Synergy Effects in the Chemical Synthesis and Extensions Of

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 as as (I)constituting constituting complex [1] athat a stable stable demonstrated reagent reagent or orthe catalyst. catalyst. reactive chemicalThe The cho choice iceproperties fell fell onon the the light light--of and and vitamin colo color-fastr B-fast12 and pigment pigment cobaloximes c cobalt-phthalocyanin,obalt [2],-phthalocyanin, as well as constituting CoPc, CoPc, 1a1 stable[3][3] [B] [B]. reagent. Its Its properties properties or catalyst. were were The then thenchoice to to fell bebe investigated, on the in light particular - and colo the r- fast nucleophilicity pigment cobalt of-phthalocyanin, its anionanion [PcCo[PcCo CoPc,II]]− 1a1a 1 [3]inin the[B] the. Itsoxidation oxidation properties stage stage were +1 +1 then of of to thethe metal metal [4]. [4].be investigated, in particular the nucleophilicity of its anion [PcCoI]− 1a in the oxidation stage +1 of TheThe nucleophilicitythe metal [4]. of [PcCo[PcCoI]]− waswas determined determined conductometrical conductometricallyly [1]. [1]. Table Table 1 shows shows the the The nucleophilicity of [PcCoI]− was determined conductometrically [1]. Table 1 shows the comparisoncomparison with with standard standard strongly strongly nucleophilic agents [5], [5], v vitaminitamin B 12s andand its its model model c cobaloxime(I),obaloxime(I), comparison with standard strongly nucleophilic agents [5], vitamin B12s and its model cobaloxime(I), whereby 1a,, together with the latter, has a value >10>10 and is therefore designated a supernucleophile. whereby 1a, together with the latter, has a value >10 and is therefore designated a supernucleophile. ◦ TableTable 1. 1.Relative Relative nucleophilicity nucleophilicity n MeInMeI= = loglog (k(kYY/kMeOHMeOH) for) for the the following following reaction reaction at at 25 25 °C C[[5].5 ]. Table 1. Relative nucleophilicity nMeI = log (kY/kMeOH) for the following reaction at 25 °C [5].

Nucleophile Y nMeI Structures of Supernucleophiles NucleophileNucleophile Y Yn MeI nMeI StructuresStructures of Supernucleophiles of Supernucleophiles MeOH 0.00 MeOHCl− MeOH 0.00 4.370.00 − Cl− 4.37 ClBr − 4.37 5.79 Br− 5.79 Br− − 5.79 CN − 6.70 − CN 6.70 CN − 6.70 I I− 7.427.42 I− 7.42 − 2 3− S2O3 S O 8.958.95 S2O3− 8.95 − Ph-S− 9.92 Ph-S− 9.92 Ph-S [PcCoI]− 9.92 10.8 I − 10.8 [PcCo[PcCoI]−Cobaloximes(I) ] 10.8 10.5–14,3 Cobaloximes(I)Cobaloximes(I)Vitamin B10.512s –14,310.5–14.3 14.4

VitaminVitamin B12s B12s 14.4 14.4

4. Protective Group Techniques 4. Protective Group Techniques 4. Protective GroupSuitable Technique protectives groups play a central role in classic chemical peptide synthesis. Although the Suitablepermanent protective protection groups playof α-amino a central and rolecarboxyl in classic functions chemical is well peptide provided synthesis. for by Z, AlthoughBOC, ALOC, Suitable protective groups play a central role in classic chemical peptide synthesis. Although the the permanentFMOC, protection TMS, benzyl of α-amino and tert and-butyl carboxyl groups, there functions is still is a wellneed providedfor selective for orthogonal by Z, BOC, intermediary ALOC, permanent protection of α-amino and carboxyl functions is well provided for by Z, BOC, ALOC, FMOC, TMS,protective benzyl andgroupstert for-butyl the groups,protection there of amino is still acid a need third for functions selective or orthogonalspecial applicati intermediaryons. A useful FMOC,protective TMS, groupssolution benzyl for is and provided the tert protection-butyl here groups,by of using amino thereβ-halogenalkyl acid is still third a need functions and βfor-halogenalkoxy selective or special orthogonal- applications.carbonyl groupsintermediary A [6], useful which protectivesolution is groups providedcan be cleavedfor here the offprotection by by using reductionβ -halogenalkylof amino in a weakly acid and thirdacidicβ -halogenalkoxy-carbonyl functionsenvironment, or speciale.g., using applicati zinc. groups Theons. ideal [ 6A], protectiveuseful which solutioncan be cleaved is providedgroup off byis here onereduction by which using in is aβ stable weakly-halogenalkyl in acidic acids environment,and and βalkaline-halogenalkoxy solutions,e.g., using-carbonyl and zinc. not The groups affected ideal [6], protective by which catalytic cangroup be iscleaved onehydrogenolysis, which off by is stablereduction and in acids whichin a andweakly can alkaline be acidiccleaved solutions, environment, off under and conditions not e.g. affected, using that by dozinc. catalytic not The attack ideal hydrogenolysis, most protective of the other protective groups (orthogonality). This method was developed [7–9] and optimized [10–13] by Eckert groupand which is one can bewhich cleaved is stable off under in conditions acids and thatalkaline do not solutions, attack most and of the not other affected protective by catalytic groups and Ugi using selective reagents following the defined mechanism of reductive fragmentation as per hydrogenolysis,(orthogonality). and This which method can was be cleaved developed off under [7–9] and conditions optimized that [ 10do– 13not] byattack Eckert most and of Ugithe usingother Scheme 1. protectiveselective reagents groups (orthogonality). following the deﬁned This method mechanism was developed of reductive [7– fragmentation9] and optimized as per [10– Scheme13] by Eckert1. and Ugi using selective reagents following the defined mechanism of reductive fragmentation as per Scheme 1. Molecules 2017, 22, 349 4 of 32 Molecules 2017, 22, 349 4 of 32 Molecules 2017, 22, 349 4 of 32

Scheme 1. Introduction of TCBOC-residueTCBOC-residue (1)(1) andand itsits cleavagecleavage byby meansmeans ofof 1b1b (3).(3). Scheme 1. Introduction of TCBOC-residue (1) and its cleavage by means of 1b (3). I The lithium salt of Cobalt(I)-phthalocyanin, Li[CoIPc] 1b (Section 3), was the selected reagent The lithium salt of Cobalt(I)-phthalocyanin, Li[CoI Pc] 1b (Section3), was the selected reagent whichThe met lithium all conditions: salt of Cobalt(I) fast reaction-phthalocyanin, at room temperature Li[Co Pc] (1bRT )( Sectionin neutral 3), environment was the selecteds, no reactionreagent which met all conditions: fast reaction at room temperature (RT) in neutral environments, no whichwith othermet all functional conditions: groups fast reaction (except at room for the temperature nitro group), (RT) in high neutral product environment yields ands, no complete reaction reaction with other functional groups (except for the nitro group), high product yields and complete withregenerat otherion functional capability groupsof the fully (except stable for reagent. the nitro The group),cleavage high of the product protective yields groups and can complete also be regeneration capability of the fully stable reagent. The cleavage of the protective groups can also be regeneratcarried oution catalytically capability of on the Co fullyIIPc 1stable with reagent.NaBH4 [12]. The Ascleavage an optimal of the protective protective group, groups the can acid also and be II carried out catalytically on CoII Pc 1 with NaBH [12]. As an optimal protective group, the acid and carriedbase-stable out catalytically2,2,2-trichlor ono-tert Co-butyloxycarbonylPc 1 with NaBH44- residue[12]. As (TCBOC)an optimal was protective created, group,which isthe in troducedacid and base-stable 2,2,2-trichloro-tert-butyloxycarbonyl-residue (TCBOC) was created, which is introduced basevia its-stable stable 2,2,2 chloride-trichlor TCBOCo-tert-butyloxycarbonylCl and can be cleaved-residue off in (TCBOC) just 1 min was using created, 1a (Scheme which 1)is [10].introduced Due to via its stable chloride TCBOC-Cl and can be cleaved off in just 1 min using 1a (Scheme1)[ 10]. Due viathe its extremely stable chloride mild conditions,TCBOC-Cl and the methodcan be cleaved has been off in successfully just 1 min using used 1a for (Scheme the semi 1)- synthesis[10]. Due to of to the extremely mild conditions, the method has been successfully used for the semi-synthesis of theunstable extremely β-lactam mild antibiotics, conditions, such the as method penicillin has and been cephalosporin successfully derivatives used for the(Figure semi 3-)synthesis [13–16] [C] of. unstable β--lactamlactam antibiotics, antibiotics, such such as as penicillin penicillin and and cephalosporin cephalosporin derivatives derivatives (Figure 33)[) [1313––1616]] [C].[C].

Figure 3. Unstable β-lactam antibiotics synthesized using protective group technique of Scheme 1. FigurFiguree 3 3.. UnstableUnstable ββ--lactamlactam antibiotics antibiotics synthesized synthesized using using protective protective group group technique technique of Scheme 11.. 5. Metal-Phthalocyanines, Hydrogenation Catalysts, Palladium-Phthalocyanin 5. Metal Metal-Phthalocyanines,-Phthalocyanines, Hydrogenation Catalysts Catalysts,, Palladium Palladium-Phthalocyanin-Phthalocyanin 5.1. Cobalt-Phthalocyanine as Reagent 5.5.1.1. Cobalt Cobalt-Phthalocyanine-Phthalocyanine as Reagent The reagent Li[CoIPc] stands out due to its almost unique selectivity: apart from the reductive fragmentation,The reagent practically Li[Co IPc]Pc] onlystands stands the outout nitro due group to its is almost reduced unique to the selectivity: primary amine a apartpart functionfrom the [17,18]. reductive All fragmentation,other normal functional practically practically groups only only the theremain nitro nitro groupintact, group iswhich isreduced reduced makes to the to 1a the primaryparticularly primary amine aminesuitable function function for [17,18]. the [in17- ,situAll18]. otherAllpreparation other normal normal offunctional aromatic functional groups o-amino groups remain-alde remainhydes intact, intact, inwhich the which Friedländermakes makes 1a particularly synthesis1a particularly reaction.suitable suitable for A the significant forin-situ the preparationin-situimprovement preparation of in aromatic the of total aromatic osynthesis-amino o-amino-aldehydes-alde of hydesthe frequently in the in theFriedländer used Friedländer anticancer synthesis synthesis drug reaction.camptothecin reaction. A A significant signiﬁcant could be improvementachieved (Scheme in in the 2), total whereby synthesis the yield of the of step frequently 6 was increased used anticancer from 20% drug to 62% camptothecin [18] and up could to 80 be %. achieved (Scheme 22),), wherebywhereby thethe yieldyield ofof stepstep 66 waswas increasedincreased fromfrom 20%20% toto 62%62% [[18]18] andand upup toto 80%.80%. Molecules 2017, 22, 349 5 of 32 Molecules 2017, 22, 349 5 of 32

SchemeScheme 2. 2.CamptothecinCamptothecin synthesis synthesis using using 1a1a inin a aFriedländer Friedländer synthesis synthesis forming forming oo--amino-benzaldehyde.amino-benzaldehyde.

5.2. Hydrogenation Catalysts 5.2. Hydrogenation Catalysts II In order to determine the capabilities of the vitamin B12-related Co Pc andII analogous metal- In order to determine the capabilities of the vitamin B12-related Co Pc and analogous phthalocyanines (MPc), the reactive and the reductive properties of MPc in particular were metal-phthalocyanines (MPc), the reactive and the reductive properties of MPc in particular were researched with the metals M = VO, Mn, Fe, Co and Pd as catalysts using the reduction agents researched with the metals M = VO, Mn, Fe, Co and Pd as catalysts using the reduction agents hydrogen and sodium borohydride [19,20]. The pronounced poisoning resistance of CoIIPc against hydrogen and sodium borohydride [19,20]. The pronounced poisoning resistance of CoIIPc against strong catalyst poisons such as I−, CN− or R-S− was impressive. strong catalyst poisons such as I−, CN− or R-S− was impressive.

5.3.5.3. Palladium-Phthalocyanine Palladium-Phthalocyanine [D] [D] AA prominent prominent role role is is played played here here by by palladium-phthalocyanin palladium-phthalocyanin2 ,2 which, which can can act act with with three three different different II I switchableswitchable speciﬁcities specificities as as Pd PdIIPcPc2 2and and Na[Pd Na[PdIPc]Pc]2a 2aas as well well as as2a 2ain in alkaline alkaline environments environments (pH (pH > > 11, 11, Figure 4), thereby generating three discrete catalyst patterns P1–P3 (Table 2 and Scheme 3) [20,21]. Figure4), thereby generating three discrete catalyst patterns P 1–P3 (Table2 and Scheme3)[ 20,21]. These areThese also partially are also orthogonal partially orthogonal to each other to and each thus other open and up thus interesting open up new interesting options for new synthesis. options This for “catalyticsynthesis. doubling” This “catalytic has been doubling successfully” has appliedbeen successfully in a one-reactor applied reaction in a one during-reactor the synthesisreaction ofduring the partialthe synthesis sequence of [13 the–16 partial], BOC-Aib-Pro-Val-Aib-OBz, sequence [13–16], BOC of-Aib the-Pro peptide-Val-Aib antibiotic-OBz, of alamethicin the peptide (Scheme antibiotic4). alamethicin (Scheme 4). Z 1 2 Table 2. Catalysis-pattern Pi (i = 1–3) of the catalyst Pd Pc transforming A-F to A-F referred to SchemeTable 3 2.. [a] Catalysis Corbobenzoxy-pattern residue. Pi (i = 1 [b]–3) 2,2,2-Trichloro- of the catalysttert Pd-butoxycarbonylZPc transforming residue. A-F1 [c]to Benzyl A-F2 referred residue. to Scheme 3. [a] Corbobenzoxy residue. [b] 2,2,2-Trichloro-tert-butoxycarbonyl residue. [c] Benzyl residue. z = 2 z = 2 1 z = 2 z = 2 z = 1 2 F A P1 P2 z = 1 F (P) F1 A P1 P2 P3 F2 (P) pH < 9 pH > 11 P3 pH < 9 pH > 11 C=C,C=C, C=N C=N Alkyl,Alkyl, Aryl Aryl +++ + + CH-CH,CH-CH, CH-NHCH-NH +++ P NO2NO, CH=O2, CH=O ArylAryl + + + NHNH2,2, CH CH33 ((P3:: CH CH22-OH)-OH) NO , CH=O, Hal Alkyl −− + NH , CH -OH, H 2NO2, CH=O, Hal Alkyl − − + NH22, CH2-OH, H − + − HalHal ArylAryl − + − H C=O, COCl, CN Alkyl, Aryl −− + CH-OH, CH2-OH, CH2-NH2 C=O, COCl, CN Alkyl, Aryl − − + CH-OH, CH2-OH, CH2-NH2 Z, CBZ [a] NH ++ − H Z, CBZ [a] NH + + − H TCBOC [b], β-Haloalkoxy NH, O −− + H TCBOC [b], -Haloalkoxy NH, O − − + H [c] −−− 1 X-Bn (X[c] = O, N, CON) Alkyl, Aryl F 1 X-Bn (X = O, N, CON) Alkyl, Aryl − − − F1 CO2R, CONR2 Alkyl, Aryl −−− F CO2R, CONR2 Alkyl, Aryl − − − F1 MoleculesMolecules2017 2017, ,22 22,, 349 349 6 6of of 32 32 Molecules 2017, 22, 349 6 of 32 Molecules 2017, 22, 349 6 of 32

z SchemeScheme 3. 3Pd. PdPczzPc as as hydrogenation hydrogenation catalyst catalyst with with 33 switchableswitchable catalysis patternspatterns P P1–1–PP3 3(Table (Table 2) 2) dependent dependent Scheme 3. Pd Pcz as hydrogenation catalyst with 3 switchable catalysis patterns P1–P3 (Table2) Scheme 3. Pd Pc as hydrogenation catalyst with 3 switchable catalysis patterns P1–P3 (Table 2) dependent onon valence valence z inz in Pd Pdz andz and basic basicityzity of of reaction reaction mediummedium ((Figure 4)).. dependenton valence on valence z in Pdz andin Pd basicandity of basicity reaction of medium reaction ( mediumFigure 4). (Figure 4).

Figure 4. Graph of the sharp crossover from P1 to P2 caused by the basicity of reaction medium. FigureFigure 4. Graph 4. Graph of the of sharpthe sharp crossover crossover from from P1 Pto1 to P2 Pcaused2 caused by by the thebasicity basicity of reaction medium. medium. Figure 4. Graph of the sharp crossover from P1 to P2 caused by the basicity of reaction medium.

Scheme 4. Reaction control by catalyst PdzPc in the one-pot synthesis of the alamethicin [13–16] sequence. Scheme 4. Reaction control by catalyst PdzPc in the one-pot synthesis of the alamethicin [13–16] sequence. z SchemeScheme 4. 4.ReactionReaction control control by by catalyst catalyst Pd PdPczPc in in the the one one-pot-pot synthesis synthesis of the thealamethicin alamethicin [ 13[13––1616]] sequence. sequence. Molecules 2017, 22, 349 7 of 32

The starting substance was the protected dipeptide BOC-Aib-Pro-OBz. After P1, the benzyl residue is selectively cleaved off with H2 at 2. After adding of TCBOC-Val-Aib-OBn the TCBOC residue can be removed with inverse selectivity after P3 at 2a through the addition of NaBH4. This leaves the benzyl residue intact. The final coupling using morpholinoethyl isocyanide delivers the protected tetrapeptide with a yield of 75% via three steps in one reactor (Scheme4). Synthesis efficiency (for this item see Section8) is Eff Synth = 75%, whereas that of the three single reactions with very good II yields in [21] is EffSynth = 23% only. The 2/H2/EtOH system is air-stable and the catalyst Pd Pc can be quantitatively recovered and re-used without further treatment. This means the catalyst 2/2a has an unusually high synergistic potential: using the same catalyst means that orthogonal reactions in a one-reactor method can proceed without prior isolation and preparation, thus saving two out of three practical synthesis steps! Therefore, the application of protective group techniques may no longer be an efficiency brake in syntheses; e.g., this method could help make the eurystatin synthesis in Section 9.2.4 even more efficient by saving up to three steps.

6. Peptide Chemistry—The Ferrocenylmethyl (Fem) Masking Group Peptide synthesis is often faced with the problem of difficult or practical insolubility of sequences in solvents if corresponding conformations of the sequences can be taken. Preventing this requires reversibly masking the peptide bonds. This is most favorably achieved using the ferrocenylmethyl (Fem) residue [22], which can simply be introduced via the easily accessible ferrocenaldehyde on the II amino function of the respective amino acid in a reductive alkylation reaction with H2 at Pd Pc and removed with trifluoroacetic acid in dichloromethane. Various human-β-endorphin sequences [23], Leu-enkephalin and hexaglycine [24] and the cyclopeptides cyclo-triglycine and cyclo-pentaglycine [25] could be produced with this method under mild conditions with far better yields than previously possible (Figure5). Also of interest is the further useful application of Pd IIPc in selective reductive alkylation. The Fem residue transfers modified properties here to the peptides:

- Lipophilisation of the peptide bonds. The Fem peptides mentioned above dissolve well in standard non-polar solvents such as ethyl acetate and ethyl acetate/hexane mixtures, even to some extent in pure hexane! This effect is particularly favorable on peptide bonds of glycine [23–25]. - Strong chromophore. Due to their high lipophility, Fem peptides can be easily and inexpensively purified using silica gel chromatography and ethyl acetate/hexane mixtures. Implementation is facilitated by the strong intrinsic orange colour of all Fem derivatives. - Electrochemical Detection (ECD). Detection following chromatography can also be done with ECD. The detection limit here is very low with 10−15 M (femto-molar!) [26]. The FeII in the ferrocene of the Fem residue is the electrophore. - Conformational effects. Strong steric hindrance and high lipophilicity of the Fem residue have a significant influence on the conformational effects of the Fem peptide.

During Leu-Enkephalin synthesis, masking of both peptide bonds on the Gly-Gly sequence prevents the formation of a side product that would occur more substantially without Fem masking [24]. In cyclo-triglycin synthesis, the strong effect of all-Fem masking is particularly evident: under mild reaction conditions (6 h at RT), the output is 63% cyclo-(Fem-Gly)3 from H-(Fem-Gly)3-OH. Cyclo-(FemGly)5 from H-(FemGly)5-OH runs with 85% yield, what from the free cyclo-(Gly)5 is obtained with 92% yield [25] (Figure5). Also, a severe solubility problem during the synthesis of the octapeptide [24–31] sequence of human-β-endorphine has been solved successfully by using Fem-residues at [30] Gly and [25] Asn-positions (Figure5)[23]. Molecules 2017, 22, 349 8 of 32 Molecules 2017, 22, 349 8 of 32 Molecules 2017, 22, 349 8 of 32

Figure 5. Synthesis of peptides otherwise hardly accessible, via their Fem-derivatives. Figure 5. Synthesis of peptides otherwise hardly accessible, via their Fem-derivatives.

7. Triphosgene—A Safe Phosgene Substitute 7. Triphosgene—AFigure Safe5. Synthesis Phosgene of peptides Substitute otherwise hardly accessible, via their Fem-derivatives. [E] The elemental analysis of triphosgene suggested a molecular formula of COCl2, which was 7. T[E]bafflingriphosgene The elementaland gave—A Saferise analysis toPhosgene the ofconclusion triphosgene Substitute that this suggested solid could a molecular be a solid formulaphosgene. of A COCln IR spectrum2, which was bafflingprovided and gave information rise to about the conclusion the composition: that i thist was solid not the could cyclic be trimeric a solid hexachlor phosgene.-1,3,5- Antrioxane, IR spectrum but [E] The elemental analysis of triphosgene suggested a molecular formula of COCl2, which was providedrather information bis(trichloromethyl)carbonate about the composition: 3. The 13C-NMR it was spectrum not the with cyclic two trimeric signals confirmed hexachlor-1,3,5-trioxane, this structure. baffling and gave rise to the conclusion that this solid could be a solid phosgene. An IR spectrum but ratherSynthesis bis(trichloromethyl)carbonate of 3 was rather simple: radical3. The chlorination13C-NMR of dimethyl spectrum carbonate with two (DMC signals, Scheme confirmed 5). provided information about the composition: it was not the cyclic trimeric hexachlor-1,3,5-trioxane, but this structure.The up-scaling of the reaction to a 20-L flask resulted in a yield per batch of approx. 20 kg (99%) rathertriphosgene bis(trichlor withomethyl)carbonate a melting point 3 of. The 80 13°C- NMR[F]. DMC spectrum is a million with two-ton signals product confirmed that is industriallythis structure . Synthesis of 3 was rather simple: radical chlorination of dimethyl carbonate (DMC, Scheme5). producedSynthesis using of 3 methanol, was rather CO simple: and O 2r (Schemeadical chlorination 5). Compound of dimethyl 3 could replace carbonate all actual (DMC reactions, Scheme of 5). The up-scaling of the reaction to a 20-L flask resulted in a yield per batch of approx. 20 kg (99%) Thephosgene up-scaling [27 –of29], the was reaction therefore to anamed 20-L flaskas triphosgene resulted in and a yieldas a crystallineper batch solidof approx. it is significantly 20 kg (99%) ◦ triphosgenetriphosgenesafer to handle with with a than a melting melting the gaseous point point phosgene of of 80 80 °CC 4 [F].,[F] as. can DMC be seen is a a inmillion million-ton Table -3.ton product product that that is is industrially industrially producedproduced using using methanol, methanol, CO CO and and O O22(Scheme (Scheme5 5).). CompoundCompound 33 couldcould replace replace all all actual actual reactions reactions of of phosgenephosgene [27 [27–29–],29], was was therefore therefore named named as as triphosgene triphosgene and and as aas crystalline a crystalline solid solid it isit significantlyis significantly safer to handlesafer to thanhandle the than gaseous the gaseous phosgene phosgene4, as can 4, as be can seen be inseen Table in Table3. 3.

Scheme 5. Triphosgene synthesis from dimethylcarbonate and chlorine.

Triphosgene is preferably used to synthesize isocyanides applied in the production of important isocyanide-based IMCRs [27–29], as described in Section 9.2. Scheme 5. Triphosgene synthesis from dimethylcarbonate and chlorine. Contrary Schemeto most opinions, 5. Triphosgene phosgene synthesis is not from just pro dimethylcarbonateduced during the and thermal chlorine. decomposition of triphosgene, instead there are two defined ways of transformation as per Scheme 6, whereby the Triphosgene is preferably used to synthesize isocyanides applied in the production of important Triphosgenethermal decomposition is preferably to phosgene, used to synthesize carbon dioxide isocyanides and tetrachlor appliedomethane in the production(pathway A of) always important isocyanide-based IMCRs [27–29], as described in Section 9.2. isocyanide-basedoccurs around IMCRs approx. [27 200–29 °],C as and described catalyses in according Section 9.2 to . a 6-element mechanism, because as is Contrary to most opinions, phosgene is not just produced during the thermal decomposition of Contrarythermodynamically to most opinions,determined, phosgene ΔH = −243 is J·g not−1. If just theproduced transformation during is enabled the thermal at relatively decomposition lower triphosgene, instead there are two defined ways of transformation as per Scheme 6, whereby the of triphosgene, instead there are two deﬁned ways of transformation as per Scheme6, whereby the thermal decomposition to phosgene, carbon dioxide and tetrachloromethane (pathway A) always thermal decomposition to phosgene, carbon dioxide and tetrachloromethane (pathway A) always occurs around approx. 200 ◦ °C and catalyses according to a 6-element mechanism, because as is occursthermodynamically around approx. determined, 200 C and ΔH catalyses= −243 J·g− according1. If the transformation to a 6-element is enabled mechanism, at relatively because lower as is thermodynamically determined, ∆H = −243 J·g−1. If the transformation is enabled at relatively lower Molecules 2017, 22, 349 9 of 32

Molecules 2017, 22, 349 9 of 32 temperatures of 80–120 ◦C, pure phosgene (pathway B) is output in a reconversion without reaction temperatures of 80–120 °C, pure phosgene (pathway B) is output in a reconversion without reaction heat, ∆H = +9 J·g−1, if an appropriate catalyst is used that also blocks the 6-element mechanism [30]. heat, ΔH = +9 J·g−1, if an appropriate catalyst is used that also blocks the 6-element mechanism [30]. Table 3. Physical, chemical, thermochemical, and toxicity data of phosgene and triphosgene [28,29]. Table 3. Physical, chemical, thermochemical, and toxicity data of phosgene and triphosgene [28,29].

DataData PhosgenePhosgene (4) (4) Triphosgene Triphosgene (3) (3) MeltingMelting point point m.p. m.p. (◦C) (°C ) –118–118 80 80 BoilingBoiling point point b.p. b.p. (◦C) (°C) 88 206 206 VaporVapor pressure pressure at 20at ◦20C (Pa/mmHg)°C (Pa/mmHg) 162,000/1215162,000/1215 20/ 20/0.150.15 RelativeRelative reactivity reactivity to MeOHto MeOH 170170 1 1 −1 ∆H (conversionH (conversion of 3 ofto 34 to) (J 4·)g (J·g) −1) -- +9 +9 −1 ∆H (decompositionH (decomposition of 3 of) (J 3·)g (J·g) −1) -- –243 –243 Toxicity LC (mg·m−3) 7 41.5 Toxicity50 LC50 (mg·m−3) 7 41.5 −3 Toxicity LC50 (mMol·m ) 0.07 0.14 Toxicity LC50 (mMol·m−3) 0.07 0.14

SchemeScheme 6. 6.The The two two pathways pathways ofof triphosgene transformation transformation [29,30]. [29,30 ].

There are reactions and processes in synthesis chemistry that run better with phosgene than with triphosgene,There are reactions as i.e., the and production processes of in high synthesis-chem isocyanato chemistry-isocyanides that run better for MCR with chemistry phosgene in than withS triphosgene,ection 9.2.6 [28 as–30]. i.e., T thehis process production was easily of high-chem up-scaled isocyanato-isocyanides to the 5 kg range and a phosgene for MCR generator chemistry in Sectionwas 9.2.6 designed[ 28–30 for]. This a 30 processkg·h−1 throughput was easily up-scaled [29]. Thus, to also the 5the kg supply range- andchain a phosgene of phosgene generator in bulk was designedquantiti fores abecomes 30 kg·h −safe1 throughputr: triphosgene [29 for]. Thus, transport also and the supply-chainstorage, phosgene of phosgene as reagent. in bulkAs a quantitieshighly becomesremarkable safer: instance, triphosgene MPc forare transportalso absolutely and stable storage, and phosgene re-usable catalysts as reagent. for Asthis aprocess highly [G] remarkable. instance, MPc are also absolutely stable and re-usable catalysts for this process [G]. 8. Synthesis Efficiency 8. SynthesisThe smallest Efﬁciency unit, the cell, of chemical synthesis is the (synthesis) step. Its evaluation criteria are: - TheA smallest logical synthesis unit, the plan cell, ofwith chemical environmentally synthesis friendly is the (synthesis) processes and step. starting Its evaluation materials criteria(STM), are: the least possible side products (additional reactions), - - A logicalaccess to synthesis and price plan of starting with environmentally materials, friendly processes and starting materials (STM), - thecost least of possible implementation side products and purifying (additional the product reactions), and - - accessforemost, to and the price yield of. starting materials, - costThis of implementation is the sum criterion and with purifying a high intrinsic the product chemical and component and the yardstick for every - synthesisforemost, step. the Itsyield significance. is well known by every chemist. The observer will drastically notice the relation between the overall yield yoa and the number of steps n as clearly shown in Table 4: To facilitateThis is theunderstanding, sum criterion intermediate with a high yields intrinsic yav are chemical applied on component a case by case and basis. the yardstick for every synthesis step. Its signiﬁcance is well known by every chemist. The observer will drastically notice the relation between the overall yield yoa and the number of steps n as clearly shown in Table4: To facilitate understanding, intermediate yields yav are applied on a case by case basis. Molecules 2017, 22, 349 10 of 32 MoleculesMolecules 2017 2017, 22, 22, 3, 49349 1010 of of 32 32

Molecules 2017, 22, 349 10 of 32 TableTableTable 4. 4. Overall OverallOverall yields yields yields y oay oa oadependent dependentdependent on on on geometric geometric geometric average average average yields yields yields y avy yav avand andand numbers numbers numbers n n nof of ofsteps steps steps of of of Molecules 2017, 22, 349 10 of 32 syntheses.syntheses.syntheses.Table 4. Overallhighlyhighhigh yieldslyly profitable profitable profitableyoa dependent shortshort short on syntheses,syntheses, syntheses, geometric average usualusual usual yields pharma pharmapharma yav andproduction, production,production, numbers n of highsteps highhigh-chem- chem of-chem researchresearchresearchsyntheses. preparations. preparations. preparations. highly profitable short syntheses, usual pharma production, high-chem Table 4. Overall yields yoa dependent on geometric average yields yav and numbers n of steps of research preparations. syntheses. highly profitable short syntheses, usual pharma production, high-chem OverOver-All-All-Yield-Yield y oayoa ( %(%) ) NumberNumber ofresearch of Steps Steps preparations. Over-All-Yield yoa (%) Number of Steps GeometricGeometric Average Average Yields Yields y avyav ( %(%) ) nn Geometric Average Yields yav (%) n 9999 9898 9595 Over90-90All -Yield y80oa80 ( %) 7070 6060 5050 Number of Steps 99 98 95 90 80 70 60 50 2 98 96 90Geometric 81 Average Yields64 yav (%49) 36 25 2 2 n2 9898 98 9696 96 9090 90 8181 6464 4949 49 36 3636 25 2525 99 98 95 90 80 70 60 50 3 3 3 9797 97 9494 94 8686 86 7373 5151 3434 34 22 2222 13 1313 2 98 96 90 81 64 49 36 25 4 4 4 9696 96 9292 92 8181 81 6666 4141 2424 24 13 1313 6.3 6.36.3 3 97 94 86 73 51 34 22 13 5 5 5 9595 95 9090 90 7777 77 5959 3333 1717 17 7.87.8 7.8 3.1 3.13.1 4 96 92 81 66 41 24 13 6.3 6 6 6 9494 94 8989 89 7474 74 5353 2626 1212 12 4.74.7 4.7 1.6 1.61.6 6 5 94 95 89 90 74 77 5359 2633 1712 7.84.7 3.1 1.6 7 7 93 93 87 87 70 70 4848 21 8.28.2 2.82.8 0.8 0.8 7 7 6 9393 8787 7070 4848 2121 8.28.2 2.82.8 0.80.8 8 9492 8985 7466 5343 1726 5.812 1.74.7 0.41.6 8 8 9292 8585 6666 4343 1717 5.85.8 1.71.7 0.40.4 79 9391 8783 7063 4839 1321 4.08.2 1.02.8 0.20.8 9 9 9191 8383 6363 3939 1313 4.04.0 1.01.0 0.20.2 108 9290 8582 6660 4335 1117 2.85.8 0.61.7 0.10.4 10 90 82 60 35 11 2.8 0.6 0.1 1010 129 9090 9189 8282 83 78 6060 6354 35393528 6.9111311 1.44.02.82.8 0.21.00.6 0.6 0.020.2 0.10.1 1212 1015 8989 9086 7878 82 74 5454 6046 28352821 6.93.5116.9 0.52.81.41.4 0.040.60.2 0.2 0.0030.10.02 0.02 1515 1220 8686 8982 7474 78 67 4646 5436 21282112 3.51.26.93.5 0.081.40.50.5 0.0040.20.040.04 0.02 0.0030.003 2020 1530 8282 8674 6767 74 55 3636 4621 124.02112 1.20.13.51.2 0.0020.50.080.08 0.040.004 0.004 0.003 20 82 67 36 12 1.2 0.08 0.004 3030 40 7474 67 5555 45 2121 13 4.04.01.5 0.010.10.1 0.0020.002 30 74 55 21 4.0 0.1 0.002 4040 50 6767 61 4545 36 13137.7 1.51.50.5 0.0010.010.01 10−13 40 40 67 67 45 45 13 13 1.51.5 0.010.01 −13−13 5050 6161 3636 7.77.7 0.50.5 0.0010.001 −1013 10 The 50number n of all 61product -generating36 steps7.7 is the second0.5 main0.001 criterion for assessing a synthesis10 . The“The number less, then betterof all” product-generatingis the motto here and steps most ischemists the second do not main realiz criterione how great for assessing the influence a synthesis. of The number n of all product-generating steps is the second main criterion for assessing a synthesis. “TheTheThe less,the number numbernumberThe the number better” n ofn of ofsteps all n isall ofproductthe isproduct all on mottoproduct synthesis-generating-generating here-generating efficiency. and steps most steps steps As is chemists is isyieldthe thethe second secondand do step notmain main main number realize criterion criterion are how primarily for for greatfor assessing assessing assessing the factual influencea synthesis a criteriaasynthesis synthesis of. the. . “The less, the better” is the motto here and most chemists do not realize how great the influence of “The“numberThe less, “less,(molThe ofthe theless,or steps betterquantity), better the is better” on ”is is synthesis theythe ”the is mottoprovidethe motto motto efficiency. here herea soundhere and and and As basismost most most yield for chemists chemists chemistsevaluating and step do dodo number a notnot synthesis.not realiz realiz areee primarilyInhowehow howcombination, great great great factualthe the theinfluence they influence influence criteria are ofa (molof of the number of steps is on synthesis efficiency. As yield and step number are primarily factual criteria thetheor number quantity),numberthereliable number of of criterionsteps they steps of provide stepsis is onfor on is synthesisthe synthesison a quantitative soundsynthesis efficiency. basisefficiency. efficiency. overall forevaluating As evaluationAs As yield yield yield and and aof synthesis. stepa step stepsynthesis, numbernumber number In i.e. combination, areare, areits primarily primarilyefficiency. primarily factual they factual factual are criteria acriteria criteria reliable (mol or(mol quantity), or quantity), they theyprovide provide a sound a sound basis basis for for evaluating evaluating aa synthesis.synthesis. InIn combination, combination, they they are area a (mol(molcriterion or or quantity), quantity), forThe the synthesis quantitativethey they provide effici provideency overall a Eff asound soundSynth evaluation (Scheme basis basis for 9 for) offollows evaluating evaluating a synthesis, from thea asynthesis. i.e.,overallsynthesis. its efficiency.yield In In y combination,oa combination, and number ofthey they steps are are a a reliablereliablereliablen criterion ofcriterion a synthesis, criterion for for the theforwhere quantitative thequantitative quantitativethe overall overall overallproduct overall evaluation evaluation yieldevaluation equals of of thea a asynthesis, synthesis,synthesis,product of i.e.i.e. alli.e., ,its theits, its efficiency. efficiency.individual efficiency. yields per The synthesis efficiency EffSynth (Scheme7) follows from the overall yield yoa and number of steps step.The A value synthesis which effici betterency reflects EffSynth the (Scheme yield is 9 the) follows average from step the yield overall yav. yieldScheme yoa 7 and represents number the of stepsdata TheThe synthesis synthesis effici efficiencyency Eff EffSynthSynth (Scheme (Scheme 9 )9 follows) follows from from the the overall overall yield yield y oayoa and and number number of of steps steps n of an synthesis,of a synthesis, where where the the overall overall product product yieldyield equals the the product product of ofall allthe the individual individual yields yields per per nn of of a asynthesis, forsynthesis, the camptothecin where where the the synthesis overall overall inproduct product Section yield5.1 yield Scheme equals equals 2 [18] the the onproduct product the basis of ofof all allthese the the evaluationindividual individual criteria. yields yields per per step.step. A value A value which which better better reflects reflects the the yield yield is is the the averageaverage step step yield yield yav y.av Scheme. Scheme 7 represents7 represents the data the data step. A value which better reflects the yield is the average step yield yav. Scheme 7 represents the data step.step.for theA Afor value value camptothecin the camptothecinwhich which better better synthesis synthesis reflects reflects in the in Sectionthe Section yield yield 5.1is 5.1is the Scheme theScheme average average2 2[ 18[18] step] step onon yield the yield basis y yavav. ofScheme. of Scheme these these evaluation 7 evaluation 7represents represents criteria. criteria. the the data data forfor the the camptothecin camptothecin synthesis synthesis in in Section Section 5.1 5.1 Scheme Scheme 2 2[18] [18] on on the the basis basis of of these these evaluation evaluation criteria. criteria.

Scheme 7. Efficiency of synthesis EffSynth of the camptothecin synthesis in Section 5.1 Scheme 2.

yi: yield of one step; n: number of steps; yoa: over-all-yield over n steps; yav: geometric average yield

Sovercheme n steps 7. Efficiency; EffSynth: efficiency of synthesis of synthesis EffSynth .of the camptothecin synthesis in Section 5.1 Scheme 2. Scheme 7. Efﬁciency of synthesis EffSynth of the camptothecin synthesis in Section 5.1 Scheme2. y i: yi: yield of one step; n: number of steps; yoa: over-all-yield over n steps; yav: geometric average yield yield of one step; n: number of steps; yoa: over-all-yield over n steps; yav: geometric average yield over over n steps; EffSynth: efficiency of synthesis. n steps; Eff : efﬁciency of synthesis. SchemeScheme 7 . 7 .Efficiency SynthEfficiency of of synthesis synthesis Eff EffSynthSynth of of the the c amptothecin camptothecin synthesis synthesis in in Section Section 5.1 5.1 Scheme Scheme 2. 2.

yiy: yieldi: yield of of one one step step; n; :n number: number of of steps steps; y; oayoa: over: over-all-all-yield-yield over over n nsteps steps; y; avyav: geometric: geometric average average yield yield

overover n nsteps steps; Eff; EffSyntSynth: hefficiency: efficiency of of synthesis synthesis. . Molecules 2017, 22, 349 11 of 32 Molecules 2017, 22, 349 11 of 32

SynthesesSyntheses ofof a product D with various numbers of steps can vary greatly in efficiency, efficiency, asas shownshown inin SchemeScheme8 8.. EvenEven whenwhen thethe yieldyield ofof the the MCR MCR is is only only moderate, moderate, its its synthesis synthesis efficiency efficiency still still is is twice twice asas highhigh asas thatthat ofof aa 3-step3-step synthesissynthesis withwith itsits goodgood yield.yield. TheThe synthesissynthesis efficiencyefficiency tooltool helpshelps toto assessassess andand forecastforecastMolecules synthesis2017synthesis, 22, 349 schemes.schemes. Section 10 concerns thethe developmentdevelopment of anan algorithmalgorithm relatingrelating11 of 32 toto thethe efficiencyefficiency ofof MCRsMCRs withwith regardsregards toto parallelparallel reactions.reactions. Syntheses of a product D with various numbers of steps can vary greatly in efficiency, as shown in Scheme 8. Even when the yield of the MCR is only moderate, its synthesis efficiency still is twice as high as that of a 3-step synthesis with its good yield. The synthesis efficiency tool helps to assess and forecast synthesis schemes. Section 10 concerns the development of an algorithm relating to the efficiency of MCRs with regards to parallel reactions.

Scheme 8.8. Case study of two ways of synthesis toto formform productproduct D.D.

9.9. Multicomponent Reactions (MCRs)(MCRs) TheThe prominent prominent role roleScheme of of Multi-Component Multi 8. Case-Component study of two Reactions ways Reactions of synthesis (MCRs) (MCRs) to inform the inproduct chemical the chemicalD. evolution evolution of the of range the range of cosmic molecules (Figure 2) to the molecules of life, such as amino acids and nucleobases, of cosmic9. Multicomponent molecules (Figure Reactions2) to the(MCRs) molecules of life, such as amino acids and nucleobases, became clearbecame as the clear selecting as the selecting agents, the agents, enzymes, the enzymes, were not yetwere available not yet at available that time. at Biologicalthat time. evolutionBiological The prominent role of Multi-Component Reactions (MCRs) in the chemical evolution of the overevolution billions over of billions years consequently of years consequently selected the selected pathway the ofpathway the enzyme-controlled, of the enzyme-controlled, highly selective highly selectiverange two of -cosmiccomponent molecules reactions. (Figure The 2) to domain the molecules of chemical of life, such synthesis as amino that acids expanded and nucleobases, exponentially two-componentbecame clear reactions. as the selecting The domain agents, theof chemical enzymes, synthesis were not yet that available expanded at that exponentially time. Biological over the over the past 200 years retained this scheme even though, since the middle of the 19th century, past 200evolution years over retained billions this of years scheme consequently even though, selected since the pathway the middle of the of enzyme the 19th-controlled, century, highly extremely extremely important MCRs such as the Strecker and Hantzsch dihydropyridine syntheses, and the importantselective MCRs two- suchcomponent as the reactions. Strecker The and domain Hantzsch of chemical dihydropyridine synthesis that syntheses,expanded exponentially and the Biginelli reactionsBiginelliover reactions represented the past 200represented a years yet small, retained a yet but thissmall, profoundly scheme but profoundly even important though, important since part ofthe the middle part wealth of of the the of wealthchemical 19th century, of reactions.chemical Onlyreactions. theextremely isocyanide-based Only important the isocyanide MCRs Passerini such-based andas thePasserini Ugi Strecker reactions and and Ugi (IMCRs)Hantzsc reactionsh indihydropyridine the (IMCRs) 20th century in syntheses, the [31 20th] gave and century access the to[31] a versatilegave accessBiginelli and to broad reactions a versatile range represented ofand prospective broad a yet range small, syntheses. of but prospective profoundly MCR chemistry syntheses.important has part MCR seen of thechemistry a verywealth fast of has upswingchemical seen a (oververy reactions. Only the isocyanide-based Passerini and Ugi reactions (IMCRs) in the 20th century [31] 500fast reviews)upswing since (over the 500 turn reviews) of the millennium,since the turn while of the the millennium, number of new while MCRs the andnumber their of application new MCRs is gave access to a versatile and broad range of prospective syntheses. MCR chemistry has seen a very increasingand their applicat steadily,ion demonstrated is increasing in steadily, some reviews demonstrated [32–41]. in some reviews [32–41]. IMCRsfast upswing [38,42 (over–50], 500 alkyne reviews)-based since [38,51 the turn–54 ]of and the Cmillennium,-H-acidic compoundwhile the number [55–60 of] -newbased MCRs MCRs in IMCRsand their [38 applicat,42–50ion], alkyne-based is increasing steadily, [38,51 –demonstrated54] and C-H-acidic in some reviews compound [32–41]. [55 –60]-based MCRs in particular have a high potential to be very diverse. Many novel MCRs [57–73] have meanwhile particular haveIMCRs a high[38,42 potential–50], alkyne to- bebased very [38,51 diverse.–54] and Many C-H novel-acidic MCRs compound [57–73 [55] have–60]-based meanwhile MCRs in become partbecome ofparticular the par ranget of the have ofrange syntheses, a high of syntheses, potential e.g., toboron-mediated e.g. be, boron very diverse-mediated.[ 62Many, [62,66],66], nov photo-inducedel photo MCRs-induced [57–73 [67] [67]have] and and meanwhile carbene-based carbene- based MCRsMCRsbecome [72] [72] such such par tas of as Nthe N-heterocyclic-heterocyclic range of syntheses, carbenes carbenes e.g., boron(NHCs). (NHCs).-mediated They They [62,66], all increase all photo increase- theinduced application the [67] application and carbeneoptions- optionsbased for MCRs for, MCRs,such asMCRs such MCR [72] as nanosystems MCRsuch as nanosystems N-heterocyclic and mechanochemical and carbenes mechanochemical (NHCs). They reactions all reactions increase [65]. the [65MCRs application]. MCRs have haveoptions been been alsofor MCRs also applied applied, in inpolymer polymersuch [74], as [74 MCR nucleoside], nucleoside nanosystems [75] [75 and and] and carbohydratemechanochemical carbohydrate [76] [reactions76 chemistry.] chemistry. [65]. Main MCRs Main field have ﬁeld of been application of applicationalso applied remains remainsin the polymer [74], nucleoside [75] and carbohydrate [76] chemistry. Main field of application remains the theproduction production of heterocyclic of heterocyclic compounds compounds and and many many natural natural products products by by means means of of M MCRCR [38, [38,42,7742,77–8888]],, leadingproduction directly oftowards heterocyclic drug compounds design and and discovery many natural [89 products–93]. Scheme by means 9 presents of MCR [38,a current42,77–88 brief], of leadingleading directly directly towards towards drug drug design design and and discovery discovery [89 [89––9393]. ].Scheme Scheme 9 presents9 presents a current a current brief briefof of well-known multicomponent reactions [35,40,55,90,94–108]. well-knownwell-known multicomponent multicomponent reactions reactions [35 [35,40,55,90,94,40,55,90,94–108108].].

Year Year MulticomponentMulticomponent Reaction Reaction MCRMCR MCRMCR product product NameName reaction reaction [a][a]

1838 1838 StreckerStrecker [95] [95]

1. R-CHO + NH3 + HCN, 2. H2O 1. R-CHO + NH3 + HCN, 2. H2O

1882 2 MeC(O)CH2CO2Et + R1-NH2 + R2-CHO Hantzsch [96] 1882 2 MeC(O)CH2CO2Et + R1-NH2 + R2-CHO Hantzsch [96]

Scheme 9. Cont. Molecules 2017, 22, 349 12 of 32

Molecules 2017, 22, 349 12 of 32

H2N-CX-NH2 + R1-CHO + R2-C(O)CH2CO2R3 1893 Biginelli [97] X = O, S

1912 R1-C(O)CHR2 + CH2O + HNMe2 Mannich [98]

1921 R1-CO2H + R2-CHO + R3-NC Passerini [99]

1956 2 R1R2CH-CHO + NH3 + S Asinger [103]

1961 R1R2NH + R3-CHO + R4-NC Ugi-3CR [101]

Ugi-4CR 1961 R1-CO2H + R2-NH2 + R3-CHO + R4-NC [100,102]

1963 Ph-NH2 + R1-CHO + R2CH=CHR3 Povarov [104]

Groebke- 1998 Bienayme- + R1-CHO + R2-NC Blackburn [90]

Scheme 9. Well-known multicomponent reactions (MCRs). [a] On the Artificial Formation of Lactic SchemeAcid 9. Well-known and a New Compound multicomponent Homologous reactions to Glycine; (MCRs). by Adolph [a] Strecker On the. Artificial Formation of Lactic Acid and a New Compound Homologous to Glycine; by Adolph Strecker. 9.1. Definition of MCR, Extensions and Optimal Reaction Conditions 9.1. DefinitionFormally, of MCR, every Extensions reaction with and Optimalthree or more Reaction reaction Conditions partners is a multicomponent reaction. The Formally,difference every from reaction1CR and 2CR with is three easily or understood, more reaction while the partners overall is chemical a multicomponent reactions almost reaction. completely occur in the latter. Nature chose this pathway at a very early stage of evolution (Figure 2). All The differenceMCRs are from characterised 1CR and by 2CR the integration is easily understood,of all reaction partners while the(components overall chemicalC) in just one reactions reaction almost completelyproduct occur and, in to the put latter. it succinctly, Nature thus chose generate this pathway addition atreactions a very which early inherently stage of evolution do not show (Figure 2). All MCRsby-products. are characterised MCRs do not by easily the fit integration into the conventional of all reaction way of partnersthinking. Small (components molecules suchC) in as just one reactionH product2O can for and, example to put be released it succinctly, in the MCR. thus generateAn exact definition addition for reactions this effect which still does inherently not exist do not show by-products.today. MCR MCRs mechanisms do not have easily been fit partly into the clarified conventional but cannot way be of easil thinking.y reproduced Small molecules[35,109]. such Statistical models for the kinetics fail because while third or higher grade collisions are highly as H O can for example be released in the MCR. An exact definition for this effect still does not exist 2 improbable, MCRs nevertheless run smoothly and rapidly. The preferred interactions of the today. MCRindividual mechanisms components have with been each partly other are clarified often not but yet cannot fully understood be easily reproducedbut do deliver [overall35,109 very]. Statistical modelsfunctional for the kinetics reactions fail such because as the while Gewald third reaction. or higher The grade thermodyn collisionsamic assessment are highly of improbable, the MCRs MCRs nevertheless[110,111 run] generally smoothly results and in rapidly. a “temperate The preferredbalance” (cf. interactions Bach’s “Well of-Tempered the individual Clavier”) components where the with each otherreacti areon oftenenergies not are yet slightly fully negative, understood reactions but do are deliver self-propelled overall and very do not functional require intensive reactions such as the Gewaldthermal control. reaction. The The atomic thermodynamic balance of the MCRs assessment is usually of theexcellent MCRs because [110, 111all molecular] generally parts results in a “temperate balance” (cf. Bach’s “Well-Tempered Clavier”) where the reaction energies are slightly negative, reactions are self-propelled and do not require intensive thermal control. The atomic balance of the MCRs is usually excellent because all molecular parts remain present in the target molecule as structural elements. Variability, diversity and complexity of the target molecules are high [112,113] and can be controlled via the arrangement and nature of the MCRs. The distinct capacity for one-reactor syntheses also render MCRs fit for large-volume productions. Molecules 2017, 22, 349 13 of 32

Moleculesremain2017 present, 22, 349 in the target molecule as structural elements. Variability, diversity and complexity 13of of 32 the target molecules are high [112,113] and can be controlled via the arrangement and nature of the MCRs. The distinct capacity for one-reactor syntheses also render MCRs fit for large-volume productions. The efﬁciency of MCRs can be increased by extensions without adding additional reaction partners, The efficiency of MCRs can be increased by extensions without adding additional reaction partners, becausebecause functional functional groups groups are are present present inin thethe STM that react react in in Domino Domino-reactions-reactions with with the thenewly newly created created functionalfunctional groups groups in in the the MCR MCR as as post-condensation post-condensation modification modiﬁcation (PCM) (PCM) and and post post-condensation-condensation cyclisationcyclisation (PCC) (PCC) [87 [87,112,112–122–122].]. Scheme Scheme 1010 showsshows examples of of several several Tandem Tandem-U-4CR/Diels-Alder,-U-4CR/Diels-Alder, Knoevenagel,Knoevenagel, Heck Heck or or UDC UDC reactions reactions as as PCCsPCCs [[8787].

SchemeScheme 10. 10.Post-condensation Post-condensation cyclisationscyclisations (PCCs) of of an an Ugi Ugi-reaction.-reaction. [a] [a] UDC: UDC: Ugi Ugi deprotection deprotection cyclization.cyclization. BOC BOC (tert (tert-butoxycarbonyl)-butoxycarbonyl)protective protective group is is cleaved cleaved by by trifluoracetic triﬂuoracetic acid. acid.

Suitable solvents for MCRs are alcohols such as methanol and ethanol, water [123–125] and ionic liquidsSuitable (ILs)solvents [126–131], forPEG MCRs-based ILs are [132] alcohols. Unconventional such as solvents methanol [133] and such ethanol,as trifluoroethanol water [ 123[134–] 125] andwere ionic also liquids investigated. (ILs) [ 126Solvent–131-free], PEG-based MCRs [135,136 ILs] also [132 provide]. Unconventional good results. solvents [133] such as trifluoroethanolEven though [134 ] MCRs were also normally investigated. run without Solvent-free catalysts, MCRs there [ are135 special,136] also applications provide good for both results. variousEven though transition MCRs metal normally catalysts run[79,116,137 without–144 catalysts,] and organic there arecatalysts special [79,145 applications–148]. for both various transitionHigh metal pressure catalysts can [at79 times,116, 137improve–144] the and results organic of a catalysts few MCRs, [79 in,145 particular–148]. when domino-[4+2] orHigh domino pressure-[3 + 2] can cyclic at timesadditions improve follow the [149 results]. of a few MCRs, in particular when domino-[4 + 2] or domino-[3Various + 2]forms cyclic of additionsthe energy followcan be [transmitted149]. by excitation of certain bonds such as carbonyl or hydroxy and amino functional groups via: microwaves (MW) [38,150–153], infrared (IR) [154] and Various forms of the energy can be transmitted by excitation of certain bonds such as carbonyl ultrasound (US) [38,155]. They can cause rather substantial effects on the MCRs. In this regard, there or hydroxy and amino functional groups via: microwaves (MW) [38,150–153], infrared (IR) [154] and are some astonishing examples in connection to thermal energy [38]. ultrasoundGreen (US) concepts, [38,155 ].based They on can rational cause considerations, rather substantial are increasingly effects on theincluded MCRs. in InMCR this chemistry regard, there are some[124,133,156 astonishing–158]. There examples is a renaissance in connection of catalyst to thermal-free synthesis energy[ [12438].]. GreenAll these concepts, criteria based provide on very rational good conditions considerations, for saving are resources increasingly and energy, included as well in as MCR chemistryenvironmentally [124,133,156-safe– 158 and]. friendly There is technology a renaissance with of regards catalyst-free to the synthesis environment [124 and]. process and safetyAll these engineering. criteria Theprovide atom very balance good is conditions usually ideal. for The saving key resources criterion in and practice, energy, synthesis as well as environmentally-safeefficiency, is calculated and and friendly evaluated technology in the following with regards appropriate to the environment examples. and process and safety engineering. The atom balance is usually ideal. The key criterion in practice, synthesis efficiency, is calculated9.2. Several and Natural evaluated Products in the and following Drugs Syntheses appropriate via MCRs, examples. Their Features and Comparisons Some syntheses of natural products should contribute as examples to understanding the 9.2.simplification Several Natural of Productschemical andsynthesis. Drugs SynthesesEfficiencies via are MCRs, calculated Their following Features andthe Comparisonsmethod in Sections 8 andSome 10, the syntheses features ofof some natural individual products syn shouldtheses are contribute discussed asand examples amazing initiatives to understanding to finding the simplification of chemical synthesis. Efficiencies are calculated following the method in Sections8 and 10, the features of some individual syntheses are discussed and amazing initiatives to finding solutions for the concerted simplification of the synthesis chemistry are proposed. First, we will look at examples with a strong reduction of the number of steps. Molecules 2017, 22, 349 14 of 32 Molecules 2017, 22, 349 14 of 32 Moleculessolutions2017 for, 22 ,the 349 concerted simplification of the synthesis chemistry are proposed. First, we will look14 of 32 solutions for the concerted simplification of the synthesis chemistry are proposed. First, we will look at examples with a strong reduction of the number of steps. at examples with a strong reduction of the number of steps. 9.2.1.9.2.1. Nifedipine Nifedipine and and Xylocain Xylocain Syntheses Syntheses 9.2.1. Nifedipine and Xylocain Syntheses InIn the the ideal ideal case, case, synthesis synthesis chemistry chemistry should should produce produce aa compoundcompound inin oneone step.step. With nifedipine 5 In the ideal case, synthesis chemistry should produce a compound in one step. With nifedipine this5 this succeeded succeeded via via Hantzsch-3CR Hantzsch-3CR (Scheme (Scheme 11 11, Reaction, Reaction (1)) (1)) [[159159].]. An efficiency efficiency > >50%50% is is now now possible possible 5 this succeeded via Hantzsch-3CR (Scheme 11, Reaction (1)) [159]. An efficiency >50% is now possible forfor the the first first time. time. In In the the synthesis synthesis ofof xylocainexylocaine (6) the conventional conventional two two-step-step synthesis synthesis (2) (2) via via Ugi Ugi-3CR-3CR for the first time. In the synthesis of xylocaine (6) the conventional two-step synthesis (2) via Ugi-3CR isis reduced reduced to to one one step step (Reaction (Reaction (3)); (3)); with with halfhalf thethe numbernumber of steps steps,, the the yield yield of of 66 isis 80 80%% [101 [101]. ]. is reduced to one step (Reaction (3)); with half the number of steps, the yield of 6 is 80% [101].

SchemeSchemeScheme 11. 11.11.Simple SimpleSimple drugs drugs synthesessyntheses (1)(1) and ( (3)3) via via MCR MCR and and analog analogousousous reactionsreactions reactions (2).(2). (2).

9.2.2. Shortened Crixivan Synthesis 9.2.2.9.2.2. Shortened Shortened Crixivan Crixivan Synthesis Synthesis Another example for a strong reduction of steps using an MCR is present in the synthesis of the AnotherAnother example example for for a a strong strong reduction reduction ofof steps using an an MCR MCR is is present present in in the the synthesis synthesis of ofthe the HIV protease inhibitor crixivan. Using Ugi-4CR the important piperazine pharmacophore 8 could be HIVHIV protease protease inhibitor inhibitor crixivan. crixivan. Using Using Ugi-4CRUgi-4CR the important piperazine piperazine pharmacophor pharmacophoree 8 could8 could be be used as a component in the large scale synthesis of crixivan (7) by the Merck Company and so the usedused as as a componenta component in in the the large large scalescale synthesissynthesis of crixivan ( (77)) by by the the Merck Merck Company Company and and so sothe the numbernumber ofof stepssteps waswas reducedreduced by six steps from 18 down to 12 (33%) ((Scheme 1212)) [160,161[160,161].]. number of steps was reduced by six steps from 18 down to 12 (33%) (Scheme 12)[160,161].

SchemeSSchemecheme 12. 12.12.Important ImportantImportant piperazine piperazinepiperazine pharmacophorepharmacophore 88 forfor shorten shorteneded CrixivanCrixivan Crixivan synthesis.synthesis. synthesis.

In both the following syntheses in Sections 9.2.3 and 9.2.4, the focus is on the number of steps and yield of the synthesis with rational efﬁciency calculation. Molecules 2017, 22, 349 15 of 32

MoleculesIn 2017both, 22 the, 349 following syntheses in Sections 9.2.3 and 9.2.4, the focus is on the number of15 steps of 32 and yield of the synthesis with rational efficiency calculation.

9.2.3.9.2.3. EicteinascidinEicteinascidin 743743 TotalTotal SynthesisSynthesis TheThe keykey stepstep of of the the synthesis synthesis of of the the natural natural compound compound ecteinascidin-743 ecteinascidin-743 (12 ()12 is) ais U-4CR a U-4CR based based on Schemeon Scheme 13[ 16213 [162], delivering], delivering the Ugithe Ugi product product11 with 11 with a 90% a 90% yield. yield.

Scheme 13. Total synthesis of eicteinascidin 743. Scheme 13. Total synthesis of eicteinascidin 743.

2/3 (24 C-atoms) and a greater part of the scaffold of the target product 12 (36 C-atoms) are generated2/3 (24 in C-atoms)one step, presented and a greater together part with of the the scaffold concentrated of the synthesis target product capacity12 of(36 this C-atoms) U-4CR. areFor generatedthe rest of inthe one synthesis step, presented another together36 traditional with the steps concentrated (!) are needed. synthesis Luckily, capacity all synthesis of this U-4CR. data were For thecomplete rest of and the synthesisavailable in another the pu 36blication traditional [162] stepsso the (!) efficiency are needed. assessment Luckily, based all synthesis on this was data exact. were complete and available in the publication [162] so the efficiency assessment based on this was exact. The complete synthesis of 12 via 45 steps gives an overall yield of yoa = 0.076% and an efficiency The complete synthesis of 12 via 45 steps gives an overall yield of yoa = 0.076% and an efficiency of EffSynth = 0.0017%. That is extremely low, but the completely distinct distribution of the numbers ofon Eff theSynth synthesis= 0.0017%. sections That is is extremely more interesting: low, but thewhile completely it brings distinct the synthesis distribution of 9 ofand the 10 numbers and their on the synthesis sections is more interesting: while it brings the synthesis of 9 and 10 and their coupling coupling by means of U-4CR to 11 (and so 2/3 of the TM 12) with nine and eight steps at yoa = 44% by means of U-4CR to 11 (and so 2/3 of the TM 12) with nine and eight steps at yoa = 44% and and EffSynth = 5%, the values practically dwindle in the following 36 steps towards 12, yoa = 1.9%, EffSynth Eff= 0.053%.Synth = One 5%, recognises the values very practically clearly dwindlethe steep indecline the following caused by 36the steps outright towards destructive12, yoa influence= 1.9%, Effof theSynth high= 0.053%. number One of steps. recognises It would very be clearlyurgently the necessary steep decline to consider caused whether by the and outright how destructivethe number influenceof synthesis of the steps high could number be extremely of steps. Itredu wouldced beusing urgently higher necessary order MCRs to consider [163] and whether in particular and how their the numbercombined of synthesisapplications steps [164 could] and be tools, extremely such as reduced multi- usingcatalysis higher (Section order 5. MCRs3). [163] and in particular their combined applications [164] and tools, such as multi-catalysis (Section 5.3). 9.2.4. Smart Eurystatin Synthesis 9.2.4. Smart Eurystatin Synthesis This synthesis of natural product eurystatin (13) [165] is well matured and reasonably short This synthesis of natural product eurystatin (13)[165] is well matured and reasonably short thanks thanks to intelligent chemical reactions considerations. Except for an additional carbonyl function to intelligent chemical reactions considerations. Except for an additional carbonyl function group there group there is a cyclopeptide-derivative from alanine, leucine and ornithine, derivatized with 2- is a cyclopeptide-derivative from alanine, leucine and ornithine, derivatized with 2-isoocteneoic acid. isoocteneoic acid. The retrosynthesis already indicates a P-3CR being the precursor molecule in the The retrosynthesis already indicates a P-3CR being the precursor molecule in the synthesis (Scheme 14). synthesis (Scheme 14). The smart application of the thermodynamically driven O-N-acyl migration of the ornithin The smart application of the thermodynamically driven O-N-acyl migration of the ornithin derivative from the hydroxyl group in the Passerini product 14 to the vicinal amino group of the derivative from the hydroxyl group in the Passerini product 14 to the vicinal amino group of the alaninol to 15 saves several conventional synthesis steps (Scheme 15). Cyclisation of 15 by coupling alaninol to 15 saves several conventional synthesis steps (Scheme 15). Cyclisation of 15 by coupling after cleavage of Bn- and Z-residues succeed directly the ring closure of the eurystatin scaffold. The after cleavage of Bn- and Z-residues succeed directly the ring closure of the eurystatin scaffold. The efficiency balance can be presented as: overall yield yoa = 29%, eight steps, synthesis efficiency EffSynth = 3.6% and average yield yav = 86%. Molecules 2017,, 22,, 349 16 of 32 Molecules 2017, 22, 349 16 of 32 efficiency balance can be presented as: overall yield yoa = 29%, eight steps, synthesis efficiency EffSynthSynth = 3.6% and average yield yavav = 86%. As the the greater greater part part of the of thesynthesis synthesis consists consists of a classical of a classical protective protective groups based groups peptide based synthesis, peptide applicationsynthesis, application of multi-functional of multi-functional catalysis fromcatalysis Section from 5.3 Section (Scheme 5.34 )(Scheme could result 4) could in the result addition in thethe deletionaddition ofdeleti threeon steps of three down steps to five.down to five.

SchemSchemee 14. Retrosynthesis of eurystatin eurystatin,,, indication for P-3CR.PP--3CR.

Scheme 15. Smart P-3CR/deprotection/acyl-migration sequence inin thethe synthesis of eurystatin.. Scheme 15. Smart P-3CR/deprotection/acyl-migration sequence in the synthesis of eurystatin. 9.2.5. Tandem-U-4CR/IMDA/ROM-RCM Synthesis 9.2.5. Tandem-U-4CR/IMDA/ROM-RCM Synthesis This synthesis is an example of highest diversity and complexity of the target molecule, which throughthroughThis suitable suitable synthesis combination combination is an example (Scheme (Scheme of highest 16) 16) diversity of of a a U-4CR and,, complexity Domino Domino-Diels of the-Alder target and molecule, a ROM which-RCM throughreaction suitablein three combination steps via the (Scheme products 16 )16 of and a U-4CR, 17 generated Domino-Diels-Alder two annulated and azepinon a ROM-RCMe,, furanfuran reaction andand inpyrrol threee heterocyclic steps via the compounds products 16 in andproduct17 generated 18 [166] and two thus annulated delivered azepinone, the starting furan approach and pyrrole for a heterocyclicreliable concerted compounds simplification in product methodology18 [166] of and the thus synthesis delivered chemistry. the starting The efficiency approach data, for y aoa reliable = 41%, concertedEffSynthSynth = 14 simpliﬁcation%, are very good methodology withith regardsregards of toto the thethe synthesis outstanding chemistry. structural The result. efﬁciency data, yoa = 41%, EffSynth = 14%, are very good with regards to the outstanding structural result. Molecules 2017, 22, 349 17 of 32 Molecules 2017, 22, 349 17 of 32 Molecules 2017, 22, 349 17 of 32

SchemeScheme 16. 16. Tande Tandemm-U-U-4CR/IMDA/ROM-4CR/IMDA/ROM--RCMRCM synthesissynthesis. [a] Intramolecular DielsDiels--AlderAlder reaction. reaction. [b] [b] Scheme 16. Tandem-U-4CR/IMDA/ROM-RCM synthesis. [a] Intramolecular Diels-Alder reaction. RingRing opening opening metathesis metathesis——ringring closure closure metathesis.metathesis. [b] Ring opening metathesis—ring closure metathesis. 9.9.2.6.2.6. Multi Multi-Function-Function-Component-Component ReactionsReactions (MFCRs(MFCRs)) [H,I] 9.2.6. Multi-Function-Component Reactions (MFCRs) [H,I] TheThe intrinsic intrinsic extension extension of of MCRs MCRs leadsleads toto anan increaseincrease of functional groups ofof thethe MCRMCR and and hence hence anan increaseThe increase intrinsic in in functional functional extension density.of density. MCRs When leadsWhen to auto auto an increase--balancingbalancing of functional functional groups groups of such such the MCR as as amino amino and hence and and ancarboxyliccarboxylic increase infunctional functional functional groups groups density. in in amino Whenamino auto-balancing acidsacids (AA)(AA) areare functionalconcerned, groups the respectivespective such as aminofunctionalfunctional and group carboxylicgroup for for functionala areaction reaction groupsmust must first first in be aminobe released released acids or or (AA) activatedactivated are concerned, [48,167].[48,167]. the respective functional group for a reaction mustThis ﬁrstThis be is is released different different or from activated from the the [ orthogonal48 orthogonal,167]. highly highly active functional isocyanate isocyanate group group (strong (strong electrophile)electrophile)This is different and and isocyanide fromisocyanide the orthogonal (strong (strong nucleophile) highlynucleophile) active functional which within isocyanate one molecule molecule group (strong I I--II (isocyanato (isocyanato electrophile)-- andisocyanide)isocyanide) isocyanide are are (strong both both lookingnucleophile) looking for for suitablewhich suitable within partners partners one moleculefor the MFCR I-I (isocyanato-isocyanide) (multifunctionalonal component component are both lookingreaction).reaction). for For suitableFor the the nomenclature nomenclature partners for the ofof MFCR thethe MFCRMFCR (multifunctional referrefer toto [38,39]. component Scheme 17 reaction). introducesintroduces For thethe nomenclatureII--II 1919, ,which which ofisis the produced produced MFCRrefer from from to formamido [ formamido38,39]. Scheme--amineamine 17 introduces by by means means theof of phosgene I-I 19, which (Scheme is produced 5) 5) [H]. [H]. from Syntheses Syntheses formamido-amine of of Lysin Lysin-- byderivativesderivatives means of 20 phosgene20 und und 21 21 (Scheme succeedsucceed 5 in)in [H]. thethe Synthesessamesame manner.manner. of Lysin-derivatives 19 reacts in an additions/Passerini20 und 21 succeed reaction inreaction the same PP-- manner.5F4CR5F4CR and 19andreacts delivers delivers in an thethe additions/Passerini additions/Passeriniadditions/Passerini reactionproductproduct P-5F4CR22 with a and 92% delivers yield [39,168].[39,168]. the additions/Passerini TheThe increaseincrease ofof productdensitydensity 22 of of with functionsfunctions a 92% isyield is accompanied accompanied [39,168]. The by by increase a a grave grave of decrease decrease density of of functions synthesis is steps steps accompanied compared compared by with a with grave a a decreasesequentialsequential of synthesissynthesis synthesis [ stepsI].[I]. compared with a sequential synthesis [I].

Scheme 17. Multi-function-component reactions (MFCRs) [39]. SchemeScheme 17.17. Multi-function-componentMulti-function-component reactions (MFCRs) [[39]39]..

Molecules 2017, 22, 349 18 of 32 Molecules 2017, 22, 349 18 of 32 Molecules 2017, 22, 349 18 of 32 9.2.7.9.2.7. Telaprevir, Telaprevir Combined, Combined MCRs MCRs for for a a 50% 50%Shorter Shorter SynthesisSynthesis 9.2.7. Telaprevir, Combined MCRs for a 50% Shorter Synthesis TheThe HCV HCV NS3 NS3 proteaseprotease inhibitor telaprevir telaprevir (23 (23) )used used against against hepatitis hepatitis C could C could be synthesized be synthesized in inless less stepsThe steps HCV by by combining combiningNS3 protease a a Ugi Ugi-3CR,inhibitor-3CR, Passerinitelaprevir Passerini-3CR-3CR (23) andused and a against abiocatalysis biocatalysis hepatitis (Scheme (Scheme C could 18) 18 be )[[169]. synthesized169 ].Thus, Thus, the in the synthesissynthesisless steps route routeby combining could could be be shortened shorteneda Ugi-3CR, byby Passerini moremore thanthan-3CR 50%50% and vs.vs. a hithertobiocatalysis predominantly (Scheme 18) peptide peptide-chemical[169]. -Thus,chemical the synthesessynthesessynthesis [ route170 [170].]. could Particularly Particularly be shortened the “right” by more section than of of50% 2323 vs.couldcould hitherto be be led led predominantly by by stereoselective stereoselective peptide U U-3CR-3CRchemical and and stereoselectivestereoselectivesyntheses [170]. P-3CR P - Particularly3CR as as well well as as the enantioselective enantioselective “right” section enzymatic enzymatic of 23 could oxidation be led byon the stereoselectivethe shorter shorter road road U to to-3CR success. success. and stereoselective P-3CR as well as enantioselective enzymatic oxidation on the shorter road to success.

Scheme 18. Telaprevir synthesis by combined U-3CR/P-3CR/enzymatic catalysis. Scheme 18. Telaprevir synthesis by combined U-3CR/P-3CR/enzymatic catalysis. Scheme 18. Telaprevir synthesis by combined U-3CR/P-3CR/enzymatic catalysis. 9.2.8. One-step Syntheses of Oxazepinones from Carbohydrates and α-Amino Acids 9.2.8. One-step Syntheses of Oxazepinones from Carbohydrates and α-Amino Acids 9.2.8. One-step Syntheses of Oxazepinones from Carbohydrates and α-Amino Acids The strong dependence of carbohydrate chemistry on protective groups is well known [171], but The strong dependence of carbohydrate chemistry on protective groups is well known [171], MCRsThe like strong Ugi reactions dependence are iofnsensitive carbohydrate to hydroxy chemistry groups on protandective thus appropriate groups is well for knownapplication [171] with, but but MCRs like Ugi reactions are insensitive to hydroxy groups and thus appropriate for application carbohydratesMCRs like Ugi asreactions carbonyl are component insensitive toto savehydroxy mate groupsrial synthesis and thus steps. appropriate This has for been application achieved with in a withonecarbohydrates carbohydrates-step U-3CR/lactonisation as carbonyl as carbonyl component ofcomponent D-ribose to save to with savemate α material-rialamino synthesis acids synthesis steps. (AA) steps. This and has This ethyl been has iso achieved beencyanoacetate achieved in a α in(Schemeone a one-step-step 19) U- 3CR/lactonisation U-3CR/lactonisation[76,172], furnishing of oxazepinones D of-ribose D-ribose with with24 αin-amino yields-amino acidsof acidsaround (AA) (AA) 50% and and up ethyl ethylto 76 iso% isocyanoacetate. cyanoacetateThe syn/anti (Schemevalues(Scheme of 19 19)24)[ are 76[76,172, 17267/33],], furnishing tofurnishing 91/9. For oxazepinonestheoxazepinones mechanism 24of the in yields U-3CR of see around Scheme 50% 50% 11 Reactionup up to to 76 76%. %(3.). The The The syn/antirewardsyn/anti valuesofvalues this of highof 24 24- areareperformance 67/33 to to 91/9. 91/9.synthesis For For the is themechanism an mechanismexceptional of thely of Uhigh the-3CR efficiency U-3CR see Scheme see of Schemeup 11 toReaction 76 11%. Reaction (3). The reward (3). The rewardof this ofhigh this-performance high-performance synthesis synthesis is an exceptional is an exceptionallyly high efficiency high efﬁciency of up to of76%. up to 76%.

Scheme 19. Carbohydrate carbonyl in U-3CR/lactonisation one-step synthesis of oxazepinones. Scheme 19. Carbohydrate carbonyl in U-3CR/lactonisation one-step synthesis of oxazepinones. Scheme 19. Carbohydrate carbonyl in U-3CR/lactonisation one-step synthesis of oxazepinones. 9.2.9. Mild Esterification by P-3CR 9.2.9. Mild Esterification by P-3CR 9.2.9. MildThe presentation Esterification of by the P-3CR diversity of methodologies in the MCR domain is rounded off by the applicationThe presentation of the Passerini of the diversity reaction of which methodologies can solve soin the many MCR practical domain problems, is rounded notably off by the The presentation of the diversity of methodologies in the MCR domain is rounded off by esterifapplicationication of under the Passeriniextremely reaction mild conditions which can according solve so to many Scheme practical 20 Reaction problems, (1) [13,173 notably]. This the thereactionesterif applicationication enables under of simple the extremely Passerini and high mild reaction-yield conditions esterification which canaccording solve of readily soto manyScheme decomposing practical 20 Reaction problems, β-Lactam (1) [13,173 notablyantibiotics]. This the withreaction excellent enables yields. simple The and reaction high- yieldbetween esterification penicillin ofV- sulfoxidreadily edecomposing, chloral and terβ-Lactamt-butyl isocyanideantibiotics with excellent yields. The reaction between penicillin V-sulfoxide, chloral and tert-butyl isocyanide Molecules 2017, 22, 349 19 of 32 esterification under extremely mild conditions according to Scheme 20 Reaction (1) [13,173]. This β reactionMolecules 2017 enables, 22, 3 simple49 and high-yield esterification of readily decomposing -Lactam antibiotics19 with of 32 excellentMolecules 2017 yields., 22, 349 The reaction between penicillin V-sulfoxide, chloral and tert-butyl isocyanide produces19 of 32 0 0 0 0 theproduces penicillin-V-sulfoxide the penicillin-V- 1sulfoxide-tert-butylaminocarbonyl-2 1′-tert-butylaminocarbonyl,2 ,2 -trichlorethylester-2′,2′,2′-trichlorethylester26 as colourless 26 as colourl crystalsess produces the penicillin-V-sulfoxide 1′-tert-butylaminocarbonyl-2′,2′,2′-trichlorethylester 26 as colourless withcrystals a yield with of a 99%.yield Cleaving of 99%. Cleaving off the alkyl off the residue alkyl (Reaction residue (Reaction (2)) furnishes (2)) furnishes25 with a 25 yield with of a 62% yield [13 of]. crystals with a yield of 99%. Cleaving off the alkyl residue (Reaction (2)) furnishes 25 with a yield of The62% mechanism [13]. The mechanism of removal of works removal according works according to Scheme 1to. Scheme 1. 62% [13]. The mechanism of removal works according to Scheme 1.

Scheme 20. Application of P-3CR for esterification reactions. Scheme 20. Application of P P-3CR-3CR for esterification esterification reactions. 10. Synthesis-Efficiency of MCRs 10. Synthesis Synthesis-Efficiency-Efficiency ofof MCRsMCRs Naturally, all calculations in Section 8 apply fully to the MCR syntheses. Parallel reactions Naturally,Naturally, all calculations calculations in Section Section8 8apply apply fully fully to to the the MCR MCR syntheses. syntheses. Parallel Parallel reactions reactions originating from the synthesis of the precursors of the components C > 1 can be added. One 3CR can originating from the synthesis of the precursors ofof thethe componentscomponents CC >> 1 can be added. One 3CR can therefore have up to two, and one 4CR up to three, parallel reactions in their precursor syntheses. As therefore havehave up to two, and one 4CR up to three, parallel reactions in their precursor syntheses. As the parallel reactions are not sequential, they do not have a multiplier character regarding yields and thethe parallel reactions are not sequential, they do not have a multiplier character regarding yields and efficiency, but must be suitably included in the overall calculation, which is a summation. The partial efficiency,efficiency, butbut mustmust bebe suitablysuitably includedincluded inin thethe overalloverall calculation,calculation, whichwhich isis a summation. The partial sections (of the parallel reactions) are incorporated into the algorithm as weight-averaged yields of sections (of(of thethe parallelparallel reactions) reactions) are are incorporated incorporated into into the the algorithm algorithm as weight-averagedas weight-averaged yields yields of the of the arithmetic mean values of the parallel reactions. The number of steps is simply the sum of all arithmeticthe arithmetic mean mean values values of the of parallel the parallel reactions. reactions. The number The number of steps ofis steps simply is simply the sum the of allsum steps of all in steps in the respective section. The algorithm can be expressed as a mathematical equation for the thesteps respective in the respective section. Thesection. algorithm The algorithm can be expressed can be expressed as a mathematical as a mathematical equation forequation the synthesis for the synthesis efficiency as shown in Figure 6. efficiencysynthesis efficiency as shown inas Figureshown6 in. Figure 6.

Figure 6. Algorithm “Sythesis efficiencies including MCRs” phrased as mathematical equation. Figure 6 6.. Algorithm “S “Sythesisythesis efficienc efﬁcienciesies including MCRs” phrased as mathematical equation.

The quantitative synthesis efficiency EffSynth specifically refers only to the concrete criteria of The quantitative synthesis efficiency EffSynth specifically refers only to the concrete criteria of yieldThe and quantitative number of synthesis steps, and efficiency is therefore Eff particularlyspecifically reliable refers only and to independent the concrete criteria of other of “soft” yield yield and number of steps, and is thereforeSynth particularly reliable and independent of other “soft” andevaluation number criteria of steps, that and can is thereforecomplement particularly this value. reliable Regarding and independent the reaction of work other-up, “soft” MCR evaluation products evaluation criteria that can complement this value. Regarding the reaction work-up, MCR products criteriacan mostly that canbe easily complement isolated this and value. purified Regarding. The lack the of reaction akin products work-up, could MCR productsbe explained can mostlyby MCRs be can mostly be easily isolated and purified. The lack of akin products could be explained by MCRs nature as formal addition reactions and their “well-tempered” reaction enthalpies. The latter are the nature as formal addition reactions and their “well-tempered” reaction enthalpies. The latter are the result of a balanced system of several reaction-parts acting with each other (see Section 9.1). result of a balanced system of several reaction-parts acting with each other (see Section 9.1). Evaluating syntheses in Sections 9.2.1 to 9.2.9 in cumulo with regards to their over-all and Evaluating syntheses in Sections 9.2.1 to 9.2.9 in cumulo with regards to their over-all and embedded MCRs efficiencies and in comparison with each other, it is significantly evident, that MCRs embedded MCRs efficiencies and in comparison with each other, it is significantly evident, that MCRs are much more able than 2CRs, to generate main parts of complex products, as demonstrated in are much more able than 2CRs, to generate main parts of complex products, as demonstrated in Molecules 2017, 22, 349 20 of 32 easily isolated and purified. The lack of akin products could be explained by MCRs nature as formal addition reactions and their “well-tempered” reaction enthalpies. The latter are the result of a balanced system of several reaction-parts acting with each other (see Section 9.1). Evaluating syntheses in Sections 9.2.1–9.2.9 in cumulo with regards to their over-all and embedded MCRs efficiencies and in comparison with each other, it is significantly evident, that MCRs are much more able than 2CRs, to generate main parts of complex products, as demonstrated in Sections 9.2.2–9.2.5 and 9.2.7. Also, complete products can be synthesized in one-step MCRs, as shown in Section 9.2.1. Even highly diverse products are easily produced from simple and low-cost STMs by a one-step MCR, as evidenced in Section 9.2.8. Another progress has happened by synchronously running of two orthogonal reactions at the same molecule, presented in Section 9.2.6. The requirements of Green Chemistry are fulfilled, such as excellent atom-efficiency, the avoidance of waste, better performing compounds, eco-compatible solvents, renewable materials, and energy reduction.

11. Multicomponent Chemistry—The Future Section9 presents the diversity of prospects for MCR chemistry in a systematic (Schemes9 and 10) and a perspective manner using illustrative examples (Schemes 11–20 The multitude of reactions and their combinations with each other and within biology opens up the exponentially growing scope of reactions for this methodology [36,109,113,174]. If one links the exponential growth of potential MCRs with their intrinsic exponentially increasing numbers of products, one can quickly discern the unique potential of this methodology which enables the production and synthesis at will of molecules of whatever structure and quantity. Syntheses via the MCR methodology allow us to achieve what Nature has already been doing for a very long time in its tried and tested manner. In comparison, the possibly virtually unlimited number of products will be attained relatively fast. Part 2 of the chemical evolution (Figure2) lies ahead and this time humans are involved. How do we achieve the afore mentioned opportunities and goals?

1. Creation of further MCRs and MFCRs that can create numerous structural elements of chemical compounds and show high diversity. 2. Creation of further MCRs of a higher order (with as many components as possible) that will exponentially increase the variability and the quantity of products. 3. Creation of further MFCRs with as many functional groups as possible that will strongly increase the complexity of products in particular. 4. Combining MCRs with each other in a rational way and number thus making it feasible to extremely decrease the number of synthesis steps. 5. Creating an algorithm in order to verify procedures 1 through 4. 6. New tandem, domino and cascade reactions to extend the MCRs or their combinations, which will further strongly decrease the number of synthesis steps. This will result in double the reduction in steps in conjunction with the MCR combinations. 7. Process development of one-reactor synthesis as a tool to reduce the number of synthesis steps. 8. Multifunctional catalysts and multi-catalysis cascades (MCC) as tools to reduce the number of synthesis steps. 9. High pressure as tool for increasing scope and yield of certain MCRs. 10. Identifying and developing new tools to simplify production. 11. Rational and practice-based efﬁciency calculation in the prognosis of planned and the analysis of syntheses performed with a feed-back effect on synthesis optimisation.

In order to support the aforementioned concept, important known data will be determined:

12. Databases (e.g., SciFinder) with information about the target products and intermediates of the synthesis plan. Molecules 2017, 22, 349 21 of 32

13. Databases (e.g., SciFinder) about the applications of the planned MCRs and their scope and limitations. Synthesis data and synthesis protocols, references and details. 14. Drug Design & Discovery. 15. Specialist literature for understanding MCRs and their mechanisms, including probable mechanisms, in order to assess undesired side reactions.

With respect to 1: New and in particular novel MCRs [38,45,61,81,82,112,113,154,157,174–178] are the basis and guarantee for high diversity and therewith the capacity to produce many structurally-different compounds. A method has been found to design MCRs going from libraries of compounds to libraries of reactions [176]. With respect to 2: In order to obtain very high product quantities using the MCRs (libraries), MCRs of a higher order with component numbers >4 are particularly suitable [163], such as 5CR [179], 7CR [180] and 8CR [181]. Table5 shows the relationship between exponential components and product numbers.

Table 5. Calculated products as function of component C or function F numbers in MCRs.

MCR STM-sets MFCR 2 4 10 30 100 2CR 4 16 100 900 10.000 P-3CR 8 64 1000 27,000 1,000,000 U-4CR 16 256 10,000 810,000 100,000,000 P-5F4CR 32 1024 100,000 24,300,000 10,000,000,000 5CR 32 1024 100,000 24,300,000 10,000,000,000 7CR 128 16,384 10,000,000 21,870,000,000 100,000,000,000,000 8CR 256 65,536 100,000,000 656,100,000,000 10,000,000,000,000,000

With respect to 3: As much as possible high complexity can be obtained by as many as possible functional groups on the components of the MCR. Just one additional functional group already causes a new dimension in the scope of reactions [39,112,113,174,182]. Further to the functional density, one has to look at the reactivity. While passive “pairs” such as amino and carboxylic groups (AAs) first have to be activated, active “pairs” such as isocyanate-isocyanide are able to enter 2 different MCRs or reactions in a highly selective way (Scheme 17)[39]. With respect to 4: The well-planned combination of MCRs (unions) [170,182–185] opens up a further method for reducing the number of synthesis steps with simultaneous structural assembly based on a modular building concept, such as Scheme 18. With respect to 5: The relative reactivities of the functional groups of the MCRs are important criteria for an algorithm which is useful when looking for new MCRs including computer-aided methods [186]. Unexpected products lead to new MCRs. Algorithm-based methods for the discovery of novel multicomponent reactions [187,188]. With respect to 6: During MCR development, suitable domino reactions are also designed, creating indole and steroid alkaloids [122]. Functional π-systems [189], norbornene [190] and A3-coupling [115] with MCRs/domino reactions were deployed for DOS. Proline-catalysed domino reactions are used for the synthesis of heterocyclic groups using MCRs [117]. MCR/domino processes develop through rational design and serendipity [114]. With respect to 7: The advantages of MCR one-pot processes are demonstrated in several examples of the production of pharmaceutical products [164,191]. With respect to 7 + 8: Suitable multifunctional catalysis can greatly contribute to make low-step syntheses using MCR. This has been performed in one-pot sequential reactions [164]. Scheme4 shows another convincing example. The process reduces a classical synthesis sequence of the peptide chemistry from three steps down to one! The efficiency of the synthesis is three times higher than the 3-step synthesis. This is achieved using the switchable catalyst Molecules 2017, 22, 349 22 of 32 palladium-phthalocyanin. The method chosen can be generally and widely used for the synthesis of peptides, and can be repeated successively in a single reactor if necessary. With respect to 9: Some MCRs could only be performed when high pressure catalysis was applied [151]. MoleculesWith 2017 respect, 22, 349 to 11: Three multicomponent reactions, among them the Strecker reaction (without22 of 32 any catalyst), have proven to be very efficient in the generation of a diversity of polyfunctionalized moleculesthe synthesis [192 of]. nonsteroidal A review provides anti-inflammatory an overview drugs: of the exploitationMulticomponent of multicomponent reactions are more reactions efficient, for thecost synthesis effective ofand nonsteroidal economical anti-inflammatory than traditional methods drugs: Multicomponent[193,194]. reactions are more efficient, cost effectiveIn Section ands 8 economicaland 10 an algorithm than traditional has been methods developed [193 ,to194 calculate]. synthesis efficiency based on hardIn criteria Sections overall8 and yield10 an and algorithm steps of has a beensynthesis. developed The algorithm to calculate also synthesis takes para efficiencyllel reactions based and on hardMCRs criteria and delivers overall an yield exact and result steps of ofthe a efficiency synthesis. even The algorithmon comprehensive also takes and parallel complex reactions syntheses. and MCRsWith and respect delivers to 14: an exactMany result capabilities of the efficiencyand properties even onof MCRs comprehensive make them and particularly complex syntheses. suitable for DrugWith Design respect and to D 14:iscoveryMany capabilities[91,177,188,195, and196 properties] primarily of MCRs with makethe higher them order particularly MCRs, suitable which can for Drugeasily Designgenerate and very Discovery large libraries [91,177 as,188 Table,195 ,5196 clearly] primarily indicates with. The the availability higher order of MCRs MCRs, has which become can easilyso diverse generate that, very in combination large libraries with as Table each5 otherclearly and indicates. with post The condensation availability of modifications MCRs has become such so as diversetandem, that, cascade in combination or domino with reactions, each other we can and now with look post at condensation an extremely modifications high structural such diversity as tandem, of cascadeproducts. or domino reactions, we can now look at an extremely high structural diversity of products.

12.12. ConclusionsConclusions ResearchResearch resultsresults relating relating to to the the aforementioned aforementioned points points are are piling piling up up in thein the literature. literature. The The time time has nowhas now come come to coordinate to coordinate these these highly highly valuable valuable individual individual results results from from the the most most diverse diverse domains domains of organicof organic (Sections (Section3–s8 3)– and8) and MCR MCR chemistry chemistry (Sections (Section9–s 119–)11 in) in accordance accordance with with the the above-mentioned above-mentioned 1515 points-scheme,points-scheme, toto bundlebundle thethe alreadyalready strongstrong individualindividual effectseffects andand toto concentrateconcentrate onon thethe actualactual synthesis.synthesis. Under t thehe fulfilment fulﬁlment of of GreenGreen Chemistry Chemistry requirementsrequirements (S (Sectionection 10 10) )the the concerted concerted simplificationsimpliﬁcation of ofthe the chemical/biological chemical/biological synthesis synthesis (Figure(Figure 7) will7) willsubsequently subsequently take great take greatstrides, strides, providing providing mankind, mankind, science scienceand the andeconomy the economy with tailor with-made tailor-made and keenly and low keenly-cost low-cost materials, materials, drugs and drugs chemistry and chemistry libraries. libraries.

Figure 7. Solution of the discrepancy in Section Prologue in performing syntheses by concerted Figure 7. Solution of the discrepancy in Section Prologue in performing syntheses by concerted simplification in an elegant and highly efficient way. simpliﬁcation in an elegant and highly efﬁcient way.

13. Biographical Data of Heiner Eckert 13. Biographical Data of Heiner Eckert A. During my search for a thesis in the Faculty of Chemistry at the Technical University of Munich, A. During my search for a thesis in the Faculty of Chemistry at the Technical University of the newly appointed Professor Ivar Ugi, who wished to be on first-name basis, immediately offered Munich, the newly appointed Professor Ivar Ugi, who wished to be on first-name basis, immediately me several topics for selection, all based around his 4CC method, the Ugi four-component offered me several topics for selection, all based around his 4CC method, the Ugi four-component condensation. A novel protective group technique needed to be developed and integrated within the 4CC-based synthesis of peptides. Ugi had just brought this idea with him from California where he was still supervising several PhD theses at his former base, the University of Southern California. While there, he met his old friend Gerhard Schrauzer (Professor at the University of California) who was researching the synthetic function-analogous complexes of vitamin B12, the cobaloximes. As this interdisciplinary project fascinated me as a “greenhorn”, I enthusiastically accepted, not realising what it meant to gain a foothold as the sole participant in this project—a valuable experience! B. I had the idea, to employ the dye-stuff cobalt-phthalocyanine as “technical vitamin B12” into the project, and this opened self-reliant work for me, which was strongly supported by Ugi. Molecules 2017, 22, 349 23 of 32 condensation. A novel protective group technique needed to be developed and integrated within the 4CC-based synthesis of peptides. Ugi had just brought this idea with him from California where he was still supervising several PhD theses at his former base, the University of Southern California. While there, he met his old friend Gerhard Schrauzer (Professor at the University of California) who was researching the synthetic function-analogous complexes of vitamin B12, the cobaloximes. As this interdisciplinary project fascinated me as a “greenhorn”, I enthusiastically accepted, not realising what it meant to gain a foothold as the sole participant in this project—a valuable experience! B. I had the idea, to employ the dye-stuff cobalt-phthalocyanine as “technical vitamin B12” into the project, and this opened self-reliant work for me, which was strongly supported by Ugi. C. The ability of the new protecting groups technology which I developed to produce highly sensitive compounds such as β-lactam antibiotics (Figure3) made me very proud. These particular characteristics of the reduced metal-phthalocyanines, and their exceptional chemically reactive features, drew the interest of Bayer AG, who have since, together with Ugi and myself, registered various patents, both in the area of pigment production [14] and in the field of chemical semi-synthesis of β-lactam antibiotics [15,16]. The respective work at Bayer was stopped after the biochemical synthesis processes were established. This decision taken by the global player already shows the limits of practicability of classic chemical multi-stage synthesis. Meanwhile I achieved my doctorate as “Dr. rer. nat.” with the grade “summa cum laude” with Ugi. D. Up to this day I consider the switchable specificity of the catalyst PdPc between three partly orthogonal catalyst patterns with their multiple application patterns as a special highlight of my work in this domain. It constitutes the basis of the “Eckert Hydrogenation Catalysts” [20]. E. One of the first preparations on the agenda at the start of my thesis work was the production of several 100 g of a chlorocarbonic acid ester from phosgene and an alcohol. Concern was manifest and initial considerations for a substitute began to arise. But it took another 10 years before an opportunity appeared. During the production of diphosgene, a substitute for phosgene that had just arrived on the market, a small amount of white solid remained following distillation and I decided to analyze it instead of discarding it. F. These results encouraged me to sell triphosgene as a commercial phosgene substitute via my newly founded company Dr. Eckert GmbH and the chemicals trade reacted very rapidly, increasingly taking over distribution. After several years, China entered production and currently provides the entire world with thousands of tons of triphosgene. G. In order to be able to greatly extend the business activities of the company, I took an interested investor on board who shortly afterwards wanted to proceed doing business on his own. And thus, at the end of the millennium, I sold the company for a share in its profits to the investor. H. The very first and successful production of isocyanato-isocyanide really was the most exciting experience of my work history in chemistry. The contradictory existence of these compounds within one molecule was assumed to be impossible by many colleagues. Two such strong, but incompatible functional groups should not be able to coexist and would react with each other at very moment of formation. This made the analytical confirmation feel even sweeter. I. After a comprehensive and diverse research in chemistry done over three decades I had time to perform the overdue habilitation [25] achieving the “venia legendi” in chemistry at Technical University of Muenchen (TUM) at the age of 59 years (Figure8). J. After two years in pension I accepted the call of the biochemistry start-up-company BSAZ Biotech (Hangzhou) Ltd. in China to become its Vice President. In August 2015, I was presented with the “Quianjiang Friendship Award 2015” for foreign experts in the city of Hangzhou and the “West Lake Friendship Award 2015” of the government of Zheijang Province in October. Molecules 2017, 22, 349 23 of 32

C. The ability of the new protecting groups technology which I developed to produce highly sensitive compounds such as β-lactam antibiotics (Figure 3) made me very proud. These particular characteristics of the reduced metal-phthalocyanines, and their exceptional chemically reactive features, drew the interest of Bayer AG, who have since, together with Ugi and myself, registered various patents, both in the area of pigment production [14] and in the field of chemical semi- synthesis of β-lactam antibiotics [15,16]. The respective work at Bayer was stopped after the biochemical synthesis processes were established. This decision taken by the global player already shows the limits of practicability of classic chemical multi-stage synthesis. Meanwhile I achieved my doctorate as “Dr. rer. nat.” with the grade “summa cum laude” with Ugi. D. Up to this day I consider the switchable specificity of the catalyst PdPc between three partly orthogonal catalyst patterns with their multiple application patterns as a special highlight of my work in this domain. It constitutes the basis of the “Eckert Hydrogenation Catalysts” [20]. E. One of the first preparations on the agenda at the start of my thesis work was the production of several 100 g of a chlorocarbonic acid ester from phosgene and an alcohol. Concern was manifest and initial considerations for a substitute began to arise. But it took another 10 years before an opportunity appeared. During the production of diphosgene, a substitute for phosgene that had just arrived on the market, a small amount of white solid remained following distillation and I decided to analyze it instead of discarding it. F. These results encouraged me to sell triphosgene as a commercial phosgene substitute via my newly founded company Dr. Eckert GmbH and the chemicals trade reacted very rapidly, increasingly taking over distribution. After several years, China entered production and currently provides the entire world with thousands of tons of triphosgene. G. In order to be able to greatly extend the business activities of the company, I took an interested investor on board who shortly afterwards wanted to proceed doing business on his own. And thus, at the end of the millennium, I sold the company for a share in its profits to the investor. H. The very first and successful production of isocyanato-isocyanide really was the most exciting experience of my work history in chemistry. The contradictory existence of these compounds within one molecule was assumed to be impossible by many colleagues. Two such strong, but incompatible functional groups should not be able to coexist and would react with each other at very moment of formation. This made the analytical confirmation feel even sweeter. I. After a comprehensive and diverse research in chemistry done over three decades I had time to perform the overdue habilitation [25] achieving the “venia legendi” in chemistry at Technical University of Muenchen (TUM) at the age of 59 years (Figure 8). J. After two years in pension I accepted the call of the biochemistry start-up-company BSAZ Biotech (Hangzhou) Ltd. in China to become its Vice President. In August 2015, I was presented with the “Quianjiang Friendship Award 2015” for foreign experts in the city of Hangzhou and the “West Molecules 2017, 22, 349 24 of 32 Lake Friendship Award 2015” of the government of Zheijang Province in October.

FigureFigure 8. 8. HeinerHeiner Eckert Eckert at at the the laboratory laboratory [J] [J]..

Acknowledgments: Thanks to Fine Heininger (Denken & Handeln) and Madeleine P. Potganski (Kleine Einheit) for technical support with the manuscript. Conﬂicts of Interest: The author declares no conﬂict of interest.

References

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Sample Availability: Samples of the compounds Enkephalines: BOC-Tyr(tBu)-FemGly-FemGly-Phe-Leu-OtBu; H-Tyr-Gly-Gly-Phe-Leu-OH (Leu-enkephaline); Human-β-endorphin-sequences: BOC-Ala-Tyr-Lys(BOC)- Lys(BOC)-FemGly-Glu(tBu)-OtBu; H-Ala-Tyr-Lys-Lys-Gly-Glu-OH; H-Lys-Asp-Ala-Tyr-Lys-Lys-Gly-Glu-OH (Octapeptide [24–31]); Cyclopeptides: H-(FemGly)3-OH; TCBOC-(FemGly)5-OH; cyclo-(FemGly)5; cyclo-(Gly)5; Organo-cobaltphthalocyanines: PcCo-CH2CH2-OH; PcCo-CH2CH2-OCO-C6H5; are available from the author.

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