Phytosphingosine, synthesis

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... 

Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-n7 o-phytosphingosine. The good stereoselectivity observed for 525 can be rationalized by a Felkin-Ahn transition state model although a chelation control mechanism could not be mled out. 

Since the synthesis of glycolipids involves the synthesis of both the lipid and the oligosaccharide portions, we shall also discuss that part of the recorded lipid synthetic work which has involved the use of carbohydrates. In fact, some of the first-recorded applications of carbohydrate molecules as chiral templates are to be found in the lipid field particularly with the use of 1,2 5,6-di-O-isopropylidene-D-mannitol [33] as a precursor of chiral glycerol derivatives for the synthesis of phospholipids and glycolipids based on glycerol and with the use of glucosamine derivatives for the synthesis of phytosphingosines [34] and since this area has not previously been reviewed, it will be treated with a more historical perspective. 

A further synthesis of phytosphingosine (11) was achieved [37] from D-galactose via 3,4,6-tri-O-benzyl-D-galactose. Reduction of the latter and subsequent acetonation gave the galactitol derivative (7), and this on mesylation and reaction with potassium... 

Murakami, T. Minamikawa, H. Hato, M. Regio- and stereocontrolled synthesis of D-erytbrosphingosine and phytosphingosine from D-glucosamine. Tetrahedron Lett. 1994,... 

Subsequently, as an application of this method, D-ribo-C18-phytosphingosine has been prepared stereoselectively from (S)-malic acid dimethyl ester 50. The electrophilic animating reaction with DTBAD proceeded with 62 % yield and the anti a-hydrazino P-hydroxy ester 51 was obtained as the major diastereomer (anti syn = 67 33). After separation of the two isomers, the synthesis of the enan- ... 

Enders D, Paleek J, Grondal C (2006a) A direct organocatalytic entry to sph-ingoids asymmetric synthesis of D-arabino- and L-ribo-phytosphingosine. Chem Commun 2006 655-657... 

Teles JH, Breuer K, Enders D, Gielen H (1999) One pot synthesis of 3,4-disubstituted l-alkyl-4H-l,2,4-triazol-l-ium salts. Synth Commun 29 1-9 Thorpe SR, Sweeley C (1967) Chemistry and metabolism of sphingolipids. On the biosynthesis of phytosphingosine by yeast. Biochemistry 6 887... 

For synthesis of phytosphingosine [40] and dihydrosphingosine [7], many methods have been reported. These utihzed a chiral pool strategy with amino acid or carbohydrate similar to that of sphingosine. 

The stereochemical features of the phytosphingosines include three consecutive chiral centers. Great efforts have been devoted to exploit how to control the stereochemistry. In the synthetic sequences, the alcohols are manipulated in a protected form which can be unmasked at later stages in the synthesis. The amino group has almost always been introduced via the azide group. 

In many cases, obtaining optically pure material is of foremost importance, particularly when the samples are used in a biological test. Because the early work on the synthesis of phytosphingosines was carried out with racemates, in this review I will focus on the work since the 1980s. 

In the first straightforward synthesis of phytosphingosine, Gigg s group11 used D-glucosamine as the starting material. Scheme 1 outlines the synthesis of N-benzoyl Cig-phytosphingosine 15. 

More recently, Murakami s group12 reported the synthesis of the phytosphingosine 22 using a modem version of Gigg s method (Scheme 2). 

In the second synthesis of phytosphingosine, outlined in Scheme 3, Gigg s group13 made possible the preparation of 1,3,4-tri-O-benzyl-L-galactitol 23 from D-galactose in good yield. They proved 23 to be an efficient starting material. 

The first asymmetric synthesis of a phytosphingosine was accomplished by Komori s group32 (Scheme 19). 

The synthesis of D-ribo-C 18-phytosphingosine 104 was achieved by a series of Wittig olefination, reduction, hydrolysis and acetylation steps. 

Kobayashi s group37 developed a new enantioselective synthesis of Cis phytosphingosine using catalytic asymmetric aldol reactions as a key step (Scheme 23). The key catalytic aldol reaction of acrolein with the ketene silyl acetal 148 derived from phenyl a-benzyloxyacetate was carried out by using tin(II) triflate, chiral diamine 149, and tin(II) oxide. The desired aldol product... 

The synthesis starts with commercially available phytosphingosine (Scheme 24). Thus 2 2 was IV-acylated with n-docosanoic acid N-hydroxysuccinimide ester. After protection of the primary alcohol, the other secondary hydroxyl groups were benzoylated and the silyl ether was deprotected to give the protected ceramide 157. 

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