Guanidines addition

Folded proteins can be caused to spontaneously unfold upon being exposed to chaotropic agents, such as urea or guanidine hydrochloride (Gdn), or to elevated temperature (thermal denaturation). As solution conditions are changed by addition of denaturant, the mole fraction of denatured protein increases from a minimum of zero to a maximum of 1.0 in a characteristic unfolding isotherm (Fig. 7a). From a plot such as Figure 7a one can determine the concentration of denaturant, or the temperature in the case of thermal denaturation, required to achieve half maximal unfolding, ie, where... 

In addition to the mechanism involving cycHc AMP, nonsugar sweeteners, eg, saccharin and a guanidine-type sweetener, have been found to enhance the production of another second messenger, inositol 1,4,5-trisphosphate (IP3), causing the closure of potassium channels and the release of... 

Several related derivatives have also been utilized in this type of synthesis. Imino-chloromethanesulfenyl chlorides (184), prepared by the controlled addition of chlorine to isothiocyanates, react with amidines (161) to give 1,2,4-thiadiazolines (185) (71T4117). Chlorocarbonylsulfenyl chloride (186), prepared by the hydrolysis of trichloromethanesulfenyl chloride with sulfuric acid, reacted with ureas, thioureas and guanidines to give 1,2,4-thiadiazolidine derivatives (187) <70AG(E)54, 73CB3391). 

Chemical lysis, or solubilization of the cell wall, is typically carried out using detergents such as Triton X-100, or the chaotropes urea, and guanidine hydrochloride. This approach does have the disadvantage that it can lead to some denaturation or degradation of the produci. While favored for laboratory cell disruption, these methods are not typically used at the larger scales. Enzymatic destruction of the cell walls is also possible, and as more economical routes to the development of appropriate enzymes are developed, this approach could find industrial application. Again, the removal of these additives is an issue. 

The wide applicability of the PK reaction is apparent in the synthesis of pyrroles, for example, 45, en route to novel chiral guanidine bases, levuglandin-derived pyrrole 46, lipoxygenase inhibitor precursors such as 47, pyrrole-containing zirconium complexesand iV-aminopyrroles 48 from 1,4-dicarbonyl compounds and hydrazine derivatives. The latter study also utilized Yb(OTf)3 and acetic acid as pyrrole-forming catalysts, in addition to pyridinium p-toluenesulfonate (PPTS). 

Villsmeier reaction on the dimethylacetal of methoxyacetaldehyde (141) with phosgene and dimethyIformamide affords the acrolein derivative, 142. Condensation of this with guanidine gives the pyrimidine, 143. (The enamine can be viewed as a latent aldehyde-the dimethylamino group is probably lost in the course of an addition elimination reaction with one of the guanidine groups.) This pyrimidine serves as starting material for sulfameter (111). ... 

Interposition of a methylene group between the phenyl ring and the heterocycle leads to the benzyldiami nopyrimidines, a class of compounds notable for their antibacterial activity. Condensation of hydrocinnamate 54 with ethyl formate leads to the hydroxymethylene derivative 55. In this case, too, the heterocyclic ring is formed by reaction with guanidine. This sequence probably involves initial addition-elimination to the forniyl carbon to form 56 cyclization in this case involves simple amide formation. Tautomerization then affords the hydroxy derivative 57. This is converted to tetroxoprim (58) by first... 

In a somewhat similar vein, alkylation of the urea derivative 109 with methyl iodide affords the S-methyl ether 110. Condensation of that with taurine (111), leads to the guanidine 112, again by an addition elimination process. The product is the anthelmintic agent netobimin (112) [271. 

Reaction of 2,3-dichlorobenzoyl chloride with cyanide ion leads to the corresponding benzoyl cyanide (141). Condensation of that reactive intermediate with aminoguanidine 142 leads to the hydrazone-like product 143. Treatment with base results in addition of one of the guanidine amino groups to the nitrile function and formation of the 1,2,4-triazine ring. The product, lamo-trigine (144), is described as an anticonvulsant agent [31]. 

Step C Preparation ofthebase-A 300 ml one-necked, round-bottomed flask, equipped with a water-cooled condenser, calcium chloride tube and magnetic stirrer is charged with anhydrous methanol (150 ml) and sodium metal (5.75 g,0.25 g atom). When the reaction is complete, the solution is treated with dry guanidine hydrochloride (26.3 g, 0.275 mol) and stirred for 10 minutes. The sodium chloride that forms is removed by filtration. The solution is concentrated in vacuo to a volume of 30 ml and the residue treated with the product of Step B, heated one minute on a steam bath and kept at 25°C for 1 hour. The product is filtered, washed well with water, dissolved In dilute hydrochloric acid and the free base precipitated by addition of sodium hydroxide to give the amllorlde product base, a solid which melts at 240.5°-241.5°C. 

Addition of 2-pyrazolines to tetrazines gave 330 (84AP237 88CZ17). The pyrazolotriazine derivative 331 was prepared (76MI6) by treating diamino guanidine with acetyl pyruvic acid ethyl ester in either acid or neutral aqueous solution (Scheme 70). 

Thereafter, molecules have been synthesised with a bicyclic ring, such as a quinoleine or an indole, inserted. Many of these compounds like zoniporide and BMS-284640 are selective NHE1 inhibitors, but some inhibit also other isoforms. Most recently, an additional group of compounds with 4-substituted (benzo[b]thiophene-2-carbonyl) guanidines has been synthesised and these are potent NHE1 inhibitors. A structurally distinct compound, S-3226, was found to be the first selective NHE3 inhibitor. 

Bicychc pyrazinones foimd in several natural products were synthesized via Michael addition of heterocyclic amines to nitro olefin followed by reduction/cyclization of the nitro group of the adduct [20] (Scheme 5). Further elaboration of the C-6 methoxycarbonyl group in pyrazinone to the n-propyl guanidine group could result in the synthesis of indoloperamine. 

In certain cases, free guanidines can also serve as precursors to Group 4 metal guanidinate complexes. The bis(guanidinato) bis(benzyl)zirconium complex [Pr NHC(NPr )2]2Zr(CH2Ph)2 was obtained by addition of 2 equivalents of... 

Unique examples of N,A/ , N "-tri(isopropyl)guanidinate complexes of Nb(V) and Ta(V) bearing additional terminal imido ligands have been obtained as depicted in Scheme 116. Depending on the reaction conditions, these reactions may also lead to the formation of compounds containing dianionic guanidinate... 

---