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Strategies for the Asymmetric Construction of Pelletierine and its Use in the Synthesis of Sedridine, Myrtine, and Lasubine
Author(s) -
Zaidan Raed K.,
Evans Paul
Publication year - 2019
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201900477
Subject(s) - chemistry , enantiomer , enantioselective synthesis , quinolizidine , intramolecular force , enantiomeric excess , epimer , stereochemistry , ketone , mandelic acid , cinchona alkaloids , cinchona , michael reaction , organic chemistry , catalysis , alkaloid
Three methods for the asymmetric synthesis of both enantiomers of pelletierine 6 are reported. Bella's proline‐based Mannich process gave ( R )‐ and ( S )‐Cbz‐protected 6 in good yields from Δ 1 ‐piperideine 14 and in reasonable enantiomeric excess (74–80 % ee ). An intramolecular aza‐Michael, cinchona‐based, organocatalytic method is also reported. With commercially available 9‐amino quinine ( 24a ) and quinidine ( 24b ) catalysts, Cbz‐protected α,β‐unsaturated ketone 23 also gave ( R )‐ and ( S )‐Cbz‐protected 6 in good yields and enantiomeric excess (90–99 % ee ). This material was used to synthesize both optically active forms of deoxyhalofuginone ( 26 ), an analogue of febrifugine which is of interest as an anti‐fibrotic agent. Finally, a resolution of racemic pelletierine using ( R )‐ and ( S )‐mandelic acid 27 is reported. This scalable method gave both enantiomers of Cbz‐ and Boc‐protected 6 in excellent enantiomeric excess (≥ 99 %). Both highly enantioenriched forms of 6 (obtained from the resolution study) were used to synthesize several alkaloids. Firstly, (–)‐( S )‐Cbz‐protected pelletierine 17 was used to prepare naturally occurring sedridine ( 32 ) and its epimer allosedridine ( 8 ). Then the preparation of both enantiomers of the quinolizidine myrtine ( 33 ) by an olefination‐intramolecular aza‐Michael sequence is reported. Finally, the synthesis of the epimeric quinolizidine alkaloids, lasubine I ( 34 ) and lasubine II ( 35 ), from (+)‐ and (–)‐Boc‐protected pelletierine ( 29 ) respectively, is discussed.