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
. 2016 Mar 15;21(3):350.
doi: 10.3390/molecules21030350.

Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations

Ziniu Zhou  1   2 , William L Scott  3 , Martin J O'Donnell  4
Affiliations

Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations

Ziniu Zhou et al. Molecules. .

Abstract

A solid-phase procedure is used to synthesize racemic peptidomimetics based on the fundamental peptide unit. The peptidomimetics are constructed around proline or proline homologues variably substituted at the amine and carbonyl sites. The procedure expands the diversity of substituted peptidomimetic molecules available to the Distributed Drug Discovery (D3) project. Using a BAL-based solid-phase synthetic sequence the proline or proline homologue subunit is both constructed and incorporated into the peptidomimetic by an α-alkylation, hydrolysis and intramolecular cyclization sequence. Further transformations on solid-phase provide access to a variety of piperazine derivatives representing a class of molecules known to exhibit central nervous system activity. The procedure works well with proline cores, but with larger six- and seven-membered ring homologues the nature of the carboxylic acid acylating the cyclic amine can lead to side reactions and result in poor overall yields.

Keywords: CNS agent.; Distributed Drug Discovery (D3); combinatorial chemistry; peptidomimetics; piperazine derivatives; proline and homologues; solid-phase organic synthesis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Fundamental peptide unit molecules 1, 2, and proline and proline homologues 3.
Scheme 1
Scheme 1
Solid-phase synthetic routes to compounds 1 and 2 using BAL-based resins.
Scheme 2
Scheme 2
Solid-phase synthesis of proline and homologues from resin-bound intermediate 10 [8,9].
Scheme 3
Scheme 3
Pilot solid-phase synthetic pathway using BAL-based aldimine resins to yield proline amide and homologues.
Scheme 4
Scheme 4
Solid-phase synthetic route (using BAL-based aldimine resins) to proline and homologues substituted on both the amine and carbonyl residues.
Scheme 5
Scheme 5
Proposed mechanism for the hydrolysis of proline/proline homologue intermediate products upon treatment with trifluoroacetic acid (TFA).
See this image and copyright information in PMC

References

    1. Scott W.L., O’Donnell M.J. Distributed drug discovery, part 1: Linking academia and combinatorial chemistry to find drug leads for developing world diseases. J. Comb. Chem. 2009;11:3–13. doi: 10.1021/cc800183m. - DOI - PMC - PubMed
    1. Scott W.L., Alsina J., Audu C.O., Babaev E., Cook L., Dage J.L., Goodwin L.A., Martynow J.G., Matosiuk D., Royo M., et al. Distributed drug discovery, part 2: Global rehearsal of alkylating agents for the synthesis of resin-bound unnatural amino acids and virtual D3 catalog construction. J. Comb. Chem. 2009;11:14–33. doi: 10.1021/cc800184v. - DOI - PMC - PubMed
    1. Scott W.L., Audu C.O., Dage J.L., Goodwin L.A., Martynow J.G., Platt L.K., Smith J.G., Strong A.T., Wickizer K., Woerly E.M., et al. Distributed drug discovery, part 3: Using D3 methodology to synthesize analogs of an anti-melanoma compound. J. Comb. Chem. 2009;11:34–43. doi: 10.1021/cc800185z. - DOI - PMC - PubMed
    1. Scott W.L., Denton R.E., Marrs K.A., Durrant J.D., Samaritoni J.G., Abraham M.M., Brown S.P., Carnahan J.M., Fischer L.G., Glos C.E., et al. Distributed drug discovery: Advancing chemical education through contextualized combinatorial solid-phase organic laboratories. J. Chem. Educ. 2015;92:819–826. doi: 10.1021/ed500135n. - DOI
    1. Scott W.L., Zhou Z., Zajdel P., Pawlowski M., O’Donnell M.J. Solid-phase synthetic route to multiple derivatives of a fundamental peptide unit. Molecules. 2010;15:4961–4983. doi: 10.3390/molecules15074961. - DOI - PMC - PubMed

Publication types

MeSH terms