Recently we identified three promising topically active antiinflammatory agents (2, 3, and 4) from a series of racemic aryl-sphingolipids that inhibit protein kinase C (PKC). We now wish to report the enantioselective synthesis of the aforementioned leads and their comparative biological profile. The individual enantiomers examined are equipotent to their racemate in vitro and in vivo. Protein kinase C (PKC) is a family of phospholipid-dependent proteins that mediate signal transduction and regulate cellular processes. Specifically, PKC plays a major role in regulating epidermal cell proliferation and differentiation, and has recently been implicated in the pathophysiology of inflammatory-hyperproliferative skin diseases such as psoriasis. For example, several reports now provide evidence of alterations in the PKC signal transduction pathway in psoriasis and indicate the potential therapeutic value of a PKC inhibitor for the treatment of this disease. The natural product sphingosine, D-(+)-erythro-l,3-dihydroxy-2-amino-4-trans-octadecene (1), and related sphingolipids are known to inhibit PKC in vitro and display antiinflammatory activity in human neutrophils. Sphingosine (1) also reduces phorbol ester-induced inflammation and epidermal hyperplasia in vivo. In our efforts to develop new topically active antiinflammatory and antiproliferative agents we have recently reported the synthesis and evaluation of a variety of racemic erythro-aryl-sphingosine analogs. As a result of these studies we have identified three promising candidates for further study, including alkynyl-phenyl- and thiophene analogs 2, 3 and 4. We now wish to report the enantioselective synthesis and biological evaluation of these candidates.