Sphingosine synthesis

Ketiospbinganlne (KS) synthclasc Sphingosine synthesis palmLtoy 1-CoA + serine KS+CQj... 

Ketosphinganine (JS) synthetase Sphingosine synthesis palmitoyl-CoA + serine - KS + C02... 

Scheme 2.32 Stereodivergent synthesis of threo- and erythro-sphingosines 124.

The aziridine-2-carboxaldehyde 56 can also serve as synthon for the synthesis of sphingosines, which are important biomembrane constituents [64]. One possible route involves the addition of an alanate to the aldehyde. In a later stage of this synthetic plan the aziridine can be opened, either via the intermediacy of an oxazoline or directly with dilute acid. Unfortunately, the reaction of aldehyde 56 with a vinylalanate has a poor diastereoselectivity of 3 2. Therefore, an alternative approach was considered, namely one involving the addition of a vinylzinc reagent to the aldehyde thereby employing our N-tritylaziridinediphenyl-methanol 51 as the chiral catalyst. Gratifyingly, only one diastereomer was obtained. Reductive removal of the trityl function, acetylation of the hydroxy... 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

This method has been applied in the enantioselective synthesis of d-erythro-sphingosine and phytosphingosine. Sphingosine became an important substance for studying signal transduction since the discovery of protein kinase C inhibition by this compound.48 Many efforts have been made to synthesize sphingosine and its derivatives.49 Kobayashi et al. reported another route to this type of compound in which a Lewis acid-catalyzed asymmetric aldol reaction was a key step. 

In the synthesis of D-eryt/zro-sphingosine (78 without BOC protection), the key step is the asymmetric aldol reaction of trimethylsilylpropynal 75 with ke-tene silyl acetal 76 derived from a-benzyloxy acetate. The reaction was carried out with 20 mol% of tin(II) triflate chiral diamine and tin(II) oxide. Slow addition of substrates to the catalyst in propionitrile furnishes the desired aldol adduct 77 with high diastereo- and enantioselectivity (syn/anti = 97 3, 91% ee for syn). In the synthesis of protected phytosphingosine (80, OH and NH2 protected as OAc and NHAc, respectively), the asymmetric aldol reaction is again employed as the key step. As depicted in Scheme 3-27, the reaction between acrolein and ketene silyl aectal 76 proceeds smoothly, affording the desired product 80 with 96% diastereoselectivity [syn/anti = 98 2) and 96% ee for syn (Scheme 3-27).50... 

Cerebrosides are major constituents of the membrane of brain cells. They are the simplest glycosphingolipids, serving as model substances for more complex lipids of this kind. Furthermore, they are credited with important properties as receptors for hormones and toxins.29 Schemes 4 13 and 4 14 provide a method for preparing sphingosine and its analogs that can be used for the synthesis of cerebroside compounds. 

The Pseudomonas putidae organisms were initially selected for their ability to use benzene as the sole carbon source and were thereafter mutated to prevent further metabolism of the cyclohexadienols produced. This provides an efficient approach to all four stereoisomers of sphingosine (Fig. 8-2)11 (see Chapter 3 for the synthesis of sphingosine compounds). 

Michel, C., Van Echten-Deckert, G., Rother, J., Sandhoff, K., Wang, E, and Merrill, A.H Jr., 1997, Characterization of Ceramide Synthesis. A Dihydroceramide desaturase intoduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. /. Biol. Chem. 111-. 22432-22437. 

The intracellular concentrations of sphingosine and SIP are governed by the activities of enzymes that catalyse their synthesis and removal. These include ceramidase, sphingosine kinase (SPHK), SIP phosphatase and SIP lyase (Figure 1). Several of these enzymes have only recently been cloned and knowledge of their respective roles and regulation is incomplete. 

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