2,6-Dimethylphenyl Propionate1

[51233-80-8]  · C11H14O2  · 2,6-Dimethylphenyl Propionate  · (MW 178.25)

(lithium, titanium, and zirconium enolates used in the stereoselective synthesis of anti2 or syn4 b-hydroxy acid derivatives)

Physical Data: bp 60-65 °C/0.05 mmHg.

Preparative Methods: the reagent is prepared in excellent yield by the reaction of the sodium or lithium salt of 2,6-dimethylphenol with propionyl chloride.2a,2b

Stereoselection in Reactions of Lithium Enolates.

The (E)-lithium enolate (2) obtained from reaction of 2,6-dimethylphenyl propionate (1) with Lithium Diisopropylamide reacts with aldehydes to afford the anti-b-hydroxy ester (3) in a highly selective or specific manner (eq 1).2-4 Table 1 illustrates the level of diastereoselection possible with a variety of structurally simple aldehydes. In general, reaction with aromatic and straight-chain aliphatic aldehydes results in lower degrees of diastereoselection than reaction with aldehydes containing branching at the a-carbon. The b-hydroxy esters are hydrolyzed to the corresponding anti-b-hydroxy acid under mild reaction conditions.

Condensations of the enolate (2) with more complex aldehydes (i.e. 5-20) containing additional functional groups and stereocenters have been reported.2b,5-12 Excellent levels of diastereocontrol are observed in formation of the 2,3-anti-b-hydroxy esters in all instances except the reaction with the a-alkoxy aldehydes.6 With aldehydes that contain resident stereocenters, the facial selectivity in the attack of enolate (2) on the aldehyde varies widely. Aldehydes (5)-(7) react with modest degrees of stereoselection (2-4:1) in favor of formation of the product predicted by Cram's rule (i.e. syn relationship between C-3 and C-4 in the b-hydroxy ester).2,11 The aldehydes possessing a phenylthio group at the a-position (8-13) yield b-hydroxy esters in which the hydroxy groups and phenylthio groups are anti with a high degree of selectivity.7 Aldehydes (14)-(19) appear to follow Cram's rule exclusively or highly selectively.8,9 Facial selectivity in reaction of lithium enolate (2) with aldehyde (20) is modest (approximately 2:1).12

Lithium enolates derived from propionate esters of other highly hindered phenols (e.g. 2,6-di-t-butyl-4-methylphenol (BHT) and 2,6-di-t-butyl-4-hydroxyanisole (DBHA)) are known to be more selective than (2) in condensation reactions with aldehydes to yield anti-b-hydroxy esters.2 However, these esters cannot be removed by simple hydrolytic procedures without complications from retro-aldol reactions. Removal of the BHT or DBHA group in these anti-b-hydroxy esters requires reduction to the corresponding 1,3-diol with Lithium Aluminum Hydride or conversion to the corresponding anti-b-hydroxy acids under oxidative conditions (e.g. Cerium(IV) Ammonium Nitrate).2b,c Yields in the latter process are highly variable.2a The oxidations are often performed on the acetate esters of the anti-b-hydroxy esters in an attempt to produce reliable yields.2b Lithium enolates derived from other esters of 2,6-dimethylphenol are reported to be highly anti selective in condensations with aldehydes.2

Reactions of Titanium Enolates.

In contrast to reactions of (E)-lithium enolate (2), (E)-titanium enolates (21) are reported to afford the syn-b-hydroxy ester predominantly (eq 2).4 The (E)-titanium enolates (21) are prepared by transmetalation of the corresponding (E)-lithium enolate. Achiral (E)-enolates (21a) yield predominantly syn-b-hydroxy esters in reactions with aldehydes (Table 2). The yield and degree of stereoselection are excellent in all cases except in reaction with pivaldehyde. With (E)-titanium enolates bearing chiral ligands (i.e. (21b) R = diacetoneglucose (DAG)), the syn-b-hydroxy ester of (R) configuration at C(2) is formed with high optical purity.

The (E)-titanium enolates (21) can be equilibrated to a mixture of (E)- and (Z)-enolates in which the (Z)-enolate (22) predominates by standing at -30 °C for several hours.4 The degree of diastereoselection in reaction of the equilibrated enolate mixture with aldehydes is not as consistently high as it is in the case of the reaction with the (E)-enolate (Table 3); however, the anti-b-hydroxy ester is usually the major product. The optical purity of the anti-isomer is very high in all cases.

Reactions of Zirconium Enolates.

Reaction of the zirconium enolate of (1) with isobutyraldehyde gave a 6:1 mixture of syn- and anti-b-hydroxy esters (4 and 3).4

Related Reagents.

(R)-(+)-t-Butyl 2-(p-Tolylsulfinyl)propionate; Ethyl Lithioacetate; Ethyl Bromozincacetate; Ethyl 2-(Methyldiphenylsilyl)propanoate; 2-Methyl-2-(trimethylsilyloxy)-3-pentanone; (S)-4-Benzyl-2-oxazolidinone; 3-Propionylthiazolidine-2-thione; (R)-(+)-3-(p-Tolylsulfinyl)propionic Acid; 1,1,2-Triphenyl-1,2-ethanediol.

1. (a) Heathcock, C. H. Modern Synthetic Methods; Scheffold, R., Ed.; VCH: Weinheim, 1992. (b) Heathcock, C. H. COS 1991, 2, Chapter 1.6. (c) Paterson, I. COS 1991, 2, Chapter 1.9. (d) Heathcock, C. H. Asymmetric Synthesis; Academic: New York, 1984; Vol. 3.
2. (a) Montgomery, S. H.; Pirrung, M. C.; Heathcock, C. H. OS 1985, 63, 99; OSC 1990, 7, 190. (b) Heathcock, C. H.; Pirrung, M. C.; Montgomery, S. H.; Lampe, J. T 1981, 37, 4087. (c) Pirrung, M. C.; Heathcock, C. H. JOC 1980, 45, 1727.
3. Pratt, A. J.; Thomas, E. J. JCS(P1) 1989, 1521.
4. Duthaler, R. O.; Herold, P.; Wyler-Helfer, S.; Riediker, M. HCA 1990, 73, 659.
5. Aggarwal, V. K.; Coldham, I.; McIntyre, S.; Warren, S. JCS(P1) 1991, 451.
6. Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. JOC 1986, 51, 3027.
7. (a) Coldham, I.; Warren, S. JCS(P1) 1992, 2303. (b) McIntyre, S.; Warren, S. TL 1990, 31, 3457. (c) Coldham, I.; Collington, E. W.; Hallett, P.; Warren, S. TL 1988, 29, 5321. (d) Aggarwal, V. K.; Coldham, I.; McIntyre, S.; Sansbury, F. H.; Villa, M.-J.; Warren, S. TL 1988, 29, 4885. (e) Aggarwal, V. K.; Warren, S. TL 1987, 28, 1925.
8. Paterson, I. TL 1983, 24, 1311.
9. (a) Born, M.; Tamm, C. HCA 1990, 73, 2242. (b) Tschamber, T.; Waespe-Sarcevic, N.; Tamm, C. HCA 1986, 69, 621.
10. Born, M.; Tamm, C. S 1991, 435.
11. Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. H. JACS 1991, 113, 5337.
12. Corey, E. J.; Reichard, G. A. JACS 1992, 114, 10677.

William A. Kleschick

DowElanco, Indianapolis, IN, USA

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