Xestospongin A [also known as araguspongine D (1)], a C-2-symmetric macrocyclic alkaloid isolated from the sponge Xestospongia exigua (Xestospongia sp.), and its C(9) epimer xestospongin C [also known as araguspongine E (2)] have been synthesized. The route capitalizes on the facile condensation between 5-halovaleraldehydes and 19-aminoalcohols to produce an oxaquinolizidine ring system in which all proper relative stereochemical relationships are controlled by equilibration. A linchpin synthesis was used to construct one key monomeric precursor-a 2,5-disubstituted thiophene derivative 26 [N=CCH2CH(OH)-2-Th-5-CH2CH2CH(CH(OMe)(2))CH2CH2CH2Cl]. A second precursor lacking the thiophene ring 38 [N=CCH2CH(OH)(CH2)(6)CH(CH(OMe)(2))CH2CH2CH2Cl] was assembled in a similar fashion. The carbinol center in each of these precursors was efficiently resolved enzymatically; lipase (PS-30) hydrolysis of the racemic acetate derivative of the thiophenemethanol derivative 26 and SP-435-catalyzed esterification of the beta-hydroxynitrile 38 proved effective.