[79618-03-4]  · C11H20OS  · (4aR)-(4aa,7a,8ab)-Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin  · (MW 200.38)


(useful chiral auxiliary for asymmetric synthesis of tertiary1 and secondary2 alcohols3)

Physical Data: mp 37-38 °C; bp 70-94 °C/0.1 mmHg (for diastereomeric mixture).

Solubility: very sol most organic solvents at 20 °C; slightly sol pentane at 0 °C; insol H2O.

Preparative Method: prepared in three steps from optically pure (+)-pulegone (eq 1).4

Handling, Storage, and Precautions: refrigerated storage is recommended. Use in a fume hood.

Asymmetric synthesis via the title reagent (1) is the result of two highly stereoselective reactions. The first involves the reaction of 2-lithio-1,3-oxathiane (5), with an aldehyde to give exclusively the equatorial addition product (6) (this reaction typically shows little aldehyde facial selectivity) (eq 2). The selectivity is due to the greatly enhanced stability of the equatorial lithium species (5) as compared to the axial isomer, a result of the stereoelectronics of the conformationally rigid oxathiane.5 Swern oxidation of the resulting carbinols allows the preparation of 2-acyloxathianes as single stereoisomers in high yield.6 Direct acylation of (5) has been achieved recently in selected cases by reaction with nitriles7 or a-heteroatom-substituted esters.8 Acyloxathianes (7) have also been prepared by acylation of the cuprate (8) (obtained from (5) and 0.5 equiv Copper(I) Iodide) with acid chlorides (eq 3).9

The ketones (7) undergo highly stereoselective additions with Grignard reagents to give tertiary alcohols or can be reduced stereoselectively to secondary alcohols. In the case of Grignard reactions, the addition generally shows very high selectivity, typically >9:1, often >95:5 (9):(10) (eq 4).10 The major isomer is that predicted to be formed by Cram's chelate rule.11,12 The kinetics of Grignard reactions with a-alkoxy ketones have been measured by Eliel et al.13 and these studies strongly support the intermediacy of a chelate structure.

When the R group of ketone (7) contains a heteroatom capable of competing with the oxathianyl oxygen for magnesium chelation, a sharp decrease or reversal in the selectivity has been observed (eq 5).14 The selectivity was restored when the heteroatom (in this case oxygen) was rendered incapable of chelation by protection with a bulky silyl group.

Ketones having a heteroatom (O or S) at a second adjacent chiral center have also been studied.15 High selectivity in the addition of a Grignard or lithium reagent was obtained in many cases, but the sterochemical outcome was found to depend on the configuration of the additional center, the organometallic reagent, and the heteroatom substituent (eq 6).15

Ytterbium-mediated additions of alkynyllithium or -magnesium reagents to (7) have also been reported to show high selectivity, but for the opposite diastereomer (10) (eq 4) from that obtained in Grignard reactions.16

Hydride reductions of (7) can be controlled to give either the (R) or (S) secondary hydroxy compound with good selectivity by choice of the reducing agent. Lithium Tri-s-butylborohydride (L-Selectride®) provided the (S)-alcohol (according to Cram's chelate rule) and Diisobutylaluminum Hydride (DIBAL) gave the (R)-carbinol in excess (eq 7).2 The DIBAL results were rationalized in terms of the open-chain Cornforth dipole model.17

Hydrolysis of the 1,3-oxathiane moiety has been accomplished under mild conditions (0 °C, 5 min) by the use of N-Chlorosuccinimide-Silver(I) Nitrate.18 This oxidative hydrolysis produces a-hydroxy aldehydes in good yields and, in addition, two diastereomeric sultines (19) (eq 8).1 The use of Iodine-AgNO3 for the oxidative hydrolysis of 1,3-oxathianes has also recently been reported.19 The tertiary a-hydroxy aldehydes are easily oxidized directly to the acids (Sodium Chlorite)20 or methyl esters (MeOH, I2, KOH)21 or are conveniently reduced to the diols by direct reduction of the hydrolysis mixture with Sodium Borohydride. The secondary a-hydroxy aldehydes could likewise be reduced to the glycols without racemization; however, oxidation required protection as the benzyl ether prior to hydrolysis. The sultines (after chromatographic separation) are reduced to the hydroxy thiol (4) by Lithium Aluminum Hydride.

Advantage has been taken of the fact that the diastereomers (9) and (10) are often easily separated by silica gel chromatography, particularly when both enantiomers of a compound are desired in pure form. Nonselective addition of (5) to 2-hexanone followed by chromatographic separation of the diastereomeric carbinols and hydrolysis of each gave both (+)- and (-)-2-hydroxy-2-methylhexanal in optically pure form.22

Hydroxy thiol (4) likewise has been used to resolve dimethyl 4-oxocyclopentane-1,2-dicarboxylate by crystallization of the mixture of the derived oxathianes. This provided the (R,R) enantiomer in >99% purity (eq 9).23

An interesting 1,4-addition to the vinyl sulfone derivative of a related 1,3-oxathiane24 has also been reported (eq 10).25

The use of stoichiometric, covalently bound chiral auxiliaries as a method of asymmetric synthesis is generally impractical and cannot compete with catalytic methods on a commercial scale. However, at the laboratory scale, the oxathiane method provides a predictable method to obtain a desired enantiomer with high selectivity. Since the intermediate compounds prior to hydrolysis are diastereomeric, they are easily separated (often by crystallization) and thus enantiomerically pure compounds are readily obtained.

Related Reagents.

Benzothiazole; Carbon Monoxide; N,N-Diethylaminoacetonitrile; N,N-Dimethyldithiocarbamoylacetonitrile; 2-Lithio-1,3-dithiane; Methylthiomethyl p-Tolyl Sulfone; 2-(Trimethylsilyl)thiazole.

1. Lynch, J. E.; Eliel, E. L. JACS 1984, 106, 2943.
2. Ko. K.-Y.; Frazee, W. J.; Eliel, E. L. T 1984, 40, 1333.
3. Reviews: Eliel, E. L. Phosphorus Sulfur 1985, 24, 73. Eliel, E. L.; Koskimies, J. K.; Frazee, W. J.; Morris-Natschke, S.; Lynch, J. E.; Soai, K. In Asymmetric Reactions and Processes in Chemistry Eliel, E. L.; Otsuka, S., Eds.; ACS: Washington, 1982; p 37. Eliel, E. L.; Frye, S. V.; Hortelano, E. R.; Chen, X.; Bai, X. PAC 1991, 63, 1591, and references therein.
4. Eliel, E. L.; Lynch, J. E.; Kume, F.; Frye, S. V. OS 1987, 65, 215.
5. Abatjoglou, A. G.; Eliel, E. L.; Kuyper, L. F. JACS 1977, 99, 8262.
6. Eliel, E. L.; Koskimies, J. K.; Lohri, B. JACS 1978, 100, 1614.
7. Eliel, E. L.; Bai, X.; Abdel-Magid, A. F.; Hutchins, R. O.; Prol, J. JOC 1990, 55, 4951.
8. Bai, X.; Eliel, E. L. JOC 1992, 57, 5162.
9. Wei, J.; Hutchins, R. O.; Prol, J., Jr. JOC 1993, 58, 2920.
10. Morris-Natschke, S.; Eliel, E. L. JACS 1984, 106, 2937.
11. Cram, D. J.; Kopecky, K. R. JACS 1959, 81, 2748.
12. Eliel, E. L. In Asymmetric Synthesis, Morrison, J. D., Ed.; Academic: New York, 1983; Vol. 2, p 125.
13. Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. JACS 1992, 114, 1778. Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. JACS 1990, 112, 6130. Frye, S. V.; Eliel, E. L.; Cloux, R. JACS 1987, 109, 1862.
14. Frye, S. V.; Eliel, E. L. JACS 1988, 110, 484. Frye, S. V.; Eliel, E. L. TL 1985, 26, 3907.
15. Bai, X.; Eliel, E. L. JOC 1992, 57, 5166.
16. Utimoto, K.; Nakamura, A.; Matsubara, S. JACS 1990, 112, 8189.
17. Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. JCS 1959, 112.
18. Corey, E. J.; Erickson, B. W. JOC 1971, 36, 3553.
19. Nishide, K.; Yokota, K.; Nakamura, D.; Sumiya, T.; Node, M.; Ueda, M.; Fuji, K. TL 1993, 34, 3425.
20. Krause, G. A.; Roth, B. JOC 1980, 45, 4825.
21. Inch, T. D.; Ley, R. V.; Rich, P. JCS(C) 1968, 13, 1693.
22. Cervantes-Cuevas, H.; Joseph-Nathan, P. TL 1988, 29, 5535.
23. Solladie, G.; Lohse, O. TA 1993, 4, 1547.
24. Frazee, W. J.; Eliel, E. L. JOC 1979, 44, 3598.
25. Isobe, M.; Obeyama, J.; Funabashi, Y.; Goto, T. TL 1988, 29, 4773.

Joseph E. Lynch

Merck Research Laboratories, Rahway, NJ, USA

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