# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 4 Ugi Four-Component Reaction (U-4 CR)
### \(\alpha\)-Acylamido Carboxamides with Four Diversity Positions  
#### 4.2.1 Amine Resin  
Whatman filter paper equipped with a photodeavable linker served as a planar cellulose support for the synthesis of small molecule macro-arrays [38]. First, cellulose filter paper was modified with a diamine spacer to enhance its reactivity (**138**, Scheme 29), followed by attachment of the photolabile linker 4-(4-(1-(Fmoc-amino)ethyl)-2-methoxy-5-nitrophenyl)butanoic acid (**139**). Modified cellulose **139** was then acylated with \(N\)-Fmoc-4-nitro-L-phenylalanine, which, upon cleavage of the Fmoc group (**140**), could be used for U-4 CR. It is important to note that the conversion at room temperature was poor, and neither a longer reaction time, multiple applications of reagents, nor microwave irradiation enhanced the yields. Finally, the rate of the Ugi reaction was successfully accelerated by water [87]. For the construction of a 96-membered macro-array, four aldehydes, six different carboxylic acids, and four isocyanides were chosen. The transformation was most sensitive to the nature of the aldehyde. While aliphatic aldehydes afforded the purest products, aromatic aldehydes were less effective. However, in all cases, the products were obtained in excellent purity. The authors speculated that the photodeavage efficiency was higher with the planar support than with PS beads. [PERSON] et al. developed the first stereoselective Ugi reaction on the solid phase using carbohydrate as a chiral auxiliary (Scheme 30) [19]. The synthesis sequence started with the laborious six-step preparation of the O-pivaloylated polymer-supported galactosylamine **145** and **146**. The Ugi reaction was performed at -40 \({}^{\circ}\)C in the presence of zinc chloride ethereate. The target products **151** were liberated with 10% TFA in DCM in the presence of anisole and were obtained in good yields and stereoselectivity. The diastereomeric ratios (D:L) of the products **151** ranged from 15:1 to 6:1, and both L- and D-isomers were isolated. The synthesis was also carried out on Merrifield hydroxymethyl resin. In this case, the resin-bound product was treated with DCM saturated with gaseous HCl in MeOH (3:1) to cleave the \(N\)-formyl and \(N\)-glycosidic bonds, releasing the amino acid amide **152**. The same amino acid amide **152** was also obtained from released product **151** upon treatment with HCl. Three years later, the same research group applied galactopyranosylamine as a chiral auxiliary in the diastereoselective U-4 CR synthesis of \(N\)-glycosated \(N\)-acylated \(\alpha\)-amino acid amides (Scheme 31) [20]. U-4 CC was carried out with resin-bound galactosylamine **153**, aldehyde, _tert_-butyl isocyanide, and formic acid in the presence of ZnCl\({}_{2}\). Similar to a previous report [19], the preparation of galactosylamine **153** was laborious. Importantly, the U-4 CC proceeded at ambient temperature (in comparison to the previously reported synthesis (Scheme 30)) [19] without any decrease in diastereoselectivity. The final cleavage was accomplished with TBAF in THF buffered with acetic acid (method A). In the case of intermediates **157** composed of EWG-containing benzaldehyde only, the products were obtained by treatment with a non-basic HF-pyridine complex (method B). The products were obtained in high yield, purity, and diastereoselectivity (di diastereomeric ratio (dr) was from 96:4 to 74:26), and the TBAF cleavage caused partial epimerization. Resin-bound galactosylamine **153** was further employed for the synthesis of piperidinones as a core structure in natural products. A library comprised of 1344 compounds of thymidinyl and 2'-deoxyuridineyl nucleoside-peptides was prepared by the Ugi reaction [72]. The library for antibacterial screening was prepared in fourteen 96-well Flexchem filter plates. The synthesis sequence started with the attachment of 5'-azadinucleoside to commercial PS/DVB-immobilized butyl diethylsilane **159** (Scheme 32).