Stereoselective alkylations of a bicyclic lactam derived from pyroglutamic acid

On the diastereoselectivity of alkylations of bicyclic lactams

“…52, 53 For alkylations using methyl halides, Meyers 10 has indicated that both electronic and steric effects have significant roles in the observed diastereoselectivity of the alkylations of the enolates derived from bicyclic lactams 2 and 5, although Houk has recently suggested that only torsional and steric influences are significant. 43 A more general explanation, originally proposed by Armstrong 30 and more recently confirmed by Madalengoitia 35 which is applicable for a range of electrophiles and consistent with existing published experimental data, suggests that two opposing factors are operating: endo-alkylation is favoured by virtue of the anti-stereoelectronic directing effect of the nitrogen lone pair, but exo-alkylation by a sterically preferred entry of the electrophile to the more open (convex) face of the bicyclic system. The relative importance of these two factors appears to depend on the size of the incoming electrophile; noteworthy, however, is that the latter would appear to be relatively unimportant for lactams of type 5, but of considerable significance for lactams of type 2, for which progressively increasing levels of exo-diastereoselection are observed for bulky electrophiles; conversely, some highly endo-diastereoselective protonations have also been reported.…”

“…The relative importance of these two factors appears to depend on the size of the incoming electrophile; noteworthy, however, is that the latter would appear to be relatively unimportant for lactams of type 5, but of considerable significance for lactams of type 2, for which progressively increasing levels of exo-diastereoselection are observed for bulky electrophiles; conversely, some highly endo-diastereoselective protonations have also been reported. 30,35 In the case of alkylations of the enolate derived from 2d, the balance of these steric and electronic effects has been altered relative to 2a so as to favour endo-alkylation, although not exclusively. One possible reason for this is the fact that the C-2 (methyl) substituent of 2d impedes closure of the bicyclic lactam system, and thereby allows the stereoelectronic directing effect of the nitrogen to operate more effectively to the now more open endo-face.…”

“…[31][32][33][34] Recent work suggests that high levels of exo-alkylation for 2a may be possible using carefully optimised conditions and/or a kinetic protonation strategy. 35 The preference for exo-alkylation in these systems has been most simply explained by assuming that the observed product ratio arises from competing reactions in which the exo-product is favoured on steric grounds, while the endo-product is kinetically favoured due to a stereoelectronic anti-directing effect from the nitrogen lone pair; 10,30,35 the exact balance of these two effects crucially depends on the size of the electrophile. However, the importance of enolate solvation has also been proposed.…”

Uncatalysed diaryldiazo cyclopropanations on bicyclic lactams: access to annulated prolines

“…We have shown that bicyclic lactams derived from pyroglutamic acid provide useful scaffolds for modification of the ring periphery by cycloaddition reactions, 27 as well as nucleophilic additions of organometallics 28,29 and amines, 30 and of interest was whether this approach could be extended to include cyclopropyl-annulated structures, especially since such systems have become of significance as GluR agonists/antagonists. 29 Recent work by Madalengoitia has accessed such systems using sulfur ylid additions, [31][32][33][34][35] but we report here that azabicyclo[3.1.0]hexanes may also be formed by direct stereoselective cyclopropanation of bicyclic lactams 1a,b (Scheme 1) using substituted diaryldiazomethanes 2a-d and 9-diazo-9H-fluorenes 3a-f (Fig. 1) under thermal conditions; some of this work has appeared earlier in preliminary form.…”

Functionalised Nitrogen Heterocycles and the Search for New Antibacterials and Bioactives

“…33 We found that these reactions were reasonably general in scope, but without full diastereoselectivity; the exo system appeared to be favoured on steric grounds although endo-selectivity was possible. 24,34,35 In related work, Liotta concluded that 'no portion of the structural framework of these lactam enolates exerts any significant steric or electronic control on the diastereofacial selectivity observed in the alkylation reactions of these bicyclic lactams and that the observed reactivity was best accounted for by solvation of the enolate', 36 and this most likely arises from the very shallow nature of the concave/convex bicyclic ring system which does not offer a strong steric bias.…”