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

Abstract

An enantioselective, biomimetic organocatalytic synthesis of 4-arylquinolizidin-2-ones, key intermediates in the synthesis of several Lythraceae alkaloids, was developed. The methodology features S-proline-mediated Mannich/aza-Michael reactions of readily available arylideneacetones and Δ 1 -piperideine. The total syntheses of (−)-lasubine II and (+)-subcosine II as well as the formal syntheses of structurally related Lythraceae alkaloids were achieved. The use of Δ 1pyrroline in the Mannich/aza-Michael reaction provides enantiomerically enriched 5-arylindolizidin-7-ones, which are precursors to nonopiate antinociceptive agents. Letter pubs.acs.org/OrgLett

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…[34] In 2019, Pansare and Virk reported the enantioselective total synthesis of (-)-lasubine II (69) and (+)-subcosine II (71) (Scheme 8). [35] They demonstrated that the key precursor to these natural products, 4-aryl quinolizidin-2-one (68), could be obtained in a single step via an organocatalytic enantioselective domino Mannich/aza-Michael reaction of 3,4-dimethoxybenzylidene acetone (66) and tripiperideine (67) using Lproline [(S)-41] as the catalyst. Further transformations of 68 afforded both 69 and 71 in short steps (Scheme 8).…”

“…Further transformations of 68 afforded both 69 and 71 in short steps (Scheme 8). [35] It should be pointed out that this methodology can be used to access intermediates similar to 68 that have been used for the synthesis of (+)-abresoline, (+)-dihydrolyfoline, (À )-decinine, lythrine, and decaline. [35] In 2016, Sun and co-workers developed an enantioselective total synthesis of hedyosumins A, B, and C (79-81) using an organocatalytic reaction as the key step (Scheme 9).…”

“…[35] It should be pointed out that this methodology can be used to access intermediates similar to 68 that have been used for the synthesis of (+)-abresoline, (+)-dihydrolyfoline, (À )-decinine, lythrine, and decaline. [35] In 2016, Sun and co-workers developed an enantioselective total synthesis of hedyosumins A, B, and C (79-81) using an organocatalytic reaction as the key step (Scheme 9). [36] Using catalyst 74, they achieved an organocatalytic enantioselective [4 + 3] cycloaddition between dienal 72 and furan 73 for the synthesis of an optically active tetracyclic skeleton 76, which was further elaborated to afford 79-81 via a multistep sequence (Scheme 9).…”

“…[32] The synthesis highlights the application of two organocatalyzed aldol reactions in the process of obtaining the key intermediates for the total synthesis. First, the cross-aldol reaction between 3-(triisopropylsilyl)propynal (35) and propanal (36) catalyzed by diarylprolinol derivative (R)-3 led to the formation of the optically active aldehyde 37, which was further converted to the key pyran intermediate 40 via several steps of synthetic maneuvers. Next, compound 42 was prepared via a self-aldol reaction of 36 using D-proline (41) as the catalyst.…”

Two Decades of Progress in the Asymmetric Intramolecular aza‐Michael Reaction

“…However, brief descriptions of the examples reported to date, including the main author, year of publication and type of catalyst employed are specified in Table 1. Strategies involving Mannich/IMAMR, [47][48][49][50][51][52][53][54][55][56][57][58][59] α-aminoxylation/ IMAMR, [60][61][62][63][64] aza-Friedel-Crafts/IMAMR, [65] cross metathesis/ IMAMR, , [18,28] aza-Morita-Baylis-Hillman/IMAMR, [66] Robinson annulation/IMAMR, [67][68][69][70][71] oxa-Mannich/IMAMR, [72] aza-Henry/IMAMR, [73] peptide coupling/IMAMR, [38] aza-Rahuhut-Currier/IMAMR, [74] Betti/IMAMR, [75] enamine formation/IMAMR [76] and carbene insertion/IMAMR [77] are collected in this table.…”