Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Mar 25;15(16):5832-5868.
doi: 10.1039/d4sc01081g. eCollection 2024 Apr 24.

Enantioselective organocatalytic strategies to access noncanonical α-amino acids

Pietro Pecchini  1 , Mariafrancesca Fochi  1 , Francesca Bartoccini  2 , Giovanni Piersanti  2 , Luca Bernardi  1
Affiliations
Review

Enantioselective organocatalytic strategies to access noncanonical α-amino acids

Pietro Pecchini et al. Chem Sci. .

Abstract

Organocatalytic asymmetric synthesis has evolved over the years and continues to attract the interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, and chemical biology. They are employed in the elaboration of peptides and proteins with enhanced activities and/or improved properties compared to their natural counterparts, as chiral catalysts, in chiral ligand design, and as chiral building blocks for asymmetric syntheses of complex molecules, including natural products. The linkage of ncAA synthesis and enantioselective organocatalysis, the subject of this perspective, tries to imitate the natural biosynthetic process. Herein, we present contemporary and earlier developments in the field of organocatalytic activation of simple feedstock materials, providing potential ncAAs with diverse side chains, unique three-dimensional structures, and a high degree of functionality. These asymmetric organocatalytic strategies, useful for forging a wide range of C-C, C-H, and C-N bonds and/or combinations thereof, vary from classical name reactions, such as Ugi, Strecker, and Mannich reactions, to the most advanced concepts such as deracemisation, transamination, and carbene N-H insertion. Concurrently, we present some interesting mechanistic studies/models, providing information on the chirality transfer process. Finally, this perspective highlights, through the diversity of the amino acids (AAs) not selected by nature for protein incorporation, the most generic modes of activation, induction, and reactivity commonly used, such as chiral enamine, hydrogen bonding, Brønsted acids/bases, and phase-transfer organocatalysis, reflecting their increasingly important role in organic and applied chemistry.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Unnatural, noncanonical amino acids (ncAAs): synthesis and utility.
Fig. 2
Fig. 2. Biologically relevant ncAAs.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3
Scheme 4
Scheme 4
Scheme 5
Scheme 5
Fig. 3
Fig. 3. Transition state of the Strecker reaction catalyzed by thiourea 3.
Scheme 6
Scheme 6
Scheme 7
Scheme 7
Scheme 8
Scheme 8
Scheme 9
Scheme 9
Scheme 10
Scheme 10
Fig. 4
Fig. 4. Interactions between catalyst 9 and substrates in the aza-Henry reaction.
Scheme 11
Scheme 11
Scheme 12
Scheme 12
Scheme 13
Scheme 13
Scheme 14
Scheme 14
Scheme 15
Scheme 15
Scheme 16
Scheme 16
Scheme 17
Scheme 17
Scheme 18
Scheme 18
Scheme 19
Scheme 19
Scheme 20
Scheme 20
Scheme 21
Scheme 21
Scheme 22
Scheme 22
Scheme 23
Scheme 23
Scheme 24
Scheme 24
Fig. 5
Fig. 5. Recently disclosed phase-transfer catalysts 22–27.
Scheme 25
Scheme 25
Scheme 26
Scheme 26
Scheme 27
Scheme 27
Scheme 28
Scheme 28
Scheme 29
Scheme 29
Scheme 30
Scheme 30
Scheme 31
Scheme 31
Scheme 32
Scheme 32
Scheme 33
Scheme 33
Scheme 34
Scheme 34
Scheme 35
Scheme 35
Scheme 36
Scheme 36
Scheme 37
Scheme 37
Scheme 38
Scheme 38
Scheme 39
Scheme 39
Scheme 40
Scheme 40
Scheme 41
Scheme 41
Scheme 42
Scheme 42
Scheme 43
Scheme 43
Scheme 44
Scheme 44
Scheme 45
Scheme 45
Scheme 46
Scheme 46
Scheme 47
Scheme 47
Scheme 48
Scheme 48
Scheme 49
Scheme 49
Scheme 50
Scheme 50
Fig. 6
Fig. 6. Bifunctional catalysts 50–54 used in the DKR of azlactones.
Scheme 51
Scheme 51
Scheme 52
Scheme 52
Scheme 53
Scheme 53
Scheme 54
Scheme 54
Scheme 55
Scheme 55
Scheme 56
Scheme 56
Scheme 57
Scheme 57
Scheme 58
Scheme 58
Scheme 59
Scheme 59
Scheme 60
Scheme 60
Scheme 61
Scheme 61
Scheme 62
Scheme 62
Scheme 63
Scheme 63
Scheme 64
Scheme 64
Scheme 65
Scheme 65
Scheme 66
Scheme 66
Scheme 67
Scheme 67
Scheme 68
Scheme 68
Scheme 69
Scheme 69
Scheme 70
Scheme 70
Scheme 71
Scheme 71
Scheme 72
Scheme 72
Scheme 73
Scheme 73
Scheme 74
Scheme 74
Scheme 75
Scheme 75
None
Pietro Pecchini
None
Mariafrancesca Fochi
None
Francesca Bartoccini
None
Giovanni Piersanti
None
Luca Bernardi
See this image and copyright information in PMC

References

    1. Wu G. Amino Acids. 2009;37:1. doi: 10.1007/s00726-009-0269-0. - DOI - PubMed
    1. Evans D. A. , Helmchen G. and Reuping M., Asymmetric Synthesis: The Essentials, 2007, pp. 3–9
    2. Gnas Y. Glorius F. Synthesis. 2006;12:1899.
    1. Corey E. J. Helal C. J. Angew. Chem., Int. Ed. Engl. 1998;37:1986. doi: 10.1002/(SICI)1521-3773(19980817)37:15<1986::AID-ANIE1986>3.0.CO;2-Z. - DOI - PubMed
    2. Helmchen G. Pfaltz A. Acc. Chem. Res. 2000;33:336. doi: 10.1021/ar9900865. - DOI - PubMed
    3. Sakthivel K. Notz W. Bui T. Barbas C. F. J. Am. Chem. Soc. 2001;123:5260. doi: 10.1021/ja010037z. - DOI - PubMed
    4. Davie E. A. C. Mennen S. M. Xu Y. Miller S. J. Chem. Rev. 2007;107:5759. doi: 10.1021/cr068377w. - DOI - PubMed
    5. Doyle A. G. Jacobsen E. N. Chem. Rev. 2007;107:5713. doi: 10.1021/cr068373r. - DOI - PubMed
    6. MacMillan D. W. C. Nature. 2008;455:304. doi: 10.1038/nature07367. - DOI - PubMed
    7. Zhang F.-L. Hong K. Li T.-J. Park H. Yu J.-Q. Science. 2016;351:252. doi: 10.1126/science.aad7893. - DOI - PMC - PubMed
    1. Shao Q. Wu K. Zhuang Z. Qian S. Yu J.-Q. Acc. Chem. Res. 2020;53:833. doi: 10.1021/acs.accounts.9b00621. - DOI - PMC - PubMed
    1. Pinazo A. Pons R. Pérez L. Infante M. R. Ind. Eng. Chem. Res. 2011;50:4805. doi: 10.1021/ie1014348. - DOI
    2. Rowland M. J. Appel E. A. Coulston R. J. Scherman O. A. J. Mater. Chem. B. 2013;1:2904. doi: 10.1039/C3TB20180E. - DOI - PubMed