Regio- and Stereoselectivity in the Titanium-Mediated Cyclopropanation of ω-Alkenoic Diesters: Application in the Diastereoselective Synthesis of Pyrrolidinone

Abstract

The titanium-mediated intramolecular cyclopropanation of w-allylic succinates leads only to cyclopropanol, arising from exclusive reactivity of one ester function. As an extension of this methodology, the diastereoselective synthesis of highly functionalized pyrrolidinone has been realized from cheap commercially available L-aspartic acid.To our knowledge, no competitive reaction has been performed in the titanium(IV)-mediated cyclopropanation reaction (Kulinkovich reaction 1 ) while two esters and a terminal double bond are present in the same molecule.Herein we describe such a reaction performed on functionalized succinates.The starting succinates were prepared using literature or adapted procedures. Thus, succinic anhydride (1) was used as a precursor to lead, after ring opening 2 then alkylation, 3 to the intermediate 2-alkenyl acids 2a-c which undergo subsequent esterification to furnish, with moderate yields, ethyl 2-propenyl succinate (3a), ethyl 2-butenyl succinate (3b) and ethyl 2-pentenyl succinate (3c), respectively. Alternatively, the same compounds could be obtained with similar yields by alkylation of w-alkenoic esters 4a-c by ethyl bromoacetate 4 (Scheme 1). Scheme 1Thus, the prepared 2-alkenyl succinates 3a-c underwent the intramolecular condensation reaction 5 and surprisingly, only one cyclopropanol 5a 6 was isolated when the reaction was performed using ethyl 2-propenyl succinate (3a) as reported in Table 1 (entry 1). Concerning the 2-homoallyl (3b, entry 2) and 2-pentenyl (3c, entry 3) succinate derivatives, irrespective of the reaction temperature, besides the recovered starting material (about 65%), a large amount of diisopropylate succinate was formed by Ti(Oi-Pr) 4 -mediated transesterification and a mixture of inseparable and unidentified products were formed. This weak reactivity could explain the absence of referenced studies.Concerning the a-allyl succinate derivative 3a, minimized molecular modeling geometry calculations 7 were performed on the intermediates involved in the cyclopropanation process. A hybrid theoretical method was applied to pinpoint the minimum and transition state on the complex potential energy surface. All structures were optimized and submitted to frequency analysis with the semiempirical PM3 method followed by a Density Functional BSLYP/6-31G* calculation. As depicted in Figure 1, after complexation of the titanium species on the double bond, a first study of theoretical calculations showed the transition state corresponding to paths a and b to be close to the intermediate A. The study was continued by comparison of both implicated formal oxatitanacyclopentanes B and O 1) EtOH (1.2 equiv) 2) LDA, -78 °C, THF Br ( ) n ( ) n COOH COOEt OEt ( ) n +1