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. 2017 Sep 15;2017(34):5015-5024.
doi: 10.1002/ejoc.201701030. Epub 2017 Sep 11.

Divergent Synthesis of Cyclopropane-Containing Lead-Like Compounds, Fragments and Building Blocks through a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide

Stephen J Chawner  1 , Manuel J Cases-Thomas  2 , James A Bull  1
Affiliations

Divergent Synthesis of Cyclopropane-Containing Lead-Like Compounds, Fragments and Building Blocks through a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide

Stephen J Chawner et al. European J Org Chem. .

Abstract

Cyclopropanes provide important design elements in medicinal chemistry and are widely present in drug compounds. Here we describe a strategy and extensive synthetic studies for the preparation of a diverse collection of cyclopropane-containing lead-like compounds, fragments and building blocks exploiting a single precursor. The bifunctional cyclopropane (E/Z)-ethyl 2-(phenylsulfanyl)-cyclopropane-1-carboxylate was designed to allow derivatization through the ester and sulfide functionalities to topologically varied compounds designed to fit in desirable chemical space for drug discovery. A cobalt-catalyzed cyclopropanation of phenyl vinyl sulfide affords these scaffolds on multigram scale. Divergent, orthogonal derivatization is achieved through hydrolysis, reduction, amidation and oxidation reactions as well as sulfoxide-magnesium exchange/functionalization. The cyclopropyl Grignard reagent formed from sulfoxide exchange is stable at 0 °C for > 2 h, which enables trapping with various electrophiles and Pd-catalyzed Negishi cross-coupling reactions. The library prepared, as well as a further virtual elaboration, is analyzed against parameters of lipophilicity (ALog P), MW and molecular shape by using the LLAMA (Lead-Likeness and Molecular Analysis) software, to illustrate the success in generating lead-like compounds and fragments.

Keywords: Cyclopropanes; Homogeneous catalysis; Molecular diversity; Small ring systems; Sulfoxides.

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Figures

Figure 1
Figure 1
Selected cyclopropane‐containing natural products and pharmaceutical compounds.
Figure 2
Figure 2
Strategies for the synthesis of cyclopropanes and designed bifunctional cyclopropane building blocks.
Scheme 1
Scheme 1
Proposed synthesis of E‐ and Z‐cyclopropyl scaffolds.
Figure 3
Figure 3
Enantiomerically pure cyclopropyl sulfides were obtained by preparative chiral SFC and analysed by X‐ray crystallography of the corresponding sulfones.
Scheme 2
Scheme 2
Scaffold derivatization by oxidation, reduction or hydrolysis.
Scheme 3
Scheme 3
Synthesis of amide‐substituted cyclopropanes through amidation and oxidation. Yields for 14/15 quoted over 2 steps from 1/2.
Figure 4
Figure 4
a) The effect of using iPrMgCl or iPrMgCl·LiCl on the stability of the cyclopropyl organometallic intermediate after various exchange periods. b) The effect of temperature on the stability of the cyclopropyl organometallic intermediate after various incubation periods.
Scheme 4
Scheme 4
Scope of electrophiles for the sulfoxide–magnesium exchange, electrophilic trap protocol. [a] Trapping with I2. [b] From the corresponding aldehyde. [c] From the corresponding ketone. [d] Using benzoyl chloride. [e] Using phenylisocyanate. [f] Using bis(4‐methoxyphenyl)disulfide. [g] Using DMF [h] Using (pin)BOiPr. [i] Using (EtO)3SiCl.
Scheme 5
Scheme 5
Substrate scope for the sulfoxide–magnesium exchange–Negishi cross‐coupling protocol.
Scheme 6
Scheme 6
Synthesis of bifunctional cyclopropanes by utilizing both synthetic handles.
Figure 5
Figure 5
The relationship between ALog P and MW for compounds prepared.
Figure 6
Figure 6
PMI plot showing the shape distribution of the synthesized compounds. Some examples have been selected to illustrate the difference between the E‐ and Z‐diastereoisomers.
See this image and copyright information in PMC

References

    1. a) Murray C. W. and Rees D. C., Angew. Chem. Int. Ed., 2016, 55, 488–492; - PubMed
    2. Angew. Chem., 2016, 128, 498;
    3. b) Goldberg F. W., Kettle J. G., Kogej T., Perry M. W. D. and Tomkinson N. P., Drug Discovery Today, 2015, 20, 11–17. - PubMed
    1. a) Lovering F., Bikker J. and Humblet C., J. Med. Chem., 2009, 52, 6752–6756; - PubMed
    2. b) Lovering F., Med. Chem. Commun., 2013, 4, 515–519;
    3. c) Ritchie T. J. and Macdonald S. J. F., Drug Discovery Today, 2009, 14, 1011–1020; - PubMed
    4. d) Ishikawa M. and Hashimoto Y., J. Med. Chem., 2011, 54, 1539–1554; - PubMed
    5. e) Morley A. D., Pugliese A., Birchall K., Bower J., Brennan P., Brown N., Chapman T., Drysdale M., Gilbert I. H., Hoelder S., Jordan A., Ley S. V., Merritt A., Miller D., Swarbrick M. E. and Wyatt P. G., Drug Discovery Today, 2013, 18, 1221–1227; - PubMed
    6. f) Yang Y., Engkvist O., Llinàs A. and Chen H., J. Med. Chem., 2012, 55, 3667–3677. - PubMed
    1. a) Nadin A., Hattotuwagama C. and Churcher I., Angew. Chem. Int. Ed., 2012, 51, 1114–1122; - PubMed
    2. Angew. Chem., 2012, 124, 1140;
    3. b) Hann M. M., Med. Chem. Commun., 2011, 2, 349–355;
    4. c) Hann M. M. and Keserü G. M., Nat. Rev. Drug Discovery, 2012, 11, 355–365. - PubMed
    1. a) Hung A. W., Ramek A., Wang Y., Kaya T., Wilson J. A., Clemons P. A. and Young D. W., Proc. Natl. Acad. Sci. USA, 2011, 108, 6799–6804; - PMC - PubMed
    2. b) Galloway W. R. J. D., Isidro‐Llobet A. and Spring D. R., Nat. Commun., 2010, 1, 80; - PubMed
    3. c) Morton D., Leach S., Cordier C., Warriner S. and Nelson A., Angew. Chem. Int. Ed., 2009, 48, 104–109; - PMC - PubMed
    4. Angew. Chem., 2009, 121, 110;
    5. d) Doveston R., Marsden S. and Nelson A., Drug Discovery Today, 2014, 19, 813–819; - PubMed
    6. e) Schreiber S. L., Science, 2000, 287, 1964–1969; - PubMed
    7. f) Foley D. J., Nelson A. and Marsden S. P., Angew. Chem. Int. Ed., 2016, 55, 13650–13657; - PMC - PubMed
    8. Angew. Chem., 2016, 128, 13850.
    1. For recent examples, see: a) Kato N., Comer E., Sakata‐Kato T., Sharma A., Sharma M., Maetani M., Bastien J., Brancucci N. M., Bittker J. A., Corey V., Clarke D., Derbyshire E. R., Dornan G. L., Duffy S., Eckley S., Itoe M. A., Koolen K. M. J., Lewis T. A., Lui P. S., Lukens A. K., Lund E., March S., Meibalan E., Meier B. C., McPhail J. A., Mitasev B., Moss E. L., Sayes M., Van Gessel Y., Wawer M. J., Yoshinaga T., Zeeman A.‐M., Avery V. M., Bhatia S. N., Burke J. E., Catteruccia F., Clardy J. C., Clemons P. A., Dechering K. J., Duvall J. R., Foley M. A., Gusovsky F., Kocken C. H. M., Marti M., Morningstar M. L., Munoz B., Neafsey D. E., Sharma A., Winzeler E. A., Wirth D. F., Scherer C. A. and Schreiber S. L., Nature, 2016, 538, 344–349; - PMC - PubMed
    2. b) Twigg D. G., Kondo N., Mitchell S. L., Galloway W. R. J. D., Sore H. F., Madin A. and Spring D. R., Angew. Chem. Int. Ed., 2016, 55, 12479–12483; - PMC - PubMed
    3. Angew. Chem., 2016, 128, 12667;
    4. c) Gianatassio R., Lopchuk J. M., Wang J., Pan C.‐M., Malins L. R., Prieto L., Brandt T. A., Collins M. R., Gallego G. M., Sach N. W., Spangler J. E., Zhu H., Zhu J. and Baran P. S., Science, 2016, 351, 241–246; - PMC - PubMed
    5. d) Davis O. A., Croft R. A. and Bull J. A., Chem. Commun., 2015, 51, 15446–15449; - PubMed
    6. e) Affron D. P., Davis O. A. and Bull J. A., Org. Lett., 2014, 16, 4956–4959. - PubMed

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