Synthesis and Absolute Configuration of Hyperaspine, an Alkaloid of the Ladybird Hyperaspis campestris

Abstract

Hyperaspine (1a), isolated from the European Coccinellidae Hyperaspis campestris, isthe first representative of a new type of ladybird alkaloids having a 3‐oxaquinolizidine skeleton. A new total synthesis of (±)‐hyperaspine starting from protected piperidin‐4‐one has been achieved. The absolute configuration of the natural alkaloid was unequivocally established to be 3S,4aS,6R,8S by HPLC analyses on a chiral column. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

A Six-Step Asymmetric Synthesis of (+)-Hyperaspine

“…Conjugate addition of a dialkylcuprate, prepared from pentylmagnesium bromide and CuI, to 7 provided nearly complete (>96% de) facial selectivity affording a 92% yield of piperidone 8 . This stereochemical outcome was anticipated on the basis of stereoelectronic arguments and literature precedent. ,6b Ma and Zhu reported that bicyclic ketone 8 is reduced with LS-Selectride to give alcohol 9b , which was esterified with inversion via the Mitsunobu reaction to provide hyperaspine 2b. Braekman and co-workers reduced racemic 8 with NaBH 4 to give a 1:1 mixture of the two inseparable epimeric alcohols .…”

“…This stereochemical outcome was anticipated on the basis of stereoelectronic arguments and literature precedent. ,6b Ma and Zhu reported that bicyclic ketone 8 is reduced with LS-Selectride to give alcohol 9b , which was esterified with inversion via the Mitsunobu reaction to provide hyperaspine 2b. Braekman and co-workers reduced racemic 8 with NaBH 4 to give a 1:1 mixture of the two inseparable epimeric alcohols . Since a stereoselective reduction of (+)- 8 to the aminal alcohol 9a is advantagous, we investigated the use of a dissolving metal reduction.…”

“…Studies by Ma and Zhu resulted in a synthesis of (−)-8-epihyperaspine2a and (+)-hyperaspine 2b in 12 and 9 steps, respectively. Braekman and co-workers recently reported a racemic synthesis of 1 in 15 steps via a protected piperidine-4-one 1 Structure of natural (+)-hyperaspine. …”

“…To our delight, treatment of 8 with Li/NH 3 in Et 2 O afforded a good yield of the desired alcohol 9a as the major diastereomer (dr 93:7 by NMR). As reported, the epimeric alcohols are difficult to separate, so conditions were developed to acylate the alcohols in situ without isolation. On workup of the Li/NH 3 reduction, addition of pyrrole 2-carbonyl chloride to the reaction mixture provided a 50% yield of (+)-hyperaspine directly from ketone 8 .…”

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

“…Other natural product syntheses have used the anodic oxidation approach, often as the first step in a synthesis campaign to functionalise a pyrrolidine or piperidine carbamate [ 86 – 87 ].…”