Three-component Passerini reaction

L. Banfi and co-workers utilized the Passerini three component reaction to prepare a 9600 member hit generation library of nor-statines. " ° These compounds are potential transition state mimetics for the inhibitors of aspartyl proteases. The authors produced the library by starting out from eight A/-Boc-a-aminoaldehydes, twenty isocyanides and sixty carboxylic acids. The key Passerini reaction occurred under mild conditions. This transformation was followed by removal of the Boc protecting group and acyl transfer. Three representative examples of the library are shown. 

Just as in one at a time synthesis, linear syntheses are the most risky and produce the lowest yields. Converging methodologies address these limitations successfully, and in combinatorial work, Ugi (four-component) and Passerini (three-component) reactions are very flexible and popular. Generally one has less control over the specific products being produced by such reactions but this is largely compensated for by the molecular diversity available in this way. 

The divalent carbon of isocyanide has a pronounced nucleophilicity and undergoes readily a-addition to nucleophiles and electrophiles (Scheme 15.9). This chemical property is the basis of the Passerini three-component reaction (Eq. (1), Scheme 15.6) and the Ugi four-component reaction (Eq. (2), Scheme 15.6). However, the two aforementioned a-isocyanoacetate-based three-component reactions (cf. Scheme 15.7 and Scheme 15.8) were both initiated by the nucleophilicity of the a-carbon. The question one could ask is can we initiate the reaction sequence by taking advantage of the nucleophilicity of the isocyano function using similar substrates It is conceivable that, if the sequence can be initiated by the nucle-ophihcity of the isocyanide, a different reaction manifold wiU be induced leading to a different multicomponent adduct. 

Wang S-X, Wang M-X, Wang D-X et al (2008) Catalytic enantioselective Passerini three-component reaction. Angew Chem Int Ed 47 388-391... 

As an example supporting the above statements regarding parallel reaction steps, parallel reactions of isocyano-isocyanate 1752b at both the isocyano and iso-cyanato groups can be accomplished in a one-pot procedure, whereby methanol is added to the isocyanato group and a Passerini three-component reaction (P-3CR) with benzaldehyde and acetic acid occurs at the isocyano group, simultaneously affording both the urethane and Passerini product moieties in l-N-(0-methyl-carbamato)-10-N -[(2-acetoxy)-3-phenylacetamido]decane 1753 in 92% yield [1289]. 

Ruijter and coworkers elegantly combined stereoselective MCR chemistry with biocatalysis to obtain telaprevir 47, which is a pharmaceutical drug (Incivek or Incivo ) for the treatment of hepatitis C (Scheme 6.4) [21]. In the fu-st step, a Passerini three-component reaction gives access to form 42, which is, upon treatment with NMM (A-methyhnorpho-line) and triphosgene, converted to isocyanide 43. The latter further reacts with the pyrroUne derivative 45 (arose from the desymmetrization of the 3,4-disubstituted meso-pyrro-lidine with monoamine oxidase-N (MAO-N, derived from... 

O-ALKYLATIVE AND SILYLATIVE PASSERINI THREE-COMPONENT REACTIONS... 

SCHEME 8.1 The classical Passerini three-component reaction. 

Metal-Catalyzed O-Alkylative Passerini Three-Component Reactions... 

A. A. Esmaedi, S. A. Ghalandarabad, S. Jannati, Tetrahedron Lett. 2013, 54, 406-408. A novel and efficient synthesis of 3,3-disubstituted indol-2-ones via Passerini three-component reactions in the presence of 4 A molecular sieves. 

J. Brioche, G. Masson, J. Zhu, Org. Lett. 2010,12,1432-1435. Passerini three-component reaction of alcohols under catalytic aerobic oxidative conditions. 

F. Leon, D. G. Rivera, L. A. Wessjohann, J. Org. Chem. 2008, 73, 1762-1767. Multiple multicomponent macrocychzations including bifunctional building blocks (MiBs) based on Staudinger and Passerini three-component reactions. 

S.-X. Wang, M.-X. Wang, D.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 2008, 47, 388-391. Catalytic enantioselective Passerini three-component reaction. 

P-3CR Passerini three-component reaction TS transition state... 

A retrosynthetic analysis of 24 using an MCR sequence is presented in Scheme 15.8. The required starting materials for the key Ugi-type 3CR were the carboxylic acid 25, cyclic imine 26, and isocyanide 28. The acid 25 could be accessed by standard peptide chemistry, while imine 26 was generated in situ from the commercially available 27 by catalytic oxidation with the enzyme MAO-N (monoamine oxidase N) from Aspergillus niger. The isocyanide 28 was accessed via a Passerini three-component reaction (P-3CR) of 29,30, and acetic acid. 

The construction of the isocyanide fragment 28 was done in three steps in which a Passerini three-component reaction (P-3CR) played a key role. Commercial (5)-2-amino-l-pentanol (32) was transformed to formamide 33 by A-formylation. Following the work of Ngouansavanh and Zhu [19], the group was able to combine... 

Isocyanide derivatives are undoubtedly the most important reactants in MCRs because they show both nucleophilic and electrophilic characters within a single functionality. For example, IMCRs include the Ugi four-component reaction (Ugi-4CR) [11, 12], the Passerini three-component reaction (Passerini-3CR) [10], the Groebke-Blackbum-Bienayme reaction [44—46], the van Leusen three-... 

Keywords Biocompatible hydrogels Complex architectures Functionalized vinyl monomers lanus-type dendrimers Modular nature Passerini three-component reaction PEGylation of proteins Photo-responsive polymers Sequence-defined structures Tailor-made materials Ugi four-component reaction... 

Sehlinger A, de Espinosa LM, Meier MAR (2013) Synthesis of diverse asymmetric a,co-dienes via the Passerini three-component reaction for head-to-tail ADMET polymerization. Macromol Chem Phys 214(24) 2821-2828... 

Li L, Kan X-W, Deng X-X, Song C-C, Du F-S, Li Z-C (2013) Simultaneous dual end-functionalization of PEG via the Passerini three-component reaction for the synthesis of ABC miktoarm terpolymers. J Polym Sci Part A Polym Chem 51(4) 865-873... 

Solleder SC, Meier MAR (2014) Sequence control in polymer chemistry through the Passerini three-component reaction. Angew Chem hit Ed 53(3) 711-714... 

Jee J-A, Spagnuolo LA, Rudick JG (2012) Convergent synthesis of dendrimers via the Passerini three-component reaction. Org Lett 14(13) 3292-3295... 

Kreye O, Kugele D, Faust L, Meier MAR (2014) Divergent dendtimer synthesis via the Passerini three-component reaction and olefin cross-metathesis. Macromol Rapid Commun... 

The Passerini three-component reaction, discovered in 1921, involves the condensation of carbonyl compounds, carboxylic acids, and isocyanides to afford the corresponding a-acyloxy carboxamides [22]. Among several advantages are the... 

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