On the basis of the previously reported polypharmacological profile of truncated d-1'-homologated adenosine derivatives [J. Med. Chem.2020, 63, 16012], the l-nucleoside analogues were synthesized using computer-aided design and evaluated for biological activity. The target molecules were synthesized from d-ribose via the key intramolecular cyclization of the monotosylate and Mitsunobu condensation. The peroxisome proliferator-activated receptor (PPAR) binding activities of l-nucleoside analogue <b>2d</b> (<i>K</i> <sub>i</sub> = 4.3 μM for PPARγ and 1.0 μM for PPARδ) were significantly improved in comparison with those of the d-nucleoside compound <b>1</b> (11.9 and 2.7 μM, respectively). In addition, the l-nucleosides showed more potent adiponectin-secretion-promoting activity than the d-nucleoside analogues.