3,5-Disubstituted indolizidine synthesis

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. 

A diastereoselective synthesis of 3,5-disubstituted indolizidines based on an intermol. addition of an allylsilane on an acyliminium ion derived from (d )-pyroglutamic acid, is described <2006TA1253>. 

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]. 

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). 

Scheme 4-316. Synthesis of disubstituted indolizidines by iron-catalyzed [4+4] ene type reaction.

Carretero and co-workers found that dqjrotection and cyclization of the vinyl-sulfone 294 produced a 4 1 mixture of 2,3-cu-disubstituted pyrrolidine 295 and its tram isomer (Scheme 40). A/-Alkylation of the nuxture. with 3-chloro-2-chloro-methylprop-l-ene followed by chromatogttqjhy led to isolation of the pure 2,3-c/s product 296, silylation and base-initiated cyclization of which gave indolizidine 297. Ozonolysis and elimination of the sulfone group yieldied another pivotal intermediate, the bicyclic enone 298. Reduction with L-Selectride afforded an inseparable nuxture of two diastereomeric alcohols 299 (9 1). Separation was accomplished only after dihydroxylation with osmium tetroxide and peracetylation of the resdting tetrols. The synthesis of ( )-241 was completed by hyc lysis of the m or tetraacetate 300. 

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