Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously. This kind of addition and reaction has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects. All these advantages, together with the high level of stereoselectivity attained in some of these reactions, will force chemists in industry as in academia to adopt this new strategy of synthesis, or at least to consider it as a viable option. The positive aspects as well as the drawbacks of this strategy are discussed in this Review.

Asymmetric multicomponent reactions (amcrs): the new frontier

Chiral nitrogen-containing compounds are widely distributed in nature and include many biologically important molecules (Chart 1). In these compounds, the nitrogen-containing units are known to play important roles for their bioactivities. For the synthesis of these chiral nitrogen-containing building blocks, use of imines as electrophiles is the most promising and convenient route.1 While many approaches using chiral imines or chiral nucleophiles have been reported,1 these diastereoselective reactions have some disadvantages. First, the procedures to introduce chiral auxiliaries to substrates and to remove them after the diastereoselective reactions are often tedious. Second, more than stoichiometric amounts of chiral sources are needed to obtain chiral compounds according to these reactions. On the other hand, catalytic enantioselective reactions provide the most efficient methods for the synthesis of chiral compounds,2 because large quantities of chiral compounds are expected to be prepared using small amounts of chiral sources. While much progress has been made recently in catalytic enantioselective reactions of aldehydes and ketones such as aldol,3 allylation,4 Diels-Alder,5 cyanation reactions,6 reduction,1b,2b etc., progress in catalytic enantioselective reactions of imines is rather slow. There are some difficulties in performing catalytic enantioselective reactions of imines. For example, in the cases of chiral Lewis acid promoted asymmetric Shū Kobayashi was born in 1959 in Tokyo, Japan. He studied chemistry at the University of Tokyo and received his Ph.D. in 1988 (Professor T. Mukaiyama). After spending 11 years at Science University of Tokyo (SUT), he moved to Graduate School of Pharmaceutical Sciences, University of Tokyo, in 1998. His research interests include development of new synthetic methods, development of novel catalysts (especially chiral catalysts), organic synthesis in water, solid-phase organic synthesis, total synthesis of biologically interesting compounds, and organometallic chemistry. He received the first Springer Award in Organometallic Chemistry in 1997.

https://chemistry.mdma.ch/hiveboard/picproxie_docs/000499541-cr980414z.pdf

Catalytic enantioselective addition to imines.

Multicomponent reactions (MCRs) receive increasing attention because they address both diversity and complexity in organic synthesis. Thus, in principle diverse sets of relatively complex structures can be generated from simple starting materials in a single reaction step. The ever increasing need for optically pure compounds for pharmaceutical and agricultural applications as well as for catalysis promotes the development of asymmetric multicomponent reactions. In recent years, asymmetric multicomponent reactions have been applied to the total synthesis of various enantiopure natural products and commercial drugs, reducing the number of required reaction steps significantly. Although many developments in diastereoselective MCRs have been reported, the field of catalytic enantioselective MCRs has just started to blossom. This critical review describes developments in both diastereoselective and catalytic enantioselective multicomponent reactions since 2004. Significantly broadened scopes, new techniques, more environmentally benign methods and entirely novel MCRs reflect the increasingly inventive paths that synthetic chemist follow in this field. Until recently, enantioselective transition metal-catalyzed MCRs represented the majority of catalytic enantioselective MCRs. However, metal contamination is highly undesirable for drug synthesis. The emergence of organocatalysis greatly influences the quest for new asymmetric MCRs.

Recent developments in asymmetric multicomponent reactions.

Stereoselective synthesis of quaternary α-amino acids. Part 1: Acyclic compounds

Asymmetric Strecker Reactions

Die [S]-α-Methyl-aminosauren 16, 17 und 18 lassen sich mit Hilfe des [4S; 5S]-(+)-5-Amino-2.2-dimethyl-4-phenyl-1.3-dioxans (des [S; S]-Enantiomeren von 2), das in grosen Mengen bei der Chloramphenicol-Synthese als Zwischenprodukt anfallt, in 80–90proz. Ausbeute nach Strecker synthetisieren. Da diese asymmetrische Strecker-Synthese mit dem [R; R]-Enantiomeren von 2 zu den entsprechenden [R]-α-Methyl-aminosauren fuhrt, ist sie stereospezifisch. Die in der ersten Stufe der Synthese auftretenden Aminonitrile 7, 8 und 9, in denen das Chiralitatszentrum der Endprodukte bereits gebildet ist, zeigen beim Stehenlassen in Losung eine asymmetrische Umlagerung 1. Art. Das Gleichgewicht der Diastereomeren, das sich nach 24 Stdn. eingestellt hat, wird NMR-spektroskopisch und chemisch quantitativ bestimmt. Durch Verseifung der Aminonitrile sofort nach ihrer Entstehung wird bewiesen, das das neue Chiralitatszentrum durch asymmetrische Synthese gebildet wird. Die Konstitutionen der Zwischenprodukte werden aufgeklart und die Mechanismen der ausgefuhrten Reaktionen diskutiert. Die allgemeine Anwendbarkeit der Synthese wird untersucht.



Asymmetric Synthesis, II. The External Asymmetric Strecker Synthesis of α-Methyl-aminoacids



The [S]-α-methyl-aminoacids 16, 17 and 18 can be obtained in 80–90% yields by the Strecker synthesis from [4S; 5S]-(+)-5-amino-2.2-dimethyl-4-phenyl-1.3-dioxane (the [S; S]-enantiomer of 2), which is available in large quantities as an intermediate in the chloramphenicol synthesis. This asymmetric Strecker synthesis is stereospecific as it gives the corresponding [R]-α-methyl-aminoacid when it is carried out with the [R; R]-enantiomer of 2. The aminonitrils 7, 8 and 9 of the first step of the synthesis containing the centre of chirality of the end products, undergo a first order asymmetric transformation standing in solution. The equilibrium of diastereomers being formed after 24 hours is n.m.r. spectroscopically and quantitatively established. Saponification of aminonitrils immediately after they have been formed indicates that the new centre of chirality is fromed by asymmetric synthesis. The constitutions of intermediate products have been established and the reaction mechanisms discussed. The general applicability of the synthesis is under investigation.

Asymmetrische Synthesen, II. Die externe asymmetrische Strecker‐Synthese von α‐Methylaminosäuren

Bei der asymmetrischen Strecker-Synthese mit (S)-(−)-1-Phenylethylamin als chiralem Hilfsreagens konnen die α-Methyl-α-aminonitrile 1–6 stereochemisch einheitlich in hoher Ausbeute (70–90%) isoliert werden. Der stereochemische Verlauf dieser Reaktionen zeigt eine Abhangigkeit von der Substitution der eingesetzten Arylalkyl-methyl-ketone, die dem bei Verwendung von (4S,5S)-(+)-5-Amino-2,2-dimethyl-4-phenyl-1,3-dioxan als chiralem Hilfsreagens vollkommen gegensatzlich ist2). Die Konfiguration am neugebildeten Chiralitatszentrum in 1–6 wird nicht durch die Lange der C-Kette beeinflust; dagegen tritt Konfigurationswechsel ein, wenn der Phenylrest der Ausgangsketone durch Methoxygruppen substituiert ist. Die optisch reinen α-Methyl-α-aminonitrile aquilibrieren in Losung. 1 –6 lassen sich nicht mit Salzsaure, sondern nur mit konz. Schwefelsaure verseifen. Aus 1, 3 und 4 entstehen die entsprechenden α-Methyl-α-aminosauren 14 – 16, wahrend die Verseifung von 2 und 5 zu uneinheitlichen Produkten fuhrt. 6 ergibt das Cyclisierungsprodukt 17.



Asymmetric Syntheses, IV. On the Asymmetric Strecker Synthesis with (S)-(−)-1-Phenylethylamine as Chiral Handle



Asymmetric Strecker synthesis with (S)-(−)-1-phenylethylamine as chiral handle affords stereochemically homogenous α-methyl-α-aminonitriles 1 –6 in high yields (70–90%). The stereochemical course of these reactions shows a dependance on the substitution of the employed arylalkyl methyl ketones which is absolutely contrary to that observed when (4S,5S)-(+)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane is used as the chiral handle2). The configuration at the newly formed center of chirality in 1 –6 is not affected by the length of the C-chain whereas a change in configuration occurs if the phenyl rings of the starting ketones are substituted by methoxy groups. The optically pure α-methyl-α-aminonitriles equilibrate in solution. 1 –6 are saponified by conc, sulfuric acid but not by hydrochloric acid. 1, 3, and 4 yield the respective α-methyl-α-amino acids 14–16, while saponification of 2 and 5 leads to inhomogenous products. 6 yields the cyclisation product 17.

Asymmetrische Synthesen, IV. Über die asymmetrische Strecker-Synthese mit (S)-(−)-1-Phenylethylamin als chiralem Hilfsreagens

Alkylmethylketone 1 werden mit [4S; 5S]-(+)-5-Amino-2,2-dimethyl-4-phenyl-1,3-dioxan (2) und Natriumcyanid/Eisessig in Methanol zu den Aminonitrilen 3 umgesetzt und uber die Lactone 4 in die entsprechenden optisch aktiven α-Methyl-α-aminosauren 5 ubergefuhrt. Durch Vergleich der ORD-Kurven von 5 mit denen bereits bekannter, strukturell ahnlicher Aminosauren wird ihre absolute Konfiguration bestimmt. Beim Einsetzen von Ketonen 1 mit geradzahliger Kohlenstoffkette im Alkylrest R entstehen α-Methyl-α-aminosauren 5 mit S-Konfiguration, wahrend Ketone 1 mit ungeradzahliger Kohlenstoffkette im Alkylrestes R α-Methyl-α-aminosauren 5 mit R-Konfiguration liefern. Bei Verzweigungen des Alkylrestes R in 1 ist die Anzahl der Kohlenstoffatome der langsten Kette masgebend. Die Konfiguration der α-Methyl-α-aminosauren 5, die aus den Aminonitrilen 3 entstehen, last sich aus der chemischen Verschiebung der Protonen dcr α-Methylgruppe von 3 voraussagen. Uber den stereochemischen Reaktionsverlauf bei der Bildung des neuen Chiralitatszentrums kann bisher keine Aussage gemacht werden.



Asymmetric Synthesis, III. Asymmetric Strecker Synthesis of Aliphatic α-Methyl-α-amino Acids



Alkyl methyl ketones 1 react with [4S; 5S]-(+)-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane (2) and sodium cyanide/acetic acid in methanol to yield aminonitriles 3. The latter are transformed via the lactones 4 into the corresponding optically active α-methyl-α-amino acids 5. Comparison of the ORD curves with those of known structurally similar amino acids makes it possible to determine the absolute configuration of 5. When ketones 1 having an even number of carbon atoms in the alkyl-chain R are used as starting materials, α-methyl-α-amino acids 5 with S-configuration are obtained, whereas ketones 1 with an uneven number of carbon atoms yield 5 with R-configuration. In the case of branched residues in 1 the configuration is dependent on the number of carbon atoms in the longest chain. The configuration of α-methyl-α-amino acids 5 formed from aminonitriles 3 may be predicted from the chemical shift of the I-methyl group in 3. It is not yet possible to give an interpretation of the stereo chemical course of the formation of the new center of chirality.

Berthold Stemmle

Papers

Asymmetrische Synthesen, II. Die externe asymmetrische Strecker‐Synthese von α‐Methylaminosäuren

Asymmetrische Synthesen, IV. Über die asymmetrische Strecker-Synthese mit (S)-(−)-1-Phenylethylamin als chiralem Hilfsreagens

Asymmetrische Synthesen, III. Die asymmetrische Strecker-Synthese von aliphatischen α-Methyl-α-aminosäuren

Asymmetric syntheses. iv. the asymmetric strecker synthesis with (s)-(-)-1-phenylethylamine as chiral handle

Asymmetrische synth. 3. mitt. die asymmetrische strecker-synth. von aliphatischen alpha-methyl-alpha-aminosaeuren