Checked by J. Madalengoitia and L. E. Overman.
1. Procedure
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
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, CDCl
3) 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 Still
2 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, CDCl
3) 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, CDCl
3) 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.
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, CDCl
3, 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, CDCl
3) 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.
13. The spectral data for the purified pyrrolidinone are as follows:
1H NMR (300 MHz, CDCl
3, 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, CDCl
3) 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° (CHCl
3,
c 1.1).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
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.
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.
Appendix
Compounds Referenced (Chemical Abstracts 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)
boron trifluoride etherate (109-63-7)
calcium hydride (7789-78-8)
sodium borohydride (16940-66-2)
argon (7440-37-1)
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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