Ugi-deprotection-cyclization

The combination of pept(o)id-introducing MCRs with subsequent and efficient post-condensation transformations, especially ring-closing protocols, is an efficient concept to produce (cyclic) pseudopeptides. The most important versions make use of protected or convertible functional building blocks to allow later condensation, specially cycfization. Most relevant are Ugi-deprotection-cyclization (UDC), Ugi-activation-cyclization (UAC), and the Ugi-deprotection-activation-cycfization (UDAC), which take advantage of the diverse functionalities incorporated into the previously synthesized MCR-adduct as bi- or polyfunctional building block (Fig. 3) [15, 16]. 

Scheme 2.60. Imidazo[l,5-o]imidazoles via Ugi-4CR/carbonyl deprotection/cyclization.

Similarly, Hulme and co-workers [184] have described an U-4CR under microwave-assisted conditions of an A/ -Boc-anthranilic acid, n-butylisonitrile, an aldehyde, and an amine resulting in the formation of the Ugi products 133 that were further used in the UDC-protocol (Ugi reaction-Deprotection-Cyclization) for lead finding (Scheme 103). 

More recently, Fei and coworkers have employed the Ugi/deprotection/activation/ cyclization strategy for their synthesis of DKPs 191 using CIC IW3 (Scheme 7.66) [74] Anhydrous HCl, which forms in situ, helps deprotect the Boc group and activates the amide carbonyl group derived from IW3. 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

Hulme et al. describes the novel use of ethyl glyoxalate in the Ugi-4CR to create ketopiperazines [31]. iV-alkylated/Boc-protected ethylene diamines 60 reacted with an isocyanide 61, a carboxylic acid 62, and ethyl 2-oxoacetate 63 in stoichiometric ratio of 1/1/1/1.25 in methanol. Deprotection and cyclization is completed using TFA and MP-carbonate (a macroporous polystyrene... 

Hulme et al. describes the use of a convertible isonitrile for the generation of a ketopiperazine library (Scheme 12) [32]. Using a mono-A -Boc diamine 68 in the classical Ugi reaction followed by Boc deprotection and base-facilitated cyclization (3 steps, 1 pot) afforded the ketopiperazine 72 in relatively high yields. 

Wyatt et al. describes the use of C- and M-protected amino acids to synthesize DKPs (Scheme 15) [35]. An M-protected amino acid 87, an aldehyde 88, a C-protected amino acid 89, and an isocyanide 90 are used to form the Ugi intermediate 91, followed by deprotection and cyclization with TFA and triethylamine. 

Rhoden CRB, Rivera DG, Kreye O, Bauer AK, Westermann B, Wessjohann LA (2009) Rapid Access to N-substituted diketopiperazines by one-pot Ugi-4CR/deprotection -I- activation/ cyclization (UDAC). J Comb Chem 11(6) 1078-1082... 

Fig. 3 The three most common modes to activate linear Ugi-products for cyclization, especially if the cyclization involves Ugi-reactive groups (e.g., acid, oxo-compound, or amine). Activation is mostly achieved with convertible isonitriles, i.e., activated amides (see text). Other MCRs follow similar concepts. With orthogonal second functionalities for cyclizations such deprotection and/or activation is not required (see below, e.g., RCM or cycloadditions)...

The Hulme group has reported two three-step, one-pot solution-phase procedures for the preparation of 2,5-diketopiperazines, based on the UDC strategy. The first method [74a] used ethyl glyoxylate as a bifunctional carbonyl input in an Ugi-4CR with amines, isocyanides, and N-Boc a-amino acids that afforded adducts 121, which were N-deprotected and cyclized to the desired products 122 (Scheme 2.44). The second method [8c] used Armstrong s convertible isocyanide 1 in a reaction with N-Boc a-amino acids, aldehydes, and amines that afforded products 123, which were deprotected and cyclized to diketopiperazines 124 (Scheme 2.44). 

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). 

The Ugi-4CR between cyclic ketones, primary amine hydrochlorides, potassium thiocyanate (or selenocyanate), and 2,2-diethoxyethyl isocyanide [91] afforded the spiro 2-thio-(or seleno)hydantoin-4-imines 166. On heating in acetic acid, compounds 166 underwent carbonyl deprotection and cyclization to spiro imidazo[l,5-ajimidazoles 167 (Scheme 2.60). 

A mixture of an F-Boc-protected diamine with a slight excess of benzoic acid, aldehyde, and isonitrile in MeOH was subjected to MW irradiation for 10-20 min at 100 °C to give the linear Ugi product 39. Subsequent deprotection of the amine group (de-Boc) induced cyclization and the final product 38 was formed after 10-20 min, again under MW irradiation, now in TFA-THF (1 1). The reaction mixture was purified by fiuorous solid-phase extraction (F-SPE) and afforded 38 in up to 67% yield. 

For example, reaction of the chiral N- and C-protected amino acid derivatives 62 and 63, respectively, with tert-butyl isocyanide 64 and benzaldehyde 65 yields the Ugi product 66. N-deprotection and cyclization under basic conditions yields the two stereoisomers 67 (R,R,R) and 68 (R,R,S), differing in the benzaldehyde-derived stereocenter. The two diastereomers can be conveniently separated using silica chromatography (Scheme 15.21). 

Carbonyl protection and deprotection is also important. Yoshihisa Kobayashi of the University of California, San Diego has devised (/. Org. Chem. 2007, 72, 3913) the isonitrile 15. Usually, the product 16 after Ugi condensation would he very difficult to hydrolyze. In the case of 16, mild acid effected cyclization to the acyl indole 17, which was easy to hydrolyze. In a different approach, Francesco Naso of the Universita di Bari has shown (Chem. Commun. 2007, 3756) that acid chlorides such as 18 condensed with 19 to give the furan 20. Such fiirans are easily oxidized, liberating the starting acid. 

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