Sphingolipids are a major component of cell membranes that play an important role in multiple biochemical processes such as cell growth, programmed cell apoptosis, stress responses, calcium homeostasis, cell migration, angiogenesis and vascular maturation. Sphingolipids are isolated from bio-organisms with a variety of specifically targeted bioactivities. For example, acetylaplidiasphingosines which were isolated from tunicates showed antibacteria and antifungal activity (Carter, J. Am. Chem. Soc. 1978, Vol. 100 (23); pp 7441-7442, which is incorporated herein by reference). In 1997, plakosides were shown to have strong immunosuppressive activity without significant cytotoxicity (Constantino, J. Am. Chem. Soc. 1978, Vol. 119 (51); pp 12465-12470, which is incorporated herein by reference).
Most natural sphingolipids are developed from D-erythro-sphingosine as the core unit. Phosphorylation yields sphingosine phosphates. These phosphorylated sphingolipids regulate a number of cellular processes with stimulatory activity including cell growth, differentiation, angiogenesis and maturation. Acylation of the amino group of the sphingosine produces ceramides, which are an important ingredients in cosmetic products for skin and hair care. Glycosylation of sphingosine results in glycosphingolipids, which have been found to have anticancer and antitumor activities.
Natural sphingolipids are isolated in trace quantities and in a heterogeneous form. Therefore, the synthesis of chemically homogenous sphingosines in high yield and enantiomeric purity is very important for drug discovery and for the cosmetics industry.
A number of synthetic strategies have been developed for producing sphingolipids, especially from sphingosine. However, these synthetic routes can still be economically impractical because of the reaction scale, poor stereoselectivity and E/Z selectivity.
From the methods reported in the literature, the most practical approach for the synthesis of sphingosine and its derivatives begins with the common amino acid, L-serine, as the starting material. It is very logical to start with naturally abundant L-serine because it bears the C-2 S-configuration and C-1 hydroxyl functionality. Garner et al developed a short method for sphingosine synthesis by producing enantiopure serine aldehyde. However, Garner's method did not allow the synthesis of high enantipurity sphingosine (i.e., ee>99%), since 1-3% epimerization occurs in the synthesis serine aldehyde (Garner, J. Org. Chem. 1987, Vol. 52 (12), pp 2361-2364, which is incorporated herein by reference). Therefore, there still exists a need for an economical, scalable, and efficient synthesis of sphingosines.
USPTO Backgrounds
USPTO Backgrounds