[104194-02-7]  · C8H14O3  · (R,R)-2-t-Butyl-5-methyl-1,3-dioxolan-4-one  · (MW 158.20) (S,S)


(cyclic acetals from (R)- and (S)-lactic acid and pivaldehyde;1b,2-6 reagents for the preparation of enantiopure a-hydroxy-a-methyl carboxylic acids by alkylation of the corresponding lithium enolate with alkyl,1b,2-4 allyl,1b,2,7,8 and benzyl1b halides, by hydroxyalkylation with aldehydes and ketones,1b,3,9,10 and by Michael addition to nitroalkenes;9,11 precursor to the 5-bromo derivative used for radical reactions;12,13 precursor to 2-t-butyl-5-methylene-1,3-dioxolan-4-one;13-15 an acceptor for radical additions;15,16 and an ene component for Diels-Alder reactions leading to cyclic, heterocyclic, and bicyclic a-hydroxy carboxylic acids14,17-19)

Physical Data: mp ca. 5 °C; bp 80 °C/20 mmHg; [a]rtD = +44.8° (c = 1.83, CHCl3) for (S,S)-(1) containing 4% (2R,5S) epimer after two recrystallizations from ether/pentane at -75 °C.

Solubility: good to excellent in all common organic solvents.

Preparative Method: on a 0.5 mol scale reagent (S,S)-(1) is prepared by condensation of Pivalaldehyde and (S)-lactic acid under acid catalysis in pentane, with azeotropic removal of the water formed. The crude product is distilled in vacuo to give 93% of a 4:1 cis/trans mixture. Two recrystallizations from pentane/ether at -75 °C furnish 60% (S,S)-(1) (cis/trans = 96:4).

Handling, Storage, and Precautions: stable for many months under an inert atmosphere in a refrigerator.

Reactions of the Enolate of (1) with Electrophiles.

Addition of the dioxolanones (1) to solutions of Lithium Diisopropylamide or Lithium Hexamethyldisilazide in THF at dry-ice temperature generates the corresponding enolates which react with alkyl halides,1b,2-4,7,8 carbonyl compounds,1b,3,9,10 and nitroalkenes9,11 almost exclusively from the face remote from the t-Bu group to give products of type (2). These can be hydrolyzed to simple a-hydroxy-a-methyl carboxylic acids or further elaborated. Four examples are shown in (3)-(6) in which the part of the molecule originating from lactic acid is indicated in bold.

Analogous Transformations with other a-Hydroxy Carboxylic Acids.

The conversion of lactic acid to products (2)-(6) is an example of the principle of self-regeneration of the stereogenic centers (SRSC) which is also applicable to b-hydroxy-, a- and b-amino acids (see Related Reagents). Many a-hydroxy carboxylic acids occur naturally, and most a-amino acids can be converted to hydroxy acids by diazotization, with retention of configuration,20 producing a host of readily available starting materials for this kind of conversion, for example in the synthesis of the antitumor alkaloid (7).21 Table 1 lists various dioxolanones (8) made from the corresponding hydroxy acids and aldehydes or ketones, together with information on reactions carried out with them. This method is also applicable to a-mercapto carboxylic acids.1,22

(R)- and (S)-t-Butyl-5-methylene-1,3-dioxolan-4-one, a Chiral a-Alkoxy Acrylate.

It is also possible to introduce an exocyclic double bond onto the dioxolanone ring, as in compounds (9)-(11), derived from lactic13,14,17-19,26 and malic12,27 acids. These a,b-unsaturated carbonyl derivatives are acceptors for radical additions12,15,16 and undergo cycloadditions with dienes14,17-19,26,27 and heterodienes.18 The Diels-Alder adduct (12) of ent-(9) with cyclopentadiene is formed14,17a,19 with exo selectivity (96:4) and serves as a precursor to norbornenone (13).14,19 Cycloadduct (14), obtained from methylenedioxolanone (9) and an open-chain triene, is also the result of an exo addition and is used in tetronolide synthesis.17b

Menthone-Derived Dioxolanones: Chiral Glycolic Acid Derivatives.28

Acetalization of menthone and phenylmenthone with glycolic acid leads to chromatographically separable mixtures of diastereoisomeric dioxolanones (15) and (16); they are precursors for chiral enolate derivatives of glycolic acid. Alkylations occur highly selectively, and the products can be solvolyzed with ethanol to give ethyl a-hydroxy carboxylates of either (R) or (S) configuration. Thus spiro compound (16b) gives the allylation product (17) (84%), from which pure ethyl (R)-2-hydroxypent-4-enoate is obtained.

Related Reagents.

1-Benzoyl-2-t-butyl-3,5-dimethyl-4-imidazolidinone; (2S,4S)-3-Benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-5-one; t-Butyl 2-t-Butyl-3-methyl-4-oxo-1-imidazolidinecarboxylate; (R)-2-t-Butyl-6-methyl-4H-1,3-dioxin-4-one; Ethyl 3-Hydroxybutanoate; Ethyl Mandelate; (R)-Methyl 2-t-Butyl-3(2H)-oxazolecarboxylate; Methyl O-Methyllactate; Phenoxyacetic Acid; (-)-8-Phenylmenthol.

1. (a) Seebach, D.; Imwinkelried, R.; Weber, T. In Modern Synthetic Methods; Springer: New York, 1986; Vol. 4, pp 125-259. (b) Seebach, D.; Naef, R.; Calderari, G. T 1984, 40, 1313.
2. Fráter, G.; Müller, U.; Günther, W. TL 1981, 22, 4221.
3. Seebach, D.; Naef, R. HCA 1981, 64, 2704.
4. Naef, R.; Seebach, D. LA 1983, 1930.
5. Hoye, T. R.; Peterson, B. H.; Miller, J. D. JOC 1987, 52, 1351.
6. Greiner, A.; Ortholand, J.-Y. TL 1990, 31, 2135.
7. Krohn, K. T 1990, 46, 291.
8. Boeckman, R. K., Jr.; Yoon, S. K.; Heckendorn, D. K. JACS 1991, 113, 9682.
9. Suzuki, K.; Seebach, D. LA 1992, 51.
10. Naef, R. Dissertation ETH Nr. 7442, 1983.
11. Calderari, G.; Seebach, D. HCA 1985, 68, 1592 (CA 1986, 105, 133 326u).
12. Kneer, G.; Mattay, J. TL 1992, 33, 8051.
13. Zimmermann, J.; Seebach, D. HCA 1987, 70, 1104.
14. Mattay, J.; Mertes, J.; Maas, G. CB 1989, 122, 327.
15. Beckwith, A. L. J. Chai, C. L. L. CC 1990, 1087.
16. Beckwith, A. L. J. CSR 1993, 22, 143.
17. (a) Roush, W. R.; Essenfeld, A. P.; Warmus, J. S.; Brown, B. B. TL 1989, 30, 7305. (b) Roush, W. R.; Koyama, K. TL 1992, 33, 6227.
18. Mattay, J.; Kneer, G.; Mertes, J. SL 1990, 145.
19. Roush, W. R.; Brown, B. B. JOC 1992, 57, 3380.
20. Brewster, P.; Hiron, F.; Hughes, E. D.; Ingold, C. K.; Rao, P. A. D. S. Nature 1950, 166, 179.
21. Ogawa, T.; Niwa, H.; Yamada, K. T 1993, 49, 1571.
22. Strijtveen, B.; Kellogg, R. M. T 1987, 43, 5039.
23. Neveux, M.; Seiller, B.; Hagedorn, F.; Bruneau, C.; Dixneuf, P. H. JOM 1993, 451, 133.
24. Greiner, A.; Ortholand, J.-Y. TL 1992, 33, 1897.
25. Krohn, K.; Rieger, H. LA 1987, 515 (CA 1987, 107, 58 713d).
26. Roush, W. R.; Brown, B. B. TL 1989, 30, 7309.
27. Kneer, G.; Mattay, J.; Raabe, G.; Krüger, C.; Lauterwein, J. S 1990, 599.
28. Pearson, W. H.; Cheng, M.-C. JOC 1986, 51, 3746; 1987, 52, 1353, 3176; Pearson, W. H.; Hines, J. V. JOC 1989, 54, 4235.

Andrea Rolf Sting & Dieter Seebach

Eidgenössische Technische Hochschule Zürich, Switzerland

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