· (MW 170.21)
(enantiopure derivative of acetoacetic acid,2-4 highly reactive Michael acceptor for CuI-doped Grignard and for Gilman reagents;2,5 component for [2 + 2] photocycloadditions;2 catalytic hydrogenation leads to the cis-disubstituted dioxanone;2,5 the dienolate generated from the reagent can be used for chain elongations at the C(6)-Me carbon6)
Physical Data: mp 59.8-60.2 °C; [a]rtD = -215° (c = 1, CHCl3).
Solubility: sol most common organic solvents; poorly sol pentane at low temperature.
Preparative Methods: acid-catalyzed acetalization of Pivalaldehyde with (R)-3-hydroxybutanoic acid8 gives the cis-1,3-dioxan-4-one (2) in 40% yield after recrystallization from ether/pentane. (Up to 60% yield can be obtained by using freshly loaded acidic ion-exchange resin and following the procedure of Seebach et al.7b Runs with up to 120 g hydroxy butanoic acid were performed in this way). Bromination with N-Bromosuccinimide leads to a mixture of brominated dioxinones which are debrominated hydrogenolytically to (1) (eq 1). The yield (2) -> (1) is ~45% after recrystallization from pentane/ether (50:3) at -20 °C.4,7 The enantiomer ent-(1) is of course equally readily available from
(S)-3-hydroxybutanoic acid.9 Both enantiomers of 3-hydroxybutanoic acid are commercially available.
Handling, Storage, and Precautions: dioxinone (1) is commercially available and is indefinitely stable as a crystalline solid stored in a dark bottle at rt.
Reactions of 4H-1,3-Dioxin-4-one (1).
The cuprate additions to (1) occur preferentially from the face trans to the t-Bu group. An example is the preparation of and correlation with mevalonolactone (4) in eq 2 by Michael addition of Lithium Diallylcuprate to give (3) and ozonolysis for degradation by one carbon.5 Two examples of the use of the dienolate derived from dioxinone (1) are shown in eqs 3 and 4. The dienolate adds to aromatic aldehydes in a 1,2-fashion with reasonable diastereoselectivities at the exocyclic carbon atom. Oxidative degradation of the major diastereoisomer (5), obtained with benzaldehyde, leads to the b-hydroxy acid (6) of (S) configuration (eq 3).6 With a,b-unsaturated aldehydes the exocyclic dienolate carbon
reacts in a Michael addition. Thus the adduct (7) is isolated (53%) in a diastereomer ratio of 20:1 (eq 4).6 Activation of the exocyclic methyl group in (1) is also realized by N-Bromosuccinimide bromination.3,4,10 The resulting 6-bromomethyldioxinone has been employed in a vineomycinone B2 synthesis: see the intermediate (8) in eq 5.11
Other Enantiopure Dioxinones for Self-regeneration of the Stereogenic Center.
The principle of preparing dioxinones from enantiopure b-hydroxy acids was also applied to 3-hydroxypentanoic acid,3,6 4,4,4-trifluoro-3-hydroxybutanoic acid,12 4,4,4-trichloro-3-hydroxybutanoic acid,13 and (S)-serine;3,14 aldehydes other than pivaldehyde and ketones15 may be used for dioxinone preparation as well. Furthermore, numerous other dioxinones have been prepared from the parent compound (1) (eqs 3, 4, 6 and 7). The dibromide intermediate (9) in the preparation of (1) can be converted to an aldehyde, which after undergoing Wittig alkenation, followed by catalytic hydrogenation, leads to the 3-hydroxyadipic acid derivative (10) shown in eq 6, in an overall yield of 55%.10 Aldol condensations of
dioxanone (2) with aldehydes and shift of the double bond from the exo- to the endocyclic position produce 2,5,6-trisubstituted dioxinones such as (11), which can be used for the preparation of 2,3-disubstituted b-hydroxycarboxylic acids: see (12) in eq 7.16,17 Such compounds are not accessible by current enantioselective aldol addition methodology. An example of the preparation of a CF3-branched 3-hydroxycarboxylic acid derivative is shown in eq 8; trifluoromethyldioxinone (13) and Lithium Di-n-butylcuprate give a dioxanone which is solvolyzed in methanol to the hydroxy ester (14).12b
Dioxinones Obtained by Resolution or Prepared with a Chiral Auxiliary.
2-Phenyl-4H-1,3-dioxin-4-ones (15) derived from formylacetate or acetoacetate can be readily prepared in enantiopure form by preparative resolution14,18 on cellulose triacetate.18 These have been used for Michael additions and hydrolysis to long-chain b-hydroxycarboxylic acids, for example the tridecanoic acid (16) from (R)-(15a).18 The cuprate adducts formed with the methylphenyldioxinone (S)-(15b) can be hydrogenolytically cleaved directly to b-branched b-hydroxy acids with benzyl protection of the hydroxy functional group; see (17) in eq 9.18
The chiral auxiliary approach involving dioxinones has been chosen by Demuth et al.19 and, most extensively, by Kaneko and his collaborators.20-22 They have used menthol esters (18) and (19) for typical diastereoselective reactions of dioxinones, with subsequent hydrolysis, for the preparation of various enantiopure products. For a review, also referring to the work of Winkler about photoreactions of rac or achiral dioxinones, see the articles by Kaneko.23,24 For a table with enantiopure dioxinones as of mid-1991, see Kinkel et al.14
- 1. Seebach, D.; Roggo, S.; Zimmermann, J. Stereochemistry of Organic and Bioorganic Transformations; Proceedings of the Seventeenth Workshop Conferences Hoechst; Bartmann, W., Sharpless, K. B., Eds; VCH: Weinheim, 1987; Vol. 17, pp 85-126.
- 2. Seebach, D.; Zimmermann, J. HCA 1986, 69, 1147.
- 3. Zimmermann, J.; Seebach, D. HCA 1987, 70, 1104.
- 4. Seebach, D.; Gysel, U.; Job, K.; Beck, A. K. S 1992, 39.
- 5. Seebach, D.; Zimmermann, J.; Gysel, U.; Ziegler, R.; Ha, T.-K. JACS 1988, 110, 4763.
- 6. (a) Seebach, D.; Misslitz, U.; Uhlmann, P. AG(E) 1989, 28, 472. (b) Seebach, D.; Misslitz, U.; Uhlmann, P. CB 1991, 124, 1845 (CA 1991, 115, 92 177g).
- 7. (a) Seebach, D.; Imwinkelried, R.; Stucky, G. AG(E) 1986, 25, 178. (b) Seebach, D.; Imwinkelried, R.; Stucky, G. HCA 1987, 70, 448 (CA, 1988, 108, 55 448f).
- 8. (a) Seebach, D.; Beck, A. K.; Breitschuh, R.; Job, K. OS 1992, 71, 39. (b) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. OS 1992, 71, 1.
- 9. (a) Seebach, D.; Sutter, M. A.; Weber, R. H.; Züger, M. F. OS 1985, 63, 1; OSC 1990, 7, 215. (b) Ehrler, J.; Giovannini, F.; Lamatsch, B.; Seebach, D. C 1986, 40, 172.
- 10. Noda, Y.; Seebach, D. HCA 1987, 70, 2137.
- 11. Tius, M. A.; Gomez-Galeno, J.; Gu, X.-q.; Zaidi, J. H. JACS 1991, 113, 5775.
- 12. (a) Acs, M.; von dem Bussche, C.; Seebach, D. C 1990, 44, 90. Beck, A. K.; Gautschi, M.; Seebach, D. C 1990, 44, 291 (CA 1991, 114, 101 862k). (b) Gautschi, M.; Seebach, D. AC(E) 1992, 31, 1083. Gautschi, M.; Schweizer, W. B.; Seebach, D. CB 1994, 127, 565 (CA 1994, 121, 107 565g).
- 13. Beck, A. K.; Brunner, A.; Montanari, V.; Seebach, D. C 1991, 45, 379 (CA 1992, 116, 174 083h).
- 14. Kinkel, J. N.; Gysel, U.; Blaser D.; Seebach D. HCA 1991, 74, 1622.
- 15. (a) Lange, G. L.; Organ, M. G. TL 1993, 34, 1425. (b) Organ, M. G.; Froese, R. D. J., Goddard, J. D., Taylor, N. J.; Lange, G. L. JACS 1994, 116, 3312.
- 16. Amberg, W.; Seebach, D. CB 1990, 123, 2429 (CA 1991, 114, 23 106a).
- 17. Pietzonka, T.; Seebach, D. CB 1991, 124, 1837.
- 18. Seebach, D.; Gysel, U.; Kinkel, J. N. C 1991, 45, 114 (CA 1991, 115, 136 015j).
- 19. Demuth, M.; Palomer, A.; Sluma, H.-D.; Dey, A. K.; Krüger, C.; Tsay, Y.-H. AG(E), 1986, 25, 1117. Demuth, M.; Mikhail, G. S 1989, 145.
- 20. Kaneko, C. Organic Synthesis in Japan. Past, Present, and Future, Noyori, R.; Ed., Tokyo Kagaku Dozin: Tokyo, 1992; pp 175-183.
- 21. Sato, M.; Murakami, M.; Kaneko, C.; Furuya, T. T 1993, 49, 8529.
- 22. See also: Jansen, U.; Runsink, J.; Mattay, J. LA 1991, 283.
- 23. Kaneko, C.; Sato, M.; Sakaki, J.-i.; Abe, Y. JHC 1990, 27, 25.
- 24. (a) Cf. also: Takeshita, H.; Cui, Y.-S.; Kato, N.; Mori, A.; Nagano, Y. BCJ 1992, 65, 2940. (b) Winkler, J. D.; Shao, B. TL 1993, 34, 3355.
Albert K. Beck & Dieter Seebach
Eidgenössische Technische Hochschule, Zürich, Switzerland
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