(R)-Pantolactone1

[599-04-2]  · C6H10O  · (R)-Pantolactone  · (MW 130.16)

(effective chiral auxiliary in diastereoselective Diels-Alder reactions,1 and for diastereoselective addition to ketenes;2 used as a chiral pool reagent; also used as a covalently bound resolving agent3)

Alternate Name: (R)-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone.

Physical Data: mp 92 °C; bp 120-122 °C/15 mmHg; [a]25D -50.7° (c 2.05, H2O).

Solubility: sol water, alcohols, benzene, ether, chlorocarbons, THF.

Form Supplied in: crystalline white solid; commercially available.

Handling, Storage, and Precautions: hygroscopic.

Availability.

Although commercially available via the degradation of pantothenic acid, (R)-pantolactone is also conveniently prepared by enantioselective reduction of its corresponding keto lactone employing homogeneous catalysis,4a-g or by microbial methods.5 The (S)-enantiomer has been prepared by inversion of the natural product in 90% yield and 97% ee via triflate activation, acetate displacement, and Lithium Hydroxide hydrolysis.6 The enantiomers were also prepared by resolution of the racemate with (R)- and (S)-phenethylamine.7 A gas chromatographic method exists for ee determination.8

Diels-Alder Reactions.

(R)-Pantolactone is one of the most effective chiral auxiliaries for preparative scale Diels-Alder additions of simple enoate esters in the presence of Lewis acids (eq 1).9

Endo-exo selectivity typically ranges from 20:1 to 45:1 with a maximum of 97.5:2.5 diastereoselection. Preparatively convenient reaction conditions are employed (CH2Cl2, CH2Cl2/cyclohexane; temp. approx. 0 °C; ca. 0.3 M concentration; and 0.1-1.0 molar equiv of Lewis acid). Products are typically crystalline and brought to high optical purity by recrystallization. Epimerization-free hydrolysis is effected with LiOH in THF/water. This procedure has been successfully applied in a nine-step synthesis of cyclosarkomycin in 17% overall yield (eq 2),10 and to syntheses of the sandalwood fragrances.11

The cyclohexane unit of the C(30) stereocenter of the C(18)-C(35) segment of FK-506 was established in excellent yield and de employing the same concept (eq 3).6

(E)-2-Cyanocinnamates have been similarly used as dienophiles. An endo-exo selectivity of 85:15 at a diastereoselectivity of 99:1 was obtained (eqs 4 and 5).12,13

Further variations in dienophile have been equally successful (eqs 6 and 7),14 including applications to the Michael reaction (eq 7)15 and in the synthesis of a prostaglandin intermediate (eq 8).16

Ketene Additions.

Reaction of the ketene derived from ibuprofen (Ar = p-isobutylphenyl) with (R)-pantolactone in the presence of simple tertiary amine bases in apolar solvents yielded a >99% de favoring the (R,R)-ester (eq 9).3 The reaction is first order in each component and possesses a pronounced deuterium isotope effect (kH/kD &AApprox; 4). The ketene from naproxen (Ar = 2-(6-methoxynaphthyl)) affords a de of 80% under similar conditions.

Extension of this work to a series of bromo- and iodoketenes proceeds with good to excellent de (eq 10).17 Reaction of the products with azide ion affords a ready entry into amino acid synthesis (eq 11). However, with R = aryl, no selectivity was noted, possibly due to base-mediated epimerization under the reaction conditions.

Chiral Pool Reagent.

(R)-Pantolactone has been used as a source of chiral fragments for synthesis. Applications include use in the syntheses of the elfamycins (eq 12)18 and the bryostatins (eq 13).19a,b It has also been used to prepare potentially useful chiral epoxide synthons possessing a quaternary gem-dimethyl carbon.20

Miscellaneous Applications.

Only one attempt to use (R)-pantolactone as an enantioselective protonating agent for enolates has been reported.21 A series of structurally diverse chiral alcohols afforded modest ee's with (R)-pantolactone affording the largest ee noted for the series. The complexities of attempting a protonation of this sort in the presence of base and under exchanging conditions are discussed. Finally, the lactone has been used to resolve chiral acids by crystallization and chromatographic techniques applied to the (R)-pantolactone-derived esters.3,22,23

Related Reagents.

(S)-Ethyl Lactate; Ethyl Mandelate; 3-Hydroxyisoborneol.


1. Helmchen, G.; Hady, A. F. A.; Hartmann, H.; Karge, R.; Krotz, A.; Sartor, K.; Urmann, M. PAC 1989, 61, 409.
2. Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.; Grabowski, E. J. J. JACS 1989, 111, 7650.
3. Duke, C. C.; Wells, R. J. AJC 1987, 40, 1641.
4. (a) Ojima, I.; Kogure, T.; Yoda, Y. OS 1985, 63, 18. (b) Ojima, I.; Kogure, T.; Terasaki, T.; Achiwa, K. JOC 1978, 43, 3444. (c) Morimoto, T.; Takahashi, H.; Fujii, K.; Chiba, M.; Achiwa, K. CL 1986, 2061. (d) Hatat, C.; Karim, A.; Kokel, N.; Mortreux, A.; Petit, F. TL 1988, 29, 3675. (e) Genet, J. P.; Pinel, C.; Mallart, S.; Juge, S.; Cailhol, N.; Laffitte, J. A. TL 1992, 33, 5343. (f) Takahashi, H.; Hattori, M.; Chiba, M.; Morimoto, T.; Achiwa, K. TL 1986, 27, 4477. (g) Hatat, C.; Karim, A.; Kokel, N.; Mortreux, A.; Petit, F. NJC 1990, 14, 141.
5. Shimizu, S.; Yamada, H.; Hata, H.; Morishita, T.; Akutsu, S.; Kawamura, M. ABC 1987, 51, 289.
6. Corey, E. J.; Huang, H. C. TL 1989, 30, 5235.
7. Nohira, H.; Nohira, M.; Yoshida, S.; Osada, A.; Terunuma, D. BCJ 1988, 61, 1395.
8. Brunner, H.; Forster, St. M 1992, 123, 659.
9. Poll, T.; Sobczak, A.; Hartmann, H.; Helmchen, G. TL 1985, 26, 3095.
10. Linz, G.; Weetman, J.; Hadey, A. A. F.; Helmchen, G. TL 1989, 30, 5599.
11. Krotz, A.; Helmchen, G. TA 1990, 1, 537.
12. Cativiela, C.; Mayoral, J. A.; Avenoza, A.; Peregrina, J. M.; Lahoz, F. J.; Gimeno, S. JOC 1992, 57, 4664.
13. Avenoza, A.; Cativiela, C.; Mayoral, J. A.; Peregrina, J. M. TA 1992, 3, 913.
14. Hanzawa, Y.; Suzuki, M.; Kobayashi, Y.; Taguchi, T.; Iitaka, Y. JOC 1991, 56, 1718.
15. Knol, J.; Jansen, J. F. G. A.; Van Bolhuis, F.; Feringa, B. L. TL 1991, 32, 7465.
16. Miyaji, K.; Arai, K.; Ohara, Y.; Takahashi, Y. U.S. Patent 4 837 344, 1989.
17. Durst, T.; Koh, K. TL 1992, 33, 6799.
18. Dolle, R. E.; Nicolaou, K. C. JACS 1985, 107, 1691.
19. (a) DeBrabander, J.; Vanhessche, K.; Vandewalle, M. TL 1991, 32, 2821. (b) Roy, R.; Rey, A. W.; Charon, M.; Molino, R. CC 1989, 1308.
20. Lavallée, P.; Ruel, R.; Grenier, L.; Bissonnette, M. TL 1986, 27, 679.
21. Gerlach, U.; Hünig, S. AG(E) 1987, 26, 1283.
22. Allan, R. D.; Bates, M. C.; Drew, C. A.; Duke, R. K.; Hambley, T. W.; Johnston, G. A. R.; Mewett, K. N.; Spence, I. T 1990, 46, 2511.
23. Mash, E. A.; Arterburn, J. B.; Fryling, J. A.; Mitchell, S. H. JOC 1991, 56, 1088.

Edward J. J. Grabowski

Merck Research Laboratories, Rahway, NJ, USA



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