molecules Review Review Synergy Effects in the Chemical SynthesisSynthesis andand Extensions of Multicomponent Reactions (MCRs)—The(MCRs)—The Low Energy Way toto Ultra-ShortUltra-Short Syntheses of Tailor-MadeTailor-Made MoleculesMolecules Heiner Eckert Heiner Eckert Department Chemie, Technische Universität München, Lichtenbergstr. 4, Garching 85747, Germany; [email protected] Chemie,; Tel.: +49 Technische-89-354-5532 Universität München, Lichtenbergstr. 4, Garching 85747, Germany; [email protected]; Tel.: +49-89-354-5532 Academic Editor: Roman Dembinski AcademicReceived: 21 Editor: December Roman 2016 Dembinski; Accepted: 13 February 2017; Published: 25 February 2017 Received: 21 December 2016; Accepted: 13 February 2017; Published: 25 February 2017 Abstract: Several novel methods, catalysts and reagents have been developed to improve organic Abstract: Several novel methods, catalysts and reagents have been developed to improve organic synthesis. Synergistic effects between reactions, reagents and catalysts can lead to minor heats of synthesis. Synergistic effects between reactions, reagents and catalysts can lead to minor heats of reaction and occur as an inherent result of multicomponent reactions (MCRs) and their extensions. reaction and occur as an inherent result of multicomponent reactions (MCRs) and their extensions. They enable syntheses to be performed at a low energy level and the number of synthesis steps to They enable syntheses to be performed at a low energy level and the number of synthesis steps be drastically reduced in comparison with ‘classical’ two-component reactions, fulfilling the rules to be drastically reduced in comparison with ‘classical’ two-component reactions, fulfilling the of Green Chemistry. The very high potential for variability, diversity and complexity of MCRs rules of Green Chemistry. The very high potential for variability, diversity and complexity of MCRs additionally generates an extremely diverse range of products, thus bringing us closer to the aim of beingadditionally able to generatesproduce tailor an extremely-made and diverse extremely range low of- products,cost materials, thus bringingdrugs and us compound closer to the libraries. aim of being able to produce tailor-made and extremely low-cost materials, drugs and compound libraries. Keywords: multicomponents; MCR; post condensation modification/cyclisation PCM/PCC; MFCR; Keywords: multicomponents; MCR; post condensation modification/cyclisation PCM/PCC; MFCR; multifunction catalysis; variability; diversity; complexity; efficiency of synthesis multifunction catalysis; variability; diversity; complexity; efficiency of synthesis 1. Prologue 1. Prologue The great discrepancy between the traditional feasibility mania and rational efficiency assessment in The great discrepancy between the traditional feasibility mania and rational efficiency assessment chemical synthesis became immediately apparent to the author while working on his thesis and in chemical synthesis became immediately apparent to the author while working on his thesis and during everyday laboratory life. On the one hand, classic peptide synthesis with an inefficient, during everyday laboratory life. On the one hand, classic peptide synthesis with an inefficient, extremely high number of synthesis steps and on the other hand, elegant multicomponent reactions extremely high number of synthesis steps and on the other hand, elegant multicomponent reactions that can make such efforts unnecessary. This double strategy in chemical synthesis has given the that can make such efforts unnecessary. This double strategy in chemical synthesis has given the author author cause to reflect (Figure 1) on how to close this gap using a consistent procedure. Thereby cause to reflect (Figure1) on how to close this gap using a consistent procedure. Thereby significant significant systemic differences in syntheses of chemical products play an essential role (Figure 2). systemic differences in syntheses of chemical products play an essential role (Figure2). FigureFigure 1. 1. ProblemProblem in in chemical chemical syntheses syntheses relating relating to to terms terms of of producibility, producibility, ecology and economy. Molecules 2017, 22, 349; doi:10.3390/molecules22030349 www.mdpi.com/journal/molecules Molecules 2017, 22, 349; doi:10.3390/molecules22030349 www.mdpi.com/journal/molecules Molecules 2017, 22, 349 2 of 32 Molecules 2017, 22, 349 2 of 32 Figure 2. Significant systemic differences in syntheses of chemical products by means of two- and Figure 2. Significant systemic differences in syntheses of chemical products by means of two- and multicomponentmulticomponent reactions, respectively.respectively. 2. Introduction 2. Introduction Special events in the author’s Vita runs synchronously alongside the scientific text and are Special events in the author’s Vita runs synchronously alongside the scientific text and are indicated by alphabetically-ordered notes in Section 13. The scientific work carried out by the author indicated by alphabetically-ordered notes in Section 13. The scientific work carried out by the author spans a wide range and encompasses the development of new methods and reagents, as well as the spans a wide range and encompasses the development of new methods and reagents, as well as the defusing of hazardous substances. These methods and reagents flow into the section on syntheses by defusing of hazardous substances. These methods and reagents flow into the section on syntheses by MCRs. Their applications in various areas of chemical synthesis include: MCRs. Their applications in various areas of chemical synthesis include: Tools, novel methods, catalysts and reagents to improve organic synthesis Tools, novel methods, catalysts and reagents to improve organic synthesis Vitamin B12 models. Structures, supernucleophilicity. Vitamin B models. Structures, supernucleophilicity. Protective12 group techniques. Peptides such as β-lactam antibiotics, N-heterocyclic compounds and β Protectivenatural substances, group techniques such as camptothecin. Peptides such, using as -lactam novel protective antibiotics, groupN-heterocyclic techniques compounds (2,2,2-trichloro and- naturaltert-butyloxycarbonyl substances, such (TCBOC as camptothecin,) residue, c usingobalt- novelphthalocyanine). protective group techniques (2,2,2-trichloro- tertMetal-butyloxycarbonyl phthalocyanines (TCBOC). Poisoning residue,-resistant cobalt-phthalocyanine). hydrogenation catalysts, palladium-phthalocyanine with Metalthree phthalocyaninesswitchable, partially. Poisoning-resistant orthogonal catalysis hydrogenation patterns, alamethicine catalysts, palladium-phthalocyanine sequence. withPeptide three chemistry switchable,. Peptides partially such orthogonal as human catalysis-β-endorphin patterns, sequences, alamethicine Leu-enkephalin, sequence. polyamino Peptideacids and chemistry cyclopeptides. Peptides, using such the as novel human- ferrocenylmethylβ-endorphin sequences, masking group. Leu-enkephalin, polyamino acidsTriphosgene and cyclopeptides,. Safe syntheses using with the noveltriphosgene ferrocenylmethyl and their up masking-scaling group.processes. TriphosgeneSynthesis efficiency. Safe syntheses. Quantitative with triphosgene assessment andof a theirsynthesis. up-scaling processes. ConcertedSynthesis simplifying efficiency synthesis. Quantitative chemistry assessment on MCR basis of a synthesis. ConcertedMulticomponent simplifying synthesis reactions chemistry (MCRs) on. Systemic MCR basis and post-MCR extensions. MCR synthesis efficiency. Special preconditions. Algorithm on efficiency. Multicomponent reactions (MCRs). Systemic and post-MCR extensions. MCRs’ future. Concerted simplification of chemical processes. MCR synthesis efficiency. Special preconditions. Algorithm on efficiency. The individual sections are seamlessly meshed, and thus methodologically produce what are to MCRs’ future. Concerted simplification of chemical processes. some extent substantial synergistic effects. All these different advantageous methods and reagents listed in Sections 3–8 are developed tools for efficient syntheses. They support multicomponent reactions in particular, Sections 9–11 through their systemic property which strongly reduces the Molecules 2017, 22, 349 3 of 32 The individual sections are seamlessly meshed, and thus methodologically produce what are to some extent substantial synergistic effects. All these different advantageous methods and reagents Moleculeslisted in 2017 Sections, 22, 349 3 –8 are developed tools for efficient syntheses. They support multicomponent3 of 32 reactions in particular, Sections9–11 through their systemic property which strongly reduces the numbernumber of of synthesis synthesisMolecules 2017 steps steps, 22, 3 49and and promoting promoting simplification simplification of of synthesis synthesis chemistry. chemistry. Nearly Nearly all all referred referred3 of 32 literliteratureature in Section Sectionss 99 andand 1111 areare reviewsreviews aboutabout thethe relativerelative domain.domain. number of synthesis steps and promoting simplification of synthesis chemistry. Nearly all referred literature in Sections 9 and 11 are reviews about the relative domain. 3.3. Vitamin Vitamin B B1212 ModelsModels [A][A] The The3. idea Vitamin was to B12 find find Models a cobalt(I)cobalt (I) complex [1] [1] that demonstrated the reactive chemical properties properties ofof v vitaminitamin B B1212 andand[A] c cobaloximesobaloximesThe idea was [2],to [2 ],find as as wella well cobalt