(4S,5S)-4-Methoxymethyl-2-methyl-5-phenyl-2-oxazoline1

(1; R = Me)

[52075-14-6]  · C12H15NO2  · (4S,5S)-4-Methoxymethyl-2-methyl-5-phenyl-2-oxazoline  · (MW 205.28) (2; R = Et)

[51594-37-7]  · C13H17NO2  · (4S,5S)-4-Methoxymethyl-2-ethyl-5-phenyl-2-oxazoline  · (MW 219.31) (3; R = ClCH2)

[54623-66-4]  · C12H14ClNO2  · (4S,5S)-4-Methoxymethyl-2-chloromethyl-5-phenyl-2-oxazoline  · (MW 239.72)

(enantiopure carboxylic ester derivatives for synthesis of enantiomerically pure or enriched 2- and 3-substituted alkanoic acids, g-butyrolactones, valerolactones, and benzovalerolactones by a-lithiation and asymmetric alkylations)

Physical Data: (1): bp 85-87 °C/0.20 mmHg; [a]CHCl3D -118°. (2): bp 91-93 °C/0.25 mmHg; [a]CHCl3D -84.2°. (3): [a]CHCl3D -84.1°.

Preparative Methods: (1) and (2): cyclocondensation of commercially available (1S,2S)-2-amino-1-phenyl-1,3-propanediol with the appropriate orthoester, followed by methylation of the free hydroxy group (eq 1).2a

Handling, Storage, and Precautions: no special precautions.

Asymmetric Alkylations.

The asymmetric synthesis of 2-alkanoic acids can be accomplished be treatment of the lithio salt of the 2-ethyl-2-oxazoline with alkyl halides followed by acidic hydrolysis of the oxazoline (eq 2).2

Alkylation of the 2-methyl-2-oxazoline (base/electrophile) results in homologated 2-oxazolines. A second alkylation sequence proceeds with asymmetric induction and results in the formation of highly substituted chiral 2-alkyl alkanoic acids. Use of ethylene oxide as the electrophile in this process allows for the formation of chiral a-substituted g-butyrolactones and a-substituted g-valerolactones with good stereoselectivity (60-80% ee; eq 3).3

Conjugate Additions to 2-Vinyloxazolines.

The 2-methyl-2-oxazoline can be converted into a phosphonate for Horner-Emmons alkenations. A variety of (E)-alkenes containing the chiral oxazoline auxiliary (a,b-unsaturated oxazolines) can be synthesized in high yields (80-93%) as the sole geometric isomer (eq 4).4 Conjugate addition of alkyllithium reagents to these Michael acceptors affords, after oxazoline hydrolysis, the 3-substituted alkanoic acids (or corresponding alcohol) with a high level of stereoselectivity (91-99% ee; eq 4).4

Use of appropriately substituted chiral a,b-unsaturated oxazolines allows access to 3-substituted d-valerolactones and 4-substituted 2-chromanones with high stereoselectivity (95-98%; eq 5).4a-c

Asymmetric Aldol Additions.

2-Ethyl-2-oxazoline takes part in aldol condensations as its boron azaenolate. The erythro selectivity for this protocol is excellent (95:5 to 98:2) but the enantioselectivity is only moderate (29-71% ee; eq 6).5

Enantioenriched a-Chloro Carboxylic Acids.

Reaction of (1S,2S)-1-phenyl-2-amino-1,3-propanediol with the ethyl imidate of chloroacetonitrile gives (-)-2-chloromethyl-4-methoxymethyl-5-phenyl-2-oxazoline (eq 7).6

Alkylation of this oxazoline is accomplished by metalation with Lithium Diisopropylamide followed by adding a premixed solution of the electrophile and 2 equiv of HMPA (eq 8). Hydrolysis of the oxazoline moiety affords the enantioenriched 2-chloroalkanoic acids, albeit with low optical purity.6

Related Reagents.

(R)-(+)-t-Butyl 2-(p-Tolylsulfinyl)propionate; Chloro(cyclopentadienyl)bis[3-O-(1,2:5,6-di-O-isopropylidene-a-D-glucofuranosyl)]titanium; 10-Dicyclohexylsulfonamidoisoborneol; Diisopinocampheylboron Trifluoromethanesulfonate; (R,R)-2,5-Dimethylborolane; 2-(o-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; (S)-4-Benzyl-2-oxazolidinone; 3-Propionylthiazolidine-2-thione; 2,4,4-Trimethyl-2-oxazoline.


1. Meyers, A. I. ACR 1978, 11, 375.
2. (a) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. JACS 1976, 98, 567. (b) Meyers, A. I.; Knaus, G. JACS 1974, 96, 6508. (c) Meyers, A. I.; Knaus, G.; Kamata, K. JACS 1974, 96, 268. (d) Meyers, A. I.; Mazzu, A.; Whitten, C. E. H 1977, 6, 971. (e) Hoobler, M. A.; Bergbreiter, D. E.; Newcomb, M. JACS 1978, 100, 8182. (f) Meyers, A. I.; Snyder, E. S.; Ackerman, J. J. H. JACS 1978, 100, 8186. (g) Byström, S.; Högberg, H.-E.; Norin, T. T 1981, 37, 2249. (h) Liddell, R.; Whiteley, C. CC 1983, 1535.
3. (a) Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. JOC 1980, 45, 2792. (b) Meyers, A. I.; Mihelich, E. D. JOC 1975, 40, 1186.
4. (a) Meyers, A. I.; Smith, R. K.; Whitten, C. E. JOC 1979, 44, 2250. (b) Meyers, A. I.; Whitten, C. E. TL 1976, 1947. (c) Ziegler, F. E.; Gilligan, P. J. JOC 1981, 46, 3874. (d) Meyers, A. I.; Whitten, C. E. JACS 1975, 97, 6266. (e) Whittaker, M.; McArthur, C. R.; Leznoff, C. C. CJC 1985, 63, 2844. (f) Meyers, A. I.; Smith, R. K. TL 1979, 2749.
5. (a) Meyers, A. I.; Yamamoto, Y. T 1984, 40, 2309. (b) Meyers, A. I.; Yamamoto, Y. JACS 1981, 103, 4278. (c) via a lithium enolate: Meyers, A. I.; Reider, P. J. JACS 1979, 101, 2501.
6. Meyers, A. I.; Knaus, G.; Kendall, P. M. TL 1974, 3495.

Todd D. Nelson & Albert I. Meyers

Colorado State University, Fort Collins, CO, USA



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