Ammonium indolizidines

Another Rhn-catalyzed decomposition of a a-diazoester as described by Sabe and coworkers [198] was used for the synthesis of indolizidine alkaloids (Scheme 6/2.8). It can be assumed that, first, an ammonium ylide is formed which then undergoes a 1,2-shift with ring-expansion. Thus, reaction of 6/2-40 with Rh2(OAc)4 led to a 72 28 mixture of 6/2-41 and 6/2-42 in 85 % yield. Cu(acac)2 can also be used with even better yields, but lower selectivity (65 35). 

An oxidative Mannich cyclization methodology allowed the synthesis of indolizidine skeletons. The oxidation of the a-silylamide 140 with ceric ammonium nitrate (CAN) formed in situ an iV-acylaminium cation, which cyclized to afford the bicyclic compound 141 (Scheme 35) <1998JOC841>. 

Stractures of 3-alkyl-5-methylindolizidines, found in thief ants, Solenopsis species (Table II), arrived at by gas chromatographic and mass spectral analysis were confirmed by coinjection and direct comparison with the synthetic sample. Indolizidine 15a from S. conjurata exhibits characteristic peaks at miz 152 (M — CHj) and 138 (M — C2H5, a base peak) as well as a parent peak at m/z 167 in the mass spectram. It corresponds to an isomer of 3-ethyl-5-methylindolizidine (15) which was prepared as a mixture of four stereoisomers by reductive amination of triketone 391 with ammonium acetate-sodium cyanoborohydride and sodium borohydride (Scheme 47). 

Petrini and co-workers used the bis(methoxymethyl)-protected nitrone 150, also derived frern L-tartrate, as an electrophile rather tfaiui as a 1,3-dipole (Scheme 21, top line) (89). In their key step, reaction with 4-ben loxybutylmagnesium bromide gave the cyclic hydroxylamine 151 in 82% yield (de 90%). Transfer hydrogenation with ammonium formate and a palladium catalyst cleaved both the hydroxylamine and the benzyl ether, affording the aminoalcohol 152. Cyclization via the corresponding primary chloride created the protected indolizidine 153, acidic hydrolysis of t ch completed this short synthesis of ( + )-132 in 16%... 

The above results are consistent with formation of an intermediate lithiated epoxide which rearranges via an ammonium ylide 88 (Scheme 15). The ketone 90 then arises from addition of the organolithium (present in excess) to the ester 89 (OH=OLi). Using -PrLi in combination with (-)-sparteine at -98°C yielded 54% of the ester-subsituted indolizidine 89 in 89% ee. A sub-stoichiometric amount of (-)-sparteine (24%) also allowed conversion to proceed to 89 with high ee (82 %), albeit at lower rate. Similarly, a sub-stoichiometric amount of (-)-a-isosparteine (24 mol %) proved to be as good as the stoichiometric combination of (-)-sparteine and i-PrLi. 

In the synthesis of (lS,8aS)-(- -)-indolizidin-l-ol (88) by Chandrasekhar and coworkeis, the aldehyde 104 derived from D-glucose was converted in situ into the N-benzyHmine, to which was added but-3-enylmagnesium bromide to give the adduct (—)-105 as the sole diastereomer in 72% yield after chromatographic purification (Scheme 10). Protection of the amine as the Cbz carbamate and hydroboration—oxidation of the terminal alkene afforded alcohol (—)-106 which, after debenzylation with ammonium formate and palladium on carbon, needed to be re-protected with Cbz. 

The group of Sas developed a novel synthetic route to polyhydrojqrlated indolizi-dines (Scheme 8). Protected a-D-mannofuranoside 41 was transformed into derivative 43 by reaction with hydroiq lamine 42 (nitrone formation) followed by intramolecular 1,3-dipolar cycloaddition. This compound was transformed into ammonium salt 44, which was then cleaved under the basic conditions, giving the desired indolizidine scaffold 45. Alternatively, compound 43 was transformed into the mesyl ester 46, which cyclized upon treatment with K2CO3, providing the bicyclic compound 47. 

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