Synthesis of -epilupinine

The key step in the total synthesis of (—)-epilupinine 253 involved the ring expansion of a proline-derived spirocyclic ammonium ylide to give 252 through a [1,2] Stevens rearrangement, as shown in Scheme 51 <1997T16565>. 

The cyclic ammonium ylide/[l,2]-shift approach has been successfully applied by West and Naidu to a key step in the total synthesis of (—)-epilupinine, one of the biologically active lupin alkaloids. Cu(acac)2-catalyzed diazo decomposition of enantiomeric pure diazoketone 160 in refluxing toluene generates a spiro ammonium ylide 161 and 162, which then undergoes [l,2]-shift to give rise to a quinolizidine skeleton as a mixture of diastereomers (95 5) (Scheme Major diastereomer 164 has enantiomeric purity of 75% ee. The partial retention of stereo-... 

A synthesis of epilupinine under physiological conditions was accomplished as follows (42). Ethyl A-benzyliminodivalerate (XXII) yields an acyloin (XXIII) which was reduced with lithium aluminum hydride to the diol XXIV, the benzyl group of which was removed by hydro-genolysis. Subsequent oxidation with periodic acid at 25°, pH 5, gave an intermediate dialdehyde which cyclized to lupinaldehyde (XXV). This unstable aldehyde on reduction with lithium aluminum hydride gives only the more stable epilupinine (XIV). 

In spite of their recognized Lewis acidity and the propensity to complex with Lewis bases (particularly in an intramolecular chelate) [8], the organoyttrium complexes can be utilized for the synthesis of nitrogen heterocycles. The protocol has been employed in a concise synthesis of ( )-epilupinine (Scheme 3) [43]. 

Radical cyclization reactions have proven to be a very efficient approach for polycyclic natural product synthesis. In many cases, the last step involves a reduction of a cyclic radical with formation of a new stereogenic center. Very good stereochemical control has been achieved with such polycyclic radicals. For example, Beckwith has reported a highly stereoselective formation of a quinolizidine ring (Scheme 19, Eq. 19.1) [41b]. This process is the key reaction in a four-step synthesis of epilupinine and the stereochemical outcome results from a stereoselective axial reduction by tin hydride of a bicyclic radical. In a related process, Tsai has prepared silylated hydroxyquinolizidine by radical cyclization to an acylsilane followed by a radical-Brook rearrangement (Scheme 19, Eq. 19.2) [42]. 

Similar cyclizations using piperidines with leaving groups at C-2 are probably mediated by iminium ions. For example, a total synthesis of epilupinine <83H(20)40i > relies on the anodic oxidation of the lactam (223) to the methoxy derivative (224), which was subsequently converted into the quinolizidine (225) through a titanium tetrachloride-mediated cyclization, a reaction that has been... 

Nucleophilic intramolecular addition of a carbon-silicon bond onto a carbon-nitrogen iminium ion is the key step of a berbine synthesis <82CC769,83H(20)417>. Thus, treatment of the isoquinolinium salt (235) with caesium fluoride in ethanol afforded (+)-xylopinine (237), presumably via the betaine (236) (Scheme 45). A silicon-directed intramolecular cyclization of a A-acyliminium ion (238) was also the key step of Speckamp s synthesis of (+)-epilupinine as shown in Scheme 46 <85JOC40I4>. 

Vinylogous urethane (248) was employed in a radical-mediated synthesis of epilupinine (Scheme 48), where its cyclization was induced by treatment with tributyltin hydride-AIBN <89T5269>. In another radical process, a very efficient synthesis of berbine was achieved by photolysis of compound (249), which induced a diradical cyclization process promoted by an excited-state electron-transfer desilylation (Scheme 49) <85TL5867>. 

This method was proved to be applicable for the total synthesis of ( )-epilupinine, in which high diastereoselectivity was achieved through an organoyttrium-catalyzed sequential cyclization/silylation reaction (Scheme 12.82) [180]. The catalytic cyclooligomerization proceeded rapidly and was unaffected by the presence of a... 

Naidu BN, West FG. A short, enantioselective synthesis of (—)-epilupinine from proline via a spirocyclic ammonium ylide. Tetrahedron 1997 53(48) 16565-16574. 

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