(2S)-(2a,3b,8ab)-Hexahydro-3-(hydroxymethyl)-8a-methyl-2-phenyl-5H-oxazolo[3,2-a]pyridin-5-one

(2S)-(1; R1 = Me, R2 = H R3 = H)

[116950-01-7]  · C15H19NO3  · (2S)-(2a,3b,8ab)-Hexahydro-3-(hydroxymethyl)-8a-methyl-2-phenyl-5H-oxazolo[3,2-a]pyridin-5-one  · (MW 261.35)

[101979-96-8] (2S)-(2; R1 = Et, R2 = H, R3 = H)

[101979-99-1]  · C16H21NO3  · (2S)-(2a,3b,8ab)-Hexahydro-3-(hydroxymethyl)-8a-ethyl-2-phenyl-5H-oxazolo[3,2-a]pyridin-5-one  · (MW 275.38) (2S)-(3; R1 = Me, R2, R3 = C4H4 (benzo))

[127998-41-8]  · C19H19NO3  · (2S)-(2a,3b,8ab)-Hexahydro-3-(hydroxymethyl)-8a-methyl-2-phenyl-5H-oxazolo[3,2-a]pyridin-5-one  · (MW 309.39)

(chiral templates for the synthesis of enantiopure 4,4-dialkyl-2-cyclohexenones, 6,6-dialkyl-2-cyclohexenones, and 4,4-dialkyl-1(4H)-naphthalenones1)

Physical Data: (1) mp 98-99 °C; [aD] +13.5°. (2) mp 83-85 °C; [aD] +12.6°. (3) mp 91 °C; [aD] +166.7°.

Preparative Methods: the chiral bicyclic lactams are easily procured via condensation of commercially available (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol and the appropriate d-keto acid (eq 1).1,2 Similar bicyclic lactams have been prepared from other amino alcohols and have been extensively utilized in the stereocontrolled formation of quaternary carbon-carbon bonds.1,3

Handling, Storage, and Precautions: no special precautions are warranted.

These compounds can be alkylated twice at the 6-position in a stereocontrolled fashion (eq 2).4,5 Treatment of the unsubstituted bicyclic lactam with Lithium Diisopropylamide and reaction of the enolate anion with an alkyl halide affords the monosubstituted product. The epimeric mixture is treated again with LDA and a second alkyl halide to give the dialkylated bicyclic lactam. The initial epimeric mixture is used directly in the second alkylation since this subsequent step proceeds via a planar enolate. It is the second alkylation that dictates the final diasteromeric ratio. The order of addition also affects the final ratio.4 Inverting the order of addition provides the antipode at position 6, although the highest diastereoselectivity is observed when the larger electrophile is added last.6 The monoalkylated bicyclic lactam can also be prepared by condensation of the amino alcohol and the appropriately substituted keto acid.1

These compounds can be partially reduced to the carbinol amine, and then hydrolyzed and cyclized to afford the enantiomerically pure 4,4-dialkyl-2-cyclohexenones (eq 3).4

In addition, Grignard addition to the lactam followed by hydrolysis of the bicyclic lactam affords either 3,4,4- or 2,6,6-trisubstituted 2-cyclohexenones, depending upon the hydrolytic conditions employed (eq 4).6

Similar manipulations with a dialkylated benzo tricyclic lactam lead to the corresponding 4,4-dialkylnaphthalenones (eq 5).7

Related Reagents.

(S)-1-Amino-2-methoxymethylpyrrolidine; trans-2,5-Bis(methoxymethyl)pyrrolidine; 10,2-Camphorsultam; 10-Dicyclohexylsulfonamidoisoborneol; a-Methyltoluene-2,a-sultam; (3S,cis)-Tetrahydro-3-isopropyl-7a-methylpyrrolol[2,1-b]oxazol-5(6H)-one.


1. Romo, D.; Meyers, A. I. T 1991, 47, 9503.
2. Meyers, A. I.; Berney, D. OSC 1993, 8, 241.
3. (a) Other amino alcohols have been used to prepare bicyclic lactams such as the title reagent. These bicyclic lactams have served as precursors to a variety of enantiomerically pure compounds that possess a quaternary stereocenter, such as 2,2-dialkyl keto acids, cyclopropanes, cyclobutanes, cyclopentenones, cyclohexenones, indanones, naphthalenones, and 3,3-disubstituted dihydronaphthalenes. For an extensive review on the utility of chiral, nonracemic bicyclic lactams, see Ref. 1. (b) A valinol-derived bicyclic lactam has been used to prepare 4,4-disubstituted 2-cyclohexenones: Meyers, A. I.; Hanreich, R.; Wanner, K. T. JACS 1985, 107, 7776.
4. Meyers, A. I.; Lefker, B. A.; Wanner, K. T.; Aitken, R. A. JOC 1986, 51, 1936.
5. Meyers, A. I.; Berney, D. JOC 1989, 54, 4673.
6. Meyers, A. I.; Lefker, B. A. T 1987, 43, 5663.
7. Wünsch, T.; Meyers, A. I. JOC 1990, 55, 4233.

Todd D. Nelson & Albert I. Meyers

Colorado State University, Fort Collins, CO, USA



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