Microwave-Assisted Intramolecular Diels-Alder Reaction For Synthesis Of Bicyclic γ-Butyrolactones And Determination Of Product Stereochemistry

Intramolecular Diels-Alder (IMDA) reactions of ester-tethered 1,3,8-nonatrienes should form either 1,3,3 a,6,7,7a-hexahydroisobenzofuran-1-ones or 1,3,3a,4,5,7a-hexahydroisobenzofuran-1-ones dependent on whether the ester carbonyl is associated with the dienophile or the diene in the substrates. These IMDA adducts are the bicyclicγ-lactones which are found in many biologically active natural products and are useful synthetic intermediates. Synthesis of 1,3,3a,6,7,7a-hexahydro- isobenzofuran-1-ones has been well described in the literature but only a few reports are known on preparation of 1,3,3a,4,5,7a-hexahydroisobenzofuran-1-ones via IMDA reactions. This thesis focuses on a general synthesis of 1,3,3a,4,5,7a-hexahydroisobenzofuran-1-ones via microwave-assisted IMDA reactions and determination of the stereochemistry of the IMDA adducts.Chapters 1 and 2 briefly introduce the general aspects of Wittig olefination and Diels-Alder cycloaddition, respectively, with an emphasis on the mechanism and stereoselectivity, and prior examples of IMDA reactions. Chapter 3 presents the main results and discussion of this thesis research. After an initial unsuccessful effort in establishing a tandem Wittig-Diels-Alder sequence for synthesis of the bicyclicγ-lactones, a stepwise synthesis of the 1,3,8-nonatrienes at room temperature was developed. It was followed by performing the IMDA reactions with controlled microwave heating (MeCN, 180℃, 1.5 h) to furnish, after silica gel column chromatographic purification, two cis lactones in 75-91% combined yields and in 87:13-90:10 diastereomer ratios. With careful spectral and X-ray crystal structural analysis, it was proved that the major cis isomer was isomerized from the initially formed trans adduct during the purification process. Therefore, our work corrects the wrong trans structure assigned for one of the major cis product reported in the literature.The detail procedures and full compound characterization are found in the Experimental Section with cited references given at the end of the thesis.