A new method for the regio- and stereoselective functionalization of two distal methylene groups of p-tert-butylcalixarene (1a) is described. Reaction of the meso bis(spirodienone) calixarene derivative 2a with bromine afforded the tetrabrominated product 3a derived from exo 1,4-additions of bromine to the diene, subunits. A phase-transfer-catalyzed reaction of 3a with aqueous NaOH/CH2Cl2 yielded the exo bis(epoxide) calixarene derivative 4. Heating 3a in a vacuum eliminated two molecules of HBr and afforded a product (5b) that retained the C-l symmetry of the starting material. X-ray analysis indicated that the calixarene derivative 5b possesses two exocyclic double bonds of E configuration. Calixarene 5b undergoes reaction with nucleophiles at the exocyclic double bonds, with concomitant bond shifts and expulsion of the bromine atoms. Selective trans monodeuteration of two methylene groups of I was achieved by reaction of 5b with NaBD4 followed by aromatization of the labeled spirodienol derivative. Reaction of 5b with RONa/ROH (R = Me, Et) afforded the methylene-substituted bis(spirodienone) derivatives 9a and 9b possessing two trans alkoxy groups. X-ray crystallography of 9b indicated that the two trans substituents are located at pseudoequatorial positions of the methylene groups. LiAlH4 reduction of the substituted bis(spirodienone) derivatives afforded calix[4]arenes incorporating trans alkoxy groups at two distal methylene positions.