13031-64-6

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A novel sphingosine, 1,2-diacetyl D-erythro-sphinganine having a characteristic almond flavour was isolated from the edible mushroom Grifola gargal. We have synthesized this sphinganine along with the three other sphingolipids, such as 1,2-diacetyl L-threo-sphinganine, D-erythro-sphinganine triacetate and L-threo-sphinganine triacetate using Garner aldehyde as the starting material involving the Grignard reaction and Mitsunobu inversion. The sphingolipids 1,2-diacetyl D-erythro-sphinganine and 1,2-diacetyl L-threo-sphinganine have been synthesized for the first time. [Figure not available: see fulltext.]

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The development of an efficient synthetic route for an optically active ceramide compound (d-erythro-CER[NDS]) is described. The route proceeds through asymmetric transfer hydrogenation in a pipes-in-series flow reactor with oxo-tethered ruthenium complex-catalyzed dynamic kinetic resolution. This synthesis was accomplished without any expensive reagents, and none of the intermediates required isolation. This resulted in a robust process that has been successfully run on a production scale.

It is an objective of the present invention to produce an anti-form of an optically active β-hydroxy-α-aminocarboxylic acid ester efficiently, simply and industrially advantageously. The objective can be accomplished by directly and selectively producing the anti-form of the optically active β-hydroxy-α-aminocarboxylic acid ester by asymmetric reduction of a β-keto-α-aminocarboxylic acid ester using an optically active amine complex as a catalyst. Further, the β-keto-α-aminocarboxylic acid ester as a raw material can be produced at a high yield by reacting a glycine derivative with a carboxylic acid derivative.

An efficient and facile synthesis of phytosphingosine and dihydrosphingosine derivatives is described with less steps and in improved overall yield (66-72%) starting from commercially available tri-O-benzyl-D- galactal. The key steps include Wittig reaction, Mitsunobu transformation, reduction, and deprotection.

The present invention relates to specific sphingolipids/sphingolipid derivatives as pharmaceutical compositions as well as their use in the preparation of medicaments for the treatment, prevention and/or amelioration of disorders relating to pathological processes in lipid rafts.

A facile synthesis of a combinatorial ceramide library and their activities in the NF-κB pathway and in apoptosis induction/prevention were demonstrated. A novel NF-κB activating molecule was discovered among ceramide containing β-galactose, and the structural requirements of ceramides for apoptosis induction was elucidated. Copyright

Sixteen kinds of chiral C4-epoxides [(-)-10a-d,(+)-10a-d,(-)-11a-d,(+)-11a-d], which are synthons in our synthetic strategy for complex lipids, have been prepared from (2Z)-2-butene-1,4-diol (6) by employing a Sharpless asymmetric epoxidation. By using the chiral C4-epoxides [(+)-10a,(-)-10a,(-)-11a,(+)-11a] as starting compounds, two pairs of enantiomeric (D-erythro, L-erythro, D-threo, and L-threo)-C18-sphingosines (1, 2, 3, 4) have been synthesized via a regioselective ring-opening of the epoxide ring with azide anion followed by reduction of the azide group to an amino group and a Wittig reaction. Furthermore, D-erythro-C18-sphingosine (1) has been converted to a palmitoyl analogue (5a) of Gaucher spleen glucocerebroside (5) through a reaction pathway including successive condensations with palmitic acid and D-glucose.

Two pairs of enantiomeric (D-erythro, L-erythro, D-threo, L-threo) C18-sphingosines have been synthesized from Z-butene-1,4-diol utilizing Sharpless asymmetric epoxidation and a regiospecific ring-opening reaction of the resulting C4-chiral epoxide with an azide anion.

(Z)-1-Trichloroacetimidoyloxyoctadec-2-ene, easily obtained from (Z)-octadec-2-en-1-ol, was iodocyclized with N-iodosuccinimide to give the 4-(1-iodohexadecyl)-2-trichloromethyl-4,5-dihidro-oxazole.From this compound, two routes were developed, either to pure (+/-)-erythro-sphinganine triacetate or to pure (+/-)-threo-sphinganine triacetate, respectively.The neutral cleavage of 4-(1-iodohexadecyl)-2-trichloromethyl-4,5,-dihydro-oxazole gave the corresponding amide which, by treatment with Amberlyst A 26 (CO3(2-) form), afforded the cis-4-hydroxymethyl-5-pentadecyl-2-trichloromethyl-4,5-dihydro-oxazole together with a minor amount of cis-2-hydroxymethyl-3-pentadecylaziridine.After hydrolysis of the oxazole and full acetylation, (+/-)-erythro-sphinganine triacetate was obtained in 70 percent yield.On the other hand, acidic cleavage of the 4-(1-iodohexadecyl)oxazole 2-amino-3-iodo-octadecan-1-ol hydrochloride, which was directly treated with Amberlyst A 26 (AcO(-) form).The product was acetylated and (+/-)-threo-sphinganine triacetate was recovered in 70 percent yield after chromatographic separation.As an alternative, 3-trichloroacetimidoyloxyoctadec-1-ene was cyclized with N-iodosuccinimide to give a 20:80 cis:trans mixture of 4-iodomethyl-5-pentadecyl-2-trichloromethyl-4,5-dihydro-oxazoles.After ring cleavage, the corresponding ring-opened hydrochlorides were obtained.The mixture was then treated with Amberlyst A 26 (AcO(-) form) and the product was directly acetylated.After silica gel chromatography, (+/-)-threo-sphinganine triacetate and (+/-)-erithro-sphinganine triacete were obtained in good yield, in the ratio 80:20.

From the iodocyclization of (E)-1-trichloroacetimido-octadec-2-ene, 5-iodo-4-pentadecyl-2-trichloromethyl-5,6-dihydro-4H-oxazine was unexpectedly obtained, whose structue was assigned from i.r. and (1)H n.m.r. spectra.The stereostructure of this oxazine was further confirmed by chemical evidence: thus, the compound was hydrolysed on silica gel to give 2-iodo-3-trichloroacetimido-octadecan-1-ol, and successive treatment with Amberlyst A 26 (CO3(2-) form) yielded cis-5-hydroxymethyl-4-pentadecyl-4,5-dihydro-oxazole, whose configuration was determined by (1)H n.m.r. data.Acidic hydrolysis of this oxazole and acetylation led to erythro-3-aminno-octadecane-1,2-diol triacetate.To ascertain definitively the structure of this triacetate, 3-trichloroacetamido-octadec-1-ene was cyclized, to yield 5-iodomethyl-4-pentadecyl-4,5-dihydro-oxazole as a 45:55 cis:trans mixture.After hydrolysis of the cis-isomer, treatment with Amberlyst A 26 (AcO(1-) form), and full acetylation, the aforementioned erythro-triacetate was obtained.Confirming the unequivocal assignment of the stereostructure of 5-iodo-4-pentadecyl-2-trichloromethyl-5,6-dihydro-4H-oxazine, its acidic cleavage gave 3-amino-1-iodo-octadecan-2-ol hydrochloride.By treatment of this salt with Amberlyst A 26 (AcO(1-) form), full acetylation of the product afforded (+/-)-erythro-sphinganine triacetate in good yield, contaminated with a minor amount of the regioisomeric 3-amino-octadecanediol-triacetate.

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