Synthesis cyclic ureas

Intramolecular trapping was also possible, as exemplified by the synthesis of cyclic ureas (Eq. 53) [275] and oxazolidin-2-ones [232,234] (Eqs. 54 and 55). 

Since the most common group of 1,3-diazocines is related to cyclic urea 104 (called, for example, perhydro-l,3-diazocine-2-one or N,N -pentamethyleneurea), a separate section is devoted to the synthesis, chemistry, and applications of 104, substituted 104, and related molecules such as thiourea 105, guanidines 106, and carbodiimide 107. 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

Molecular models suggest that such a P -connection between remote alkenyl residues in a dimer is possible. To check whether it really occurs under the conditions of the metathesis reaction, we synthesized the monoloop tetra-urea compounds 16, in which one of the non-cyclic urea residues is substituted by a bulky group which cannot penetrate the loop (Scheme 5.18). (The synthesis is analogous to that of 15, introducing in the final two steps the bulky residue first.). 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

Nefzi A, Ostresh JM, Meyer JP, Houghten RA, Solid phase synthesis of heterocyclic compounds from linear peptides cyclic ureas and thioureas, Tetrahedron Lett., 38 931-934, 1997. 

Buprofezin / A, / S (Cyclic urea) ) N NC(CH,j)3 N 0 CH(CHj)2 Probable chitin synthesis and prostaglandin inhibitor. Hormone disturbing effect, leading to suppression of ecdysis... 

Petersen, H., Synthe,ses of cyclic ureas by o-urcidoalkylation. Synthesis, 243, 1973. 

A convenient method for the synthesis of 2-imidazolines with long-chain alkyl or aralkyl substituents at C-2 involves heating a carboxylic acid with a suitable cyclic urea (or thiourea) (Scheme 92) (B-57MI40800). 

In recent years, many more studies were devoted to the synthesis of thienopy-rimidinones and their derivatives. There are two types of such structures depending on the position of the C = O group, viz., the A structure containing the amide group and the B structure, a cyclic urea. 

A MW-assisted protocol for the direct synthesis of cyclic ureas has been developed that proceeds expeditiously in the presence of ZnO (Scheme 8.19). 

The cycHc urea moiety provides structural rigidity as well as hydrogen-bonding possibihties similar to those of the imidazoles described above. The corresponding 2-imidazolones have been prepared on a soHd phase by tandem aminoacylation of a resin-bound allylic amine with an isocyanate followed by intramolecular Michael addition [73]. However, due to the paucity of data presented on the characterized compounds and the brief experimental procedure, this synthesis is not discussed in detail. Access to cyclic ureas or thioureas has also been obtained by reaction with carbonyl- or thiocarbonyldiimidazole through a cyclo-release mechanism [74—76]. 1,3-Dihydroimidazolones have been obtained by treatment of ureido acetals with TFA and subsequent conversion in an intramolecular cyclization via an N-acyliminium ion [77]. 

Acid-induced reactions of silicon-containing unsaturated compounds with A -acyliminium intermediates have proven particularly useful. Allylsilanes lead to the corresponding allyl-substituted products. This reaction proceeds well even for -lactams (equation 49). 5.86 j, g penicillin-derived 4-acetoxyazet-idinone (91) reacts with excess allylsilane in refluxing dichloroethane, catalyzed by TMSOTf, to produce as the sole product trans compound (92). A -Acyliminium ions generated from cyclic ureas and carbamates (93) likewise yield allylated products with virtually complete trans stereoselectivity (equation SO). Allylstannanes react under somewhat milder conditions than allylsilanes, requiring only a catalytic amount of BFsZ EtjO at room temperature for a 3-lactam system (equation 51). This allylstannane procedure was applied to cyclic carbamate systems for the stereoselective synthesis of several isomers of statine. Thus, ethoxycarbamate (94) reacts with methallyltributylstannane in excellent yield and dia-stereoselectivity (equation 52). ... 

The resin-bound polyamine was used as a template for the solid-phase synthesis of a range of heterocyclic compounds, such as cyclic ureas 25 and cyclic thioureas 26. This work exemplifies our ongoing efforts on the solid-phase assembly of individual acyclic and heterocyclic compounds and combinatorial libraries using short peptides as starting materials. 

Figure 15 Synthesis of positional scanning heterocyclic libraries (diethyltriamines 24, cyclic ureas 25, and cyclic thioureas 26) derived from dipeptides.

Many biologically active compounds contain cyclic ureas, including inhibitors of human immunodeficiency virus (HIV) protease and HIV replication [70]. Kim et al. [71] presented an illustration of the synthesis of oligomeric cyclic ureas as nonnatural biopolymers. Applying the libraries from libraries [72] concept, triamines [65] such as those described earlier were used as templates for the generation of different heterocyclic compounds such as cyclic ureas, cyclic thioureas, and bicyclic guanidines [65]. The cyclizations to obtain the five-membered ring cyclic ureas and cyclic thioureas were... 

Cyclic ureas have many applications as intermediates in the preparation of biologically active molecules. The conventional methods involve cyclization of 1,2-diamines with phosgene or oxidative carbonylation of diamines. Varma and coworkers developed a direct synthesis of cyclic ureas from urea and diamines in the presence of ZnO using microwaves. The major advantage of the method is that the reaction is accelerated by exposure to microwave irradiation the byproducts were, moreover, easily eliminated compared with traditional methods [32]. 

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