Development of bifunctional organocatalysts and application to asymmetric total synthesis of naucleofficine I and II

Abstract

The proline-type organocatalysts has been efficiently employed to catalyze a wide range of asymmetric transformations; however, there are still many synthetically useful and challenging transformations that remain unachievable in an asymmetric fashion. Herein, a chiral bifunctional organocatalyst with a spirocyclic pyrrolidine backbone-derived containing fluoro-alkyl and aryl sulfonamide functionalities, are designed, prepared, and examined in the asymmetric Mannich/acylation/Wittig reaction sequence of 3,4-dihydro-β-carboline with acetaldehyde, acyl halides, and Wittig reagents. As a result, the spirocyclic pyrrolidine trifluoromethanesulfonamide catalyst can facilitate this versatile sequence as demonstrated by 18 examples displaying excellent enantioselectivity (up to 94% ee), as well as moderate to good yields (up to 54% over 3 steps). As a practical application, the asymmetric total synthesis of naucleofficine I (1a) and II (1b) in ten steps have been accomplished.

Fig. 1

Design of asymmetric synthesis of monoterpenoid alkaloids. Retro-synthesis involves Diels–Alder reaction and Mannich/acylation/Wittig sequent reaction

Fig. 2

The substrate scope of the Mannich/Acylation/Wittig reaction. Reaction condition: 2a (0.1 mmol), acetaldehyde (0.3 mmol), (S,S)-Cat 1 (0.02 mmol), and Et₃N (0.05 mmol), in 0.5 mL DCE and 0.5 mL H₂O, then acyl halide 3 (0.15 mmol) and Wittig reagent 4 (0.2 mmol). Isolated yield over three steps. Enantiomeric excess determined by HPLC analysis. a The scope of 3,4-dihydro-β-carboline substrates. b The scope of 3,4-dihydro-isoquinoline substrates

Fig. 3

Further transformation. Thermocatalytic hetero-Diels–Alder reaction mainly obtained the cis-product of C3 and C15

Fig. 4

Gram-scale synthesis of 5o. Reactions were performed with 10% mol (R,R)-Cat 1

Fig. 5

Asymmetric total synthesis of naucleofficine I and II. The key steps include O-hetero-Diels–Alder cycloaddition, hydroformylation, and double bond isomerization