(3S,cis)-Tetrahydro-3-isopropyl-7a-methylpyrrolol[2,1-b]oxazol-5(6H)-one1

(3S,cis)

[98203-44-2]  · C10H17NO2  · (3S,cis)-Tetrahydro-3-isopropyl-7a-methylpyrrolol[2,1-b]oxazol-5(6H)-one  · (MW 183.28) (3R,cis)

[123808-97-9]

(chiral template for synthesis of enantiomerically pure cyclopropanes, cyclobutanes, cyclopentenones, pyrrolidines, pyrrolidinones, and a,a-disubstituted g-keto acids1)

Physical Data: bp 76-80 °C/0.05 mmHg; [a]D 95.5°.

Preparative Methods: the richly functionalized chiral bicyclic lactam is easily procured by condensation of commercially available (S)-valinol and levulinic acid in 86% yield (eq 1).2 Similar bicyclic lactams have been prepared from other amino alcohols.3 These bicyclic lactams have served as precursors to a variety of enantiomerically pure compounds that possess quaternary stereocenters. An extensive review on the utility of chiral, nonracemic bicyclic lactams is available.1

General Considerations.

The title reagent can be sequentially alkylated a to the carbonyl group in a stereocontrolled fashion (eq 2).1 Lithiation of the parent bicyclic lactam with s-Butyllithium and reaction with an alkyl halide affords the monoalkylated product. The epimeric mixture is treated again with s-BuLi and a second alkyl halide to give the dialkylated bicyclic lactam. The initial epimeric mixture is used directly in the second alkylation since this step proceeds via a planar enolate. It is the second alkylation that dictates the final diastereomeric ratio. The opposite stereochemistry at C-6 can be obtained by inverting the order of electrophile addition.

Reduction and hydrolysis of the bicyclic lactam followed by aldol cyclization affords enantiomerically pure 4,4-dialkyl-2-cyclopentenones (eq 3).2,4

More highly functionalized cyclopentenones can be accessed by organolithium addition to the carbonyl group instead of hydride reduction with Sodium Bis(2-methoxyethoxy)aluminum Hydride (Red-Al).5

a-Substituted g-keto acids, upon condensation with b-amino alcohols, afford bicyclic lactams containing a-substitutents such as aryl groups. In this case, only one metalation-alkylation sequence is required to form the chiral, nonracemic a,a-disubstituted bicyclic lactam (eq 4).4b

The angular 7a-phenyl bicyclic lactam can be prepared by the cyclocondensation of 3-benzoylpropionic acid and (S)-valinol in 85% yield.6 Dialkylation of this lactam also affords cleanly the a,a-disubstituted compound. Lactam hydrolysis releases chiral, nonracemic a,a-disubstituted g-keto carboxylic esters (or acids) (eq 5) and 3,3-disubstituted dihydronaphthalenes may be obtained via cyclization.6

When the bicyclic lactam is substituted with a 3-hydroxypropyl group in the 6-position, acidic hydrolysis gives a bridged bicyclic acetal lactone (eq 6).7

An a-(4-bromobutyl) group can be used as a latent organolithium species by means of bromine-lithium exchange. Intramolecular addition of the organometallic tether to the carbonyl group, followed by lactam hydrolysis and aldol cyclization, affords enantiomerically pure hydrinden-2-ones (eq 7).8

a,b-Unsaturation may be introduced into the bicyclic lactams by standard a-selenation-oxidation methodology. The lactam can now behave as a chiral enone in photochemical [2 + 2] cycloadditions. The lactam moiety can be easily detached owing to its amide and aminal features; thus chiral, nonracemic cyclobutanes are obtained upon hydrolysis (eq 8).9

These unsaturated, bicyclic lactams are also precursors to a variety of chiral nonracemic cyclopropanes. Treatment of the parent a,b-unsaturated lactam with Dimethylsulfoxonium Methylide generates the endo cyclopropanated adduct (eq 9).3b,10

Diels-Alder cycloadditions occur on the endo face when the unsaturated bicyclic lactam is treated with 1,3-dienes such as Isoprene (eq 10).11 Ester reduction followed by organolithium addition to the lactam carbonyl group and subsequent hydrolysis affords a variety of enantiopure functionalized cyclohexenes.11

Cyclopropyl-containing carbocycles can be prepared from the initial [4 + 2] cycloadducts by an N-acyliminium ion-enamide rearrangement. The unsaturated bicyclic lactam also undergoes 1,3-dipolar cycloadditions with azomethine ylides.12 Reduction of the bicyclic lactam with alane followed by hydrogenation affords enantiomerically pure 2-substituted pyrrolidines (eq 11).13

5,5-Disubstituted pyrrolidinones are formed when the bicyclic lactam is treated with Allyltrimethylsilane/Titanium(IV) Chloride. The remaining phenylglycinol moiety is cleaved with Li/NH3 (see Lithium Amide) (eq 12).14 Further reduction with Lithium Aluminum Hydride affords 2,2-disubstituted pyrrolidines.

Reduction with Triethylsilane allows for the formation of enantiomerically pure 5-substituted pyrrolidinones and 2-substituted pyrrolidines in the same manner.15

Conjugate addition of organocuprates to the unsaturated bicyclic lactams (see above) affords rapid access to chiral, nonracemic 3- and 4-substituted pyrrolidines16 and trans-2,3-disubstituted pyrrolidines.17

Related Reagents.

(S)-1-Amino-2-methoxymethylpyrrolidine; trans-2,5-Bis(methoxymethyl)pyrrolidine; 10,2-Camphorsultam; 10-Dicyclohexylsulfonamidoisoborneol; (2S)-(2a,3b,8ab)-Hexahydro-3-(hydroxymethyl)-8a-methyl-2-phenyl-5H-oxazolo[3,2-a]pyridin-5-one; (4S,5S)-4-Methoxymethyl-2-methyl-5-phenyl-2-oxazoline; a-Methyltoluene-2,a-sultam; (R,R)-1,2-Diphenyl-1,2-diaminoethane N,N-Bis[3,5-bis(trifluoromethyl)benzenesulfonamide].


1. (a) Romo, D.; Meyers, A. I. T 1991, 47, 9503. (b) Meyers, A. I.; Berney, D. OSC 1993, 8, 241.
2. Meyers, A. I.; Wanner, K. T. TL 1985, 26, 2047.
3. (a) Meyers, A. I.; Lefker, B. A.; Sowin, T. J.; Westrum, L. J. JOC 1989, 54, 4243. (b) Meyers, A. I.; Romo, D. TL 1989, 30, 1745.
4. (a) Meyers, A. I.; Lefker, B. A. JOC 1986, 51, 1541. (b) Meyers, A. I.; Bienz, S. JOC 1990, 55, 791.
5. (a) Meyers, A. I.; Lefker, B. A. T 1987, 43, 5663. (b) Meyers, A. I.; Lefker, B. A. TL 1987, 28, 1745.
6. (a) Meyers, A. I.; Wallace, R. H.; Harre, M.; Garland, R. JOC 1990, 55, 3137. (b) Meyers, A. I.; Harre, M.; Garland, R. JACS 1984, 106, 1146.
7. Meyers, A. I.; Romine, J.; Robichaud, A. J. H 1990, 30, 339.
8. Meyers, A. I.; Snyder, L. B. SL 1991, 863.
9. Meyers, A. I.; Fleming, S. A. JACS 1986, 108, 306.
10. (a) Meyers, A. I.; Romine, J. L.; Fleming, S. A. JACS 1988, 110, 7245. (b) Meyers, A. I.; Wallace, R. H. JOC 1989, 54, 2509. (c) Romo, D.; Romine, J. L.; Midura, W.; Meyers, A. I. T 1990, 46, 4951. (d) Romo, D.; Meyers, A. I. JOC 1992, 57, 6265.
11. (a) Meyers, A. I.; Busacca, C. A. TL 1989, 30, 6973. (b) Meyers, A. I.; Busacca, C. A. TL 1989, 30, 6977. (c) Busacca, C. A.; Meyers, A. I. JCS(P1) 1991, 2299.
12. Fray, A. H.; Meyers, A. I. TL 1992, 33, 3575.
13. Meyers, A. I.; Burgess, L. E. JOC 1991, 56, 2294.
14. Burgess, L. E.; Meyers, A. I. JACS 1991, 113, 9858.
15. Burgess, L. E.; Meyers, A. I. JOC 1992, 57, 1656.
16. Meyers, A. I.; Snyder, L. JOC 1993, 58, 36.
17. Meyers, A. I.; Snyder, L. JOC 1992, 57, 3814.

Todd D. Nelson & Albert. I. Meyers

Colorado State University, Fort Collins, CO, USA



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