Indolizidine alkaloids hydrogenation

Yttrium-catalyzed diene cyclization/hydrosilylation was applied to the synthesis of aliphatic nitrogen heterocycles such as the indolizidine alkaloid ( )-epilupinine. l-Allyl-2-vinylpiperidine 30 was synthesized in four steps in 59% overall yield from commercially available ( )-2-piperidinemethanol (Scheme 10). Treatment of 30 with phenylsilane and a catalytic amount of Gp 2YGH3(THF) gave silylated quinolizidine derivative 31 in 84% yield, resulting from selective hydrometallation of the A-allyl G=G bond in preference to the exocyclic vinylic G=G bond. Oxidation of the crude reaction mixture with tert-huVf hydrogen peroxide and potassium hydride gave (i)-epilupinine in 51-62% yield from 30 (Scheme 10). 

As a final test of the synthetic strategy in the indolizidine alkaloid field, Weinreb turned to the fungal neurotoxin slaflamine (132) (82JA7065). Methylol acetate 125 was prepared in several steps from amide 124. When methylol acetate 125 was heated in refluxing o-dichlorobenzene, a separable 1 1.8 mixture of epimeric Diels-Alder adducts 127 and 128 (82%) was obtained via the N-acylimine intermediate 126. Catalytic hydrogenation of adduct 127, followed by basic hydrolysis, produced acid lactam 129. Curtius rearrangement of this compound led to carbamate lactam 131 (70JA7615) and to racemic slaflamine (132) (Scheme 18). 

The 5,6,8-trisubstituted indolizidine alkaloids form another class of amphibian skin alkaloids that has grown enormously since the first member of this group was reported in 1997. At present approximately 70 such alkaloids have been tentatively or positively identified.As has so often happened with minor or trace components of the skin extracts, very few of them have been characterized completely, and the relative configurations are almost entirely unknown other than for a few in which strong or weak Bohlmann bands in the FTIR spectra imply cis- or iram-relationships respectively between the hydrogen atoms on C-5 and C-8a. 

Liebeskind s synthesis of (lil,4il,9aS)-quinolizidine 251AA (2297), referred to above, was an extension of the route his team had previously used in the synthesis of 5,8-disubstituted indolizidine alkaloids (cf. Scheme 241 Section 6.2.5). In brief, the chiral molybdenum complex (—)-1909 was converted in six steps into the 2,3-iraHS-2,6-n 5-tetrahydropyr-idine (2S,3il,6il)-(—)-2298 (Scheme 293). Tandem hydrogenation of the alkene and hydrogenolysis of the protecting groups followed by ring closure of the amino alcohol (—)-2299 under Mitsunobu conditions then completed the synthesis of (—)-quinolizidine 251AA (2297) (Scheme 293). 

Application of this methodology led to the synthesis of indolizidine and quinolizidine alkaloids. Condensation of 228 with benzyl amine followed by aza-annulation produced dihydropyridone 229 (Scheme 16).59-74 Stereoselective hydrogenation in the presence of Na2CC>3... 

Besides the main alkaloids, about 20 minor P. A with different side chains, 15 allopumiliotoxins (with an OH-group at C-7 of the indolizine system), and 10 ho-mopumiliotoxins (with a quinolizidine system instead of indolizidine as the skeleton) as well as about 25 decahydroquinolines have been found however, the exact structures of some of them are still unknown. The minor alkaloids differ from the P. in the side chains which may be hydrogenated, oxidized, methylated, or shortened P. A and B exhibit cardiotonic and myotonic activities and are thus of pharmaceutical interest. Furthermore they have an effect on sodium ion channels. Subcutaneous injections of 50 pg P. A or 20 pg P. B in mice are lethal. The decahydroquinolines on the other hand are less toxic (injection of 400 pg P. C causes death of mice) and influence nicotine receptors as well as sodium and potassium channels. 

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