Indolizidines 3,5-disubstituted

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

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... 

Disubstituted indolizidine 207A 1,4-Disubstituted quinolizidine 217A ... 

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). 

The 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines are the more common structural patterns found in amphibian skin[21]. None of these alkaloids has so far been reported from any other source. In addition, the biological activity of only a few 5,8-disubstituted indolizidines has been investigated due to the isolation in minute quantities from the skin. Among them, the relative stereochemistry of quinolizidine 2071 was anticipated to be 75 by our chiral synthesis of 76[35] followed by stereocontrolled synthesis of 75[36]. A sample of synthetic racemate of 75 had produced the best separations on GC analysis with (3-dextrin chiral column[36]. 

A direct route to 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines was reported by Barluenga and co-workers <02OL1971> (Scheme 30). Hetero-Diels-Alder reaction followed by reduction and desilylation gave good yields of the key piperidine core 51. Further elaboration of the hydroxymethyl side chain followed by RCM and hydrogenation gave the targets in moderate yields. 

Optical rotations of 5,8-disubstituted indolizidines are given in Table... 

The amphibian quinolizidines appear to be 1,4-disubstituted ring homologs of the 5,8-disubstituted indolizidines. A characteristic Bohlmann band pattern in their FTIR spectra, which is broader and less intense than that... 

There have been no studies on the biological activity of the above quinolizidine alkaloids. It is expected that they, like the 5,8-disubstituted indolizidines and other lipophilic dendrobatid alkaloids, will be noncompetitive blockers of nicotinic receptor-channels. 

Indolizidine and quinolizidine alkaloids found in amphibians and ants were studied by Daly and co-workers who classified them in two different classes, A and B, Fig. (1) [2,15-17]. The former include 3,5- and 5,8-disubstituted indolizidines, 5,6,8-trisubstituted indolizidines and 1,4- and 4,6-disubstituted quinolizidines that can be derived from straight-chain carbon precursors. The latter contain one or more isoprene units, and include pumiliotoxins (PTX-A), allopumiliotoxins (a//o-PTX-A or... 

Bohlmann absorption band at 2784 cm indicated the cis relationship of protons H-5 and H-9 (5Z,92), trans antiparallel to the nitrogen lone pair, in accordance with the spectral features of 5,8-disubstituted indolizidines. The existence of three methyl triplets in the H NMR spectrum pointed to a trisubstituted indolizidine nucleus and the analysis of the H 2D COSY NMR spectrum, as well as the J coupling values observed and molecular modelling of the proposed structure, revealed that H-9, H-6 and H-5 occupied axial positions, according to the relative configuration depicted for indolizidine 223A.)... 

The spectral features of 1,4-disubstituted quinolizidines are quite similar to those of the 5,8-disubstituted indolizidine analogues. Their mass spectra are characterised by a major fragment arising from a-cleavage of the alkyl side-chain at C-4 and by an additional peak at m/z 110 (C H 2N+, ca. 30-50%) in ion-trap spectra, arising from a subsequent retro Diels-Alder process, Fig. (5). Since, as seen for the indolizidine analogues, the alkyl substituent at C-l is commonly a methyl group the base peak of... 

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