Method of preparing sphingosine derivatives

{
  "publication_number": "US5110987A",
  "country": "US",
  "kind": "A",
  "title": "Method of preparing sphingosine derivatives",
  "abstract": "A method of preparing a substituted derivative of sphingosine comprising the steps of reducing serine methyl ester by a hydride reagent to form an aldehyde or aldehyde derivative, adding acetylide anions to the aldehyde to form an erythro-isomer or propargyl alcohol and inverting the propargyl alcohol by S N 2 inversion to form a threo-isomer. Either isomer can then be deprotected to form an alkyne with a 2-aminopropane 1,3-diol head group; this alkyne can be reduced to form sphingosine or a sphingosine derivitive which can be functionalized at the 4 and 5 positions to form a substituted derivative of sphingosine.",
  "claims": [
    "1. A method of preparing a threo-isomer of a derivative of sphingosine, wherein said derivative of sphingosine comprises the formula: ##STR9## wherein X and Y are selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkylamino and wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl, comprising the steps of: a) adding acetylide anions to an aldehyde or a derivative of said aldehyde that is capable of forming said derivative of sphingosine in substantially the same manner as said aldehyde to form an erythro-isomer of propargyl alcohol, said aldehyde having the formula: ##STR10## b) inverting said propargyl alcohol by S N 2 inversion to form a threo-isomer of propargyl alcohol; c) acidifying said threo-isomer to form a diol having the formula: ##STR11## wherein R is selected from the group consisting essentially of hydrogen, alkyl and aryl; d) cleaving said diol to form an amine having the formula: ##STR12## e) reducing said amine to form an alkene having the formula: ##STR13## and f) adding a functional group selected from the group consisting of hydrogen, hydroxyl, alkoxy, amino, alkylamino, and dialkylamino to the 4 and 5 position of said alkene to form said threo-isomer of a derivative of sphingosine.",
    "2. The method of claim 1, wherein said acetylide anions comprise alkali acetylides.",
    "3. The method of claim 1, wherein said acetylide anions comprise 1-lithiopentadecyne.",
    "4. The method of claim 1, wherein said S N 2 inversion is a Mitsunobu inversion.",
    "5. The method of claim 1, wherein said substituted derivative of sphingosine has a 2-aminopropane 1,3 diol head group.",
    "6. The method of claim 1, further comprising the step of adding a functional group to said derivative of sphingosine to form a compound of the formula: ##STR14## wherein W is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein X is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Y is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Z is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 2 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 3 is selected from the group consisting essentially of hydrogen, alkyl and aryl.",
    "7. A method of preparing a threo-isomer of a derivative of sphingosine, wherein said derivative of sphingosine comprises the formula: ##STR15## wherein X and Y are selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkylamino and wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl, comprising: a) reducing serine methyl ester by a hydride reagent to from an aldehyde or aldehyde derivative that is capable of forming said derivative of sphingosine in substantially the same manner as said aldehyde, said aldehyde having the formula: ##STR16## b) adding acetylide anions to said aldehyde or aldehyde derivative to form an erythro-isomer of propargyl alcohol; c) inverting said propargyl alcohol by S N 2 inversion to form a threo-isomer of propargyl alcohol; d) acidifying said threo-isomer to form a diol having the formula: ##STR17## wherein R is selected from the group consisting essentially of hydrogen, alkyl and aryl; e) cleaving said diol to form an amine having the formula: ##STR18## f) reducing said amine to form an alkene having the formula: ##STR19## and g) adding a functional group selected from the group consisting of hydrogen, hydroxyl, alkoxy, amino, alkylamino, and dialkylamino to the 4 and 5 position of said alkene to form said threo-isomer of a derivative of sphingosine.",
    "8. The method of claim 7, wherein said hydride reagent is an aluminum hydride reagent.",
    "9. The method of claim 7, wherein said hydride reagent is lithium aluminum hydride.",
    "10. The method of claim 7, wherein said reduction of serine methyl ester is accomplished by DIBAL reduction.",
    "11. The method of claim 7, wherein said acetylide anions comprise alkali acetylides.",
    "12. The method of claim 7, wherein said acetylide anions comprise 1-lithiopentadecyne.",
    "13. The method of claim 7, wherein said S N 2 inversion is a Mitsunobu inversion.",
    "14. The method of claim 7, wherein said substituted derivative of sphingosine has a 2-aminopropane 1, 3 diol head group.",
    "15. The method of claim 7, further comprising the step of adding a functional group to said derivative of sphingosine to form a compound of the formula: ##STR20## wherein W is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein X is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Y is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Z is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 2 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 3 is selected from the group consisting essentially of hydrogen, alkyl and aryl.",
    "16. The method of claim 1, wherein said derivative of sphingosine comprises the formula: ##STR21## wherein W is hydroxyl; wherein X is hydrogen; wherein Y is hydroxyl; wherein Z is hydroxyl; wherein R 1 is alkyl; wherein R 2 is hydrogen, and wherein R 3 is hydrogen.",
    "17. A method of preparing an erythro isomer of a derivative of sphingosine, wherein said derivative of sphingosine comprises the formula: ##STR22## wherein X and Y are selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkylamino and wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl, comprising the steps of: a) adding acetylide anions to an aldehyde or a derivative of said aldehyde that is capable of forming said derivative of sphingosine in substantially the same manner as said aldehyde to form an erythro-isomer of propargyl alcohol, said aldehyde having the formula: ##STR23## b) acidifying said propargyl alcohol to form a diol having the formula: ##STR24## wherein R is selected from the group consisting essentially of hydrogen, alkyl and aryl; c) cleaving said diol to form an amine having the formula: ##STR25## d) reducing said amine to form an alkene having the formula: ##STR26## and e) adding a functional group selected from the group consisting of hydrogen, hydroxyl, alkoxy, amino, alkylamino, and dialkylamino to the 4 and 5 position of said alkene to form said erythro-isomer of a derivative of sphingosine.",
    "18. The method of claim 17, wherein said acetylide anions comprise alkali acetylides.",
    "19. The method of claim 17, wherein said acetylide anions comprise 1-lighiopentadecyne.",
    "20. The method of claim 17, wherein said substituted derivative of sphingosine has a 2-aminopropane 1,3-diol head group.",
    "21. The method of claim 17, further comprising the step of adding a functional group to said derivative of sphingosine to form a compound of the formula: ##STR27## wherein W is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein X is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Y is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Z is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 2 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 3 is selected from the group consisting essentially of hydrogen, alkyl and aryl.",
    "22. A method of preparing an erythro isomer of a derivative of sphingosine, wherein said derivative of sphingosine comprises the formula: ##STR28## wherein X and Y are selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkylamino and wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl, comprising: a) reducing serine methyl ester by a hydride reagent to form an aldehyde or aldehyde derivitive that is capable of forming said derivative of sphingosine in substantially the same manner as said aldehyde, said aldehyde having the formula: ##STR29## b) adding acetylide anions to an aldehyde or aldehyde derivative to form an erythro-isomer of propargyl alcohol; c) acidifying said erythro-isomer to form a diol having the formula: ##STR30## wherein R is selected from the group consisting essentially of hydrogen, alkyl and aryl; d) cleaving said diol to form an amine having the formula: ##STR31## e) reducing said amine to form an alkene having the formula: ##STR32## and f) adding a functional group selected from the group consisting of hydrogen, hydroxyl, alkoxy, amino, alkylamino, and dialkylamino to the 4 and 5 position of said alkene to form said erythro-isomer of a derivative of sphingosine.",
    "23. The method of claim 22, wherein said hydride reagent is an aluminum hydride reagent.",
    "24. The method of claim 22, wherein said hydride reagent is lithium aluminum hydride.",
    "25. The method of claim 22, wherein said reduction of serine methyl ester is accomplished by DIBAL reduction.",
    "26. The method of claim 22, wherein said acetylide anions comprise alkali acetylides.",
    "27. The method of claim 22, wherein said acetylide anions comprise 1-lithiopentadecyne.",
    "28. The method of claim 22, wherein said substituted derivative of sphingosine has a 2-aminopropane-1,3-diol head group.",
    "29. The method of claim 22, further comprising the step of adding a functional group to said derivative of sphingosine to form a compound of the formula: ##STR33## wherein W is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein X is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Y is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkamino; wherein Z is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 2 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 3 is selected from the group consisting essentially of hydrogen, alkyl and aryl.",
    "30. A method of preparing a threo-isomer of sphingosine or a derivative thereof, wherein said derivative of sphingosine comprises the formula: ##STR34## wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl, comprising the steps of: a) adding acetylide anions to an aldehyde or a derivative of said aldehyde that is capable of forming said sphingosine or derivative thereof in substantially the same manner as said aldehyde to form an erythro-isomer of propargyl alcohol, said aldehyde having the formula: ##STR35## b) inverting said propargyl alcohol by S N 2 inversion to form a threo-isomer of propargyl alcohol; c) acidifying said threo-isomer to form a diol having the formula: ##STR36## wherein R is selected from the group consisting essentially of hydrogen, alkyl and aryl; d) cleaving said diol to form an amine having the formula: ##STR37## and e) reducing said amine to form an alkene having the formula: ##STR38##",
    "31. The method of claim 30, wherein said acetylide anions comprise alkali acetylides.",
    "32. The method of claim 30, wherein said acetylide anions comprise 1-lithiopentadecyne.",
    "33. The method of claim 30, wherein said S N 2 inversion is a Mitsunobu inversion.",
    "34. The method of claim 30, wherein said derivative of sphingosine has a 2-aminopropane 1,3-diol head group.",
    "35. The method of claim 30, further comprising the step of adding a functional group to said derivative of sphingosine to form a compound of the formula: ##STR39## wherein W is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Z is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 3 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 3 is selected from the group consisting essentially of hydrogen, alkyl and aryl.",
    "36. A method of preparing an erythro-isomer of sphingosine or a derivative thereof, wherein said derivative of sphingosine comprises the formula: ##STR40## wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl, comprising the steps of: a) adding acetylide anions to an aldehyde or a derivative of said aldehyde that is capable of forming said sphingosine or derivative thereof in substantially the same manner as said aldehyde to form an erythro-isomer of propargyl alcohol, said aldehyde having the formula: ##STR41## b) acidifying said propargyl alcohol to form a diol having the formula: ##STR42## wherein R is selected from the group consisting essentially of hydrogen, alkyl and aryl; c) cleaving said diol to form an amine having the formula: ##STR43## and d) reducing said amine to form an alkene having the formula: ##STR44##",
    "37. The method of claim 36, wherein said acetylide anions comprise alkali acetylides.",
    "38. The method of claim 36, wherein said acetylide anions comprise 1-lithiopentadecyne.",
    "39. The method of claim 36, wherein said derivative of sphingosine has a 2-aminopropane 1,3-diol head group.",
    "40. The method of claim 36, further comprising the step of adding a functional group to said derivative of sphingosine to form a compound of the formula: ##STR45## wherein W is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein Z is selected from the group consisting essentially of hydrogen, hydroxyl, alkoxy, amino, alkylamino and dialkyamino; wherein R 1 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 2 is selected from the group consisting essentially of hydrogen, alkyl and aryl; wherein R 3 is selected from the group consisting essentially of hydrogen, alkyl and aryl.",
    "41. The method of claim 1, wherein approximately equal molar ratios of said acetylide anions and said aldehyde react.",
    "42. The method of claim 7, wherein approximately equal molar ratios of said acetylide anions and said aldehyde react.",
    "43. The method of claim 17, wherein approximately equal molar ratios of said acetylide anions and said aldehyde react.",
    "44. The method of claim 22, wherein approximately equal molar ratios of said acetylide anions and said aldehyde react.",
    "45. The method of claim 30, wherein approximately equal molar ratios of said acetylide anions and said aldehyde react.",
    "46. The method of claim 36, wherein approximately equal molar ratios of said acetylide anions and said aldehyde react."
  ],
  "cpc": [
    "C07C 215/24",
    "C07C 271/16",
    "C07D 263/06"
  ],
  "assignees": [
    "UNIV EMORY"
  ],
  "filing_date": "1988-06-17",
  "publication_date": "1992-05-05",
  "grant_date": "1992-05-05",
  "priority_date": "1988-06-17",
  "application_number": "US-20839088-A",
  "family_id": "22774438",
  "citations": [
    "GB1444552A",
    "US2194294A",
    "US4463192A"
  ]
}