Abstract:The zwitterionic aza-Claisen rearrangement of optically active 3-pyrrolidine acryl esters and various acid chlorides to generate optically active azoninones proceeds with high simple diastereoselectivity (internal asymmetric induction) and a complete 1,3-chirality transfer. The reaction path observed depends on the substitution pattern of the allylic system: while the more electron-rich alkylated allyl amine formed predominantly von Braun type products, the a,P-unsaturated esters could be rearranged with high yields. The azoninones thus obtained were treated with electrophiles, inducing regio-and diastereoselective transannular ring contractions. The resulting indolizidinones should be useful key intermediates in alkaloid synthesis.

The ketene-Claisen reaction was first described by D. Bellui in 1978 as an intermolecular variant of the [3.3] sigmatropic rearrangement of allyl and thioallyl ethers."I Recently, it was reported that allyl sulfides, in particular, can be rearranged under very mild conditions chemoselectively with the expected 1,3-chirality transfer from the C-S to a C-C bond. Furthermore, excellent 1,2-asymmetric induction was found when an optically active C -0 functionality was located x to the nascent C-C bond.[*] The reaction was also employed in the syntheses of medium-sized rings (7-13 ring atoms).[31 Until now the rearrangement was restricted to activated ketenes like chloroalkyl-and dichloroketene. Ally1 amines have been used in ketene-Claisen reactions only rarely. The few reported cases focused on conformationally fixed bicyclic systems or amines bearing an unhindered terminal olefinic unit.[41 Here, we report on the synthesis of optically active[51 hexahydroazoninones by a zwitterionic aza-Claisen reaction with complete 1,3-chirality transfer from chiral allyl amines.f5IAs starting compounds we used the ally1 amines 3, 6, and 9. The proline methyl ester 2 was synthesized from L-( -)-proline (1) by Clarke-Eschweiler methylationr6I and subsequent esterification (Scheme I).['] In a one-pot reaction 2 was reduced with diisobutylaluminum hydride (DIBAH) in situ to give the aldehyde; Horner olefination provided amino ester 3. Amino esters 6 and 9 were prepared by analogous sequences starting from truns-and cis-4-hydroxy-~-proline (4) and (7), respectively. Prior to the one-pot reduction/chain extension reaction, the free O H group was protected as a terr-butyldimethylsilyl (TBDMS) ether in 5 and S.rsl The diastereomeric purity of amino esters 3, 6, and 9 was determined by 'H and I3C N M R spectroscopy (see Table I) and by HPLC analysis. ['] Special two-phase conditions were developed for the Claisen rearrangement of ally1 amines 3, 6, and 9. A slurry of the amine and solid potassium carbonate in anhydrous chloroform at 0 "C was treated with acetyl chloride and 20 to 30 mol YO of trimethylaluminium. The corresponding partially hydrogenated azoninones 14, 15, and 16 were isolated in 65 to 84% yield (Scheme 2). In considering the reaction mechanism it seemed reasonable to assume that the acyl ammonium salt 10 forms initially. This intermediate could be attacked either by the nucleophilic halide ion in a von Braun type S, reaction["] generating the chlorides 11 and/or 12, or by a base (e.g. the chloride ion) which could deprotonate the a-position of the activated carbony1 group. The resulting zwitterionic intermediate 13 could then undergo 1) Acyl ammonium-salt 10 was detected in the reaction mixture at low temperatures by 'H and I3C N M R spectroscopy.2) Halides of type 11 and 12 were isolated in products of the rearrangement. Apparently the reaction path taken is determined by the bulk of the alkyl substituent on acyl ammonium salt 10: N-benzylated amino esters underwent the von Braun reaction to yield amides 11 and 12, whe...

No abstract

Indolizidinones can be employed as key intermediates in efficient asymmetric synthesis of naturally occurring indolizidine alkaloid analogues. The 5,7-dimethylindolizidine (Ð)-8a-epi -dendroprimine was formed by a diastereoselective methylationÐ reduction sequence of the lactam function. The (Ð)-5,6-dimethylindolizidine was generated via the same key step including an additional quasi 1,2-methyl shift: an intramolecular enamine alkylation is followed by regioselective reductive cyclopropane ring opening.(Ð)-Dendroprimine 1 is an indolizidine alkaloid with unknown biological activity isolated and characterized by LŸn-ing from Dendrobium primulinum Lindl (Orchidaceae) in 1965. 1 The correct relative configurations of the stereogenic centers were determined after the synthesis of the racemic compound and its diastereomers (e.g. 2 ) by the same group, 1 the absolute configuration has been investigated in 1972 by measuring CD-spectra of some degradation products. 2 In 1979 Sonnet confirmed the results by NMR-spectroscopic analyses. 3 Until now, no synthesis of optically active dendroprimine 1 and its epimers like 2 has been described. Figure 1Our synthesis started from the known indolizidinone 4 which could be generated in six steps from L -(Ð)-proline including a stereoselective zwitterionic aza-Claisen rearrangement followed by a regio-and diastereoselective transannular ring junction as the key steps; overall yield was >50 %. 4 First efforts were carried out to distinguish the carboxylic groups: DIBALH-5 or Red-Al ® -reductions 6 gave unselectively the amino alcohol 6 and the desired hydroxymethyl lactam 5 in varying yields, the reaction with NaBH 4 in MeOH 7 led to 5 chemoselectively in the modest yield of about 50%. The best results were achieved using Li(Et) 3 BH, 8 a reagent which is normally known to reduce amides to the corresponding primary alcohols: about 81% of the hydroxymethyl lactam 5 could be isolated, and no reduction of the amide function was observed.The next sequence removed the hydroxyl group as well as the phenylselenyl substituent. After activating the hydroxyl group as a thiocarboxylic ester 7 and radical reduction with AIBN and tributyl stannane (BartonÐMcCombie), 9 the 7-methylindolizidinone 8 was generated in about 50% over two steps. The second methyl group at C-5 was stereoselectively introduced employing a one-pot procedure: After initial treatment of the lactam 8 with one equivalent of methylmagnesium chloride, the in situ formed iminium salt was reduced with NaBH 4 /HOAc. 11 The stereoselectivity was efficiently directed by the Òopen book effectÓ, the hydride ion exclusively attacks from the less hindered face parallel to the bridgehead hydrogen. The (Ð)-8a-epi -dendroprimine 2 was isolated as the hydrochloride in 55% yield, all spectral data were in good agreement with those published in the literature. 10