Convertible isocyanide-resin

The use of resin-bound convertible isocyanides such as the universal Rink isocyanide-resin [18], the safety-catch linker isocyanide-resin [8b, 19] the cyclo-hexenyl isocyanide-resin [8b], and the carbonate convertible isocyanide-resin [20] has found interesting applications in solid-phase Ugi-4CR and post-condensation transformations [21] (Scheme 2.9). 

Cyclohexenyl Isocyanide-resin Carbonate Convertible Isocyanide-resin... 

Scheme 2.48. Diketopiperazines from carbonate convertible isocyanide resin.

Such a strategy follows the philosophy of resin capture, as introduced by Armstrong and Keating Keating TA, Armstrong RW. Postcondensation modifications of Ugi four-component condensation products 1-isocyano-cyclohexane as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc 1996 118 2574-2583. See also Brown SD, Armstrong RW. Synthesis of tetrasubstituted ethylenes on solid support via resin capture. J Am Chem Soc 1996 118 6331-6332. 

Gilley CB, Kobayashi Y (2008) 2-nitrophenyl isocyanide as a versatile convertible isocyanide rapid access to a fused y-lactam (3-lactone bicycle. J Org Chem 73 4198 204 Chen JJ, Golebiowski A, Klopfenstein SR, West L (2002) The universal Rink-isonitrile resin applications in Ugi reactions. Tetrahedron Lett 43 4083 085 Hulme C, Peng J, Morton G, Salvino JM, Herpin T, Labaudiniere R (1998) Novel safety-catch linker and its application with a Ugi/De-BOC/Cyclization (UDC) strategy to access carboxylic acids, 1, 4-benzodiazepines, diketopiperazines, ketopiperazines and dihydroqui-noxalinones. Tetrahedron Lett 39 7227-7230... 

Keating, T. A. Armstrong, R. W. Postcondensation Modifications of Ugi Four-Component Condensation Products 1-Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture, J. Am. Chem. Soc. 1996, 118, 257. 

The convertible isocyanide also enables transformation of the secondary amide in the Ugi product to a carboxylic acid, ester, or thioester, which is thus amenable to further functionalization. The aforementioned templates are all readily accessible via manufacture in 96-well plates using 96-well plate liquid handlers. The initial condensations are optimal with excess aldehyde (2 equiv.), which can be subsequently removed via a simple scavenging and filtration step with PS-TsNHNH2.18 Several universal resin-bound isocyanides have also been developed to exploit UDC methodology for the generation of the above heterocyclic products. 

The Kennedy group at Array BioPharma described an elegant synthesis of 2,5-diketopiperazines employing the resin-bound carbonate convertible isocyanide (CCI resin see Scheme 2.9) [20], Ugi products 133 were converted into esters 134 and then deprotected and transformed into diketopiperazines 135 (Scheme 2.48). 

Another example was reported by Ugi and co-workers in a study concerning the synthetic applications of convertible (jS-isocyanoethyl)alkyl carbonates [7a]. A solid-phase extension of the same procedure has been reported by the Kennedy group [20] at Array BioPharma who employed the resin-bound carbonate convertible isocyanide. 

A solid-phase extension of the UDC strategy for the preparation of highly pure and diverse arrays of l,4-benzodiazepine-2,5-diones has been reported. The method employed Wang resin-bound a-amino adds [75]. Another interesting solid-phase synthesis of l,4-benzodiazepine-2,5-diones was reported by Chen et al. [18b] that employed the Rink-isocyanide resin as the convertible isocyanide. 

The selected example by Keating et al. [39] reported the use of resin capture on a small solution model library (five individuals) produced by Ugi 4CC using a "convertible isocyanide (details for this library synthesis were given in the section on multiple-component condensations), as is described in Figure 15. A slight excess of the final cyclohexenamides was incubated with the support under anhydrous HC1/THF for 5 h at 55°C, then the resins were washed repeatedly and cleaved with 20% TFA in DCM for 20 min at room temperature. The cleavage solutions resulted to be the pure carboxylic acids (quantitative yields and >95% HPLC purities). 

TA Keating, RW Armstrong. Postcondensation modifications of Ugi four-component condensation products 1-isocyanocyclohexene as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc 118 2574-2583, 1996. 

It can be easily synthesized from Fmoc-protected rink resin 306 by Fmoc deprotection using 20% piperidine followed by formylation using formic acid (5 equivalents), pyridine (1 equivalent), and diisopropylcarbodiimide (5 equivalents). The rink resin formamide 8p can be converted to the desired CIC Izi by treating with POCI3 and MA -diisopropylethylamine (DIEPA) at 0°C (Scheme 7.95). The rink resin isocyanide Izc is odorless and stable under refrigeration over a period of 12 months. Furthermore, the process provides an excellent yield and quality of the product on a larger scale (50 g). 

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