Exocyclic pathways

In contrast, the reaction of 1,3-disustituted aminoaUenes proceeds exclusively through an exocyclic pathway (Eq. 4.98). 

A formal pathway is shown in Scheme 5 for an endocyclic system, as was shown in Scheme 2 for an exocyclic pathway. The obvious difference is that, after the formation of the monoanion of the hydrate and the intramolecular attack, the next step in Scheme 5 involves fission to give separate species containing the hydrolysed ester group and the catalytic moiety... 

The displacement reactions which give dihydro-benzothiophene are exocyclic pathways the alternative displacements are forced, and refuse, to follow an endocyclic pathway. The clear preference for the exocyclic pathway cannot, in the case of radical V, be assigned to differences in leaving group ability. For radical V, R CaHs, the leaving groups in the two competing displacements are both CH2- for R CeHs,... 

This genera] scheme could be used to explain hydrogen exchange in the 5-position, providing a new alternative for the reaction (466). This leads us also to ask whether some reactions described as typically electrophilic cannot also be rationalized by a preliminary hydration of the C2=N bond. The nitration reaction of 2-dialkylaminothiazoles could occur, for example, on the enamine-like intermediate (229) (Scheme 141). This scheme would explain why alkyl groups on the exocyclic nitrogen may drastically change the reaction pathway (see Section rV.l.A). Kinetic studies and careful analysis of by-products would enable a check of this hypothesis. 

Deamination, the hydrolytic loss of exocyclic amino groups on the DNA bases, is typically a very slow reaction. For example, deamination of cytosine residues in dnplex DNA occnrs with a half-life of about 30,000 years under physiological conditions, and the deamination of adenine residues is still more sluggish. " Alkylation at the N3-position of cytosine (Scheme 8.5) greatly increases the rate of deamination (ty2 = 406 h). Deamination of 3-methyl-2 -deoxycytidine proceeds 4000 times faster than the same reaction in the unalkylated nucleoside. Alkylation of the N3-position in cytosine residues also facilitates deglycosylation (Jy2 = 7700 h, lower pathway in Scheme 8.5), but the deamination reaction is 20 times faster and, therefore, predominates. ... 

Scheme 14-1. General in-line monoanionic mechanism of phosphodiester cleavage transesterification catalyzed by hairpin ribozyme the first proton transfer (PT1), the nucleophilic attack (Nu), and the exocyclic cleavage (Cl) steps are shown, and the Oip and O2p pathways are indicated by blue and red colored hydrogens, respectively. For the uncatalyzed model reaction in solution, the Ojp and O2p pathways are energetically equivalent...

Fragmentation of amino acid-derived spirophosphorane 128 has been analyzed using field desorption (FD), El, and Cl mass spectrometry <1997RCM1825, 1997CCL629>. In spiro-crypta cyclophosphazene derivatives 129, the major decomposition pathway involved the initial cleavage of a P-Cl bond rather than cleavage of an exocyclic P-N bond as is normally seen for cyclophosphazenes <2004JST139>. 

L, loading module DH, dehydratase KS, p-ketosynthase KR, ketoreductase MT methyltransferase PS, pyran synthase DHh and KRh are DH and KR-like sequences, together with the FkbH domain, they are involved in the formation of D-lactate starter unit HMG-CS, hydroxy-methyl-glutaryl CoA synthase. Acyl-carrier-protein domains are shown as small filled balls with chain attached by the thiol group. The box shows the HMG-CS pathway for the formation of exocyclic enoate. 

In vitro studies of DNA interactions with the reactive ben-zo[a]pyrene epoxide BPDE indicate that physical binding of BPDE occurs rapidly on a millisecond time scale forming a complex that then reacts much more slowly on a time scale of minutes (17). Several reactive events follow formation of the physical complex. The most favorable reaction is the DNA catalyzed hydrolysis of BPDE to the tetrol, BPT (3,5,6,8,17). At 25°C and pH=7.0, the hydrolysis of BPDE to BPT in DNA is as much as 80 times faster than hydrolysis without DNA (8). Other reactions which follow formation of physical complexes include those involving the nucleotide bases and possibly the phosphodiester backbone. These can lead to DNA strand scission (9 34, 54-56) and to the formation of stable BPDE-DNA adducts. Adduct formation occurs at the exocyclic amino groups on the nucleotide bases and at other sites (1,2,9,17,20, 28,33,34,57,58). The pathway which leads to hydrocarbon adducts covalently bound to the 2-amino group of guanine has been the most widely studied. 

The addition of allenyl ether-derived anions to Weinreb [4] or to morpholino amides [5] follows a slightly different pathway (Eq. 13.2). For example, the addition of lithioallene 6 to Weinreb amide 7 at -78 °C, followed by quenching the reaction with aqueous NaH2P04 and allowing the mixture to warm to room temperature leads to cyclopentenone 9 in 80% yield [6]. The presumed intermediate of this reaction, allenyl vinyl ketone 8, was not isolated, as it underwent cyclization to 9 spontaneously [7]. These are exceptionally mild conditions for a Nazarov reaction and are probably a reflection of the strain that is present in the allene function, and also the low barrier for approach of the sp and sp2 carbon atoms. What is also noteworthy is the marked kinetic preference for the formation of the Z-isomer of the exocyclic double bond in 9. Had the Nazarov cyclization of 8 been conducted with catalysis by strong acid, it is unlikely that the kinetic product would have been observed. 

The selective 1,4-reduction of a,p-unsaturated carbonyl compounds is always a challenge, but it has been met successfully by the use of dithionite under phase-transfer conditions. Reduction proceeds in high yield to the total exclusion of saturated or allylic alcohols (Table 11.10) [5, 6], Exocyclic and endocyclic conjugated C=C double bonds are reduced with equal ease, whereas non-conjugated double bonds remain intact. The predominant reduction pathway for conjugated dienoic... 

A pathway (Scheme I) (8.9) for the hydrolysis of oligoglycosides by lysozyme that differs from the previously accepted mechanism (Scheme II) (3,10-12) is described in this section. The alternative pathway, suggested by results of a 55-ps MD simulation of the lysozyme (GlcNAc)e complex (1), is consistent with the available experimental data and with stereoelectronic considerations. Experimental data have demonstrated that Glu 35 and Asp 52 are essential, as shown by recent site-directed mutagenesis results (13.) which corroborate chemical modification studies (3.14 and references cited therein), and that the reaction proceeds with retention of configuration at Ci Q and references cited therein). A fundamental feature of the alternative pathway is that an endocyclic bond is broken in the initial step, in contrast to the exocyclic bond cleavage in the accepted mechanism. 

Chen and co-authors in their work [50] offered key stages for mechanism of heterocyclization leading to compounds 25 and 26 (Scheme 12). The reaction sequence for azolopyrimidines 25 formation is very similar to that published in [47] and presented in Scheme 9. Pathway to tetrahydroderivatives 26, in opinion of [50], also includes at the beginning Knoeveganel condensation. Further step of the reaction in this case should be the addition of exocyclic NH2 group of aminoazole to enone fragment of unsaturated ester, with subsequent cyclization of the adduct formed into final tetrahydropyrimidine (Scheme 14). 

Two pathways were considered a dipolar cycloaddition across S(l) and N(4) (path (a)) and a dipolar cycloaddition across S(l) and the exocyclic nitrogen N(exo) (path (b)) (Figure 5). The reactions are, however, facilitated by more electrophilic isocyanates (RSO2NCO > RCONCO > ArNCO > Alkyl NCO) disfavoring path (a), and the observed reactivity order of the starting heterocycles ((85a) > (85b) (85c)) is in better agreement with path (b). The expected intermediate (86) was successfully trapped when the bulky t-butyl group was introduced in position... 

Analogously, the thermal formation of fused strained tricycles 77 can be rationalized by a mechanism which includes an exocyclic diradical intermediate 80 through an initial carbon-carbon bond formation, involving the proximal allene carbon and the internal alkene carbon atom (path C, Scheme 28). The alternative pathway leading to tricyclic 2-azetidinones 77 is proposed in path D (Scheme 28). This proposal involves an endocyclic diradical intermediate 81 arising from the initial attack of the terminal olefinic carbon onto the central allene carbon. The final ring-closure step of the diradical intermediates account for the cyclobutane formation. 

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