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. 2020 Mar 25;142(12):5627-5635.
doi: 10.1021/jacs.9b12457. Epub 2020 Mar 11.

A Selenourea-Thiourea Brønsted Acid Catalyst Facilitates Asymmetric Conjugate Additions of Amines to α,β-Unsaturated Esters

Yingfu Lin  1   2 , William J Hirschi  3 , Anuj Kunadia  2 , Anirudra Paul  1   2 , Ion Ghiviriga  4 , Khalil A Abboud  5 , Rachael W Karugu  3 , Mathew J Vetticatt  3 , Jennifer S Hirschi  3 , Daniel Seidel  1   2
Affiliations

A Selenourea-Thiourea Brønsted Acid Catalyst Facilitates Asymmetric Conjugate Additions of Amines to α,β-Unsaturated Esters

Yingfu Lin et al. J Am Chem Soc. .

Abstract

β-Amino esters are obtained with high levels of enantioselectivity via the conjugate addition of cyclic amines to unactivated α,β-unsaturated esters. A related strategy enables the kinetic resolution of racemic cyclic 2-arylamines, using benzyl acrylate as the resolving agent. Reactions are facilitated by an unprecedented selenourea-thiourea organocatalyst. As elucidated by DFT calculations and 13C kinetic isotope effect studies, the rate-limiting and enantiodetermining step of the reaction is the protonation of a zwitterionic intermediate by the catalyst. This represents a rare case in which a thiourea compound functions as an asymmetric Brønsted acid catalyst.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Examples of catalytic enantioselective additions of N-nucleophiles to conjugate acceptors and concept for bifunctional catalysis with α,β-unsaturated ester substrates.
Figure 2.
Figure 2.
Proposed catalytic cycle for the addition of amines to α,β-unsaturated esters catalyzed by a selenourea-thiourea catalyst. The stereogenic center is formed during C–N bond formation. Subsequent proton transfers may follow an intramolecular proton transfer path (shown in blue) or direct C-protonation (shown in red).
Figure 3.
Figure 3.
Lowest energy transition structures for C–N bond formation leading to (R)- and (S)-enantiomers of 2azwit.
Figure 4.
Figure 4.
Experimental 13C KIEs for benzyl crotonate (numbers in parentheses represent the standard deviation in the last digit as determined from six independent measurements).
Figure 5.
Figure 5.
Possible transition states consistent with experimental KIEs.
Figure 6.
Figure 6.
Lowest energy transition structures for catalyst-mediated direct C-protonation of (R)- and (S)-enantiomers of 2azwit.
Figure 7.
Figure 7.
Comparison of experimental and predicted KIEs for the C–N bond-forming transition structure R-TSC–N (shown in red) and the direct C-protonation transition structure R-TSC-prot (shown in green).
Figure 8.
Figure 8.
Computed reaction coordinate diagram (qRRHO) depicting the proposed pathway leading to (R)- and (S)-enantiomers of 2a.
Scheme 1.
Scheme 1.. Substrate Scope
aReaction mixture was partially heterogeneous. bReaction was performed at room temperature. cReaction was performed at a 0.025 M concentration of amine.
Scheme 2.
Scheme 2.
Kinetic Resolution of Cyclic 2-Arylamines
See this image and copyright information in PMC

References

    1. Selected reviews on β-amino acids:
    2. Cardillo G; Tomasini C Asymmetric synthesis of β-amino acids and α-substituted β-amino acids. Chem. Soc. Rev 1996, 25, 117–128.
    3. Liu M; Sibi MP Recent advances in the stereoselective synthesis of β-amino acids. Tetrahedron 2002, 58, 7991–8035.
    4. Seebach D; Beck AK; Capone S; Deniau G; Grošelj U; Zass E Enantioselective Preparation of β2-Amino Acid Derivatives for β-Peptide Synthesis. Synthesis 2009, 2009, 1–32.
    5. Weiner B; Szymanski W; Janssen DB; Minnaard AJ; Feringa BL Recent advances in the catalytic asymmetric synthesis of beta-amino acids. Chem. Soc. Rev 2010, 39, 1656–1691. - PubMed
    1. Rulev AY Aza-Michael reaction: achievements and prospects. Russ. Chem. Rev 2011, 80, 197.
    1. Selected reviews on asymmetric conjugate additions with N-nucleophiles:
    2. Xu L-W; Xia C-G A Catalytic Enantioselective Aza-Michael Reaction: Novel Protocols for Asymmetric Synthesis of β-Amino Carbonyl Compounds. Eur. J. Org. Chem 2005, 2005, 633–639.
    3. Vicario JL; Badía D; Carrillo L; Etxebarria J; Reyes E; Ruiz N The asymmetric aza-Michael reaction. A review. Org. Prep. Proced. Int 2005, 37, 513–538.
    4. Enders D; Wang C; Liebich JX Organocatalytic Asymmetric Aza-Michael Additions. Chem. - Eur. J 2009, 15, 11058–11076. - PubMed
    5. Krishna PR; Sreeshailam A; Srinivas R Recent advances and applications in asymmetric aza-Michael addition chemistry. Tetrahedron 2009, 65, 9657–9672.
    6. Wang J; Li P; Choy PY; Chan ASC; Kwong FY Advances and Applications in Organocatalytic Asymmetric aza-Michael Addition. ChemCatChem 2012, 4, 917–925.
    7. Vinogradov MG; Turova OV; Zlotin SG Recent advances in the asymmetric synthesis of pharmacology-relevant nitrogen heterocycles via stereoselective aza-Michael reactions. Org. Biomol. Chem 2019, 17, 3670–3708. - PubMed
    1. Mailyan AK; Eickhoff JA; Minakova AS; Gu Z; Lu P; Zakarian A Cutting-Edge and Time-Honored Strategies for Stereoselective Construction of C-N Bonds in Total Synthesis. Chem. Rev 2016, 116, 4441–4557. - PubMed
    1. Sibi MP; Shay JJ; Liu M; Jasperse CP Chiral Lewis Acid Catalysis in Conjugate Additions of O-Benzylhydroxylamine to Unsaturated Amides. Enantioselective Synthesis of β-Amino Acid Precursors. J. Am. Chem. Soc 1998, 120, 6615–6616.
    2. Sugihara H; Daikai K; Jin XL; Furuno H; Inanaga J Catalytic conversion of conjugated enones into optically active α-keto aziridines using chiral rare earth metal complexes. Tetrahedron Lett. 2002, 43, 2735–2739.
    3. Jin XL; Sugihara H; Daikai K; Tateishi H; Jin YZ; Furuno H; Inanaga J Chiral rare earth metal complex-catalyzed conjugate addition of O-alkylhydroxylamines. An efficient synthetic entry into optically active 2-acyl aziridines. Tetrahedron 2002, 58, 8321–8329.
    4. Yamagiwa N; Matsunaga S; Shibasaki M Heterobimetallic Catalysis in Asymmetric 1,4-Addition of O-Alkylhydroxylamine to Enones. J. Am. Chem. Soc 2003, 125, 16178–16179. - PubMed
    5. Yamagiwa N; Qin H; Matsunaga S; Shibasaki M Lewis Acid-Lewis Acid Heterobimetallic Cooperative Catalysis: Mechanistic Studies and Application in Enantioselective Aza-Michael Reaction. J. Am. Chem. Soc 2005, 127, 13419–13427. - PubMed

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