An Unexpected Access to a New Sphingoid Base Containing a Vinyl Sulfide Unit

Abstract

An unexpected access to a new sphingoid base containing a vinyl sulfide unit is described. The process involves the ‘one-pot’ regioselective opening of an epoxide with a thiolate, followed by intramolecular acyl transfer, base-promoted elimination, and final hydrolysis. Excess sodium hydride and high dilution conditions are required for optimal yields. The process is amenable to a variety of thiolates. The resulting compounds can be regarded as new hybrid sphingoid bases that combine some structural motifs present in other reported sphingolipid analogues.

amino alcohol - epoxide - thiolate - elimination - olefin - sphingolipids

References and Notes

1 Munoz-Olaya JM. Matabosch X. Bedia C. Egido-Gabas M. Casas J. Llebaria A. Delgado A. Fabrias G. ChemMedChem  2008,  3:  946 

2

The higher ^³ J value found for C4-H in the major isomer was indicative of the E-stereochemistry. Compound 3A (major isomer): δ = 6.32, (d, J = 14.9 Hz, 1 H), minor isomer: δ = 6.11, (d, J = 9.5 Hz, 1 H).

3 Bedia C. Canals D. Matabosch X. Harrak Y. Casas J. Llebaria A. Delgado A. Fabrias G. Chem. Phys. Lipids  2008,  156:  33 

4 Ager DJ. Prakash I. Schaad DR. Chem. Rev.  1996,  96:  835 

5

Minimizations were carried out with the MM2 package found in Chem3D ultra (version 9.0) from Cambridge Soft.

6 Koviach JL. Chappell MD. Halcomb RL. J. Org. Chem.  2001,  66:  2318 

7 Triola G. Fabrias G. Casas J. Llebaria A. J. Org. Chem.  2003,  68:  9924 

8 Grijalvo S. Matabosch X. Llebaria A. Delgado A. Eur. J. Org. Chem.  2008,  150 

9

The nucleophilic thiolate required for the opening of epoxide 1 can arise from deprotonation of the starting thiol by the transient alkoxide 4A (see Scheme  [²] ).

10

In light of these results, we cannot rule out at this point the possibility that the excess NaH reported in our previous work (ref. 1) was lower than assumed, probably due to adventitious reagent hydrolysis over prolonged storage.

11

Reactions carried out at higher concentration (0.05 M relative to epoxide 1) failed to give 3B, even in the presence of excess base (NaH/1 molar ratio 15:1). Concentrations between 0.05 and 0.02 M afforded variable mixtures of 2B and 3B.

12

Typical Procedure
A solution of 0.60 mmol of the required thiol in DMF (5 mL) was added dropwise over an ice-cooled suspension of NaH (250 mg of a 60% dispersion in mineral oil, 6.0 mmol) in DMF (10 mL) under Ar. Once the addition was complete, the reaction mixture was allowed to warm to r.t. and stirred for an additional 30 min until a suspension formed. A solution of epoxide 1 (100 mg, 0.4 mmol) in DMF (5 mL) was next added dropwise to the above suspension, and the reaction mixture was heated to 40 ˚C. After stirring for 4 h, the reaction was cooled to r.t. and quenched with H₂O (2.5 mL), dried with anhyd MgSO₄, and filtered. The solids were washed with Et₂O (3 × 5 mL) and the combined filtrates were evaporated to dryness to afford a crude residue, which was purified by flash chromatography. Data for compounds reported in Table  [²] are collected in the Supporting Information.

13

For example, the major E-isomers of a series of amides of 3A could be easily purified by conventional chromatog-raphic methods. Unpublished results.

14 Friestad GK. Jiang T. Fioroni GM. Tetrahedron  2008,  64:  11549 

15 Santos MA. Moreira R. Mini-Rev. Med. Chem.  2007,  7:  1040