Annulation of the known vinylogous urethane 4 with a-methyleneglutaric anhydride (3) is the key reaction in a seven step enandospecific synthesis of the ACE inhibitor, A58365A (1). The importance of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension has led to widespread interest in the design and discovery of new structural types with this capability. 1 Recently, workers at Eli Lilly & Co. have utilized a newly developed screening method to detect the presence of ACE inhibitors in the culture filtrate of Srreprnmyces chromofwcus NRRL 15098. 2*3 Isolation and characterization of the active constituents led to the assignment of a novel hydroxy-indolizidine structure for A58365A (1) and a homologous hydroxy-quinolizidine structure for A58365B (2). 4,5 Compounds 1 and 2 were found to be effective inhibitors of ACE at nanomolar concentrations. As part of a program aimed at evaluating the structural parameters necessary for their activity, the syntheses of 1 and 2 were undertaken. In this Letter we report the first total synthesis of 1.
1 A58365A 2 A563658
An important goal was that the final products emerge in enantiomerically homogeneous form in the natural L-configuration. We hoped that this objective might be accomplished for compound 1 by starting with Lpyroglutamate as the chiral educt. The four step conversion of commercially available L-pyroglutamic acid to vinylogous urethane 4 was carried out as previously described in the racemic series.6 The annulation of 4 with amethyleneglutaric anhydride (3)7 proceeded in refluxing benzene to form hexahydroindolizidine 5 in 95% yield as a ca. 2:l mixture of diastereomers.8 Esterification (diazomethane) of 5 gave dimethylester 6 in 98% yield. A mixture of 6 and two equivalents of 2,3-dicyano-S,6-dichloroquinone (DDQ) in p-dioxane was allowed to reflux for 12h. A 41% yield of pyridone 7 was obtained. Stirring 7 in methanol over palladium/carbon in an atmosphere