Biomimetic Total Syntheses of (+)-Dihydrolyfoline and (−)-5-epi-Dihydrolyfoline

Abstract

The first asymmetric total syntheses of (+)-dihydrolyfoline and (-)-5-epi-dihydrolyfoline have been achieved in five and six steps with 4.6% and 14% overall yields, respectively, in which the chiral biaryl axes were constructed in a highly regioselective and stereoselective manner via a biogenetic enzymatic oxidative couplings of phenols, and the requisite quinolizidinone cores were prepared by an enzymatic Mannich reaction.

Biomimetic Organocatalytic Approach to 4-Arylquinolizidine Alkaloids and Application in the Synthesis of (−)-Lasubine II and (+)-Subcosine II

“…The present one-step syntheses of 11 , 16 , and 17 and the two-step synthesis of 18 compare favorably with the shortest multistep syntheses of these quinolizidinones reported to date ( 11 : five steps from 2-pyrrolidone, 40% overall, or five steps from methyl 5-chloropenanoate, 30% overall; 16 : five steps from piperidine, 14.7% overall; 17 : six steps from piperidine, 2% overall; 18 : 12 steps from 3-(benzyloxy)-4-methoxybenzaldehyde, 14.8% overall). In addition, with the exception of 18 , the reported syntheses require separation of the undesired diastereomeric 4-arylquinolizidin-2-one products that are invariably obtained and their subsequent isomerization to the diastereomers that are required for the natural product targets.…”

“…The synthesis of these alkaloids has also been extensively investigated. A common theme in all of these syntheses − is the multistep construction of a suitable 4-arylquinolizidin-2-one (such as 11 ) as the key starting material followed by reduction to the corresponding 4-aryl-2-hydroxyquinolizidine (such as 1 ). Elaboration to the macrolactone-containing target is then achieved by linking the 4-aryl substituent and the hydroxy group with the appropriate carboxylic acid that is incorporated either directly or is constructed in the ring-closing step (Figure ).…”

“…Notably, the diastereomeric (4 S ,9a R ) quinolizidinone product was not observed in any of these reactions. The conversion of 18 to (+)-abresoline ( 4 ), 16 to (+)-dihydrolyfoline ( 19 ), 11 to (−)-decinine ( 7 , via 2 ), and 17 to lythrine ( 5 ) and decalin ( 8 ) is reported.…”

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

“…In the rst of these reports, the crape myrtle constituents (+)-dihydrolyfoline (380; non-natural enantiomer) and (À)-5-epi-dihydrolyfoline (381) were obtained via horseradish peroxidase-catalysed oxidative cyclisation of the bisphenols 378 and 379, respectively (Scheme 49). 181 Although a single coupling product was formed in both cases, indicating high regio-and diastereoselectivity, the reaction towards 381 proceeded with signicantly higher yield (50-66%) than that leading to 380 (15-21%). The coupling precursors 378 and 379 were prepared in a 4-5 step sequence that involved a lipasecatalysed Mannich reaction between O-benzylated isovanillin (376) and (S)-pelletierine (302, itself an alkaloid) as another enzymatic transformation.…”

Rhodium–N-Heterocyclic Carbene Catalyzed Hydroalkenylation Reactions with 2-Vinylpyridine and 2-Vinylpyrazine: Preparation of Nitrogen-Bridgehead Heterocycles

“…Quinolizine-based derivatives belong to this interesting family . However, the usual instability of these species precludes their isolation, and consequently, they have been alternatively obtained as quinolizidines, quinolizinium salts, or quinolizinones . Moreover, examples of formation of pyrido­[1,2- a ]­pyrazines are even more scarce .…”