Glycidyl Tosylate1

(R)-(-)

[113826-16-5]  · C10H12O4S  · Glycidyl Tosylate  · (MW 228.29) (S)-(+)

[70987-78-9]

(chiral C3 synthon;2 undergoes regio- and stereoselective ring opening at C-3 with alcohols in the presence of BF3.OEt2,3-8 Li2CuCl4-catalyzed Grignard reagents,9,10 and carbanions (with11 and without BF3.OEt2);12-15 undergoes direct attack at the C-1 position by nucleophiles, including aryl oxides9,16-26)

Physical Data: mp 47.5-48.5 °C; racemate mp 37.5-39 °C.9 [a]25D (S) enantiomer (&egt;97% enantiomeric excess) +18.1° (c 2.1, CHCl3),9 (R) enantiomer (~94% enantiomeric excess) -17.0° (c 2.75, CHCl3).4

Solubility: v sol chloroform, methylene chloride, and THF; insol hexane.

Form Supplied in: white solid; commercially available.

Analysis of Reagent Purity: enantiomeric purity can be assessed by the following procedures. Procedure A (no derivatization): Chiral HPLC on a Diacel OD column (10 mm, 0.46 × 25 cm); flow, 0.7 mL min-1; 99:1 hexane-2-propanol; tR: (S) enantiomer, 51.2 min; (R) enantiomer, 53.9 min.27 Procedure B: the reagent is opened to the iodohydrin; the crude iodohydrin is esterified with (R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetyl (MTPA) chloride; the resulting crude MTPA ester is analyzed by chiral HPLC and 1H NMR.28

Preparative Methods: the title reagent (1) is obtained in 40% overall yield by the zeolite-modified Sharpless asymmetric epoxidation of allyl alcohol, using D-(-)-diisopropyl tartrate (DIPT) to obtain (S)-(1) and L-(+)-DIPT to obtain (R)-(1), followed by in situ low-temperature tosylation of glycidol.28 Alternatively, (R)- and (S)-(1) can be prepared by direct sulfonylation of commercially available chiral Glycidol. Note that the relative configuration of (R)-glycidyl tosylate is the same as that of (S)-glycidol.

Purification: multiple recrystallizations from 5:1 ether-petroleum ether, seeding (before refrigeration) each time with pure material.28

Handling, Storage, and Precautions: mutagenicity via reactions with biological nucleophiles has been assessed by using the Ames test in Salmonella typhimurium and by analysis of in vivo chromosomal aberrations.29 (S)-(1) was more mutagenic than (R)-(1).29 Use in a fume hood.

Displacement Reactions.

Aryl oxides attack (R)- or (S)-(1) at the C-1 position, displacing the tosylate group and affording aryloxymethyloxiranes (2) in good yield (see examples in Table 1). The latter react with amines in aqueous alcohol, yielding b-adrenergic blocking agents of high enantiomeric excess.9 The regioselectivity for attack at the C-1 vs. C-3 position of (1) is very high, i.e. &egt;97:3 in DMF at rt9 and 85:15 in refluxing acetone.18 The ratio of C-1:C-3 attack on the related substrates, (S)-glycidyl 3- or 4-nitrobenzenesulfonate, by 1-naphthol in DMF at rt is >99.8:0.02.9 A comparison of the C-1:C-3 product ratio obtained from several glycidyl arenesulfonates suggested that attack by aryl oxide nucleophiles at C-1 is enhanced when the electron deficiency of the leaving group is increased (see Table 1).9

Reaction of Catechol with (R)- or (S)-(1) (Potassium Carbonate, DMF, 60 °C, 27 h;25 or Sodium Hydride, DMF, rt, 10 h26) affords (S)- or (R)-2-hydroxymethyl-1,4-benzodioxane in yields of 72%25 and 18-21%26 (eq 1).

Ring-Opening Reactions.

Epoxide opening takes place at the C-3 position of (1) with a wide variety of nucleophiles, as summarized below.

Alcohols and Benzenethiol.

These react with (1) in methylene chloride or chloroform, generally at rt, in the presence of catalytic Boron Trifluoride Etherate (eq 2). The following alcohols have been used (yields in parentheses): benzyl alcohol (81-84%);3b,4,8 1-hexadecanol (80%);3 Cl(CH2)6OH (80%);5 Cl(CH2)16OH (85%);5 methanol (100%);7 MeO2C(CH2)5OH (89%).6 Benzenethiol gives 3-phenylthio-2-hydroxy-1-tosyloxypropane in 81-83% yield.3b The 4-methylbenzene- and 3- nitrobenzenesulfonate derivatives of glycidol give exclusive formation of the C-3-opened product in the BF3-mediated reaction,3,4 whereas the t-butyldiphenylsilyl ether derivative of glycidol gives a regioselectivity (C-3 vs. C-2 isomer ratio) of 89:11 with benzyl alcohol, 93:7 with benzenethiol, and 90:10 with long-chain alcohols.3b

Halide and Azide Anions.

These also open the epoxide regioselectively at the C-3 position. Addition of Li2CuBr4 results in bromide addition at the C-3 position of rac-(1), forming 3-bromo-1,2-propane 1-O-tosylate in 70-76% yield in THF or acetonitrile at rt, or 1,3-dibromo-2-propanol in 82% yield in refluxing acetonitrile.30 Hydrofluorination takes place with KHF2 under solid-liquid phase transfer conditions, but the yield of fluorohydrin is very low (eq 3).31 Azidotrimethylsilane adds in the presence of a Lewis acid catalyst (eq 3).32 Addition of cyanide ion is achieved by using Diethylaluminum Cyanide in toluene.9

Addition of concentrated HCl to solid (S)-(1) at rt, followed by treatment of the ring-opened intermediate with sodium ethyleneglycolate, forms (R)-epichlorohydrin in 54% yield.33a The analogous reaction was carried out using (S)-glycidyl mesylate in 85%33b and 68% yield,33c and with rac-(1).33d

Carbanions.

These add to the C-3 position of (S)-(1), affording epoxides (3) after intramolecular displacement of the tosylate group and in situ ring closure of the ring-opened intermediate (eq 4). Deprotonation of oxirane (3) leads to rearrangement to cyclopropane derivatives.11a,12,13

There are many examples of BF3.OEt2 promoted openings of (1) by carbanions, including sulfone-stabilized anions,11a vinylic anions,11b allylic anions,14 and phosphonate-stabilized anions.15 For example, the lithium anion of trans-1,2-Bis(tributylstannyl)ethylene opens (S)-(1) in the presence of BF3.OEt2 in THF at -78 °C, affording trans-1-(tributylstannyl)-5-tosyl-4-hydroxypent-1-ene in 50% yield; the latter is converted into oxirane (3) in 76% yield on treatment with powdered Sodium Hydroxide in monoglyme.11b

The carbanion derived from pentacarbonyl(methoxymethylcarbene)chromium(0) reacts with (R)-(1) in the presence of BF3.OEt2 to give a lactone in low yield after oxidation of the ring-opened intermediate.14

Lithium diethylmethanephosphonate adds to rac-(1) in the presence of BF3.OEt2 at -78 °C to afford a phosphonate ester in good yield (eq 5).15

Organometallic Reagents.

The major product of the Dilithium Tetrachlorocuprate(II)- or Copper(I) Iodide-catalyzed Grignard reaction in THF or ether at low temperature arises from epoxide opening rather than from direct tosylate displacement (Table 2).9,10

Organolithium reagents add to (R)- and (S)-(1) as shown in eq 6.9

Hydride addition to (S)-(1) is achieved by use of BH3 in THF with 0.05 equiv of Sodium Borohydride, forming (S)-1-O-tosyloxy-2-hydroxypropane in 81% yield.9

Miscellaneous Addition Reactions.

Alkylation of MeC(OEt)=N-O- Na+ with (R)-(1) gives (S)-N-(oxiranylmethoxy)ethanimidic acid ethyl ester in 34% yield.34 Reaction of (S)-(1) with guanosine occurs at the N-7 position, giving (after deribosylation) (S)-7-(3-O-p-tolyl-2,3-dihydroxypropyl)guanosine in 56% yield.35

Fatty acid anhydrides react with (R)- and (S)-(1) in the presence of BF3.OEt2, giving a glyceryl tosylate with two identical fatty acid ester linkages in 76% yield.36

Reaction of (S)-(1) with acetonitrile at low temperature in the presence of BF3.OEt2 gives an oxazoline that is unstable at rt (eq 7).9


1. For a review of syntheses involving nonracemic glycidol and related 2,3-epoxy alcohols, see: Hanson, R. M. CRV 1991, 91, 437.
2. For a review of recent syntheses of glycerolipids from (1) and other glycidyl derivatives and other precursors, see: Bittman, R. In Phospholipids Handbook; Cevc, G., Ed.; Dekker: New York, 1993; pp 141-232.
3. (a) Guivisdalsky, P. N.; Bittman, R. TL 1988, 30, 4393. (b) Guivisdalsky, P. N.; Bittman, R. JACS 1989, 111, 3077. (c) Guivisdalsky, P. N.; Bittman, R. JOC 1989, 54, 4637. (d) Guivisdalsky, P. N.; Bittman, R. JOC 1989, 54, 4643.
4. Ali, S.; Bittman, R. Biochem. Cell Biol. 1990, 68, 360.
5. Berkowitz, W. F.; Pan, D.; Bittman, R. TL 1993, 34, 4297.
6. Kazi, A. B.; Hajdu, J. TL 1992, 33, 2291.
7. Deveer, A. M. Th. J.; Dijkman, R.; Leuveling-Tjeenk, M.; van den Berg, L.; Ransac, S.; Batenburg, M.; Egmond, M.; Verheij, H. M.; De Haas, G. H. B 1991, 30, 10034.
8. Byun, H.-S.; Bittman, R. TL 1989, 30, 2751.
9. Klunder, J. M.; Onami, T.; Sharpless, K. B. JOC 1989, 54, 1295.
10. Bertrand, P.; Gesson, J.-P. SL 1992, 889.
11. (a) Baldwin, J. E.; Adlington, R. M.; Bebbington, D.; Russell, A. T. CC 1992, 1249. (b) Biskupiak, J. E.; Grierson, J. R.; Rasey, J. S.; Martin, G. V.; Krohn, K. A. JMC 1991, 34, 2165.
12. Narjes, F.; Schaumann, E. S 1991, 1168.
13. Narjes, F.; Bolte, O.; Icheln, D.; König, W. A.; Schaumann, E. JOC 1993, 58, 626.
14. Lattauda, L.; Licandro, E.; Maiorana, S.; Molinari, H.; Papagni, A. OM 1991, 10, 807.
15. Racha, S.; Li, Z.; El-Subbagh, H.; Abushanab, E. TL 1992, 33, 5491.
16. Collington, E. W.; Finch, H.; Montana, J. G.; Taylor, R. J. K. JCS(P1) 1990, 1839.
17. Iguchi, S.; Iwamura, H.; Nishizaki, M.; Hayashi, A.; Senokuchi, K.; Kobayashi, K.; Sakaki, K.; Hachiya, K.; Ichioka, Y.; Kawamura, M.; CPB 1992, 40, 1462.
18. Hammadi, A.; Crouzel, C. TA 1990, 1, 579.
19. Krause, H. W.; Schmidt, U.; Foken, H. Pharmazie 1992, 47, 838.
20. Vo, D.; Wolowyk, M. W.; Knaus, E. E. Drug Des. Discovery 1992, 9, 69.
21. Gustavson, L. M.; Nelson, W. L. Drug Metab. Dispos. 1988, 16, 217.
22. Talaat, R. E.; Nelson, W. L. Drug Metab. Dispos. 1988, 16, 212.
23. Dasher, W. E.; Klein, P.; Nelson, W. L. JMC 1992, 35, 2374.
24. Gerken, M.; Grimm, M.; Raab, E.; Hoffmann, D.; Straub, R. Eur. Patent Appl. 485 894, 1992 (CA 1993, 117, 131 503y).
25. Delgado, A.; Leclerc, G.; Lobato, C.; Mauleon, D. TL 1988, 29, 3671.
26. Marciniak, G.; Delgado, A.; Leclerc, G.; Velly, J.; Decker, N.; Schwartz, J. JMC 1989, 32, 1402.
27. Shaw, C. J.; Barton, D. L. J. Pharm. Biomed. Anal. 1991, 9, 793. For chiral HPLC on a Chiracel OB-H column, see Chen, J.; Shum, W. TL 1993, 34, 7663.
28. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. JACS 1987, 109, 5765.
29. Sinsheimer, J. E.; Chen, R.; Das, S. K.; Hooberman, B. H.; Osorio, S.; You, Z. Mutat. Res. 1993, 298, 197.
30. Ciaccio, J. A.; Heller, E.; Talbot, A. SL 1991, 248.
31. Landini, D.; Albanese, D.; Penso, M. T 1992, 48, 4163.
32. (a) Sutowardoyo, K. I.; Sinou, D. TA 1991, 2, 437. (b) Emziane, M.; Lhoste, P.; Sinou, D. S 1988, 541. (c) Sinou, D.; Emziane, M. TL 1986, 27, 4423.
33. (a) Takle, A.; Kocienski, P. T 1990, 46, 4503; an erroneous assignment of configuration of the starting material (1) was apparently made. (b) Baldwin, J. J.; Raab, A. W.; Menster, K.; Arison, B. H.; McClure, D. E. JOC 1978, 43, 4876. (c) Pirrung, M. C.; Dunlap, S. E.; Trinks, U. P. HCA 1989, 72, 1301. (d) Nakabayashi, N.; Masuhara, E.; Iwakura, Y. BCJ 1966, 39, 413.
34. Stanek, J.; Caravatti, G.; Frei, J.; Capraro, H. G. JMC 1992, 35, 1339.
35. Sessler, J. L.; Magda, D. J.; Lynch, V.; Schiff, G. M.; Bernstein, D. I. Nucleosides Nucleotides 1989, 8, 431.
36. Ali, S.; Bittman, R. JOC 1988, 53, 5547.

Robert Bittman

Queens College of The City University of New York, Flushing, NY, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.