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.

Indoles in multicomponent processes (MCPs).

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit

Asymmetric domino reactions. Part A: Reactions based on the use of chiral auxiliaries

In the past decade, the asymmetric synthesis of chiral nonracemic isoquinoline alkaloids, a family of natural products showing a wide range of structural diversity and biological and pharmaceutical activity, has been based either on continuation or improvement of known traditional methods or on new, recently developed, strategies. Both diastereoselective and enantioselective catalytic methods have been applied. This review describes the stereochemically modified traditional syntheses (the Pictet–Spengler, the Bischler–Napieralski, and the Pomeranz–Fritsch–Bobbitt) along with strategies based on closing of the nitrogen-containing ring B of the isoquinoline core by the formation of bonds between C1–N2, N2–C3, C1–N2/N2–C3, and C1–N2/C4–C4a atoms. Methods involving introduction of substituents at the C1 carbon of isoquinoline core along with syntheses applying various biocatalytic techniques have also been reviewed.

Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015

The first enantioselective syntheses of the Ipecacuanha alkaloid emetine (1) and the Alangium alkaloid tubulosine (2) is described employing a domino Knoevenagel/hetero-Diels-Alder reaction and an enantioselective catalytic transfer hydrogenation of imines as key steps. Thus, hydrogenation of the imine 15 with the catalyst (R,R)-16 gives the tetrahydroisoquinoline 14 with 95 % ee which was transformed into the aldehyde (1S)-7. The three-component domino reaction of (1S)-7 with 6 and 8 led to 19, which in a second domino process was treated with K(2)CO(3) in methanol followed by a hydrogenation to give the benzoquinolizidine 4 together with the diastereomers 22 and 23 in a overall yield of 66 %. Further transformation of 4 with the amines 3 and 5 yielded enantiopure emetine (1) and tubulosine (2), respectively. In addition, starting from 19 the novel benzoquinolizidine alkaloid 34 was synthesised; this compound resembles the vallesiachotamine alkaloid dihydroantirhin 31, which has not been isolated so far but probably must also exist in nature.

Enantioselective Total Syntheses of the Ipecacuanha Alkaloid Emetine, the Alangium Alkaloid Tubulosine and a Novel Benzoquinolizidine Alkaloid by Using a Domino Process

I. Müller

Papers

Enantioselective Total Syntheses of the Ipecacuanha Alkaloid Emetine, the Alangium Alkaloid Tubulosine and a Novel Benzoquinolizidine Alkaloid by Using a Domino Process