6-Membered rings nucleophilic hydroxylation

Cyclic structures can form as a result of side reactions. One of the most common examples is the formation of diketopiperazines during the coupling of the third amino acid onto the peptide chain (Fig. 7). Intramolecular amide bond formation gives rise to a cyclic dipeptide of a six-membered ring structure, causing losses to the sequence and regeneration of the hydroxyl sites on the resin. The nucleophilic group on the resin can lead to fiuther unwanted reactions [14]. 

The five-membered ring can also be formed by intramolecular nucleophilic attack of an alkoxide on a carbamate such as for the formation of 196 from 195 <1997T9553>, by dehydration of fV-carbamate-pipecolic acid derivatives <2002EJO3936>, by treatment of amino-amides under Eschweiler-Clarke conditions <1999TA3371>, or by treatment of hydroxyl aminonitriles with silver trifluoroacetate <2002JA2951> (Scheme 57). 

Ah initio calculations to map out the gas-phase activation free energy profiles of the reactions of trimethyl phosphate (TMP) (246) with three nucleophiles, HO, MeO and F have been carried out. The calculations revealed, inter alia, a novel activation free-energy pathway for HO attack on TMP in the gas phase in which initial addition at phosphorus is followed by pseudorotation and subsequent elimination with simultaneous intramolecular proton transfer. Ah initio calculations and continuum dielectric methods have been employed to map out the lowest activation free-energy profiles for the alkaline hydrolysis of a five-membered cyclic phosphate, methyl ethylene phosphate (247), its acyclic analogue, trimethyl phosphate (246), and its six-membered ring counterpart, methyl propylene phosphate (248). The rate-limiting step for the three reactions was found to be hydroxyl ion attack at the phosphorus atom of the triester. ... 

We observed that cyclic esters (lactones) may be formed when the carboxyl electrophile and hydroxyl nucleophile are in the same molecule (see Section 7.9.1). Similarly, cyclic amides are produced when carboxyl and amine groups are in the same molecule, and are again most favoured when this results in the generation of strain-free five- or six-membered rings. Cyclic esters are termed lactones, whereas cyclic amides are in turn called lactams. The nomenclature of lactams is similar... 

Lactam antibiotics are natural or semisynthetic compounds whose basic nuclear structure consists of a -lactam ring coupled to a thiazolidine (five-membered) or a dihydrothiazine (six-membered) ring to form the penicillin or cephalosporin nucleus, respectively. To those nuclei, various side chains that determine most of the properties of the different -lactams are attached. All members of this group of antibiotics are readily attacked at the -lactam nitrogen by nucleophilic reagents such as hydroxyl ions, alcohols, and primary amines, as well as by secondary amines. They are also susceptible to electrophilic attack at both the... 

The amino group is more nucleophilic than the hydroxyl group, and has, therefore, a greater tendency to react with the anomeric center. In solution, 5-amino-5-deoxyhexoses and 6-amino-6-deoxyhexuloses are present completely in six-membered ring-forms, containing the nitrogen atom in the ring 4-amino-4-deoxyaldoses are, to a considerable extent,... 

Fructose can cyclize into a fivc-membered ring known as a furanose. The hydroxyl group on which carbon of fructose behaves as a nucleophile during the formation of a furan ... 

Reactions of cyclopropanones with nucleophiles frequently lead to ring enlargement reactions since the formation of four-membered rings from the reactive intermediates is accompanied by a considerable reduction in strain energy. Thus, 2 reacts with diazomethane to form cyclobutanone96>, with hydrazoic acid to form (3-lactam 76,89) and, under special conditions, with amines and hydroxyl amine derivatives to form N-sub-stituted (3-lactams 87> (Scheme 24). 

Surprisingly, additions of electrophiles, radicals, and nucleophiles to methylene cyclopropane have rarely been executed under synthetic conditions. A sequence leading to the complement inhibitor K-76 published recently" very smartly takes advantage of a methylenecyclopropane participation in the polyene cyclization shown in equation 197. Hydroxylation of the vinylcyclopropane double bond and hydrogenolysis of the three membered ring are subsequent essential reactions. 

All of these experiments strongly indicate that the alkaline hydrolysis of the sugar orthoacetates is a nucleophilic displacement reaction. Any one of the three carbon atoms of the five-membered ring may be attacked. Since the hydroxyl ion must approach the tetrahedron of the attacked carbon atom in the direction of the center of the face opposite the vertex occupied by the group to be displaced, it is evident that the reaction must be accompanied by the inversion of configuration of the attacked carbon atom. It is quite certain that the attack does not take place on carbon atom 2, because in such a case the reaction product would be the epimeric sugar derivative. Therefore, either carbon atom 1 or the central carbon atom of the orthoester group is attacked. In the first case, the reaction is as follows. 

Sulfonylmercuration of conjugated dienes occurs using PhSOjNa and HgClj. (vii) Intramolecular Nucleophiles. Suitably placed hydroxyl, amine and carboxyl groups in the alkene can act as the nucleophile and give rise to cyclic products. Five-membered rings frequently are formed, e.g. ... 

Formation of cyclic acetals by sugar hydroxyls generally retards nucleophilic displacements at the anomeric centre of the same sugar residue. In the case of 4,6-benzylidene derivatives, the mechanism of deactivation appears to be that the dipole of the C6-06 bond is constrained with its positive end directed towards the anomeric centre.In the case of the 1,2-diketals, the deactivation arises from the increased difficulty of forming half-chair or boat conformations in a six-membered ring, which is part of a traw -fused decalin structure. 

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