5,8-disubstituted indolizidine alkaloids

The mass spectra of 3,5-disubstituted indolizidine alkaloids usually show two major peaks corresponding to the loss of each of the alkyl chains by a-cleavage unless a methyl substituent group is present at C-3 or C-5 (the corresponding [M-15J+ fragment has small intensity). In ion-trap mass spectra, an additional peak at m/z 124, arising from a McLafferty type fragmentation, is also present. Fig. (2). 

Fig. 8. Recently synthesized 3,5-disubstituted indolizidine alkaloids fiom amphibians.

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

Fig. 9. Recently synthesized 1,4-disubstituted quinolizidine and S,8-disubstituted indolizidine alkaloids and related compounds.

Scheme 234 Initial stages in the generalized approach to 5,8-disubstituted indolizidine alkaloids by Toyooka Nemoto and coworkers. Reactants (a) n-BuLi, CICO2R (b) LIHMDS, 2-NTf2-5-CI-py, THF, -78 to -40 °C (c) (PPh3)4Pd, CO, MeOH, NEts, DMF (d) R CuLi, Et20, —78 to —30 °C (e) Super-hydride, THF, 0 °C (f) Swern oxidation (g) (Et0)2P0CH2C02Et, NaH, THF, 0 °C.

Specific apphcations of the Liebeskind second-generation strategy to the synthesis of 5,8-disubstituted indolizidine alkaloids are shown in Scheme 241. From the chiral scafibld (—)-1909 the 2,3-trans-2,6-ds-tet-rahydropyridine (2S,3R,6R)- —)-t920 was obtained in six steps. Tandem... 

A versatile new approach that holds promise for the synthesis of a wide range of 5,8-disubstituted indolizidine alkaloids, although at present only as the racemates, has been reported by Shenvi and his team (Scheme 256). The process, which effectively results in a stereoselective hydroamination, entails hydroboration of dienyl amines 2032 in the presence of molecular iodine... 

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). 

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

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