# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 5 U-4 CR Followed by Cyclative Cleavage
### Diketopiperazines  
Diketopiperazines were synthesized via the Ugi reaction either on classical solid-phase support (resin beads) [6, 45, 46], or on cellulose filter paper [62]. Two different approaches leading to diketopiperazines were reported by [PERSON] et al. [46]. The first one involved a five-step synthetic sequence (not included in this review), while the second one utilized U-4 CC followed by cyclative cleavage (product **213**, Scheme 37) and afforded products in higher yields. Two solid supports were tested, namely, 4-(hydroxymethyl)phenylacetamidomethyl (PAM) **207** and TentaGel S-OH **208** resins. The latter polymer afforded the products in higher yields, while the reaction on PAM resin required DCE as a cosolvent. The yields were mostly dependent on the aldehyde. While the aliphatic aldehydes reacted within minutes, aromatic aldehydes and ketones (not shown in the scheme) required a reaction time of several hours. It is important to note that the Ugi reaction tolerated hindered amino acids, such as valine, in contrast to the classical approach consisting of a five-step synthetic sequence. The authors also synthesized diketomorpholines (cf. Scheme 45).  
The Ugi/deBoc/cyclization (UDC) strategy, first reported by [PERSON] and coworkers [91], was applied for the synthesis of a 400-membered library of diketopiperazines intended as luminescence inhibitors of the bacterial symbiont Vibrio fischeri [62]. Cellulose membrane ([PERSON] chromatography paper) **137** was used as a solid support, and neither a spacer nor a linker was required to attach the first BB, Fmoc-\(\alpha\)-amino acid (Scheme 38). Deprotection of the amino group (**214**) was followed by U-4 CR with five different Boc-\(\alpha\)-amino acids, four aldehydes, and four isocyanides. Linear Ugi-product **218** triggered acid-mediated Boc cleavage, which was followed by spontaneous cyclative cleavage to produce target diketopiperazines **219**. Gaseous ammonia was used to deprotonate the amino group.  
**Scheme 38. SPS of diketopiperazines via the UDC strategy.**A 576-member library of spirodiketopiperazines as potent, selective CCR5 antagonists, was readily prepared through U-4 CR [45]. Two different isocyanide resins (**40** and **57**, Scheme 39) were based on aminomethyl and Rink amide resins, respectively. In the Ugi reaction, cyclative cleavage of monocyclic precursors **223** and **224** was induced at elevated temperature in the presence of acetic acid. To expand the diversity at the R1 position, an Alloc-protected piperidinone was incorporated (resin **223a**). The Alloc-protecting group was removed, the secondary amine was reductively alkylated with an aldehyde (resin **226**), and the product was released upon Boc removal. For hit identification, the Ugi reaction was performed with eight piperidinones, nine amines, and eight amino acids to prepare a 576-member library. The synthesis was also studied in the solution phase.  
Universal Rink-isocyanide resin **57** (Scheme 40) was utilized for U-4 CR, leading to diketopiperazines **231**[6]. U-4 CR yielded linear resin-bound \(\alpha\)-acylamino carboxamides **230**, which was deprotected. Cyclative cleavage in 10% AcOH in DCE at elevated temperature led to the desired diketopiperazines **231** with excellent purity. The formation of benzodiazeppines **258** and 5-substituted \(1H\)-tetrazoles **433** was also investigated (cf. Schemes 44 and 73, respectively).