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Synlett 2005(14): 2183-2186  
DOI: 10.1055/s-2005-872242
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Enantioselective Total Synthesis of arabino-Phytosphingosine

Doo Young Jung, Sol Kang, Suk Bok Chang, Yong Hae Kim*
Center for Molecular Design and Synthesis, Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, 305-701, Korea
Fax: +82(42)8695818; e-Mail: kimyh@kaist.ac.kr;
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Publication History

Received 22 June 2005
Publication Date:
22 July 2005 (online)

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Abstract

Enantioselective total synthesis of arabino-phytosphingosine has been achieved in 8 steps employing Claisen rearrangement and Fleming-Tamao oxidation as key steps. Installation of all chiral centers present in arabino-phytosphingosine was achieved through the use of asymmetric catalysis. This synthesis provides one of the most efficient routes to prepare 2-amino-1,3,4-triol moiety.

Key words

amino alcohol - enantioselective synthesis - total synthesis - sphingolipids - Claisen rearrangement

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Experimental Procedure for the Synthesis of Allylsilane 3.
A freshly prepared solution of LDA (2.1 equiv) in THF under argon was cooled down to -78 °C. To the above solution, the allylic ester 4 was added rapidly. The resulting mixture was left to stir for 3 min and then treated with 3.0 equiv of TMSCl. This solution was allowed to warm to r.t. and stirred for further 2 h. The reaction was quenched with dilute aq HCl and extracted with EtOAc. The extract was dried over MgSO4, filtered and concentrated under reduced pressure to give crude carboxylic acid. The crude product was dissolved in the mixed solvent of MeOH-benzene (1:1) and treated with TMS-diazomethane (2.0 equiv). The mixture was stirred for 30 min at r.t. and concentrated in vacuo to give crude γ,δ-unsaturated methyl ester 3. The crude ester 3 was purified by silica gel column chromatography using EtOAc-n-hexane = 1:8 as eluents. 1H NMR (300 MHz, CDCl3): δ = 7.45-7.48 (m, 2 H), 7.24-7.33 (m, 3 H), 5.29 (m, 1 H), 5.14 (m, 1 H), 4.87 (br d, 1 H), 4.31 (br t, 1 H), 3.52 (s, 3 H), 2.05 (m, 1 H), 1.95 (m, 2 H), 1.38 (s, 9 H), 1.24 (br s, 24 H), 0.86 (t, 3 H), 0.31 (d, 6 H). 13C NMR (75 MHz, CDCl3): δ = 0.3, 1.1, 12.9, 22.8, 23.1, 28.4, 30.1, 30.6, 30.7, 32.5, 33.7, 50.4, 53.5, 71.0, 127.8, 128.4, 128.9, 133.6, 133.9, 140.4, 158.1, 170.9. MS (EI): m/z calcd for C31H53NO4Si: 544.29; found: 545.3900.

22

Experimental Procedure for the Synthesis of arabino -Phytosphingosine.
To a solution of acetonide 9 in CH2Cl2, 8 equiv of NaHCO3 was added. The resulting mixture was cooled to 0 °C and then, 4 equiv of MCPBA were added in one portion. The resulting mixture was allowed to warm to r.t. over 6 h. The reaction was quenched by the addition of sat. aq Na2SO3 solution and extracted with CH2Cl2. The resulting organic layer was washed twice with sat. aq NaHCO3 solution, dried over anhyd MgSO4, filtered and concentrated in vacuo. The crude epoxide 2 was dissolved in anhyd THF and cooled to 0 °C. It was treated with 2 equiv of lithium triethylboro-hydride and allowed to stir for additional 2 h. The reaction was quenched with dilute aq HCl and extracted with EtOAc. The extract was dried over MgSO4, filtered and concentrated under reduced pressure to give crude alcohol 10. The resulting crude alcohol 10 was purified by silica gel column chromatography using EtOAc-n-hexane = 1:4 as eluents. The alcohol 10 was placed in a round-bottom flask and the mixture of TFA-HOAc (1: 1) was added. To the above mixture was added 2.0 equiv of mercury trifluoroacetate. After 15 min of stirring, 4 equiv of peracetic acid (40 wt% in acetic acid) were added and stirring was continued overnight with exclusion of light. The reaction mixture was diluted with Et2O and washed successively with excess amount of aq NaHCO3 solution and aq Na2SO3 solution. The combined aqueous layer was again extracted with Et2O several times. The resulting organic layer was washed with sat. aq NaHCO3 solution twice, dried over anhyd MgSO4, filtered and concentrated in vacuo. To the resulting crude arabino-phytosphingosine was added THF and it was treated with excess pyridine and Ac2O. The reaction was quenched with dilute aq HCl and extracted with EtOAc. The extract was dried over MgSO4, filtered and concentrated under reduced pressure to give crude tetraacetyl arabino-phytosphingosine (1). The resulting crude 1 was purified by silica gel column chromatography using EtOAc-n-hexane = 1:5 as eluents to give pure tetraacetyl arabino-phytosphingosine whose spectral data are identical with those reported in literature. [10b] 1H NMR (300 MHz, CDCl3): δ = 5.63 (d, 1 H), 5.19 (dd, 1 H), 5.00 (dt, 1 H), 4.60 (m, 1 H), 4.00 (d, 2 H), 2.11 (s, 3 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 1.99 (s, 3 H), 1.54 (br s, 2 H), 1.24 (br s, 24 H), 0.88 (t, 3 H). [α]D 25 -24.7 (c 1.0, CHCl3); lit. [α]D 25 -25.1 (c 1.5, CHCl3).