And the Passerini reaction

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

Many protease/peptidase inhibitor peptidomimetics include a-ketoamide moieties as key bioactive functionalities and the Passerini reaction provides a facile entry for their preparation through the oxidation of a-hydroxy amides. Researchers at Schering-Plough have utilized this strategy to synthesize a variety of a macrocyclic a-ketoamides towards the development of Hepatitis C virus (HCV) NS3 protease inhibitors. Aldehyde 56 was treated with allylisocyanide and acetic acid to give a-acyloxyamide... 

Another approach that has been used in combinatorial chemistry is the use of a one-pot reaction such as the well-known Ugi multicomponent reaction " and the Passerini reaction. Multicomponent reactions are reactions in which three or more reactants come together in a single reaction vessel to form a new product that displays aspects of all the components. The reactions may be carried out in solution or on a solid support. ... 

The sequential use of the organocatalytic a-amination of aldehydes by azodicar-boxylates with another process has provided a useful tool for the synthesis of complex molecules. Thus, the combination of the amination of linear aldehydes catalyzed by (5)-proline (20) and the Passerini reaction allowed the rapid access to norstatine based peptidomimetics albeit with low diastereoselectivities (36-98% yield, up to 4 1 dr) [27]. Moreover, the enantioselective synthesis of y-amino-a,P-unsaturated esters can be performed via the sequential a-amination-Homer-Wadsworth-Emmons olefination of aldehydes catalyzed by (5)-proline (20,10mol%) affording the expected products in high yields and enantioselectivities (85-90% yield, ee 92-99%) [28]. 

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. The following mechanism has been postulated ... 

The first MCR involving isocyanides (IMCR) was reported in 1921 with the Passerini reaction (P-3CR) [8], and over the years these reactions have become increasingly important and have been highlighted in several publications (for discussions, see below). Another older MCR which leads to (non-natural) a-amino acids is the Bucherer-Bergs reaction (BB-4CR), which was first reported in 1929 [9]. This type of transformation is closely related to the Strecker reaction, with C02 employed as a fourth component. 

It should be mentioned that the Passerini reaction has also been used by Marcac-cini s group to prepare p-lactams [24], oxazoles [25], and furanes [26]. Natural products have also been accessed using this procedure as one of the key steps. The syntheses of azinomycin by Armstrong [27] and eurystatin A by Schmidt [28] represent two good examples of this procedure. 

Bossio R, Marcaccini S, Pepino R (1991) Synthesis of isocyanides and related compounds. Synthesis of oxazole derivatives via the Passerini reaction. Liebigs Ann Chem 1107-1108... 

Because of the retained isocyano functionality, the dihydropyridone MCR product 85 can be used in various follow-up (multicomponent) reactions. For example, the Passerini reaction between 85, a carboxylic acid, and an aldehyde or ketone produces a series of dihydropyridone-based conformationally constrained depsipeptides 86 [171]. The subsequent Passerini reaction could also be performed in the same pot, resulting in a novel 6CR toward these complex products containing up to seven points of variation. Reaction of 85 with an aldehyde or ketone and amine component resulted in the isolation of dihydrooxazolopyridines (DHOPs, 87) [172] via a similar approach as the 2,4,5-trisubstituted oxazole variant toward 42 reported by Tron and Zhu (Fig. 15) [155]. The corresponding DHOPs (87), which... 

The Passerini reaction is a condensation between a carbonyl, a carboxylic acid and an isocyanide to form an ot-acyloxycarboxamide (Scheme 1) [5],... 

D. Marquarding, G. Gokel, P. Hoffmann u. I. XJgi, The Passerini Reaction and Related Reactions, in I. 

Utilizing a postcondensation modification of the Passerini reaction,48 both Banff and workers at Amgen49 recognized the potential for a one-pot, two-step transformation to produce nor-statines with the general structure 104 containing three points of potential diversity. Recognizing their... 

Scheme 13. Application of the Passerini reaction for the preparation of nor-statines. Reagents and conditions (i) 0.1 M solutions in MeOH, 18 h, RT, then PS-TsNHNH2 in CH2C12. (ii) Ten percent trifluoroacetic acid (TFA) in CH2C12. (iii) PS-iV-me thy I morphol i lie in CH2C12.

Finally a fourth way to achieve asymmetric induction in the Passerini reaction is by way of a chiral catalyst, such as a Lewis acid. This approach is not trivial since in most cases the Lewis acid replaces the carboxylic acid as third component, leading to a-hydroxyamides or to other kinds of products instead of the classical adducts 7 (vide infra). After a thorough screening of combinations of Lewis acids/ chiral ligands, it was possible to select the couple 13 (Scheme 1.6), which affords clean reaction and a moderate ee with a model set of substrates [17]. Although improvements are needed in order to gain higher ees and to use efficiently sub-stoichiometric quantities of the chiral inducer, this represents the first example of an asymmetric classical Passerini reaction between three achiral components. 

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

The Passerini reaction between a-chloroketones, isocyanides, and carboxylic acids afforded a-acyloxy-jS-chlorocarboxamides 52, which, on treatment with an excess of powdered KOH in tetrahydrofuran, underwent O-deacylation followed by a Darzens-type O-alkylation to give the functionalized oxiranes 53. When carboxamides 52 were treated with an excess of CsF, with or without a phase-transfer catalyst, a different ring closure took place to afford 3-acyloxy-2-azetidinones 54 in high yields (Scheme 2.21) [46]. 

Davidson s synthesis consists of the cydization of a-acyloxyketones with ammonia or ammonium acetate to give 2,4,5-trisubstituted oxazoles. The Passerini reaction between arylglyoxals, carboxylic acids, and isocyanides afforded N-substituted 2-acyloxy-3-aryl-3-oxopropionamides 83 in high yields. Upon heating with an excess of ammonium acetate in acetic acid, compounds 83 were cydized to N,2,4-trisubstituted oxazole-5-carboxamides 84 in fair yields [59]. A large number of a-acyloxy-jS-ketoamides can be prepared by changing the reaction components, so the method provides straightforward access to a variety of oxazole-5-carboxamides (Scheme 2.30). 

In summary, the Passerini reaction (and related modifications) are beginning to find utility in the drug discovery process, albeit confined to lead generation and... 

The Passerini reaction is a useful method for the synthesis of substituted a-acyloxy carbocyclic acids. This is another reaction that one might assume an epoxide would not survive. Reaction of an epoxy aldehyde with benzoic and TosMIC provided the Passerini product in good yield as a mixture of diastereomers <07SL83>. 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

The Passerini reaction is typically carried out at high concentrations of starting materials in aprotic solvents (generally DCM), at or below room temperature. The reaction shows a high substrate scope and variation of all three components is extensively possible. 

Since the Passerini reaction is accelerated in aprotic solvents, it is assumed that the reaction follows a nonionic pathway. The most plausible mechanism of the reaction is depicted in Scheme 2 ([25] and see for review [26] [13]). 

Probably one of the first examples of SRR is performed by Ugi and co-workers, who replaced the carbonyl component 6 of the Passerini reaction by a different electrophile, i.e., imine 47, which resulted in the well-known Ugi reaction affording 13 (Scheme 6) [29]. 

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