A Short Synthesis of γ-Lycorane using Ni/AcOH Mediated Radical Cyclisation

Abstract

A short synthesis of (±)-g-lycorane 6 is described using two different radical cyclisations. The key step is the formation of tetrahydroindolone 9 by a nickel-promoted 5-endo radical cyclisation. This is followed by a tributylstannane-mediated 6-endo ring closure to the tetracyclic lactam 10 which is readily reduced to (±)-g-lycorane 6.N-Alkenyl-trichloroacetamides 1 undergo unusual 5-endo-trig radical cyclisation when treated with Bu 3 SnH and AIBN, affording saturated g-lactams 2 (Scheme 1). 1 In contrast, we recently reported that unsaturated lactams 3 are formed when the same trichloroacetamides are treated with nickel powder and acetic acid in refluxing 2-propanol. 2 A 5-endo cyclisation of the radical derived from 1 is also involved, but the ensuing radical A is not reduced as in the Bu 3 SnH-mediated cyclisation: a surprisingly easy oxidation occurs in this case giving the corresponding cation B which undergoes elimination, further reduction and a final elimination of HCl to give lactam 3. This results in the one-step creation of a new carbon-carbon bond and the introduction of two double bonds. 3 The oxidation step is still not clear and occurs presumably via electron transfer to the starting trichloroacetamide 1 with the possible intervention of traces of cupric ions in the medium. Scheme 1A wide range of such tetrahydroindolones can therefore be obtained since the method is tolerant of many functional groups and requires simple starting materials. Moreover, the presence of the diene system in a structure such as 3 allows a great variety of further transformations. We have recently implemented this unusual radical chemistry in a short approach to Erythrina alkaloids 4 using an intramolecular Friedel-Crafts cyclisation between an electron-rich aromatic ring on the side chain R and the acyliminium arising from protonation of the diene moiety (connection at C-7a, indole numbering in compound 3). 5 Amaryllidaceae alkaloids 6 are also ideal synthetic targets for our methodology. Ring closure at C-7 of the diene system using 6-endo radical cyclisation 7 or intramolecular Heck reaction 8 should allow the rapid construction of Lycorine-type alkaloids. On the other hand, connection at C-3 or C-3a could serve to construct Montanine-type or Crinane-type alkaloids.Recently an asymmetric synthesis of (-)-g-lycorane has been reported using a 5-endo radical cyclisation, 9 which prompts us to disclose our own results concerning the synthesis of this class of alkaloids. Figure 1Lycorine 4 is representative of the large class of Amaryllidaceae alkaloids (Figure 1). Most synthetic efforts have been devoted to the total synthesis of this alkaloid and its reduced congeners, a-and g-lycorane, 5 and 6. 6 We present in this paper a very short synthesis of g-lycorane 6, as an illustration of our new methodology. 10,11 Condensation of cyclohexanone with the piperonal derived amine 7 12 followed by acylation with trichloroacetyl chloride afforded trichloroacetamide 8 13 in 73% yield. Subsequent treatment with nickel powder, acetic...

Short Total Synthesis of (±)‐γ‐Lycorane by a Sequential Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck Addition Reaction

“…Hydrogenation of the conjugated double bonds in 34 by use of an H‐cube hydrogenation flow reactor by using a mixture of ethanol and ethyl acetate as solvent to aid solubility, with a flow rate of 0.5 mL min −1 and 10 % palladium on charcoal as catalyst at 65 °C and 60 bar pressure gave the reduced product 35 in almost quantitative yield (97 %). Reduction following literature precedent by using lithium aluminium hydride completed the synthetic route to give the total synthesis of (±)‐γ‐lycorane 5 in 85 % yield (Scheme ) …”

Oxidative Dearomatization of 4,5,6,7‐Tetrahydro‐1H‐indoles Obtained by Metal‐ and Solvent‐Free Thermal 5‐endo‐dig Cyclization: The Route to Erythrina and Lycorine Alkaloids

“…The acquirement of 3 g , 3 i , and 3 j completed the formal total syntheses of a whole pleiad of alkaloid structures, namely (±)‐3‐demethoxy‐1,2‐dihydroerysotramidine and (±)‐3‐demethoxy‐1,2‐dihydroerythraline, (±)‐erysotramidine, which could be further transformed into (±)‐erysotrine and (±)‐erythravine, and finally, (±)‐γ‐lycorane (Scheme ). To achieve another formal synthesis of the rearranged alkaloid tetrahydroerythraline, hexahydroapoerysopine dimethyl ether indolone 3 k was subjected to intramolecular ligand‐free Heck cyclization under Jeffery conditions .…”

“…According to the literature, both natural product classes can be retrosynthetically traced back to a common intermediate, 5,6‐dihydro‐1 H ‐indol‐2(4 H )one 3 . In the case of a Lycorine framework: n =1, X=Hal, and with respect to an Erythrina core: n =2, X=H,– (Scheme ). These indolones, in turn, could be envisioned as oxygenated forms of 4,5,6,7‐tetrahydroindoles 2 , which are extensively employed as highly functionalized indole precursors—valuable intermediates in the numerous syntheses of alkaloids and drugs, such as S ‐(−)‐pindolol and (±)‐chuangxinmycin, (−)‐goniomitine, arcyriacyanin A, 6,7‐secoagroclavine, psilocin and psilocybin via the intermediary of 4‐hydroxyindole, and, finally, (±)‐γ‐lycorane …”

The Fascinating Chemistry of α‐Haloamides

“…Compound C , an advanced intermediate along the synthesis of the racemic alkaloid γ‐lycorane, has been prepared by way of two successive radical cyclizations (Scheme ) . In detail, the trichloroacetamido precursor A , in the presence of Ni(0) powder and acetic acid in refluxing 2‐propanol, generated the α‐amidyl radical ( I ) which cyclized in a 5‐endo‐trig mode.…”