- Enantioselective Synthesis of N-Alkylamines through β-Amino C-H Functionalization Promoted by Cooperative Actions of B(C6F5)3and a Chiral Lewis Acid Co-Catalyst
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We disclose a catalytic method for β-C(sp3)-H functionalization of N-alkylamines for the synthesis of enantiomerically enriched β-substituted amines, entities prevalent in pharmaceutical compounds and used to generate different families of chiral catalysts. We demonstrate that a catalyst system comprising of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg- or Sc-based complex, promotes the highly enantioselective union of N-alkylamines and α,β-unsaturated compounds. An array of δ-amino carbonyl compounds was synthesized under redox-neutral conditions by enantioselective reaction of a N-alkylamine-derived enamine and an electrophile activated by the chiral Lewis acid co-catalyst. The utility of the approach is highlighted by late-stage β-C-H functionalization of bioactive amines. Investigations in regard to the mechanistic nuances of the catalytic processes are described.
- Chang, Yejin,Cao, Min,Chan, Jessica Z.,Zhao, Cunyuan,Wang, Yuankai,Yang, Rose,Wasa, Masayuki
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supporting information
p. 2441 - 2455
(2021/02/16)
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- Catalytic Deuterium Incorporation within Metabolically Stable β-Amino C-H Bonds of Drug Molecules
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An efficient deuteration process of β-amino C-H bonds in various N-alkylamine-based pharmaceutical compounds has been developed. Catalytic reactions begin with the action of Lewis acidic B(C6F5)3 and Br?nsted basic N-alkylamine, converting a drug molecule into the corresponding enamine. The acid/base catalysts also promote the dedeuteration of acetone-d6 to afford a deuterated ammonium ion. Ensuing deuteration of the enamine then leads to the formation of β-deuterated bioactive amines with up to 99% deuterium incorporation.
- Chang, Yejin,Yesilcimen, Ahmet,Cao, Min,Zhang, Yuyang,Zhang, Bochao,Chan, Jessica Z.,Wasa, Masayuki
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supporting information
p. 14570 - 14575
(2019/10/11)
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- Catalytic Michael/Ring-Closure Reaction of α,β-Unsaturated Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of (?)-Paroxetine
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A highly enantioselective tandem Michael/ring-closure reaction of α,β-unsaturated pyrazoleamides and amidomalonates has been accomplished in the presence of a chiral N,N′-dioxide–Yb(OTf)3complex (Tf: trifluoromethanesulfonyl) to give various substituted chiral glutarimides with high yields and diastereo- and enantioselectivities. Moreover, this methodology could be used for gram-scale manipulation and was successfully applied to the synthesis of (?)-paroxetine. Further nonlinear and HRMS studies revealed that the real catalytically active species was a monomeric L-PMe2–Yb3+complex. A plausible transition state was proposed to explain the origin of the asymmetric induction.
- Zhang, Yu,Liao, Yuting,Liu, Xiaohua,Yao, Qian,Zhou, Yuhang,Lin, Lili,Feng, Xiaoming
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p. 15119 - 15124
(2016/10/11)
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- Highly enantioselective organocatalytic cascade reaction for the synthesis of piperidines and oxazolidines
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The synthesis of piperidines and piperidines derivatives in enantiopure fashion has been a challenging goal for organic chemists. In this report we developed a nice cascade reaction for piperidine derivatives based in an amidomalonate Michael addition to enals followed by an intramolecular hemiaminal formation with good yields and enantioselectivities. Moreover we studied the 'in situ' intramolecular cyclization of this hemiaminals with alcohols forming fused piperidine-oxazolidines.
- ?íhalová, Sylva,Valero, Guillem,Schimer, Ji?í,Humpl, Marek,Dra?ínsky, Martin,Moyano, Albert,Rios, Ramon,Vesely, Jan
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scheme or table
p. 8942 - 8950
(2011/12/01)
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- Stereospecific construction of substituted piperidines. Synthesis of (-)-paroxetine and (+)-laccarin
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Short and efficient enantioselective syntheses of (-)-paroxetine and (+)-laccarin are described based on the highly stereospecific cleavage of C(3)-substituted 1,3-cyclic sulfamidates. The Royal Society of Chemistry.
- Bower, John F.,Riis-Johannessen, Thomas,Szeto, Peter,Whitehead, Andrew J.,Gallagher, Timothy
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p. 728 - 730
(2007/10/03)
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- Application of the chiral base desymmetrisation of imides to the synthesis of the alkaloid jamtine and the antidepressant paroxetine
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The synthesis of the alkaloid jamtine and the antidepressant paroxetine have been addressed by a strategy involving asymmetric desymmetrisation of prochiral imides by a chiral lithium amide base. A short reaction sequence, starting with a cyclohexane fused succinimide, led to the structures originally reported for the alkaloid jamtine and its derived N-oxide. The structures synthesised are shown not to correspond with those originally reported. A second sequence involves desymmetrisation of a 4-arylglutarimide, and provides a short enantioselective synthesis of the drug substance paroxetine.
- Gill, Christopher D.,Greenhalgh, Daniel A.,Simpkins, Nigel S.
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p. 9213 - 9230
(2007/10/03)
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