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). 

Universal Rink Isocyanide-resin Safety Catch Linker Isocyanide-resin... 

Chen and co-workers at Procter and Gamble developed a traceless synthesis of 2,5-diketopiperazines [18b] by employing the universal Rink-isocyanide resin. The Ugi-4CR between the resin, aldehydes, amines, and N-Fmoc-protected a-amino acids afforded the resin-bound dipeptide derivatives 131 which were N-deprotected on treatment with piperidine in DMF. Cyclization by heating with 10% AcOH in DCE smoothly provided the desired diketopiperazines 132 in good yields (Scheme 2.47). 

Scheme 2.48. Diketopiperazines from carbonate convertible isocyanide resin.

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. 

An alternative approach towards the PASP synthesis of isocyanides was developed by Bradley [100,101]. It involved the use of a polymer-supported sul-fonyl chloride in the presence of base to afford the dehydration of formamides (Scheme 21). The formamides required could be easily prepared by reaction of the corresponding amines with a formylated benzotriazole resin. Opti-... 

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. 

For the preparation of the 2,5-diketopiperazines 9-57 and 1,4-benzodiazepine-2,5-diones 9-58, respectively, the isocyanide 9-54 was either treated with an aldehyde and an amino acid, or with an aldehyde and an anthranilic acid, to give either 9-55 or 9-56, using the conditions depicted in Scheme 9.11. Further transformations include liberation from the resin with KOtBu forming N-acyloxazolidones and treatment with NaOMe to afford the corresponding esters, which are then cy-clized to the desired products 9-57 and 9-58 under acidic conditions. 

Multicomponent Ugi reaction a resin-bound amino acid is reacted with an aldehyde, isocyanide, and a second amino acid in a one-pot reaction to form the Malkylated cyclic precursor dimer. ... 

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... 

The cyclization completes within 2-4- h, and the purified product 55 is obtained in 65-75% yield. The solid phase synthesis is conducted with the same starting materials however, resin bound isocyanide is used and yields are greater than 90% based on the resin loading. 

The scope and limitations of the solid-supported symthesis of bicyclic diketopi-perazines 165 as peptide p-tum mimetic were further investigated by Golebiowski et al. [52]. The four-component Ugi reaction of a-iV-Boc-diaminopropionic acid resin ester 160 (an amine input) and optically active a-bromoacid 163 with various isocyanides 166 and aldehydes 167 yields a series of bicyclic diketopiperazines 165 (Scheme 28). 

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. 

They produced an 18-member library of a-acylamino amides, in acceptable to high yields and purity, from a variety of isocyanides, aldehydes and carboxylic acids by using an amino-functionalised TentaGel resin (TentaGel S RAM). The developed procedure represents a rapid and efficient way of synthesising a-acylamino amides, simplifying the tedious purifications, which can usually accompany multi-component reactions. 

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. 

An example of this strategy is shown in Scheme 1.32 [82, 84], On varying the isocyanide, the dienophile, the amine and the furaldehyde, analogues of 91 could be obtained in 70-89% yields and with drs between 83 17 and 92 8. This Ugi/ IMDA tandem methodology has been employed also in the solid phase, by anchoring the amine component to a suitable resin [82, 84]. 

Analogously, the reaction between phenylglyoxal, isobutylamine, n-butyl isocyanide, and benzoic acid afforded 3-oxo-3-phenylpropanoic amide 85 which was cy-clized to diphenylimidazol-5-carboxamide 86 in very high yield (Scheme 2.31) [60], The procedure was extended to solid-phase synthesis by employing resin-bound isocyanides. Wang resin was preferred to Rink resin because of its stability. The reaction of the resin-bound isocyanides 87 with supporting Ugi reagents afforded the... 

The Hulme group also developed an interesting resin-bound isocyanide, the safety-catch linker (Scheme 2.9), which was employed in the synthesis of sev-... 

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). 

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