Base Catalyzed Ring Closure

In the process of chain-lengthening addition of the third residue (or a peptide) to a dipeptide derivative is an ambiguous step. Alkyl esters of dipeptides undergo spontaneous cyclization and produce 2,5-diketopiperazines  

In diketopiperazines (DKP-s) both amides are cis, that is the carbonyl oxygen atom and the amide hydrogen are on the same side of the C—N partial double bond. Accordingly, cyclization requires the energy consuming conversion of the more stable transoid to the less stable cisoid form. The energy liberated in the 

A different base catalyzed cyclization was observed during the saponification of peptide esters in which the N-terminal residue was blocked by the 

The cyclization products (hydantoins) are cleaved by excess alkali to give urea derivatives, dicarboxylic acids with the structure 

This side reaction can become quite significant if R is hydrogen, that is when glycine is the second residue in the sequence, because glycine is the only amino acid that can readily by di-acylated at the amino group. 

---

An example of a whole-cell process is the two-step synthesis of an enantiopure epoxide by asymmetric reduction of an a-chloro ketone (Scheme 6.4), catalyzed by recombinant whole cells of an Escherichia coli sp. overexpressing an (R)-KRED from Lactobacillus kefir and GDH from Thermoplasma acidophilum, to the corresponding chlorohydrin, followed by non-enzymatic base-catalyzed ring closure to the epoxide [17]. 

Bourguignon and coworkers in their preparation of thieno[2,3-6]pyrazine used methyl-pyrazine (364 Scheme 107) (80JHC257) as starting material. The chlorination of (364) yields 2-chloro-3-methyl- and 2-chloro-6-methyl-pyrazine in a ratio of 80 20. Without separation this mixture is treated with ethyl mercaptoacetate in the presence of sodium ethoxide to give (365) in 91% yield (based on 2-chloro-3-methylpyrazine). Oxidation of the methyl group to an aldehyde function and subsequent base catalyzed ring closure yields (366), which is transformed to (363) by the method depicted already in Scheme 106. 

Base-catalyzed ring closure of the isothiocyanate derivative (127) gives the pyrazolo-[l,5-a][l,3,5]triazine (128 Scheme 41) <74JHC199>. The sulfur may be removed with Raney nickel in ammonium hydroxide. Another example of this versatile route is the formation of (130) in Scheme 42. However, the starting material (129) also has a hydrazone group... 

The synthesis of 10-substituted corroles from dideoxybiladiene-ac dihydrobromides has recently been reported by Paolesse, et al Here, base-catalyzed ring closure of 2.84 was found to afford the 10-carboxymethyl-substituted corroles 2.87. The 10-substituted free-base corroles 2.88 and 2.89 were also prepared in this way (Scheme 2.1.18). Using a similar strategy, but starting from dideoxybiladiene salt 2.90, Paolesse and coworkers synthesized the 5-methoxycarbonyl-substituted corrole 2.91 (Scheme 2.1.19). 

Tosyl iodide, which is easily prepared by the reaction of the sodium salt of p-toluenesulfinic acid with iodine, is a useful reagent for cleavage of vinylcyclopropanes, resulting in functionalized 5-iodopent-2-enyl sulfones (Table 6). ° Experimentally, a dichloromethane solution of the vinylcyclopropane was added to tosyl iodide and propylene oxide in dichloromethane at 40°C. The mechanism probably involved both free-radical and cationic intermediates, and was sensitive to solvent polarity. The resulting 5-iodopent-2-enyl sulfones were formed with Z configuration which enabled their use in subsequent base-catalyzed ring-closure reactions. 

Aziridines2 )3-Iodoazides, available by the addition of iodine azide to olefins, undergo reduction of the azide function followed by base-catalyzed ring closure to aziridines. The most satisfactory reagent for this purpose is lithium aluminum hydride, which can accomplish both reaction steps since it is a Lewis acid as well as a reducing agent. Competing side reactions are elimination of the elements... 

Condensation of 4-benzoyl-6-chloropyridazin-3-amine with 1,1,1-triethoxyethane, followed by base-catalyzed ring closure, gives the corresponding 7-ethoxy compound.19... 

The use ort/io-cyanoanilines provides an effective means to prepare 4-aminoquinolines by base-catalyzed ring closure onto the cyano group <97BCJ 1697>. In one example the use of DMSO/KO-r-Bu offers a mild base system for the Thorpe-Ziegler reaction <97H(45)483>. 

Sequential base-catalyzed ring closure of diazopropionylpyrazolone (162) and thermal rearrangement of the diazabicycloheptanone (163) gave diazepinone (164) and its 1,5-dihydro isomer (Scheme 24) <85JOC2141>. 

Kinetic studies of the base-catalyzed ring closure of co-aminoalkyl hydrogen sulfates have also been carried out (Table 4). The relative rates reveal an order of 5 > 3 > 4, which is the same as that of the co-halo-alkylamines. These cyclizations, like those of the haloalkylamines, were first order in substrate and zero order in base. Hence the reaction sequence probably occurs as shown in Eq. (3). 

---