Synthesis and conformational analysis of a dimerising eight-membered lactam dipeptide

Synthesis and conformational analysis of a type VIb β-turn mimetic based on an eight-membered lactam

“…The conformational analysis of the lactam 3 in solution was considered next. However, evaluation under the conditions used previously for the analysis of the cis-lactam dipeptide ent-4 23 was nearimpossible, owing to the poor solubility of 3 in chlorinated solvents. 1 H NMR spectroscopy was employed, with the measurements being conducted in polar solvents, such as 2).…”

“…The synthesis of the trans-disubstituted eight-membered lactam 3 proceeded with remarkable ease and efficiency, following the route optimised for the cis-disubstituted analogue 4, reported in the preceding paper. 23 The most advanced common intermediate is the (Z)-octenoic acid 6. This was condensed with auxiliary 7 30 to give the carboximide 8 in 88% yield (Scheme 1).…”

“…The absolute stereochemistry of compounds 3 and 4 follows from the X-ray crystal structure of the ester 19 and the fact that the enantiomer of compound 4 had been prepared by an independent route. 23 In summary, the synthesis of the trans-disubstituted lactam dipeptide 3, has been achieved in 11 steps, starting from (Z)octenoic acid 6, the overall yield being up to 23%. Furthermore, in addition to being extremely efficient, the synthesis delivers simple lactam precursors such as 15 which can readily be elaborated for use in peptide synthesis.…”

“…20 We have previously reported the synthesis of the disubstituted seven-membered lactams, trans-1 and cis-2 21,22 and a further step was to evaluate the analogous eight-membered lactams trans-3 and cis-4. 23 In a recent publication, Katzenellenbogen et al reported the synthesis and conformational evaluation of the unsaturated ten-membered homologue cis-5. 24 Molecular mechanics conformational searching and NMR studies indicated that tetrapeptide derivatives of cis-5 constrain the four relevant torsion angles to within 30Њ of those predicted for an ideal type I β-turn.…”

Stoichiometric asymmetric processes

“…324 An interesting practical observation has been made in the quenching of such enolates with trisyl azide. 325,326 Reproducible yields (75-95%) of the desired azides were obtained by addition of the solid trisyl azide in one portion at Ϫ78 ЊC. Electrophilic amination of enolates of chiral dithianes has been achieved with dibutyl azodicarboxylate giving relatively good levels of stereoselectivity, but with some loss of stereochemical integrity of the products that may have resulted during derivatisation procedures.…”