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Org. Synth. 1996, 73, 221
DOI: 10.15227/orgsyn.073.0221
S-(−)-5-HEPTYL-2-PYRROLIDINONE. CHIRAL BICYCLIC LACTAMS AS TEMPLATES FOR PYRROLIDINES AND PYRROLIDINONES
[2-Pyrrolidinone, 5-heptyl-, (S)-]
Submitted by M. A. Tschantz, L. E. Burgess, and A. I. Meyers1.
Checked by J. Madalengoitia and L. E. Overman.
1. Procedure
A. (+)-3-Phenyl-5-oxo-7a-heptyl-2,3,5,6,7,7a-hexahydropyrrolo[2,1-b]oxazole. A clean, 500-mL, round-bottomed flask, equipped with a magnetic stirring bar and a Dean-Stark trap, is charged with 12.5 g of 4-ketoundecanoic acid (62.4 mmol) (Note 1), 8.56 g of (S)-(+)-2-Phenylglycinol (62.4 mmol) (Note 2), and 150 mL of toluene. The solution is heated at reflux with stirring for 20 hr and then cooled to room temperature. The solution is concentrated at reduced pressure, and the residual yellow oil is purified by flash chromatography on silica gel (Note 3) employing 3:1 hexane/ethyl acetate as the eluent to provide 14.5–16.2 g of the bicyclic lactam (77–86%) as a light yellow oil (Note 4).
B. (+)-N-[2-(1-Hydroxy-2-phenethyl)]-5-heptyl-2-pyrrolidinone. An oven-dried, 1-L, one-necked, round-bottomed flask, equipped with a magnetic stirring bar and fitted with a rubber septum, is flushed with argon and charged with 14.1 g of the bicyclic lactam (46.7 mmol) prepared above and 270 mL of dry dichloromethane (Note 5). The resulting solution is cooled to −78°C, using an external dry ice-acetone bath, and stirred for 15 min. Then 13.4 mL of triethylsilane (84.1 mmol) (Note 6) and 93 mL (93 mmol) of a 1.0 M solution of titanium tetrachloride in CH2Cl2 (Note 7) are successively added dropwise via syringe under an argon atmosphere (Note 8). The solution is stirred at −78°C for 1.5 hr and then allowed to warm to room temperature and stir at that temperature for 1 hr. The mixture is recooled to 0°C and carefully quenched with saturated ammonium chloride via syringe (CAUTION: vigorous reaction!). The resulting solution is diluted with 120 mL of water, transferred to a 1-L separatory funnel, and extracted with three 75-mL portions of dichloromethane. The combined organic extracts are dried over sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to afford a crude mixture containing the product. Purification of the product by flash chromatography, using 1:1 (v/v) hexane/ethyl acetate as eluent, provides the hydroxypyrrolidinone (12.6 g, 89%) as a pale yellow oil (Note 9).
C. S-(−)-5-Heptyl-2-pyrrolidinone. An oven-dried, 1-L, two-necked, round-bottomed flask, equipped with a glass-covered stirring bar, is charged with 12.4 g of (+)-N-[2-(1-hydroxy-2-phenethyl)]-5-heptyl-2-pyrrolidinone (40.8 mmol), 24 mL of anhydrous ethyl alcohol (410 mmol), and 100 mL of dry tetrahydrofuran (THF). One neck is fitted with an acetone-dry ice cooled cold finger condenser bearing an argon inlet/outlet vented through a mineral oil bubbler, and the other neck with a second gas inlet valve. With stirring, the solution is cooled to −78°C using an external acetone-dry ice bath, and ammonia (~200 mL) is condensed into the flask through the gas inlet valve. The gas inlet is replaced with a stopper, the acetone-dry ice bath is removed, and 2.83 g of lithium wire (408 mmol) (Note 10) is added in small portions by removal of the stopper. The resulting blue solution is allowed to stir and reflux for 30 min (Note 11). The reaction mixture is carefully quenched with a small amount of ammonium chloride (solid) until disappearance of the blue color. The cold finger is removed, and the resulting solution is allowed to warm to room temperature over 4 hr (CAUTION: ammonia is evolved). The residual milky solution is concentrated under reduced pressure, and the remaining semisolid is diluted with water (100 mL) and dichloromethane (150 mL) and stirred for 30 min. The two layers are separated, and the aqueous layer is extracted four times with 50-mL portions of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The yellow residue is subjected to flash chromatography (Note 3) and (Note 12), employing a 4:1 hexane/ethyl acetate solution as eluent, to afford 4.64 g (62%) of the desired pyrrolidinone as a pale yellow solid, mp 43–44°C (Note 13). CAUTION: The minor reaction by-product, phenethyl alcohol, which has a distinct benzene-like odor, is an inhibitor of DNA and RNA synthesis in vitro.
2. Notes
1. Tschantz, M. A.; Burgess, L. E.; Meyers, A. I. Org. Synth., Coll. Vol. IX 1998, 530.
2. (S)-(+)-2-Phenylglycinol is commercially available, or may be prepared by reducing (S)-(+)-2-phenylglycine as follows: A 1-L, three-necked, round-bottomed flask is charged with 200 mL of dry THF under an argon atmosphere. Portionwise, 10.01 g of sodium borohydride (264.6 mmol) is added, followed by the dropwise addition of 65.1 mL of boron trifluoride etherate (528.7 mmol). The colorless suspension is stirred for 15 min, followed by portionwise addition of 20.00 g of (S)-(+)-2-phenylglycine (132.2 mmol). (CAUTION: exotherm and gas evolution!). The resulting suspension is heated at reflux for 12 hr and then is allowed to cool to room temperature followed by quenching with methanol until gas evolution ceases. The reaction mixture is concentrated under reduced pressure to yield a colorless solid that is taken up in 400 mL of 20% aqueous sodium hydroxide solution. The basic solution is extracted three times with 200-mL portions of dichloromethane, the combined organic layers are dried over sodium sulfate, and concentrated under reduced pressure to yield 14.72 g (81%) of (S)-(+)-2-phenylglycinol as a colorless solid: mp 72–74°C, [α]D +32.2°; 1H NMR (300 MHz, CDCl3) δ: 3.52 (dd, 1 H, J = 10.7, 8.3), 3.71 (dd, 1 H, J = 10.7, 4.4), 4.01 (dd, 1 H, J = 8.2, 4.4), 7.23–7.35 (m, 5 H).
3. Merck 951 grade silica gel was used. Chromatography was performed in the manner described by Still2 using ~ 20:1 (w/w) of silica gel to crude product.
4. The spectral data of the purified bicyclic lactam are as follows: 1H NMR (300 MHz, CDCl3) δ: 0.85 (t, 3 H, J = 6.4), 1.13–1.72 (m, 12 H), 2.13 (m, 1 H), 2.33 (ddd, 1 H, J = 13.4, 9.7, 2.5), 2.57 (ddd, 1 H, J = 17.3, 10.2, 2.5), 2.81 (m, 1 H), 4.05 (dd, 1 H, J = 8.7, 7.3), 4.62 (t, 1 H, J = 8.5), 5.17 (t, 1 H, J = 7.7), 7.20–7.36 (m, 5 H); 13C NMR (75.5 MHz, CDCl3) δ: 14.0, 22.5, 23.9, 29.1, 29.5, 30.9, 31.6, 33.3, 36.3, 57.5, 72.8, 102.7, 125.4, 127.3, 128.6, 140.1, 179.3; IR (thin film) cm−1: 2954–2856, 2362, 1715, 1458, 1364, 1031, 699.
5. Dichloromethane was freshly distilled over calcium hydride.
6. Triethylsilane was purchased from Aldrich Chemical Company, Inc. and used without further purification.
7. Titanium tetrachloride was purchased from Fluka Chemical Corporation and used without further purification.
8. The checkers used an internal thermometer and maintained the reaction temperature between −78° and −70°C during the addition.
9. The spectral data of the purified hydroxyalkyl lactam are as follows: 1H NMR (300 MHz, CDCl3, 5 mg/mL) δ: 0.86 (t, 3 H, J = 6.6), 1.05–1.40 (m, 11 H), 1.58 (m, 1 H), 1.75 (m, 1 H), 2.07 (m, 1 H), 2.40–2.59 (m, 2 H), 2.95 (s (br), 1 H), 3.33 (m, 1 H), 3.95 (dd, 1 H, J = 12.3, 3.3), 4.22 (dd, 1 H, J = 12.3, 7.8), 4.41 (dd, 1 H, J = 7.8, 3.3), 7.20–7.37 (m, 5 H); 13C NMR (75.5 MHz, CDCl3) δ: 14.0, 22.6, 24.1, 24.5, 29.1, 29.4, 31.3, 31.7, 32.3, 59.3, 62.3, 64.1, 127.2, 127.8, 128.7, 137.5, 176.8; IR (thin film) cm−1: 3377 (br), 2959–2856, 1668, 1451, 1420, 1285, 1064, 702. The 1H NMR signal for the proton of the OH group (δ 2.95) was found to be concentration dependent.
10. Lithium wire was purchased from Aldrich Chemical Company, Inc., and was cut into small pieces.
11. The solution should remain blue for the duration (30 min). More lithium may be added if necessary.
12. The final product is difficult to visualize during TLC analysis. Ninhydrin (5% w/v in ethanol) or ceric ammonium nitrate (5 g in 100 mL of aqueous 1 M H2SO4) are effective.
13. The spectral data for the purified pyrrolidinone are as follows: 1H NMR (300 MHz, CDCl3, 5 mg/mL) δ: 0.86 (t, 3 H, J = 6.4), 1.25–1.75 (m, 13 H), 2.20–2.35 (m, 3 H), 3.61 (quintet, 1 H, J = 6.9), 6.09 (s (br), 1 H); 13C NMR (75.5 MHz, CDCl3) δ: 14.0, 22.6, 25.8, 27.3, 29.1, 29.4, 30.2, 31.7, 36.7, 54.7, 178.2; IR (thin film) cm−1: 3204 (br), 2956–2856, 1700, 1463, 1387, 1311, 1266. [α]D −9.7° (CHCl3, c 1.1).
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Chiral bicyclic lactams are excellent precursors to a wide variety of chiral, non-racemic carbocycles including cyclopentenones, cyclohexenones, cyclopropanes, indanones, naphthalenones, and asymmetric keto acids.3 4 Recently they have been applied to the synthesis of chiral, non-racemic pyrrolidines and pyrrolidinones,5 6 7 8 that are medicinally and synthetically important molecules.9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 The three-step procedure described here provides an efficient route (overall yield: 46%) to (S)-5-heptyl-2-pyrrolidinone of high enantiomeric purity. The scheme below illustrates this reaction.
TABLE

R

Yield of 1

Yield of 2

Yield of 3

83%

88%

89%

89%

85%

65%

84%

94%

81%
The first step is the formation of the chiral bicyclic lactam 1 involving the cyclodehydration of a 4-keto acid (p. 530) and (S)-2-phenylglycinol. Interestingly only a single diastereomer (NMR) of 1 is formed. The second step, the crucial reduction of the N,O-ketal, probably proceeds via an N-acyl iminium ion in which allylic 1,3-interactions dictate the facial selectivity of hydride delivery.6,7 The resulting N-substituted 5-alkylpyrrolidinones 2 were typically obtained in >94% diastereomeric excess as determined by the isolation of each diastereomer via flash chromatography. The final step, cleavage of the chiral auxiliary, takes advantage of the benzylic C-N bond to expose the free amide by dissolving metal reduction. Although the chiral "auxiliary" is destroyed, the relatively low cost of both antipodes of phenylglycine make this procedure attractive as a preparative method for both antipodes of the pyrrolidinones.
References and Notes
  1. Department of Chemistry, Colorado State University, Fort Collins, CO 80523.
  2. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
  3. Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503 and references therein;
  4. Meyers, A. I.; Berney, D. Org. Synth., Coll. Vol. VIII 1993, 241.
  5. Meyers, A. I.; Burgess, L. E. J. Org. Chem. 1991, 56, 2294;
  6. Burgess, L. E.; Meyers, A. I. J. Am. Chem. 1991, 113, 9858;
  7. Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656 and references therein;
  8. Meyers, A. I.; Snyder, L. J. Org. Chem. 1992, 57, 3814.
  9. In natural products: (a) Daly, J. W.; Spande, T. F. in "Alkaloids: Chemical and Biological Perspectives"; Pelletier, S. W.; Ed.; Wiley: New York, 1986; Vol. 4, Chapter 1;
  10. Hart, D. J. in "Alkaloids: Chemical and Biological Perspectives"; Pelletier, S. W.; Ed.; Wiley: New York, 1988; Vol 6, Chapter 3;
  11. Elbein, A. D.; Molyneux, R. J. "Alkaloids: Chemical and Biological Perspectives"; Pelletier, S. W.; Ed.; Wiley: New York, 1987, Vol. 5, Chapter 1;
  12. Gellert, E. "Alkaloids: Chemical and Biological Perspectives"; Pelletier, S. W.; Ed.; Wiley: New York, 1987, Vol. 5, Chapter 2;
  13. Hiemstra, H.; Speckamp, W. N. in "The Alkaloids"; Brossi, A., Ed.; Academic Press: New York, 1988, Vol. 32, Chapter 4;
  14. Massiot, G.; Delaude, C. in "The Alkaloids"; Brossi, A., Ed.; Academic Press: New York, 1986; Vol 27, Chapter 3;
  15. Jones, T. H.; Blum, M. S.; Fales, H. M. Tetrahedron 1982, 38, 1949;
  16. Jones, T. H.; Blum, M. S.; Howard, R. W.; McDaniel, C. A.; Fales, H. M.; Dubois, M. B.; Torres, J. J. Chemical Ecology 1982, 8, 285;
  17. Rüeger, H.; Benn, M. Heterocycles 1983, 20, 1331;
  18. Stevens, R. V. Accts. Chem. Res. 1977, 10, 193;
  19. Stevens, R. V. In "The Total Synthesis of Natural Products:, ApSimon, J., Ed.; Wiley: New York, 1977; Vol. 3, p. 439.
  20. As medicinally important agents: (l) Rigo, B.; Fasseur, D.; Cherepy, N.; Couturier, D. Tetrahedron Lett. 1989, 30, 7057;
  21. Nilsson, B. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1990, 33, 580;
  22. Lundkvist, J. R. M.; Wistrand, L.-G.; Hacksell, U. Tetrahedron Lett. 1990, 31, 719;
  23. Garvey, D. S.; May, P. D.; Nadzan, A. M. J. Org. Chem. 1990, 55, 936;
  24. Heffner, R. J.; Joullié, M. M. Tetrahedron Lett. 1989, 30, 7021;
  25. Silverman, R. B.; Nanavati, S. M. J. Med. Chem. 1990, 33, 931;
  26. Bick, I. R. C.; Hai, M. A. in "The Alkaloids"; Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 24, Chapter 3;
  27. Aronstam, R. S.; Daly, J. W.; Spande, T. F.; Narayanan, T. K.; Albequerque, E. X. Neurochemical Res. 1986, 11, 1227;
  28. Hino, M.; Nakayama, O.; Tsurumi, Y.; Adachi, K.; Shibata, T.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1985, 38, 926;
  29. Humphries, M. J.; Matsumoto, K.; White, S. L.; Molyneux, R. J.; Olden, K. Cancer Res. 1988, 48, 1410;
  30. Jimenez, A.; Vazques, D. in "Antibiotics", Hahn, F. E., Ed.; Springer Verlag: Berlin, 1979; Vol. 5, Part 2, pp. 1–19 and references cited therein.
  31. As chiral auxiliaries: (w) Whitesell, J. K. Chem. Rev. 1989, 89, 1581–1590;
  32. See "Asymmetric Synthesis"; Morrison, J. D.; Ed.; Academic Press: New York, 1983, Vol. 2.
  33. As chiral bases: (y) Tomioka, K. Synthesis 1990, 541 and references therein;
  34. Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S. Tetrahedron 1990, 46, 523;
  35. Cox, P. J.; Simpkins, N, S. Tetrahedron: Asymmetry 1991, 2, 1.
  36. As chiral ligands: (bb) Kagan, H. B. in "Asymmetric Synthesis"; Morrison, J. D , Ed.; Academic Press: New York, 1985; Vol. 5, Chapter 1;
  37. Doyle, M. P.; Pieters, R. J.; Martin, S. F.; Austin, R. E.; Oalmann, C. J.; Müller, P. J. Am. Chem. Soc. 1991, 113, 1423 and references cited therein.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

(+)-N-[2-(1-Hydroxy-2-phenethyl)]-5-heptyl-2-pyrrolidinone

S-(−)-5-HEPTYL-2-PYRROLIDINONE

H2SO4

ethyl alcohol,
ethanol (64-17-5)

ammonia (7664-41-7)

ethyl acetate (141-78-6)

methanol (67-56-1)

ammonium chloride (12125-02-9)

sodium hydroxide (1310-73-2)

sodium sulfate (7757-82-6)

toluene (108-88-3)

dichloromethane (75-09-2)

phenethyl alcohol (60-12-8)

lithium,
Lithium wire (7439-93-2)

magnesium sulfate (7487-88-9)

Tetrahydrofuran,
THF (109-99-9)

(S)-(+)-2-phenylglycine (2935-35-5)

hexane (110-54-3)

titanium tetrachloride (7550-45-0)

phenylglycine (103-01-5)

argon (7440-37-1)

boron trifluoride etherate (109-63-7)

calcium hydride (7789-78-8)

sodium borohydride (16940-66-2)

ninhydrin (938-24-9)

ceric ammonium nitrate

TRIETHYLSILANE (617-86-7)

(S)-5-heptyl-2-pyrrolidinone,
2-Pyrrolidinone, 5-heptyl-, (S)- (152614-98-7)

(+)-3-Phenyl-5-oxo-7a-heptyl-2,3,5,6,7,7a-hexahydropyrrolo[2,1-b]oxazole (132959-41-2)

4-Ketoundecanoic acid (22847-06-9)

(S)-(+)-2-Phenylglycinol,
(S)-2-phenylglycinol (20989-17-7)

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