Concise Total Synthesis of (-)-D-erythro-Sphingosine and Sphingosine-1-Phosphate Pubblico

Abstract

A short and efficient synthesis of high enantiopurity (-)-D-erythro-sphingosine has been achieved in 71% yield over 6 steps from N-Boc-L-serine. The key steps are high yield, racemization-free, palladium-catalyzed, copper(I)-mediated coupling of the thiophenyl ester of N-Boc-O-TBS L-serine with E-1-pentadecenyl boronic acid and the highly diastereoselective reduction of the resulting peptidyl ketone with LiAl(OtBu)3. Using this concise route (-)-D-erythro-sphingosine can be prepared on large scale and in high enantio- and diastereopurity (ee >99%, de up to 99%).

Table of Contents

Table of Contents 1. Introduction...1 2. Results and Discussion...6

2.1 Synthesis of L-Serine Derived Thiol Ester...6 2.2 Cross Coupling Reactions...8 2.3 Asymmetric Reduction...9 2.4 Completion of Total Synthesis of (-)-D-erythro-Sphingosine...12 2.5 Synthesis Sphingosine Derivatives...13

3. Conclusions...18 4. References...19 5. Experimental section...22

List of Schemes Scheme 1. Garner's sphingosine synthesis...2 Scheme 2. Synthesis of sphingosine via Horner-Wadsworth-Emmons reaction...3 Scheme 3. Cross-metathesis strategy...3 Scheme 4. Liebeskind thio-organic cross coupling...5 Scheme 5. Synthesis of high enantiopurity peptidic ketone...5 Scheme 6. Retrosynthetic analysis...6 Scheme 7. Synthesis of thiol ester with high enantiopurity...6 Scheme 8. The solvent effect of cross coupling...7 Scheme 9. Racemization of O-silylation...8 Scheme 10. Diastereoselective chelation-controlled reduction of β-hydroxyketone...9 Scheme 11. Hydroxyl-directed ketone reduction gives the anti-diol...10 Scheme 12. Diastereoselective reduction...10 Scheme 13. Racemization of desilylation...11 Scheme 14. syn- and anti- Selective reduction of N-protected β-amino ketone...11 Scheme 15. anti- Selective reduction...12 Scheme 16. Completion of total synthesis of (-)-D-erythro-sphingosine...13 Scheme 17. Synthesis of sphingosine triacetate derivative...13 Scheme 18. Glycosylation with glucose penta-acetate...15 Scheme 19. Koenig-Knorr glycosylation...15 Scheme 20. Using glycodonor as nucleophile...16 Scheme 21. Tf2O mediated glycosylation...16 Scheme 22. O-Functionalized derivatives...17 Scheme 23. Synthesis of sphingosine-1-phosphate...17

List of Tables

Table 1. Synthesis of various N-protected serine thiophenyl esters...7 Table 2. The Cross-Coupling...9 Table 3. Phosphorylation of N-Boc serine thiophenyl ester...14

List of Figures Figure 1. (-)-D-erythro-Sphingosine...1 Figure 2. Typical Sphingolipids...1 Figure 3. Liebeskind-Srogl cross coupling...4 Figure 4. Proposed transition state...12 Figure 5. Intramolecular hydrogen bonding interaction...14

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	MS
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Parola chiave	sphingosine sphingolipid ceramide
Committee Chair / Thesis Advisor	Liebeskind, Lanny S, Emory University
Committee Members	Conticello, Vincent, Emory University Padwa, Albert, Emory University

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