Indolizidine alkaloids asymmetric synthesis

Swainsonine is a trihydroxylated bicyclic indolizidine alkaloid with four chiral centres, whose relative stereochemistry was determined by X-ray crystallographic analysis and the absolute configuration was deduced on the basis of biosynthetic and asymmetric induction studies, and then confirmed by an enantiospecific synthesis from D-mannose [2a]. 

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). 

Alder reaction [524, 525]. Danishefsky et al. have used nitroso dienophiles for the synthesis of mitomycin K and antibiotics of the FR 900482 family, the latter ones are structurally unique aziridino-l,2-oxazine derivatives [526-529]. An approach directed to the cephalotaxus alkaloids has been worked out by Fuchs et al. [530], and several indolizidine alkaloids have been prepared by Keck s [531] and Kibayashi s groups [532,533]. Kibayashi et al. also synthesised Nuphar piperidine alkaloids in enantiomerically pure form by means of an asymmetric nitroso Diels-Alder reaction [534]. 

The asymmetric synthesis of indolizidine alkaloids is described utilizing a palladium-catalyzed amination process. Ionization of an allylic carbonate provides a symmetrical rr-allyl palladium complex, subsequent reaction with a protected homoallylamine gave the product in 93% yield and >99.5% ee (eq 5). ... 

By incorporating a chiral auxiliary, (+ )-rrans-2-(a-cumyl)cyclohexyl (TCC), into pyridinium salt 688, Comins and co-workers were assured of excellent asymmetric induction in a divergent synthesis of three 5,8-disubstituted amphibian indolizidine alkaloids (Scheme 93) (467,499). Addition of but-3-enylmagnesium bromide to 688 yielded the dlhydropyridone 689 as a single diastereomer in 91% yield after recrystallization. After a series of functional group manipulations, the C-8 methyl group was introduced stereoselectively by enolate alkylation (690 -> 691),... 

The indolizidine alkaloid (+ )-monomorine I (373), isolated from Pharaoh s ant Mono-morium pharaonis, is the first example of an indolizidine alkaloid found in the animal kingdom. One enantioselective total synthesis of 373 exploits an asymmetric cycloaddition of nitrone 370 to the chiral allylic ether 369, which is prepared from 349. The conversion of 349 to a tosylate followed by treatment with -propylmagnesium bromide in the presence of... 

SCHEME 11.52 A flexible approach toward the total synthesis of various indolizidine alkaloids based on the asymmetric vinylogous Mannich reaction as key step. 

New asymmetric synthesis of the indolizidine alkaloids (-l-)-monomorine I (673) and (—)-indolizidine 195B (674) has been achieved from sulfinimine-derived chiral building blocks N-sulfinyl-5-amino-p-ketophosphonate (671) via 3-oxopyrrolidine phosphonates (672) (Scheme 169). ... 

Kiewel, K., Tallant, M. and Sulikowski, G.A. (2001) Asymmetric Heck cyclization route to indolizidine and azaazulene alkaloids synthesis of (+)-5-epiindolizidine 167B and indolizidine 223AB. Tetrahedron Lett., 42, 6621-3. 

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