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J. Escalante, M. A. Gonza´lez-Tototzin / Tetrahedron: Asymmetry 14 (2003) 981–985
3. Conclusions
4.2.2.
( )-1-(3,3-Dimethyl-2-oxo-1-phenyl-butyl)-4-
phenyl-azetidin-2-one rac-7. The general procedure was
followed for ring expansion, and after 1 min 1.1 mol
equiv. of pivaloyl chloride was added. Purification of
the crude product by flash chromatography (hex/
AcOEt, 10:00:10) afforded 83% yield of rac-7. Color-
In this paper, we present a new method for the prepara-
tion of enantiomerically pure g-lactams (4S,5R)-5 and
(4R,5S)-5. The interest for these g-lactams as chiral
auxiliaries is given by their potential to be used in the
intramolecular protective formation of g-amino acids.
Further studies to explore these g-lactams as new chiral
auxiliaries in the synthesis of amino acids are in
progress.
1
less crystals, mp 77–79°C. H NMR (200 MHz, CDCl3)
l 1.33 (s, 9H), 2.78 (dd, Jgem=17.6 Hz, Janti=6.2 Hz,
1H), 3.13 (dd, Jgem=17.6 Hz, Jsy4n=8.4 Hz, 1H), 3.38
(ddd, Janti=6.2 Hz, Jsyn=8.4 Hz, J=5.2 Hz, 1H), 5.30
4
(d, J=5.2 Hz, 1H), 7.10–7.35 (m, 10H). 13C NMR (50
MHz, CDCl3) l 26.3, 39.9, 42.2, 46.5, 70.1, 125.4,
126.2, 127.0, 127.6, 127.9, 128.2, 129.0, 129.1, 140.9,
141.2, 173.4, 180.9.
4. Experimental
4.1. General
4.3. ( )-1-Benzyl-trans-4,5-diphenyl-pyrrolidin-2-one
rac-8
TLC: Merck-DC-F254 plates; detection by UV light.
Flash column chromatography:13 Merck silica gel
(0.040–0.063 mm). Mp: Mel-Temp apparatus; not cor-
rected. Optical rotations were determined in a Perkin–
A mixture 1:1 of solvents THF/DMF was added to the
trans-4,5-diphenyl-pyrrolidin-2-one (rac-5) at 0°C in an
ice-water bath. This suspension was treated with 2.2
mol equiv. of NaH and 1.1 mol equiv. of benzyl
bromide. The ice-water bath was removed and stirring
continued at room temperature over night. The mixture
was filtered, evaporated and purified by flash chro-
matography (hex/AcOEt, 10:00:10) afforded 84%
yield of rac-8. Colorless oil. 1H NMR (200 MHz,
CDCl3), l 2.71 (dd, Jgem=17.1 Hz, Janti=7.8 Hz, 1H),
1
Elmer 241 polarimeter at the sodium D-line. H NMR
spectra: Varian Oxford 400 MHz, Varian Mercury 200
MHz. 13C NMR spectra: Varian Oxford 100 MHz,
Varian Mercury 50 MHz. Chemical shifts (l) in ppm
downfield from the integral TMS reference; the cou-
pling constants (J) in Hz. X-Ray: APEX-Bruker dif-
fractometer. The structures were solved by direct
methods using the program SHELXS.14
3.06 (dd, Jgem=17.1 Hz, Jsyn=9.1 Hz, 1H), 3.34 (ddd,
Flasks, stirring bars and hypodermic needles used for
the generation and reactions of organolithiums were
dried for 12 h at 120°C and allowed to cool in a
desiccator over anhydrous CaSO4. Anhydrous solvents
were obtained by distillation from benzophenone
ketyl.15 The n-BuLi employed was titrated according to
the method of Juaristi et al.16
3
Janti=7.8 Hz, Jsyn=9.1 Hz, J=6.1 Hz, 1H), 4.30 (d,
3J=6.1 Hz, 1H), 3.51, 5.20 (AB, J=J%=14.3, 2H),
6.95–7.45 (m, 15H). 13C NMR (50 MHz, CDCl3) l
38.6, 44.8, 47.7, 69.5, 127.1, 127.2, 127.2, 127.7, 128.4,
128.7, 128.8, 128.9, 129.1, 136.2, 139.4, 141.7, 174.2.
4.4. General procedure for the g-lactam-5 resolution
4.2. General procedure for the ring expansion
A solution of rac-5 in THF was cooled to −78°C before
slowly adding 1.1 mol equiv. of n-butyllithium in hex-
ane (2.4 M). The resulting solution was stirred at −78°C
for 10 min and further at room temperature for 15 min,
and treated successively with the resolution agent (N-
Under N2 a dry flask fitted with magnetic stirrer and a
solution of the appropriate b-lactam17 in anhydrous
THF was cooled to −78°C before the slow addition of
1.1 mol equiv. of n-BuLi in hexane (2.4 M). The
resulting solution was stirred at −78°C for 30 min and
then quenched with a saturated ammonium chloride
solution and then with 10 mL of water. The aqueous
phase was extracted with three 10 mL portions of
CH2Cl2. The combined organic extracts were dried
(Na2SO4), filtered and evaporated to give the crude
product. The crude material was recrystallized from
mixtures of MeOH and CH2Cl2 to yield the pure g-
lactam.
phthalyl-L-alanine or D
-alanine chloride).19 The mixture
was stirred at the same temperature for 1 h and treated
with saturated ammonium chloride solution and then
with water. The aqueous phase was extracted with
CH2Cl2. The combined extracts were dried (Na2SO4),
filtered and evaporated to give the crude product.
Purification of the crude product was accomplished by
flash chromatography (hexane/AcOEt) and then by
recrystallization from hexane/AcOEt yielding the corre-
sponding diastereomer.
4.2.1. ( )-trans 4,5-Diphenyl-pyrrolidin-2-one rac-5. 87%
1
yield as white crystals, mp 215–218°C. H NMR (400
4.4.1.
2-[1(S)-Methyl-2-oxo-2-(5-oxo-2(R),3(S)-
MHz, CDCl3) l 2.70 (dd, Jgem=16.5 Hz, Janti=8.8 Hz,
1H), 2.87 (dd, Jgem=16.5 Hz, Jsy3n=9.9 Hz, 1H), 3.40
(ddd, Janti=8.8 Hz, Jsyn=9.9 Hz, J=7.7 Hz, 1H), 4.70
diphenyl-pyrrolidin-1-yl)-ethyl]-isoindole-1,3-dione 10a.
90% Yield; mp 188–189°C; [h]2D5=−61.9 (c 1.1, CHCl3);
1H NMR (400 MHz, CDCl3) l 1.87 (d, J=7.2 Hz, 3H),
2.76 (dd, Jgem=18.4 Hz, Janti=2.4 Hz, 1H), 3.22 (dd,
3
(d, J=7.7 Hz, 1H), 6.36 (s, 1H), 7.15–7.35 (m, 10H).
13C NMR (100 MHz, CDCl3) l 39.2, 51.0, 65.3, 126.5,
127.1, 127.7, 127.9, 128.7, 128.8, 141.4, 141.8, 176.1.
MS, m/z 237 (M+). X-Ray crystallographic structure in
Fig. 2.18
Jgem=18.4 Hz, Jsyn=8.8 Hz, 1H), 3.41 (ddd, Janti=2.4
3
3
Hz, Jsyn=8.8 Hz, J=2.4 Hz, 1H), 5.32 (d, J=2.4 Hz,
1H), 6.02 (c, 1H), 7.16–7.40 (m, 10H), 7.68 (dd, J=2.8
Hz, J%=5.6 Hz, 2H), 7.82 (dd, J=2.8 Hz, J%=5.6 Hz,