Total Synthesis of (−)‐Crinine. Use of Tandem Cationic Aza‐Cope Rearrangement/Mannich Cyclizations for the Synthesis of Enantiomerically Pure Amaryllidaceae Alkaloids

Abstract

The total synthesis of enantiomerically pure (-)-crinine (1) in 10 steps and 6% overall yield from cyclopentene oxide is reported. The key step was the rearrangement of 7 upon reaction with AgNO, at 25 "C to give cis-perhydroindolone 8 in 81 % yield.Although the total synthesis of Amaryllidaceae alkaloids has been the object of intense in~estigation,)~), few methods have been developed for preparing these alkaloids in optically active form. To our knowledge, the pioneering synthesis of (+)-maritidine by the Yarnada group [4] represents the only published enantioselective synthesis of a member of the widely occurring 5,l Ob-ethanophenanthridine class of Amaryllidaceae alkaloid?). In this paper, we report the first efficient method for preparing enantiomerically pure alkaloids of this type. Specifically, we detail the total synthesis of (-)-crinine (1)6) in 10 steps and 6 % overall yield from cyclopentene oxide.The starting point for the synthesis of 1 (see Scheme) was aminoalcohol 3, which is available on a large scale from the reaction [7] of cyclopentene oxide with the aluminium amide 2 formed from (R)-a-methylbenzylamine and trimethylal~minium~).Although this reaction gave 3 and its (lS, 2s)-diastereoisomer 4 in equal amounts, these aminoalcohols were easily separated by chromatography on silica gel to afford 3 (m.p. 7475°C) in 45% yield. Reaction of the hydrochloride salt of 3 with paraformaldehyde and KCN [ I] provided the oily aminoacetonitrile 5 in 92 % yield. Swern oxidation [lo] of 5 followed by recrystallization of the crude product from CH,Cl,/hexane afforded the 0x0 derivative 6 (m.p. 83-84°C) in 95% yield. Crystalline 6 could be stored at 0 "C without epimerization, however attempted purification on silica gel yielded a 1 : 1 Part 14 in the series 'Synthesis Applications of Aza-Cope Rearrangements'; for Part 13, see [l]. On sabbatical leave from the Agricultural Chemicals Research Laboratories of the Sunkyo Company, Tokyo, Japan. For recent reviews, see [2]. For new approaches for preparing these alkaloids in racemic form, see, inter uliu, [3]. Several enantioselective syntheses of structurally related Sceletium alkaloids have been described, see [5]. For the determination of the absolute configuration of this alkaloid, see [6]. A wide variety of enantiomerically pure 2-aminoalcohols are easily prepared in this way [8]. The absolute configuration of 3 was established [8] by conversion to (-)-(lR, 2R)-2-aminocyclopentanol[9].

gem-Dibromocyclopropanes and enzymatically derived cis-1,2-dihydrocatechols as building blocks in alkaloid synthesis

“…They display a rather fascinating array of biological properties including immuno-stimulatory, antimalarial, anticholinergic, and apoptosis-inducing behaviors [4][5][6][7]. For example, crinine {5 [8], m.p. = 207-209 °C, [α] D = −26.1° (c = 0.26, CHCl 3 )} displays antimalarial properties [9] while the enantiomerically related vittatine {6 [10], m.p.…”

Enantioselective Synthesis of Amaryllidaceae Alkaloids (+)‐Vittatine, (+)‐epi‐Vittatine, and (+)‐Buphanisine

“…[14] Among them, however, asymmetric access to the vital quaternary centers was entirely achieved by the diastereoselective induction of the pre-existing stereocenters in chiral substrates or auxiliaries. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] To address this topic, three biologically interesting Amaryllidaceae alkaloids, (+)-vittatine, (+)-epi-vittatine, and (+)-buphanisine (Figure 1), were selected as our synthetic targets for developing a method-oriented strategy. Despite the above-mentioned substantial progress in the construction of the related chiral all-carbon quaternary centers, the exploration of alternative strategies, especially to create such stereocenters in a catalytic enantioselective manner, is still of high demand in the asymmetric synthesis of cis-aryl hydroindole alkaloids.…”

“…The asymmetric synthesis of chiral all-carbon quaternary stereogenic centers is one of the most challenging and dynamic research areas in modern organic synthesis. [6] 5) cycloaddition reaction; [7] 6) Michael addition; [8] 7) epoxide ring opening; [9] 8) intramolecular Heck reaction; [10] 9) intramolecular carbene insertion; [11] 10) intramolecular carbonyl-ene reaction; [12] 11) intramolecular radical cyclization; [13] and 12) intramolecular zirconiummediated diene reductive cyclization. [6] 5) cycloaddition reaction; [7] 6) Michael addition; [8] 7) epoxide ring opening; [9] 8) intramolecular Heck reaction; [10] 9) intramolecular carbene insertion; [11] 10) intramolecular carbonyl-ene reaction; [12] 11) intramolecular radical cyclization; [13] and 12) intramolecular zirconiummediated diene reductive cyclization.…”

“…[2] Encompassing the asymmetric assembly of the quaternary stereocenters in cisaryl hydroindole alkaloids, various approaches for the direct formation of a carbon-carbon bond centered on the sterically congested chiral quaternary carbon atom have been extensively developed over the past four decades, as mainly exemplified by: 1) 3,3-sigmatropic rearrangement; [3] 2) semipinacol rearrangement; [4] 3) a-alkylation of carbonyls or addition of enolates generated in situ by oxy-Cope rearrangement; [5] 4) Mannich reaction initiated by aza-Cope rearrangement. [6] 5) cycloaddition reaction; [7] 6) Michael addition; [8] 7) epoxide ring opening; [9] 8) intramolecular Heck reaction; [10] 9) intramolecular carbene insertion; [11] 10) intramolecular carbonyl-ene reaction; [12] 11) intramolecular radical cyclization; [13] and 12) intramolecular zirconiummediated diene reductive cyclization. [14] Among them, however, asymmetric access to the vital quaternary centers was entirely achieved by the diastereoselective induction of the pre-existing stereocenters in chiral substrates or auxiliaries.…”

“…Despite the above-mentioned substantial progress in the construction of the related chiral all-carbon quaternary centers, the exploration of alternative strategies, especially to create such stereocenters in a catalytic enantioselective manner, is still of high demand in the asymmetric synthesis of cis-aryl hydroindole alkaloids. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] To address this topic, three biologically interesting Amaryllidaceae alkaloids, (+)-vittatine, (+)-epi-vittatine, and (+)-buphanisine ( Figure 1), were selected as our synthetic targets for developing a method-oriented strategy. These structurally related molecules with a bridged polycyclic ring system were originally found in some Amaryllidaceae plants such as Hippeastrum vittatum, Nerine bowdenii, Crinum erubescens, and Sternbergia sicula.…”