoxy benzamide (36) (Scheme 9). Surprisingly, this reaction did not produce the expected compound 38, as was previously observed, but yielded the indolino benzoxazepinone derivative 37 instead.…”

“…Gibberellic acid, 14 adrenosterone, 14 quinine, 14 pleuromutilin, 17 abietic acid, 18 sinomenine, 19 and yohimbine 20,21 (Figure 1) are some of the examples of natural products that were employed in CtD strategies, yielding several interesting first-in-class therapeutic leads and novel chemotypes. Indolo [2,3-a]quinolizines, 23−25 camptothecins, 26 arborescidines, 27 balasubramide, 28 crypowelliin C, 29 strychnohirsutine, 30 vincamine, 31 akagerine, 32 vinburnine, 33 and mostueine 34 are among the various structural options representing biologically significant alkaloids (Figure 2). Structures in these classes vary significantly in their core scaffold substitution patterns, including various members that are characterized by variable ring-fusion patterns and exhibit interesting and different biological activities.…”

Total Synthesis of ent-Dihydrocorynantheol by Using a Proline-Catalyzed Asymmetric Addition Reaction

“…In the course of our research for the synthesis of chiral 1-substituted 1,2,3,4-tetrahydro-β-carboline derivatives, we found that 9-tosyl-3,4-dihydro-β-carboline ( 1 ) is a good substrate for the asymmetric addition of methyl ketones in the presence of ( S )-proline . We further investigated the reaction using various methyl ketone derivatives, and found that the use of 3-ethyl-3-buten-2-one resulted in concise asymmetric synthesis of ent -dihydrocorynantheol.…”