Ugi/Pictet-Spengler

El Kaim L, Gageat M, Gaultier L, Grimaud L (2007) New Ugi/Pictet-Spengler multicomponent formation of polycyclic tfiketopiperazines Irom isocyanides and a-keto acids. Synlett 3 500-502... 

Moreover, polycyclic indole alkaloid-type molecules 225 with a ketopiperazine were prepared by Wang et al. using Ugi-Pictet-Spengler process [68]. Ketocar-boxylic acids 227 were used as bifunctional substrates in Ugi reaction to yield lactams of varying ring sizes (Scheme 41). A diastereomer of hexacyclic indole derivative was crystallized and yielded X-ray diffraction suitable crystal to assign the stereochemistry. 

Another example of Ugi/Pictet-Spengler two-step procedure was employed by El Kaim et al. to prepare polycyclic 1,4-diketopiperazines 228 [69]. The four-component Ugi reaction of homoveratryl isocyanide 229 and a-ketocarboxylic acids 230 allows the formation of Ugi products, which were treated with trifluor-oactic acid to afford tricychc 2,5-diketopiperazines 228 in a Pictet-Spengler-type cyclization (Scheme 42). 

Scheme 42 Ugi/Pictet-Spengler formation of 2,5-diketopiperazine 228 and two representative 3D conformations of 228A (blue) and 228C (cyan)...

Scheme 2 El Kaims synthesis of DKPs using an Ugi/Pictet-Spengler combination...

El Kaim and coworkers introduced a new variation for the formation of polycyclic DKPs via Ugi/Pictet-Spengler multicomponent combination [35]. The reaction of homoveratryl isocyanide with different aldehydes, amines, and a-keto acids leads to the expected Ugi-adducts, which are not isolated. Addition of trifluoroacetic acid promotes a cyclodehydratation affording the tricyclic DKPs (Scheme 2). 

The diastereomeric mixture of l,3,4,6,7,lll>hexahydro-2/T-pyrazino LI, 2-bj isoqu inoline-1,4-d iones 497 was prepared in four-component Ugi/ Pictet-Spengler two-step procedure when aldehydes/ketones, a-ketoa-cids, 2-(3,4-dimethoxyphenyl)ethyl isocyanide and primary amines were stirred in MeOH, and then the evaporated reaction mixture in TFA (07SL500). 

In some of the examples, i.e., Ugi/Diels-Alder and Ugi/Pictet-Spengler, the reactions were performed in a single pot (although step-wise), but in the majority of the examples the Ugi intermediate was first isolated. 

M. A. Cano-Herrera, L. D. Miranda, Chem. Commun. 2011, 47, 10770-10772. Expedient entry to the piperazinohydroiso-quinoline ring system using a sequential Ugi/Pictet-Spengler/ reductive methylation reaction protocol. 

W. Wang, S. Ohio, E. Herdtweck, A. Domling, J. Org. Chem. 2011, 76, 637—644. Polycyclic compound by Ugi-Pictet-Spengler sequence. 

Almorexant is a first-in-class orexin receptor antagonist that was undergoing Phase III clinical trials for insomnia until 2011. The tetrahydroisoquinoline derivative was originally discovered from a series of Ugi/Pictet-Spengler reaction products. Originally developed by Actelion, from 2007 Almorexant was being reported as a potential... 

A general strategy towards praziquantel derivatives 217 was developed by Liu et al. based on an Ugi four-component condensation (Ugi-4CR) followed by a Pictet-Spengler cyclization (PS-2CR) [66]. The variations of the groups and sub-stitutents in these scaffolds arise from the four starting materials isocyanide 218, aldehyde 219, amine 214, and carboxylic acid 220 (Scheme 39). This process produces ketopiperazine fused ring systems that mimic the scaffold of praziquantel. 

Pauson-Khand cycloaddition Pictet-Spengler reaction Ugi four-component condensation Wittig reaction (and Homer-Emmons condensation)... 

The Pictet-Spengler reaction has been combined with Ugi multi-component chemistry to construct a number of polycyclic indoles. Isonitrile derivatives prepared from tryptamine (or methyl tryptophanate), a carboxylic acid and formaldehyde condense with aminoacetaldehyde diethyl acetal. A few examples employed substituted aldehydes [352]. 

More than 200 million people are worldwide affected by schistosomiasis, which is a neglected tropical sickness. Praziquantel 424 is currently the only drug approved against this disease. Domling and Khoury have reported a very short Ugi four-component reaction followed by Pictet-Spengler cyclization to obtain praziquantel 424 in greater than 75% yield (Scheme 6.64) [131]. Ninety percent of infected people live in sub-Saharan Africa where cheap preparations of drugs... 

SCHEME 6.64 Four-component Ugi reaction followed hy Pictet-Spengler cyclization to obtain praziquantel 424. 

Other reactions that have been applied in the Ugi postmodification strategy are the aza-Wittig reaction [80-84] and copper-catalyzed processes [85, 86], More recently, Domling and coworkers have developed a new approach for the synthesis of polycyclic compounds via Ugi MCR followed by a Pictet-Spengler reaction [87-89]. In 2011, apro-tocol for the rapid access to quinolin-2-(l//)-one scaffold was reported by a sequential 4-component Ugi-Knoevenagel condensation [90]. Hulme et al. have introduced a one-pot, two-step protocol for large-scale production of libraries of novel peptidomimetic-like fcM-pyrrolidinone tetrazoles via the Ugi-3CR-azide reaction of tethered keto ester methyl... 

The discovery synthesis of Almorexant starts with an Ugi three-component reaction (Ugi-3CR) between benzaldehyde (4), 2-(3,4-dimethoxyphenyl)ethanamine (5), and methyl isocyanide (6) affording product 7, which in a post-Pictet-Spengler reaction with 3-(4-(trifluoromethyl)phenyl)propanal (8) in the presence of strongly acidic conditions gives the end product Almorexant (9). Clearly, the synthesis is not stereoselective and yields four different stereoisomers, of which only one is biologically highly active (Scheme 15.3). 

Scheme 153 Discovery synthesis of Almorexant involving a one-pot Ugi-3CR and Pictet-Spengler-2CR reaction.

The latest and most convergent addition to the manifold PZQ-(76) syntheses was described by Cao and Domling (Scheme 15.26) [38]. This efficient synthesis employs, as a key step, an Ugi four-component reaction (U CR) between the readily available cheap starting materials phenylethyl isocyanide (84), formaldehyde (86), amino acetaldehyde dimethyl acetal (85), and cyclohexane carboxylic acid (87). The Ugi reaction gives the advanced intermediate 88 in quantitative yield under mild conditions. Compound 88 can be converted into PZQ-(76) by a Pictet-Spengler reaction under strongly acidic conditions. Overall, this short two-step process affords PZQ-(76) from inexpensive and readily available starting materials in 70% yield. 

Pictet-Spengler Reaction Sharpless Dihydroxylation Staudinger Reaction Ugi Four Component Condensation Weinreb Amide... 

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