Synthesis of Optically Active Indolizidines: (-)-8a-epi-Dendroprimine and (-)-7,8-Dehydro-5,6-dimethylindolizidine

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

Advances in Aza‐Claisen‐Rearrangement‐Induced Ring‐Expansion Strategies

“…Their long‐term research program focused on flexible access to substituted indolizidinone skeletons by using ACRs for the synthesis of structurally diverse natural products and drugs . Early examples included ring expansions that employed the zwitterionic ACR of 2‐vinylpyrrolidines for the synthesis of indolizidine alkaloids, such as castanospermine analogues, pumiliotoxin 251D, and dendroprimine . Key features include the zwitterionic‐ACR‐induced ring expansion of 2‐vinylpyrrolidine 9 and stereoselective transannulation that utilize the planar chirality of unsaturated 9‐membered lactams ( 12 a versus 12 b ; Figure ).…”

Flexible Synthesis of Planar Chiral Azoninones and Optically Active Indolizidinones

“…With a set of defined amino esters in hand, the zwitterionic aza‐Claisen rearrangement3–6 to induce ring expansion was investigated using chloroacetyl fluoride and phenylacetyl fluoride as the standard ketene sources 19,20. Generally, allylamines 6 and 7 and an excess of acid fluoride were dissolved in dry dichloromethane in the presence of solid potassium carbonate, and trimethylaluminum was added at 23 °C.…”

“…Furthermore, ester VI could be converted into lactam VII , which served as a key intermediate in the synthesis of dendroprimines (Figure 1). 6…”

Planar Chirality − Synthesis and Transformations of 8- to 10-Membered Heterocycles Bearing (E)-Olefins

“…Some intraannular distances in 102 are listed in Table 5. One indolizidinone, 115 (R 1 , R 4 , R 5 = H, R 3 = CO 2 Et), had been employed as a key intermediate in a total synthesis of a dendroprimine (indolizidine alkaloid) 50…”