Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold Laure Konnert, Frédéric Lamaty, Jean Martinez, Evelina Colacino To cite this version: Laure Konnert, Frédéric Lamaty, Jean Martinez, Evelina Colacino. Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold. Chemical Reviews, American Chemical Society, 2017, 117 (23), pp.13757-13809. 10.1021/acs.chemrev.7b00067. hal-02385289 HAL Id: hal-02385289 https://hal.archives-ouvertes.fr/hal-02385289 Submitted on 5 Mar 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Review Cite This: Chem. Rev. 2017, 117, 13757−13809 pubs.acs.org/CR Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold Laure Konnert,* Fredérić Lamaty, Jean Martinez, and Evelina Colacino* Universitéde Montpellier, Institut des Biomoleculeś Max Mousseron UMR 5247 CNRS − Universiteś Montpellier - ENSCM, Place E. Bataillon, Campus Triolet, cc 1703, 34095 Montpellier, France ABSTRACT: The review highlights the hydantoin syntheses presented from the point of view of the preparation methods. Novel synthetic routes to various hydantoin structures, the advances brought to the classical methods in the aim of producing more sustainable and environmentally friendly procedures for the preparation of these biomolecules, and a critical comparison of the different synthetic approaches developed in the last twelve years are also described. The review is composed of 95 schemes, 8 figures and 528 references for the last 12 years and includes the description of the hydantoin-based marketed drugs and clinical candidates. CONTENTS 5.4.4. Use of Benzotriazole Carbonyl Deriva- tives 13769 1. Introduction 13758 5.4.5. Activation by Formation of Carbamates 13769 2. Hydantoins as Clinical Candidates and Marketed 5.4.6. From Urea and Other Activation Meth- Drugs 13758 ods 13769 2.1. Clinical Candidates 13758 6. 1,3,5- and 1,3,5,5-Substituted Hydantoins 13769 2.1.1. BMS-587101 13758 6.1. Substitution of the Hydantoin Core 13769 2.1.2. GLGP-0492 13760 6.2. Use of Isocyanates 13770 2.2. Marketed Drugs 13760 6.3. Use of Urea Derivatives 13771 2.2.1. Phenytoin and Fosphenytoin 13760 6.4. Activation with Carbonyl Donors 13771 2.2.2. Ethotoin 13760 6.5. Miscellaneous 13772 2.2.3. Nilutamide 13760 7. Alkylidene Hydantoins 13773 2.2.4. Nitrofurantoin 13760 7.1. Non-substituted 5-Alkyl/Arylidene Hydan- 2.2.5. Dantrolene 13760 toins 13773 3. 5- and 5,5-Disubstituted Hydantoins 13760 − 7.2. 1-Substituted 5-Alkyl/Arylidene Hydantoins 13773 3.1. Bucherer Bergs Reaction 13761 7.3. 3-Substituted 5-Alkyl/Arylidene Hydantoins 13774 3.2. Use of Isocyanates and Formation of Urea 7.4. 1,3,5-Alkyl/Arylidene Hydantoins 13774 Derivatives 13761 8. Spirohydantoins 13775 3.3. Biltz-Type Synthesis, Preparation of Pheny- 8.1. 5,5-Spirohydantoins 13775 toin Derivatives 13762 8.1.1. The Bucherer−Bergs Reaction 13775 3.4. Substitution at Position C-5 13762 8.1.2. Reaction with (Iso)cyanates and Urea 3.5. Metal-Catalyzed Procedures 13762 Derivatives 13775 4. 1- and 1,5-Disubstituted Hydantoins 13763 8.2. 1-Substituted or 3-Substituted 5-Spirohydan- 4.1. Use of Isocyanates and Ureas 13763 toins 13775 4.2. Biltz Synthesis 13763 N 8.3. 1,3-Disubstituted 5-Spirohydantoins 13776 4.3. Alkylation/Acylation at -1 Position 13764 8.3.1. From Methylene Hydantoins 13776 4.4. Miscellaneous 13765 8.3.2. From Diverse Substrates 13776 4.5. Hydantoins Derived from Guanosine and 9. Fused Hydantoins 13778 Analogues 13765 9.1. 1,5-Bicyclic Hydantoins 13778 5. 3- and 3,5-Disubstituted Hydantoins 13766 N 9.2. Polycyclic Fused 1,3,5-Trisubstituted Hydan- 5.1. Alkylation/Acylation at the -3 Position 13766 toins 13779 5.2. Use of Isocyanates 13766 9.2.1. Tetrahydroisoquinoline Hydantoins 13779 5.3. Miscellaneous 13767 9.2.2. Tetrahydro-β-carboline Hydantoins 13780 5.4. 3-Substituted Hydantoins from Amino Acids 13767 9.2.3. Miscellaneous 13780 5.4.1. Use of Isocyanates 13767 10. Aminohydantoins 13780 5.4.2. Use of 1,1-Carbonyldiimidazole (CDI) 13768 5.4.3. Use of (Tri)phosgene 13769 Received: January 30, 2017 Published: June 23, 2017 © 2017 American Chemical Society 13757 DOI: 10.1021/acs.chemrev.7b00067 Chem. Rev. 2017, 117, 13757−13809 Chemical Reviews Review 10.1. 1-Aminohydantoins 13780 compounds are highlighted (mono-, di-, or trisubstituted 10.2. 3-Aminohydantoins 13782 hydantoins on the C-5, N-1/N-3 positions, fused and polycyclic 10.3. 5-Aminohydantoins 13783 systems, spiro-, alkylidene or amino- hydantoins), including their 11. Hydantoins as Ligands in Organometallic Com- use as organometallic ligands (Figure 1). One of the advantages plexes 13784 12. Asymmetric Synthesis of Hydantoins 13785 12.1. 5,5-Disubstituted Hydantoins 13785 12.1.1. Bucherer−Bergs Synthesis 13785 12.1.2. Other Procedures 13785 12.2. 1,5-Disubstituted Hydantoins 13785 12.3. 3,5-Substituted Hydantoins 13785 12.3.1. Alkylation of Position C-5 13785 12.3.2. Miscellaneous 13785 12.4. 1,3,5-Trisubstituted Hydantoins 13786 12.4.1. Use of Isocyanates 13786 12.4.2. Synthesis of BIRT-377, Generation of a Chiral Quaternary Center 13787 12.4.3. Use of Urea Derivatives 13788 12.5. 5,5-Spirohydantoins 13789 12.5.1. Bucherer−Bergs Reaction 13789 12.5.2. Reaction with Isocyanates and Urea Derivatives 13789 12.6. 1,3-Disubstituted Spirohydantoins 13789 12.6.1. From Methylene Hydantoins 13789 12.6.2. From Other Substrates 13789 12.7. Fused Hydantoins 13791 12.7.1. 1,5-Bicyclic Hydantoins 13791 12.7.2. Polycyclic Fused 1,3,5-Trisubstituted Hydantoins 13792 13. Preparation of Amino Acids from Hydantoins 13792 13.1. Chemical Hydrolysis 13792 Figure 1. Hydantoin core and the classes of hydantoins. 13.2. Enzymatic Hydrolysis of Hydantoins 13793 14. Conclusions 13794 ff Author Information 13794 of organizing the review from the point of view of the sca old Corresponding Authors 13794 (and not considering the general method to access it) is the possibility to overview at a glance all of the available procedures ORCID 13794 fi Notes 13794 to access a speci c family of compounds. This approach is very valuable not only for synthetic chemists Biographies 13794 fi References 13794 but also for a broader readership in the eld of medicinal Note Added after ASAP Publication 13809 chemistry, where target oriented syntheses is a must. The preparation of thiohydantoins will not be treated, being usually obtained similarly to hydantoins, but in the presence of thio- 1. INTRODUCTION based reactants, or by transformation of the hydantoin scaffold by common thionation reactions (e.g., Lawesson’s method). Over the past decade, the synthetic and pharmaceutical interest Reviews on their preparation were already reported.9,10 More- for imidazolidine-2,4-diones, or hydantoins, has not faded and over, the detailed description of the diverse biological activities has given rise to more than 3000 publications and patents in displayed by hydantoin scaffolds is out of the scope of the review, methodological and medicinal chemistry. Several reviews have − and it would deserve a separate submission. focused on the synthesis of these five-membered heterocycles,1 3 referencing their preparation methods from the main, historical 2. HYDANTOINS AS CLINICAL CANDIDATES AND 4 5 6 ones such as the Read, Bucherer−Bergs, or Biltz syntheses to MARKETED DRUGS more modern ones, such as multicomponent reactions (MCRs), Many biological properties have been attributed to compounds which enabled libraries of hydantoinic compounds to be 7,8 containing a hydantoin moiety, as illustrated throughout the obtained through simple routes. Since Meusel and Gütschow’s 3 following sections of this review. Several of them have last review in 2004, novel synthetic routes to various hydantoin demonstrated strong bioactivity and thus have been led through structures have been explored, as well as advances brought to the clinical trials,11,12 and some of them have been commercialized as classical methods in the aim of producing more sustainable and pharmaceuticals.13 In this section a short overview of hydantoin- environmental-friendly procedures for the preparation of these containing clinical candidates (from 2004 to 2016) and marketed biomolecules. This paper is updating the progress in the drugs is given, the structures of which are depicted in Figures 3 chemistry of hydantoins and references the publications from and 4. 2004 to May 2016. It is organized in a different perspective than the previous report from 2004: hydantoins are grouped 2.1. Clinical Candidates according to the substitution pattern on the principal backbone 2.1.1. BMS-587101. BMS587101 is a spirocyclic hydantoin and the synthetic strategies for the preparation of each family of which was developed by Bristol-Myers Squibb and showed 13758 DOI: 10.1021/acs.chemrev.7b00067 Chem. Rev. 2017, 117, 13757−13809 Chemical Reviews Review Figure 2. X-ray crystal structures of BMS-587101 (left) and BMS-688521 (right) bound to the I-Domain of LFA-1 (image reproduced with permission from ref 15. Copyright 2014 American Chemical Society). Figure 3. Hydantoin clinical candidates. Figure 4. Hydantoin marketed drugs. biological activity as a leukocyte function-associated antigen-1 688521,15 showing a 4- to 8-fold improvement in human in (LFA-1) antagonist.