2-Methyl-2-(trimethylsilyloxy)-3-pentanone1

[72507-50-7]  · C9H20O2Si  · 2-Methyl-2-(trimethylsilyloxy)-3-pentanone  · (MW 188.38)

(lithium enolate used in the synthesis of syn-b-hydroxy acids, aldehydes, and ketones)

Physical Data: bp 71-75 °C/15 mmHg.

Preparative Methods: prepared in four steps from propionaldehyde in 14-33% overall yield;2 in three steps from Acetone Cyanohydrin in 40% overall yield;3 and in two steps from 3-hydroxy-3-methyl-2-butanone in 55% overall yield.4

Handling, Storage, and Precautions: use in a fume hood.

Stereoselection in Reactions of Lithium Enolates.

The (Z)-lithium enolate (2), obtained from the reaction of 2-methyl-2-trimethylsilyloxypentan-3-one (1) with Lithium Diisopropylamide, reacts with aldehydes to afford syn-b-hydroxy ketones (3) exclusively (eq 1).2,3,5 The synthetic utility of (3) is demonstrated by conversion to b-hydroxy acids (4), b-hydroxy aldehydes (5), and other b-hydroxy ketones by straightforward procedures (eqs 2, 3, and 4).2,3,5,6 Table 1 illustrates examples of condensations of (2) with simple aldehydes and subsequent conversions to (4), (5), and (6).

The reaction of (2) with aldehydes containing additional functional groups and stereocenters has been reported (eq 5, Table 2).2,3,9,10 In all instances the stereoselection is high in favor of aldol product of syn relative stereochemistry at the a- and b-positions (7 and 8), but the degree of stereoselection at the b- and g-positions is highly variable. Only 2,4-dimethylpent-3-enal exhibits a high level of diastereoselection in formation of the product predicted by Cram's rule (7); this product has been used to prepare the C-1 to C-7 fragment of erythronolide A.10 Additional examples of aldol condensations of (2) with complex aldehydes are given in (eq 6).9 When R and R are H, the ratio of (9):(10) is 5.7:1. When R is Et and R is Me, the ratio of (9):(10) is 3:1. It is noteworthy that significantly higher levels of diastereocontrol are achieved in the synthesis of compounds with the same relative stereochemistry as (7) (R = Ph, X = Me; 98:2) and (9) (R = Et, R = Me; >98:2) using propionate equivalents (11)8a and (12),8b respectively.

Aldol reactions of lithium enolates of higher homologs of propionate equivalent (1) have been studied in the context of natural product syntheses and yield similar levels of stereoselection.9 The amino sugars (±)-ristosamine and (±)-megalosamine and the nucleus of crassin acetate were prepared using this methodology.9 Aldol reactions of (2) generated from chiral bases or in the presence of chiral solvents yield products of low to moderate levels of optical purity.10 Asymmetric aldol reactions are best accomplished using other methods.1 Michael additions of (2) have been shown to be highly stereoselective in some instances.11

Stereoselection in Reactions of Other Enolates and Enol Derivatives.

A few examples of reactions of boron, magnesium, and tin enolates of (1) and Lewis acid-catalyzed reactions of enol silanes derived from (1) have been reported.12-15 The boron enolate formed by reaction of (1) with Di-n-butylboryl Trifluoromethanesulfonate and Diisopropylethylamine yields syn aldol products.12 The magnesium enolate formed from (2) by exchange with Magnesium Bromide yields a higher ratio (5:1) of chelation to nonchelation controlled product than (2) in reaction with (R)-3-benzyloxymethoxy-2-methylpropionaldehyde (see Table 2).13 Excess tin enolate of (1) reacts with b-lactam (13) to give (14) and its 1a-epimer in a 95:5 ratio.14 In contrast to the enolates, enol silane (15) reacts with benzaldehyde to afford primarily anti aldol product (16) with Boron Trifluoride Etherate (16:3 (R = Ph) = 5:1) or Titanium(IV) Chloride (16:3 (R = Ph) = 9:1) as a catalyst.15a Reaction of (15) with (S)-2-benzyloxypropionaldehyde catalyzed by Tin(IV) Chloride gave a single isomer (17) that possessed the same relative stereochemistry as the minor isomer in the reaction with (2) (see Table 2).15b

Related Reagents.

(S)-4-Benzyl-2-oxazolidinone; 10,2-Camphorsultam; (R)-(+)-t-Butyl 2-(p-Tolylsulfinyl)propionate; 10-Dicyclohexylsulfonamidoisoborneol; Diisopinocampheylboron Trifluoromethanesulfonate; (R,R)-2,5-Dimethylborolane; 2,6-Dimethylphenyl Propionate; Ethyl 2-(Methyldiphenylsilyl)propanoate; a-Methyltoluene-2,a-sultam; 3-Propionylthiazolidine-2-thione; (R,R)-1,2-Diphenyl-1,2-diaminoethane N,N-Bis[3,5-bis(trifluoromethyl)benzenesulfonamide]; 1,1,2-Triphenyl-1,2-ethanediol.


1. (a) Heathcock, C. H. In Modern Synthetic Methods; Scheffold, R., Ed.; VCH: Weinheim, 1992. (b) Heathcock, C. H. COS 1991, 2, Chapter 1.6. (c) Kim, B. M.; Williams, S. F.; Masamune, S. COS 1991, 2, Chapter 1.7. (d) Heathcock, C. H. Asymmetric Synthesis; Academic: New York, 1984; Vol. 3. (e) Heathcock, C. H. Comprehensive Carbanion Chemistry; Buncel, E.; Durst, T. Eds.; Elsevier: Amsterdam, 1984; Vol. 2. (f) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
2. Young, S. D.; Buse, C. T.; Heathcock, C. H. OSC 1990, 7, 381.
3. (a) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. JOC 1980, 45, 1066. (b) Bal, B.; Buse, C. T.; Smith, K.; Heathcock, C. H. OSC 1990, 7, 185.
4. Smith, A. B., III; Levenberg, P. A.; Jerris, P. J.; Scarborough, R. M., Jr.; Wovkulich, P. M. JACS 1981, 103, 1501.
5. (a) Pilli, R. A.; Murta, M. M. SC 1988, 18, 981. (b) Kusakabe, M.; Sato, F. JOC 1989, 54, 3486. (c) Heathcock, C. H.; Finkelstein, B. L.; Jarvi, E. T.; Radel, P. A.; Hadley, C. R. JOC 1988, 53, 1922.
6. White, C. T.; Heathcock, C. H. JOC 1981, 46, 191.
7. (a) Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. JOC 1985, 50, 2095. (b) Brooks, D. W.; Kellogg, R. P. TL 1982, 23, 4991. (c) Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pirrung, M. C.; White, C. T.; Van Derveer, D. JOC 1980, 45, 3846.
8. (a) Mori, I.; Ishihara, K.; Heathcock, C. H. JOC 1990, 55, 1114. (b) Heathcock, C. H.; Pirrung, M. C.; Buse, C. T.; Hagen, J. P.; Young, S. D.; Sohn, J. E. JACS 1979, 101, 7077.
9. (a) Heathcock, C. H.; Montgomery, S. H. TL 1983, 24, 4637. (b) Dauben, W. G.; Saugier, R. K.; Fleischhauer, I. JOC 1985, 50, 3767.
10. (a) Shioiri, T.; Ando, A. T 1989, 45, 4969. (b) Heathcock, C. H.; White, C. T.; Morrison, J. J.; Van Derveer, D. JOC 1981, 46, 1296.
11. Oare, D. A.; Heathcock, C. H. JOC 1990, 55, 157.
12. Danda, H.; Hansen, M. M.; Heathcock, C. H. JOC 1990, 55, 173.
13. Collum, D. B.; McDonald, J. H., III; Still, W. C. JACS 1980, 102, 2118.
14. Shirai, F.; Nakai, T. JOC 1987, 52, 5491.
15. (a) Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. JOC 1986, 51, 3027. (b) Reetz, M. T.; Kesseler, K.; Jung, A. T 1984, 40, 4327.

William A. Kleschick

DowElanco, Indianapolis, IN, USA



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