b-Methyl-b-propiolactone1

(±)

[3068-88-0]  · C4H6O2  · b-Methyl-b-propiolactone  · (MW 86.10) (R)

[32082-74-9] (S)

[65058-82-4]

(three-carbon homologating reagent for synthesis of chiral b-methyl carboxylic acids1)

Physical Data: mp -43.5 °C; bp 71-73 °C/29 mmHg; d 1.056 g cm-3. (R)-isomer: [a]20D -27.8° (c 4.14, CHCl3); (S)-isomer: [a]22D +28.8° (c 4.30, CHCl3).

Solubility: misc alcohol, acetone, ether, chloroform.

Form Supplied in: colorless oil; the racemic form is widely available.

Preparative Methods: by ring-closure of 3-bromobutyric acid with Sodium Carbonate,2a or by hydrogenation of Diketene.2b The optically active forms are obtained in the same manner starting from (R)- or (S)-3-bromobutyric acid, which may be resolved with the (S) form of 1-(1-Naphthyl)ethylamine.3 Asymmetric aldol condensation using an enantiopure iron acetyl complex followed by cyclization,3c or asymmetric hydrogenation of diketene catalyzed by a chiral ruthenium complex,3d also gives the optically active b-lactone.

Handling, Storage, and Precautions: can be stored in the refrigerator for several months without noticeable changes; cancer suspect reagent; should be handled with due care.

General Discussion.

b-Methyl-b-propiolactone is particularly useful as a reactive four-carbon building block. Like b-Propiolactone, b-methyl-b-propiolactone undergoes a variety of ring-opening reactions in which the regiochemistry is dependent on the nature of the nucleophile (eq 1). Addition to the carbonyl carbon predominates in reactions with organolithium4 or Grignard reagents,5 giving a,b-unsaturated ketones (2) or 1,3-diols (3). Organocadmium reagents4 effect C-O bond fission to give b-methyl carboxylic acids (4).

Selective b-attack is best accomplished by the use of organocopper reagents (eq 2).6 Organocuprates prepared from 2 equiv of Grignard reagents and 1 equiv of Copper(I) Iodide give b-methyl carboxylic acids (4) in better yields than when the corresponding organolithium reagents are used. In the presence of a catalytic amount of a copper(I) salt, Grignard reagents also attack at the b-carbon to give the same products in good yields.7

The Potassium complex of 18-Crown-6 or Potassium Naphthalenide effects ring-opening to give acetates or their alkylated derivatives in good yield (eq 3). Treatment of the reaction mixture obtained from b-methyl-b-propiolactone and potassium-18-crown-6 with hydrochloric acid or alkyl halides gives the acetate (5) or its alkylated derivative (6), respectively.8 The a,b-unsaturated carboxylic acid (7) or its ester (8) is formed by the action of the potassium naphthalenide-18-crown-6 complex.9

b-Methyl-b-propiolactone is useful as a four-carbon building block for terpenoid synthesis (eq 4). Citronellic acid (9) is prepared by reaction with the homoprenyl Grignard reagent; pulegone (10), citronellol (11), geraniol, and nerol (12) can be obtained by further functional group manipulations.10

Optically active (R)- and (S)-b-methyl-b-propiolactone serve as versatile reagents for the synthesis of 3-sulfinylbutyric acid11 and for various natural products in optically active form. (S)-ar-Turmerone (13) is obtained by reaction of the (R)-enantiomer with a di-p-tolylcopper reagent followed by functional group manipulation (eq 5).3a (R,R)-Phytol (15) is prepared by ring-opening with the Grignard reagent (14) followed by the chain-elongation reaction (eq 6).12 (R,Z)-Trogodermal (18), an insect pheromone of Trogoderma inclusum, is synthesized by using the cis-alkenylcopper reagent (17) (eq 7).13 The enantiomeric purity of the final natural products is 83-84% ee. Comparison of this value with that of the starting (S)-(+)-3-bromobutyric acid (90% ee) indicates that these magnesiocuprate coupling reactions occur with &egt;92% inversion of configuration at the b-position of the (R)-(+)-b-methyl-b-propiolactone.3a

1,3-Dimethyl-2,9-dioxabicyclo[3.3.1]nonane (19), an insect pheromone, has been synthesized starting from (R)-(1) via ring-opening at the acyl carbon followed by conjugate addition to the resulting a,b-unsaturated ketone (eq 8).14

Related Reagents.

N-Benzyloxycarbonyl-L-serine b-Lactone; a,b-Butenolide; g-Butyrolactone; Dihydro-5-(hydroxymethyl)-2(3H)-furanone; b-Ethynyl-b-propiolactone; b-Propiolactone.


1. (a) Zaugg, H. E. OR 1954, 8, 305. (b) Fujisawa, T.; Sato, T. J. Synth. Org. Chem. Jpn. 1982, 40, 618 (CA 1982, 97, 198 011y). (c) Pommier, A.; Pons, J. M. S 1993, 441.
2. (a) Agostini, D. E.; Lando, J. B.; Shelton, J. R. J. Polym. Sci. A-1 1971, 9, 2775. (b) Sixt, J. U.S. Patent 2 763 664, 1956, (CA 1957, 51, 5115b).
3. (a) Sato, T.; Kawara, T.; Nishizawa, A.; Fujisawa, T. TL 1980, 21, 3377. (b) Sato, T.; Naruse, K.; Fujisawa, T. TL 1982, 23, 3587. (c) Davies, S. G. Aldrichim. Acta 1990, 23, 31. (d) Ohta, T.; Miyake, T.; Takaya, H. CC 1992, 1725.
4. Stuckwisch, C. G.; Bailey, J. V. JOC 1963, 28, 2362.
5. (a) Gresham, T. L.; Jansen, J. E.; Shaver, F. W.; Bankert, R. A. JACS 1949, 71, 2807. (b) Kutner, A.; Perlman, K. L.; Lago, A.; Sicinski, R. R.; Schnoes, H. K.; DeLuca, H. F. JOC 1988, 53, 3450.
6. Fujisawa, T.; Sato, T.; Kawara, T.; Kawashima, M.; Shimizu, H.; Ito, Y. TL 1980, 21, 2181. Kawashima, M.; Sato, T.; Fujisawa, T. T 1989, 45, 403.
7. Sato, T.; Kawara, T.; Kawashima, M.; Fujisawa, T. CL 1980, 571. Normant, J. F.; Alexakis, A.; Cahiez, G. TL 1980, 21, 935.
8. Jedlinski, Z.; Kowalczuk, M.; Misiolek, A. CC 1988, 1261.
9. Kowalczuk, M.; Kurcok, P.; Glowkowski, W.; Jedlinski, Z. JOC 1992, 57, 389.
10. Fujisawa, T.; Sato, T.; Kawara, T.; Noda, A.; Obinata, T. TL 1980, 21, 2553.
11. Breitschuh, R.; Seebach, D. S 1992, 25, 1170.
12. Fujisawa, T.; Sato, T.; Kawara, T.; Ohashi, K. TL 1981, 22, 4823.
13. Sato, T.; Naruse, K.; Fujisawa, T. TL 1982, 23, 3587.
14. Sato, T.; Itoh, T.; Hattori, C.; Fujisawa, T. CL 1983, 1391.

Tamotsu Fujisawa & Makoto Shimizu

Mie University, Japan



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