Synthesis of a bicyclic oxo-γ-lactam from a simple caprolactam derivative

Abstract

Reaction of caprolactams with an axial ester substituent with base gives the 6-azabicyclo-[3.2.1]octane ring system via Dieckmann cyclization.

Does the Exception Prove the Rule? A Comparative Study of Supramolecular Synthons in a Series of Lactam Esters

“…The synthesis of caprolactam ester 12 has been described earlier. 19 Preparation of pyroglutamates 1 and 2 (Steglich esterification). Commercially availab le pyroglutamic acid (1 eq.)…”

“…Methyl ( 10 ) and ethyl 7-cycloheptanonecarboxylate ( 11 ) were synthesized from cycloheptanone using the respective dialkylcarbonate and sodium hydride. The synthesis of caprolactam ester 12 has been described earlier …”

“…Though, the dihedral angle of the amide region increases to -27.9(3) °; the conformational changes in the rest of molecule are less pronounced (Figure 11a The relationship of the ester position and reactivity has studied for caprolactam ester 12 and enantholactam ester 8. While 12 featuring an axial ester undergoes a transannular Dieckmann cyclization when treated with the strong base lithium bis(trimethylsilyl)amide (LiHMDS), 19 the enantholactam 8 with its equatorial ester shows no reaction. We suppose that the switch from axial (12) to equatorial (8) is a main reason for this behavior (Figure 12).…”

“…12 Comparative studies on monocyclic lactams and especially simply substituted derivatives are unsatisfyingly rare. [13][14][15][16][17][18] As part of our ongoing studies on bridged lactams 19 we became interested in a series of small and medium-sized lactams featuring a carboxylic acid or a respective ester in the Nα position. In detail we discuss here the synthesis and the X-ray structures of pyroglutamates 1 (iso-propylester) and 2 (tert-butylester), pyrohomoglutamic acid methyl ester (3) and its respective acid (4), the Nα disubstituted caprolactam [20][21][22][23][24][25] 5 and the three enantholactam 26,27 esters 6-8 ( Figure 2); additionally, we deliver full analytic a l characterization.…”

“…As a result, we are able to present a comprehensive study on the solid state behavior of this synthetically useful type of compound and discuss the general influence of ring size and substitution pattern on the COOH and COOR moieties at the N α position of lactams. The respective moieties can adopt either an axial or an equatorial site, which is of crucial importance for their reactivity, e.g., in transannular cyclization reactions. ,, For steric reasons only ester groups in axial positions will allow such conversions (Figure ). Despite the axial and the equatorial conformation being connected via equilibrium in solution, the molecular structures of the title compounds deliver valuable insights into their reactive conformation and give most beneficial information on distances and interactions in and between the molecules.…”