87905-98-4Relevant articles and documents
Synthesis and Structural Elucidation of 1,2-Disubstituted 3-Fluoropiperidines
Evans, Paul,Fischer, Pauline,Müller-Bunz, Helge,Morris, Morgan
, (2020/02/28)
The work described details the reaction between Selectfluor and a series of 1-carbonyloxy and 1-sulfonyl 2-piperidines in order to generate 3-fluoro-2-methoxypiperidines 3a–f. Their subsequent reaction with allyltrimethylsilane, in the presence of BF3 and TiCl4, is then reported. Studies involving a combination of single-crystal X-ray crystallography and NMR spectroscopy indicate that the allylation process is cis-selective for both carbamate and sulfonamide variants and that optimal levels of diastereoselectivity are obtained using the N-2-nitrobenzene sulfonyl (2-Ns) group. In this manner, the synthesis of a series of 2-allyl 3-fluoro-substituted piperidines (5a, c–f) was achieved. The conversion of both the cis and trans-N-tosyl adducts (5d) into 3-fluorinated analogues of the natural products pelletierine (10) and coniine (11) is subsequently detailed.
Strategies for the Asymmetric Construction of Pelletierine and its Use in the Synthesis of Sedridine, Myrtine, and Lasubine
Zaidan, Raed K.,Evans, Paul
, p. 5354 - 5367 (2019/06/25)
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 Δ1-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.
Asymmetric synthesis of (?)- and (+)-neodichroine/hydrachine A from (+)- and (?)-febrifugine
Smullen, Shaun,Evans, Paul
, p. 1627 - 1629 (2018/03/29)
A new asymmetric approach to both enantiomers of the quinazolinone-containing natural product febrifugine is reported. Utilising a proline-mediated aminooxylation-Horner-Wadsworth-Emmons sequence provides the key optically active 2,3-disubstituted piperidine intermediate 7 in high enantioselectivity but poor overall yield (7 steps, 3%, 98% ee). This intermediate has been used to prepare both naturally occurring (+)-febrifugine (1) and its (?)-enantiomer. In turn, each were then used to synthesise, for the first time, both enantiomers of the claimed natural product neodichroine/hydrachine A. Spectroscopic data for the synthetic compound matched the claimed structure. However, the specific rotation differed in both magnitude and sign from the isolation work.
