Efficient Synthesis of (−)‐Corynoline by Enantioselective Palladium‐Catalyzed α‐Arylation with Sterically Hindered Substrates

Abstract

Sterically hindered substrates can be employed in an enantioselective palladium-catalyzed α-arylation with the chiral monophosphorus ligand BI-DIME. This process enabled an efficient synthesis of the antidepressant (S)-nafenodone, a four-step enantioselective synthesis of the Sceletium alkaloid (+)-sceletium A-4, a concise five-step enantioselective synthesis of (-)-corynoline, as well as a three-step preparation of (-)-DeN-corynoline.

α-C(sp3)-H Arylation of Cyclic Carbonyl Compounds

“…However, most of the asymmetric methods are limited to transition metal catalytic systems, problems such as how to realize green procedures and relatively small range of substrates remains to investigate. For example, Ni(0) catalyst is highly toxic, aryl halides with ortho hindered substituent have low compatibility in palladium catalytic system [ 107 ], asymmetric α -arylation of amino acids, and control of α -C(sp 3 )-H arylation through free radical process, etc., need to be solved.…”

Efficient Synthesis of (−)‐Corynoline by Enantioselective Palladium‐Catalyzed α‐Arylation with Sterically Hindered Substrates

“…Next, the formation of apiperidine ring was pursued. Radical dibromination at two benzylic position with AIBN/NBS gave dibromide 17;t reatment with methylamine then provided tertiary amine 18 [14] in 37 %y ield over two steps.A subsequent Büchner-Curtius-Schlotterbeck reaction [18] in the presence of TMSCHN 2 /nBuLi successfully converted the sterically hindered indanone 18 into (À)-corynolon 19 in 56 %y ield. LAH reduction completed the enantioselective synthesis of (À)-corynoline (4), [19] whose spectra were in full agreement with those of commercially available material and reported data.…”

“…Among various palladium pre-cursors screened, Pd(OAc) 2 was the best in terms of yield (entries 3a nd [8][9][10]. Further screening of solvent and base demonstrated that toluene and NaOtBu were ag ood combination for ah igh yield and good enantioselectivity ( Table 1, entries [11][12][13][14][15][16][17][18][19][20]. Theb ase exerted as ignificant effect on the yield.…”

“…The absolute configuration of 9a was determined by analogy according to the X-ray structure of 9f. [14] [b] Yields of isolated products. [c] Determined by HPLC analysis on aChiralcel AD-H column.…”

“…Te tralone substrates were also applicable,providing products 9z and 9aa in excellent enantioselectivities and yields. Thea bsolute configuration of 9f was determined by its X-ray structure, [14] in which the benzylic all-carbon quaternary center was assigned as S with (R)-BI-DIME as the ligand. Arylation of 7a with as calemic composition of L1 showed ag ood linear relationship between the enantiopurities of the ligand and product 9a,indicating that the reaction was catalyzed by apalladium catalyst with asingle BI-DIME ligand.…”