Succinimide, nucleophilic attack

The most important degradation mechanism of asparagine and glutamine residues is formation of an intermediate succinimidyl peptide (6.63) without direct backbone cleavage (Fig. 6.29, Pathway e). The reaction, which occurs only in neutral and alkaline media, begins with a nucleophilic attack of the C-neighboring N-atom at the carbonyl C-atom of the Asn side chain (slow step). The succinimide ring epimerizes easily and opens by hydrolysis (fast step), as shown in Fig. 6.27, to yield the iso-aspartyl peptide (6.64) and the aspartyl peptide (6.65) in a ratio of 3 1. 

Compound 23 is the active alkylating agent. The a-carbon atom is acti ated toward nucleophilic attack, permitting it to alkylate the nitrogen of the deprotonated succinimide 5 to give TV-butenylimide 7. This releases triphenylphosphine oxide (Ph3P=0). Thus, in the overall process DFAD is reduced to hydrazine derivative 22, whereas triphenylphosphine is oxidized to triphenylphosphine oxide. 

Scheme 61, yielded thiazole 200 as the major product, along with minor amounts of carbinol 201 [152]. On the other hand, treatment of the imine formed from 199 and p-methoxyphenylamine with catalytic tetrabutylammonium cyanide, produced suc-cinimide derivative 202. In both cases, the process is initiated by nucleophilic attack to the carbaldehyde C=0 (or azomethine s C=N) group, which is followed up by an anionic rearrangement. A variation of the above process using as catalysts /V-heterocyclic carbenes (NHC) derived from base treatment of azolium, imidazo-lium, or triazolium salts, has also been developed to access gem-disubstituted succinimides [153, 154]. Unfortunately, an attempt of kinetic resolution of racemic 4-formyl (3-lactams by using chiral NHC resulted in moderate selectivities only [154]. 

In a study of NIS-promoted additions to glycals it was noted that when the nu-cleophilicity of the alcohol was low, a competing reaction occurred whereby the succinimide anion itself acted as a nucleophile, attacking the anomeric carbon.76,77... 

More synthetic routes to the l-(hydroxymethyl)pyrrolizidines have been reported. Two groups3,4 have published the same route to ( )-isoretronecanol (3) (Scheme 1). The key step is the nucleophilic attack of succinimide anion on the cyclopropylphosphonium salt (1), followed by intramolecular Wittig reaction to generate the unsaturated pyrrolizidinone ester (2). Catalytic reduction and reduction with a hydride yielded ( )-isoretronecanol (3). Flitsch and Wernsmann achieved a higher overall yield (62%) by carrying out the first step in boiling xylene.3... 

Enamines (19 n =3-12) undergo nucleophilic attack by succinimide to give the fused cyclopropanes (20) subsequently, the two heterocyclic substituents can be displaced by various nucleophiles. ... 

NIS-promoted iodocarbocychzation reaction of various functionalized 1,5-enynes occurs via a 5-endo diastereoselective process to form iodo-functionalized cyclopentenes (Scheme 6.22). Initially, the iodonium ion activates the alkynyl functionality through jt-coordination. Upon nucleophilic attack of the alkenyl moiety in an anti fashion, an iodocyclization reaction occurs and a carbocation is formed. Further, proton abstraction by the succinimide anion affords the iodo-functionalized cyclopentenes [26]. 

Through several experiments, Ishihara s group found that P(OPh)3 was inactivated during generation of the dibrominated by-product. In other words, P(OPh)3 was inactivated by nucleophilic attack of the succinimide anion to the bro-mophosphonium salt, which is the active species [47]. The bromide anion was generated at the same time, which led to formation of the dibrominated by-product (Scheme 9.30). Therefore, the nucleophilic attack of the succinimide anion to the bromophosphonium salt must be avoided if this reaction is to be successful. 

A stereospecific dichlorination can be applied onto an epoxide using a (NCS)/PPh3 protocol. It has been proposed that the preformed PPh3-succinimide complex activates the epoxide, followed by a nucleophilic attack with the chloride anion (Scheme 42.17). 

It was known in the early 70 s that unsymmetrically substituted anhydrides and im-ides can undergo highly regioselective transformations, e.g. to lactones and lactams, respectively (see Scheme 6.23) [166]. The growing importance of such products as synthetic intermediates raised the issue of control of regioselectivity, and several authors attempted to identify the factors at play [167-169]. The emphasis was on metal hydride reductions of succinic anhydrides to y-lactones, and succinimides to hydroxypyrrolidinones. Suess [167], Rosenfield and Dunitz [47], and independently Kayser and Morand [169], proposed that the approach of a nucleophile to the less substituted carbonyl group can actually be more hindered if there is indeed a strong preference for rearside attack. The two pathways are compared in Scheme 6.24. 

It is plausible that the first steps in the mechanism of the Corey-Kim oxidation involve the initial Sn2 reaction between the sulfide nucleophile and the NCS that bears the electrophilic chlorine to form an intermediate sulfonium chloride species and a succinimide anion that in turn attacks the newly formed electrophilic sulfonium to yield... 

Cleavage of benzylic sulphoxides and t-butyl dialogues with N-bromo- or -chloro-succinimides gives the benzyl or t-butyl halide and an ethyl alkane-pr arene-sulphinate, the ethanol in the CHCh used as solvent providing the nucleophile for attack at sulphur on the intermediate bromosulphoxonium cation. " Use of an optically active sulphoxide leads to the conclusion that the reaction is largely of SnI character. 

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