484
J. Am. Chem. SOC.1988,110, 484-489
Asymmetric Synthesis Based on 1,3-0xathianes. 4. Mechanism of Asymmetric Induction in the Reactions of Oxathianyl Ketones' Stephen V. Fryet and Ernest L. Eliel* Contribution from the W. R. Kenan, Jr. Laboratories, Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27514. Received May 4 , 1987
Abstract: The stereoselectivityof the reaction between oxathianyl ketones 7-14, which contain two possible sites of chelation, and methylmagnesium bromide, L-Selectride (Aldrich), and diisobutylaluminum hydride has been studied in order to illuminate the factors involved in the high levels of asymmetric induction obtained in the oxathiane system. Models A, B, and C (Figure 1) are proposed to rationalize the experimental results. A is the Cram chelate rule2 model, while B and C correspond to the Cornforth dipolar model3 or the Felkin model with L = oxygen of the ~ x a t h i a n e .The ~ stereoselectivities observed support the assumption that chelation of an organometallic reagent with the carbonyl and ether oxygens of the oxathiane is necessary for a high degree of asymmetric induction and show that competing chelation to an exocyclic ether oxygen may be prevented by protection with a triisopropylsilyl (TIPS) group.
The mechanism of asymmetric induction in the reactions of chiral a-alkoxy ketones has been a subject of continued speculation since the first systematic study by Cram and K ~ p e c k y .Recently ~ workers in the field of asymmetric synthesis have begun to explore the mechanistic basis for stereoselection in greater d e ~ t h and ~-~ theoretical approachesiOhavebeen used in an attempt to reduce the plethora of available to a reasonable (consistently predictive) number. Synthetic work in our laboratoryL2has shown that the results of addition of chelating nucleophiles to chiral 1,3-oxathianyl ketones, which proceeds in very high diastereomeric excess (90-100% de), can be explained in terms of Cram's chelate rule2 while addition of nonchelating nucleophiles such as diisobutylaluminum hydrideLJ2d~'3gives the product of opposite configuration (Uanti-Cram chelate" product) in moderate to good stereoselectivity. In order to explain these results and to obtain evidence for the role of chelation in additions to oxathianyl ketones beyond the simple observation that the product predicted by Cram's chelate rule predominates, we have synthesized the benzyl-, trityl-, and silyl-protected a- and @-hydroxyketones 7-14 and examined their reactivity toward methylmagnesium bromide, L-Selectride (Aldrich), and diisobutylaluminum hydride.9b We expected that if endocyclic chelation between the carbonyl oxygen, the Lewis acidic reagent, and the oxathiane oxygen (Figure 1, structure A) is in fact the controlling factor in the high diastereofacial selectivity normally observed,I2 the presence of the exocyclic ether oxygen with its potential for competitive chelation6 should change the stereochemical course of reactions with these substrates. We also felt that if the acyclic oxygen proved deleterious to the stereoselectivity, prevention of chelation by this oxygen would be a synthetically desirable goal. We now report the results of these studies; protection of the exocyclic oxygen by a triisopropylsilyl (TIPS) group inhibits competing chelation very effectively.
Results Ketones 7-14 and 2912e were prepared by condensation of aldehydes 1-614and acetaldehyde with the lithium salt of the parent oxathiane 12j followed by Swern oxidation as shown in Scheme I. These ketones were then reduced or alkylated to give the corresponding secondary and tertiary carbinols, respectively, with the results reported in Table I. The product mixtures were analyzed for diastereomeric excess (de) by proton N M R with use of the ratio of the 'H signals due to the C(2) protons of the oxathiane or by 13CNMR with use of the ratio of signals due to several corresponding carbons. In the reaction of 8 and 10 with CH,MgBr at -78 OC the very high selectivity rendered identi'Current address: Glaxo Laboratories, 5 Moore Dr., Research Triangle Park, NC 27709.
0002-7863/88/ 1510-0484$01.50/0
fication of signals due to the minor diastereomer difficult, and therefore 8 and 10 were also alkylated with CH3Li at room temperature to provide a mixture of diastereomers in which each epimer could be readily identified. The relative configuration of 24 and 25 was established by deprotection to give the common diol 27, and their absolute configuration was ascertained by by homologation conversion of 25 into (S)-(+)-meval~lactone~~ (see Experimental Section). The relative configuration of 21 and 22 was similarly established by deprotection to give 23 while their absolute configuration was determined by conversion of 22 into 32 (Scheme 11) which has been correlated to diethyl (S)-(-)acetylcitramalate.'% The absolute configuration of the secondary oxathianyl carbinols 15-20 was proven by conversion to 33 and 34 (Scheme 111) of known configuration.13 The configuration of 28 was not determined directly; however, the isomer produced in
(1) Paper 111: KO,K.-Y.; Frazee, W. J.; Eliel, E. L.Tetrahedron 1984, 40, 1333. See also ref 12a, b, and i for previous discussions of the basis for the high stereoselectivity in this system. (2) Cram, D. J.; Kopecky, K. R. J. Am. Chem. SOC.1959.81, 2748. See also ref 12a. (3) Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. SOC. 1959, 112. (4) Chtrest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199. (5) (a) Reetz, M. T.; Kessler, K.; Schmidtberger, S.; Wenderoth, B.; Steinbach, R. Angew. Chem. 1983, 1511. (b) Reetz, M. T.; Maus, S. Tetrahedron 1987, 43, 101. (c) Reetz, M. T.; Hiillmann, M.; Seitz, T. Angew. Chem. Int. Ed. Engl. 1987,26,477. (d) Reetz, M. T.; Hiillmann, M. J . Chem. Soc., Chem. Commun. 1986, 1600. (e) Reetz, M. T. Angew. Chem. Int. Ed. Engl, 1984, 23, 556. (0 Reetz, M. T., In Organotitanium Reagents in Organic Synthesis; Springer-Verlag: Berlin, 1986. (6) Keck, G. E.; Castellino, S. J. Am. Chem. SOC.1986, 108, 3847. (b) Kahn, S. D.;Keck, G. E.; Hehre, W. J. Tetrahedron Lett. 1987, 279. (c) Keck, G. E.; Castellino, S. Tetrahedron Lett. 1987, 281. (d) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 265. (7) Lodge, E. P.; Heathcock, C. H. J . Am. Chem. SOC.1987, 109, 3353. (8) Mead, K.; Macdonald, T. L. J . Org. Chem. 1985, 50, 422. (9) (a) Frye, S. V.; Eliel, E. L.; Cloux, R. J. Am. Chem. SOC.1987, 109, 1862. (b) For a preliminary report of this work see: Frye, S. V.; Eliel, E. L. Tetrahedron Lett. 1986, 3223. (10) (a) Anh, N. T. In Topics in Current Chemistry; Springer-Verlag: Houk, K. N. J . Am. Chem. SOC.1987, Berlin, 1980; p 145. (b) Wu, Y.-D.; 109, 908. (11) Karabatsos, G. J. J. Am. Chem. SOC.1967,89, 1367. Cieplak A. S. J. Am. Chem. SOC.1981, 103, 4540. (12) (a) Eliel, E. L. In Asymmetric Synthesis; Morrison, .I.D.,Ed.; Academic: New York, 1983; Vol. 2, p 125. (b) Eliel, E. L.; Morris-Natschke, S. J . Am. Chem. SOC.1984, 106, 2937. (c) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943. (d) KO,K.-Y.; Eliel, E. L. J . Org. Chem. 1986, 51, 5353. (e) Frye, S. V.; Eliel, E. L. J . Org. Chem. 1985, 50, 3402. (f) Kogure, T.; Eliel, E. L. J . Org. Chem. 1984, 49, 576. (8) Frye, S. V.; Eliel, E. L. Tefrahedron Lett. 1985, 3907. (h) Ohwa, M.; Eliel, E. L. Chem. Lett. 1987, 41. (i) Eliel, E. L. Phosphorus and Sulfur 1985, 24, 73. (j)Eliel, E. L.; Lynch, J. E.; Kume, F.; Frye S. V. Org. Synth. 1987, 65, 215.
0 1988 American Chemical Society
J . A m . Chem. SOC.,Vol. 110, No. 2, 1988 485
Asymmetric Synthesis Based on 1,3- Oxathianes
c
B
A
Figure 1. Models for nucleophilic addition to oxathianyl ketones. Scheme I1
Scheme I
1.6
2 E
