Asymmetric syntheses of derivatives of βand γ-aryl and α-alkyl amino acids using n-Buli/(-)-sparteine

Full text of DOI:10.1021/jo9817568

J . Org. Chem. 1999, 64, 1705-1708
1705
yl)-3-phenylallyllithium‚(-)-sparteine. This configura-
tionally stable complex affords products with high enan-
tioenrichments on reactions with different electrophiles.6
Treatment of 4 with 1.1 equiv of n-BuLi/(-)-sparteine and
carbon dioxide gives a γ-amino acid which on subsequent
hydrogenation and esterification provides (S)-5 in 52%
overall yield with 96:4 er. Lithiation of 4 with n-BuLi/
(-)-sparteine followed by methyl chloroformate, subse-
quent hydrogenation, and removal of Boc group gives
(R)-5 in 41% yield with 92:8 er.7 Efficient cyclization
using t-BuMgCl and removal of the p-methoxyphenyl
group using CAN give 3-phenyl γ-lactam 6 in 72% and
71% overall yields. Thus, either enantiomer of the enan-
tioenriched 3-phenyl γ-lactam 6 can be obtained by this
approach.8
Asym m etr ic Syn th eses of Der iva tives of â-
a n d γ-Ar yl a n d r-Alk yl Am in o Acid s Usin g
n -Bu Li/(-)-Sp a r tein e
Bong J in Kim, Yong Sun Park,1 and Peter Beak*
Department of Chemistry, University of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
Received August 27, 1998
Recent studies have established that reactions of
organolithium species complexed to (-)-sparteine can
afford highly enantioenriched products in lithiation-
substitution sequences.2 We have reported the aymmetric
syntheses of R-, â-, and γ-aryl amino acids and esters
from N-Boc arylmethylamine derivatives by a lithiation-
substitution sequence using n-BuLi/(-)-sparteine.3 We
report applications of this methodology to enantioselec-
tive syntheses of 4-phenyl-â-lactams, 3-phenyl-γ-lactams,
and an R-alkyl amino acid.
Highly enantioenriched â-phenyl amino acid derivative
(S)-1 can be obtained from the reaction of N-Boc-N-(p-
methoxyphenyl)benzylamine with 4-bromo-2-methyl-2-
butene in the presence of n-BuLi/(-)-sparteine and
subsequent oxidation with O3 and J ones reagent in 76%
overall yield with 93:7 er.3 When 1 is treated with SOCl2
in MeOH, the methyl ester of 1 is obtained in 92% yield.
Cylization of the ester is efficiently carried out with
t-BuMgCl in THF at -5 °C to provide 4-phenyl â-lactam
(S)-2 in 93% yield with 94:6 er.4 Alkylation of the C-3
position of the lactam ring 2 is performed with LDA and
various electrophiles to afford (3R,4S)-3a in 91% yield,
(3S,4S)-3b in 85% yield and (3S,4S)-3c in 70% yield.5
A further example of the synthetic potential of the
methodology for amino acid synthesis is illustrated by
the oxidative conversion of (S)-8 to enantioenriched
amino acid (S)-9. The enantioenriched R-methyl-substi-
tuted p-methoxybenzylamine (S)-8 is produced in 85%
yield with 95:5 er by the treatment of 7 with n-BuLi/(-
)-sparteine complex and MeOTf. For the synthesis of
N-Boc alanine methyl ester (S)-9, (S)-8 is treated with
CAN to remove the p-methoxyphenyl group in 56% yield.
The N-Boc-R-methyl p-methoxybenzylamine is oxidized
with RuO4 for 48 h to the corresponding acid which on
esterification and Boc protection gives the methyl ester
(S)-9 with 94:6 er in 42% overall yield.9,10
In summary, we have demonstrated n-BuLi/sparteine
complex is effective as a chiral base for the asymmetric
syntheses of 3-alkyl-4-phenyl â-lactams, 3-phenyl-γ-lac-
tams, and an R-alkyl amino acid ester. Application of this
We have reported that N-Boc-N-(p-methoxyphenyl)-
cinnamylamine (4) can be selectively deprotonated by
n-BuLi/(-)-sparteine to form η3-N-Boc-N-(p-methoxyphen-
(6) Weisenburger, G. A.; Beak, P. J . Am. Chem. Soc. 1996, 118,
12218. Pippel, D. J .; Weisenburger, G. A.; Wilson, S.; Beak, P. Angew.
Chem., Int. Ed. 1998, 37, 2522.
(7) The absolute configuration of 6 is based on comparison to the
ureides from (R)-1-(1-naphthyl)ethyl isocyanate of previously assigned
authentic enantiomers. Pirkle, W. H.; Robertson, M. R.; Hyun, M. H.
J . Org. Chem. 1984, 49, 2433.
(1) Department of Chemistry, Konkuk University, Seoul, Korea, 143-
701.
(2) (a) Nozaki, H.; Aratani, T.; Toragata, T.; Noyori, R.; Tetrahedron,
1971, 27, 905. (b) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 1422. (c) Beak, P.; Basu, A.; Gallagher, D. J .;
Park, Y. S. Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552. (d)
Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282 and
references therein.
(3) Park, Y. S.; Beak, P. J . Org. Chem. 1997, 62, 1574.
(4) Holley, R. W.; Holley, A. D. J . Am. Chem. Soc. 1949, 71, 2124.
(5) The assignment of relative configuration of C-3 and C-4 positions
of the lactam ring is based on coupling constant in 1H NMR (J ) 2.4
Hz). The ratio of two epimers at hydroxy benzylic position of 3c is 50:
50 based on 1H NMR of 3c (4.64 and 5.38 ppm)
(8) We reported that the reaction of the N-Boc-N-(p-methoxyphenyl)-
benzylamine lithium intermediate with ClCO2Me and CO2 also pro-
vided the opposite configuration with ClCO2Me proceeding through a
retentive pathway and CO2 proceeding through an invertive pathway.
Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J . Am. Chem. Soc. 1997,
119, 11561.
(9) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless B. J . Org.
Chem. 1981, 46, 3936.
(10) We previously reported that N-Boc-R-ethylbenzylamine was
oxidized into 2-aminobutyric acid hydrochloride in 41% yield with 97:3
er using RuO4. Park, Y. S.; Boys, M. L.; Beak, P. J . Am. Chem. Soc.
1996, 118, 3757.
10.1021/jo9817568 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/06/1999

1706 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
tion, and concentration in vacuo. The crude product was further
purified by chromatography to give 3b as a colorless oil (25 mg,
85% yield).13 1H NMR (CDCl3, 500 MHz) δ 2.37 (s, 3H), 3.73 (s,
3H), 4.12 (d, 1H, J ) 2.5 Hz), 5.42 (d, 1H, J ) 2.5 Hz), 6.78 (d,
J ) 9.0 Hz, 2H), 7.20 (d, J ) 9.0 Hz, 2H), 7.25-7.36 (m, 5H);
13C NMR (CDCl3, 100.5 MHz) δ 29.8, 55.2, 55.4, 71.6, 114.1,
118.2, 126.0, 128.6, 129.0, 130.5, 136.4, 156.1, 159.5, 199.0 ; mass
spectrum (70 eV) m/e (relative intensity) 295 (M+, 30), 252 (7),
196 (15), 149 (100), 134 (23). Anal. Calcd for C18H17NO3: C,
73.20; H, 5.80; N, 4.74. Found: C, 73.45; H, 5.82; N, 4.52.
approach to the syntheses of a variety of enantioenriched
natural and unnatural amino acids and their derivatives
should be useful. Further work to develop synthetic
utilities of this methodology is in progress.
3(S)-(1′-Hyd r oxy-1′-p h en ylm eth yl)-1-(4-m eth oxyp h en yl)-
4(S)- p h en yla zetid in e-2-on e (3c). To a solution of (S)-2 (25
mg, 0.1 mmol) in THF (1.5 mL) at -78 °C was added LDA (2.0
M in heptane, 1.3 equiv). The reaction mixture was stirred for
30 min at -78 °C, and then benzaldehyde (4 equiv) was added.
Workup consisted of addition of water, extraction of the aqueous
layer with diethyl ether twice, extraction of the combined diethyl
ether extracts with sat. NH4Cl solution, drying over anhydrous
MgSO4, filtration, and concentration in vacuo. The crude product
was further purified by chromatography to give 3c as a colorless
oil (25 mg, 70% yield). 1H NMR (CDCl3, 400 MHz) δ 2.45 (d, J
) 4.0 Hz, 1H), 3.42 (dd, J ) 2.4 and 3.8 Hz, 1H), 3.73 (s, 3H),
5.12 (d, 1H, J ) 2.0 Hz), 5.39 (dd, 1H, J ) 4.0 and 3.8 Hz), 6.78
(d, J ) 9.2 Hz, 2H), 6.94 (m, 2H), 7.18-7.23 (m, 10H); 13C NMR
(CDCl3, 125 MHz) δ 55.7, 57.7, 66.8, 73.1, 114.3, 118.4, 125.7,
126.7, 128.3, 128.6, 128.8, 129.0, 131.1, 137.6, 141.0, 156.1, 165.1;
mass spectrum (70 eV) m/e (relative intensity) 359 (M+, 33), 234
(40), 198 (42), 137 (100), 98 (92). Anal. Calcd for C23H21NO3: C,
76.86; H, 5.89; N, 3.89. Found: C, 76.86; H, 6.14; N, 3.51.
Me t h yl-N -(4-m e t h oxyp h e n yl)-2-p h e n yl-4-a m in o-(Z)-
bu ten oa te ((S)-5). To a solution of (-)-sparteine (0.6 mL, 1.1
equiv) in toluene (15 mL) at -78 °C was added n-BuLi (1.6 M
in hexane, 1.62 mL, 1.1 equiv). The reaction was stirred for 20
min at -78 °C, and a solution of N-Boc-N-(4-methoxyphenyl)-
3-phenyl-(E)-2-propen-1-amine (4) (0.802 mg, 2.37 mmol) in
toluene (15 mL) was added at -78 °C. The resulting reaction
mixture was stirred at -78 °C for 5 h, and carbon dioxide gas
was bubbled through the reaction mixture until yellow color
disappeared (about 5 min). The reaction mixture was stirred for
30 min at -78 °C and quenched with MeOH before the mixture
was allowed to warm to room temperature. Workup procedure
consisted of following steps: addition of water (20 mL), extrac-
tion of the toluene layer with water (10 mL), extraction of
combined the aqueous layer, adjustment of the pH to 4.0 with
acetic acid, and extraction of the acidic aqueous solution with
diethyl ether. The combined diethyl ether extracts were dried
over anhydrous MgSO4. Filtration and concentration in vacuo
resulted in a crude residue which was purified by chromatog-
raphy with 0.03:10:40 AcOH/ethyl acetate/petroleum ether. The
Exp er im en ta l Section
1-(4-Methoxyphenyl)-4(S)-phenylazetidin-2-one (2). (S)-1 (604
mg, 1.7 mmol) was stirred at room temperature for 2 h in 15
mL of MeOH containing excess thionyl chloride to give the
corresponding Boc-deprotected methyl ester (445 mg, 92% yield).
1H NMR (CDCl3, 400 MHz) δ 2.80 (d, 2H, J ) 6.8 Hz), 3.65 (s,
3H), 3.70 (s, 3H), 4.27 (br, 1H), 4.76 (t, 1H, J ) 6.8 Hz), 6.52-
7.38 (m, 9H). Cyclization of the methyl ester (210 mg, 0.73 mmol)
was carried out with t-BuMgCl (1.0 equiv) in THF at 0 °C for
1.5 h to give (S)-2 as a white solid 173 mg (93% yield) mp 90-
92 °C (lit.11 94-96 °C racemic); 1H NMR (CDCl3, 400 MHz) δ
2.89 (dd, 1H, J ) 15.0 and 2.4 Hz), 3.50 (dd, 1H, J ) 15.0 and
5.7 Hz), 3.69 (s, 3H), 4.93 (dd, 1H, J ) 5.7 and 2.4 Hz), 6.75 (d,
J ) 9.0 Hz, 2H), 7.20-7.35 (m, 7H); 13C NMR (CDCl3, 100.5
MHz) δ 46.7, 54.0, 55.3, 114.2, 118.0, 125.8, 128.4, 129.1, 131.3,
138.2, 155.8, 164.0; mass spectrum (70 eV) m/e (relative inten-
sity) 253 (M+, 27), 211 (10), 196 (17), 149 (100), 134 (22). Anal.
Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.91;
H, 6.07; N, 5.76.
The enantiomeric ratio of (S)-2 was determined to be 94:6 in
favor of the S-enantiomer by chiral HPLC analysis using racemic
material as a standard (Whelk-O: 15% v/v 2-propanol in hexane;
a flow rate of 2.0 mL/min; a detection wavelenth of 254 nm).
The S- enantiomer (major) had a retention time of 13.8 min,
and R-enantiomer (minor) had a retention time of 10.0 min.
3(R)-Eth yl-1-(4-m eth oxyp h en yl)-4(S)-p h en yla zetid in -2-
on e (3a ). To a solution of (S)-2 (23 mg 0.09 mmol) in THF (1.2
mL) at -78 °C was added LDA (2.0 M in heptane, 1.3 equiv).
The reaction mixture was stirred for 30 min at -78 °C, and EtI
(4 equiv) was added. Workup consisted of addition of water,
extraction of the aqueous layer with diethyl ether twice, extrac-
tion of the combined diethyl ether extracts with sat. NH4Cl
solution, drying over anhydrous MgSO4, filtration, and concen-
tration in vacuo. The crude product was further purified by
chromatography to give a pure product 3a as a white solid (23
mg, 90% yield).12 mp 125-126 °C; 1H NMR (CDCl3, 400 MHz) δ
1.09 (t, J ) 5.8 Hz, 3H), 1.83-1.89 (m, 1H), 1.90-2.03 (m, 1H),
3.02-3.05 (m, 1H), 3.73 (s, 3H), 4.62 (d, 1H, J ) 2.4 Hz), 6.77
(d, J ) 7.2 Hz, 2H), 7.22 (d, J ) 7.2 Hz, 2H), 7.25-7.38 (m, 5H);
13C NMR (CDCl3, 125 MHz) δ 11.4, 21.9, 55.4, 60.7, 61.9, 114.2,
118.1, 125.8, 128.2, 129.1, 131.3, 138.3, 155.8, 167.2; mass
spectrum (70 eV) m/e (relative intensity) 281 (M+, 41), 196 (24),
149 (100), 132 (52), 117 (46). Anal. Calcd for C18H19NO2: C,
76.84; H, 6.81; N, 4.98. Found: C, 76.69; H, 6.81; N, 4.96.
3(S)-Acetyl-1-(4-m eth oxyp h en yl)-4(S)-p h en yla zetid in -2-
on e (3b). To a solution of (S)-2 (25 mg, 0.1 mmol) in THF (1.5
mL) at -78 °C was added LDA (2.0 M in heptane, 1.3 equiv).
The reaction mixture was stirred for 30 min at -78 °C, and
methyl acetate (4 equiv) was added. Workup consisted of
addition of water, extraction of the aqueous layer with diethyl
ether twice, extraction of the combined diethyl ether extracts
with sat. NH4Cl solution, drying over anhydrous MgSO4, filtra-
product
N-Boc-N-(4-methoxyphenyl)-2(S)-phenyl-4-amino-3-
butenoic acid was dissolved in 20 mL of ethanol with 10%
palladium on activated carbon (54 mg) and hydrogenated under
20 psi hydrogen for 1 h. The resulting mixture was filtered
through the Celite pad and washed with ethanol (8 mL) five
times. The solvent was evaporated under reduced pressure, and
the residue was purified by flash chromatography with 0.03:10:
40 AcOH/petroleum ether/ethyl acetate to give (57% yield, 404
1
mg) of a colorless oil. H NMR (CDCl3, 400 MHz) δ 1.38 (s, 9H),
2.0 (m, 1H), 2.30 (m, 1H), 3.58 (m, 3H), 3.78 (s, 3H), 6.82 (d, J
) 8.8 Hz, 2H), 7.03 (m, 2H), 7.22-7.29 (m, 5H); 13C NMR (CDCl3,
100.5 MHz) δ 28.1, 31.3, 48.7, 55.2, 80.1, 113.9, 127.4, 127.8,
128.5, 134.8, 137.7, 154.9, 157.5, 178.7.; mass spectrum (70 eV)
m/e (relative intensity) 385 (M+, 16), 329 (12), 285 (85), 136 (100),
120 (18).
To a solution of N-Boc-N-(4-methoxyphenyl)-2(S)-phenyl-4-
aminobutanoic acid (294 mg, 0.763 mmol) in methanol (7 mL)
at 0 °C was added thionyl chloride (0.556 mL, 7.63 mL), and
the mixture was stirred at room temperature for 1 h. The
reaction mixture was heated to 60 °C for 1 h, cooled to room
temperature, and then concentrated under reduced pressure.
The residue was dissolved in water and ethyl acetate, and the
pH was adjusted to 7-8 with sat. sodium bicarbonate solution
in an ice bath. The organic layer was separated, and the aqueous
(11) Kono, S.; Ebato, T., Shiboya, S. J . Chem. Soc., Perkin Trans. 1,
1980, 2105. Shu, K.; Mitsuharu, A.; Masaru, Y. Tetrahedron Lett. 1995,
36, 5773.
(12) (a) Futjieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K.
J . Am. Chem. Soc. 1997, 119, 2060. (b) Annunziata, R.; Cinquini, M.;
Cozzi, F.; Molteni, V.; Schupp, O. Tetrahedron 1996, 52, 2573. (c) Rita,
A. Mauro, C.; Franco, C.; Valentina, M.; Olaf, S. J . Org. Chem. 1996,
61, 8293.
(13) Palomo, C.; Cossio, F. P.; Arrieta, A.; Odriozola, J . M.; Oiatbide,
M.; Ontoria, J . M. J . Org. Chem. 1989, 54, 5736.

Notes
J . Org. Chem., Vol. 64, No. 5, 1999 1707
layer was extracted with ethyl acetate. The combined organic
layer was dried over anhydrous magnesium sulfate and conce-
trated under reduced pressure. The crude product was purified
by chromatography with 4:1 petroleum ether/ethyl acetate to
afford 228 mg of 5 (92% yield) as pale yellow oil. 1H NMR (CDCl3,
500 MHz) δ 2.06-2.09 (m, 1H), 2.38-2.42 (m, 1H), 3.06 (t, J )
6.6 Hz, 2H), 3.66 (s, 3H), 3.74 (s, 3H), 3.73 (t, J ) 7.5 Hz, 1H),
6.53 (d, J ) 9.0 Hz), 6.72 (d, J ) 9.0 Hz, 2H), 7.26-7.36 (m, 5H)
13C NMR (CDCl3, 125.5 MHz) δ 33.1, 42.9, 49.2, 52.1, 55.8, 114.2,
114.9, 127.4, 127.9, 138.6, 142.2, 152.2, 174.3; mass spectrum
(70 eV) m/e (relative intensity) 299 (M+, 40), 268 (5), 136 (100),
121 (15). Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68.
Found: C, 71.71; H, 6.91; N, 4.52.
3-P h en yl-2-p yr r olid on e ((S)-6). A solution of (S)-5 (102 mg,
0.341 mmol) in dry tetrahydrofuran (3 mL) was cooled to -10
°C, and tert-butylmagnesium chloride (1 M in hexane, 0.341 mL,
0.341 mmol) was added under nitrogen. The reaction mixture
was stirred for 1.5 h at same temperature. The resulting solution
was quenched with water (10 mL) and extracted with ethyl
acetate (15 mL) three times. The extract was dried with
anhydrous magnesium sulfate, concentrated under reduced
pressure, and purified by flash chromatography with 20% ethyl
acetate in petroleum ether to afford 85 mg (93% yield) of the
product as a white solid. mp: 113-114 °C; 1H NMR (CDCl3, 500
MHz) δ 2.27 (m, 1H), 2.63 (m, 1H), 3.80 (s, 3H), 3.88 (m, 3H),
6.91 (d, 2H, J ) 9.2 Hz), 7.25-7.36 (m, 5H), 7.58(d, J ) 9.2 Hz,
2H); 13C NMR (CDCl3, 125.5 MHz) δ 27.7, 47.1, 49.4, 55.4, 114.0,
121.5, 128.0, 127.1, 137.8, 139.4, 156.6, 173.7; mass spectrum
(70 eV) m/e (ralative intensity) 267 (M+, 100), 150 (35), 136 (45),
120 (32). Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24.
Found: C, 76.18; H, 6.34 N, 5.26.
The enantiomeric ratio of the product was determined to be
96:4 in favor of the S-enantiomer by chiral HPLC analysis, using
racemic material as a standard (Chiakpak AD: 30% v/v 2-pro-
panol in hexane; a flow rate of 1.0 mL/min; a detection wavelenth
of 254 nm. The S-enantiomer (major) had a retention time of
27.9 min, and the R-enantiomer (minor) had a retention time of
14.9 min.
Ammonium cerium(IV) nitrate (0.974 mg, 1.616 mmol) was
dissolved in water (1.2 mL) and slowly added to ice cooled
solution of 3(S)-phenyl-1-(4-methoxyphenyl)-2-pyrrolidone (158.6
mg, 0.592 mmol) in acetonitrile (1.2 mL). The reaction mixture
was stirred for 30 min, and the resulting solution was concen-
trated under reduced pressure at a 35 °C bath temperature. The
residue was triturated with ethyl acetate (20 mL). Filtration,
concentration, and purification by chromatography on silica gel
with 3:1 petroleum ether/ethyl acetate gave 3(S)-phenyl-2-
pyrrolidone. mp 104-105 °C (lit.14 84-85 °C racemic) 1H NMR
(CDCl3, 500 MHz) δ 2.25 (m, 1H), 2.60 (m, 1H), 3.46 (t, J ) 9.0
Hz), 6.9 (br, 1H), 7.25-7.36 (m, 5H); 13C NMR (CDCl3, 125.5
MHz) δ 30.7, 40.6, 127.1, 128.0, 139.3, 179.0; mass spectrum
(70 eV) m/e (relative intensity) 161 (M+, 81), 117 (100), 103 (23),
91 (32). Anal. Calcd for C10H11NO: C, 74.51; H, 6.88; N, 8.69.
Found: C, 74.36; H, 6.89 N, 8.55.
For determination of absolute configuration, 6 was converted
to N-[(S)-1-(naphthyl)ethyl]-3(S)-phenyl-2-pyrrolidone-1-carbox-
amide. A solution of 3(S)-phenyl-2-pyrrolidone (35 mg, 0.217
mmol) and (R)-(-)-(1-naphthyl)ethyl isocyanate (44.4 mg, 0.225
mmol) in 3.0 mL of dry benzene was refluxed for 24 h, cooled to
room temperature, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
with 10% ethyl acetate in petroleum ether. The major diaste-
reomer eluted first (high Rf diasteriomer), and the minor
diastereomer eluted next (low Rf diastereomer). The major
diastereomeric ureides were isolated; 70 mg (90% yield). Major
diastereomer (high Rf): mp 146-147 °C (lit.7 147-148 °C): 1H
NMR (CDCl3, 500 MHz) δ 1.66 (d, J ) 7.0 Hz, 3H), 2.15-2.24
(m, 1H), 2.47-2.53 (m, 1H), 3.79-3.91 (m, 2H), 4.03-4.08 (m,
1H), 5.79-5.94 (overlapping quartets, 1H), 7.11-8.11 (m, 12H),
8.89 (d, J ) 7.0 Hz, 1H); mass spectrum (70 eV) m/e (relative
intensity) 358 (M+, 38), 343 (22), 270 (20), 197 (29), 182 (14),
171 (14), 170 (100), 163 (21), 161 (12), 118 (12), 107 (49). Anal.
Calcd for C23H22N2O2: C, 77.09; H, 6.15; N, 7.82. Found: C,
76.84; H, 6.38; N, 7.46. The absolute configuration was assigned
by comparism of preparative HPLC retention times to reference
data. The first eluted diastereomer was reported to have (S)-
configuration.7
3-P h en yl-2-p yr r olid on e ((R)-6). From methyl N-(4-meth-
oxyphenyl)-2(R)-phenyl-4-aminobutanoate (113.4 mg, 0.38 mmol)
was obtained N-(4-methoxyphenyl)-3(R)-phenyl-2-pyrrolidone
(85 mg, 84%) as a white solid. mp: 113-114 °C; 1H NMR (CDCl3,
500 MHz) δ 2.27 (m, 1H), 2.63 (m, 1H), 3.80 (s, 3H), 3.88 (m,
3H), 6.91 (d, 2H, J ) 9.2 Hz), 7.25-7.36 (m, 5H), 7.58 (d, J )
9.2 Hz, 2H). 13C NMR (CDCl3, 125.5 MHz) δ 27.7, 47.1, 49.4,
55.4, 114.0, 121.5, 128.0, 127.1, 137.8, 139.4, 156.6, 173.7.
The enantiomeric ratio of the product was determined to be
88:12 in favor of the S-enantiomer by chiral HPLC analysis using
The enantiomeric ratio of (S)-5 was determined to be 96:4 in
favor of the S-enantiomer by chiral HPLC analysis using racemic
material as a standard (Chiralpak AD: 10% v/v 2-propanol in
hexane; a flow rate of 2.0 mL/min; a detection wavelenth of 254
nm) The S-enantiomer (major) had a retention time of 9.0 min,
and the R-enantiomer (minor) had a retention time of 11.4 min.
Meth yl N-(4-Meth oxyph en yl)-2-ph en yl-4-am in obu tan oate
((R)-5). To a solution of (-)-sparteine (0.3 mL, 1.1 equiv) in dry
toluene (7.5 mL) at -78 °C was added n-BuLi (1.6 M in hexane,
0.81 mL, 1.1 equiv). The reaction was stirred for 20 min at -78
°C, and then a solution of 4 (0.404 mg, 1.18 mmol) in dry toluene
(7.5 mL) was added at -78 °C. The resulting reaction mixture
was stirred at -78 °C for 1 h, and methyl chloroformate (0.101
mL, 1.3 equiv) was added. The reaction mixture was stirred for
1 h at -78 °C and then quenched with MeOH. This mixture
was allowed to slowly warm to room temperature. Workup
consisted of addition of water (20 mL), extraction of the aqueous
layer with diethyl ether, extraction of the combined diethyl ether
extracts with sat. NH4Cl solution, drying over anhydrous MgSO4,
filtration, and concentration under reduced presssure. The crude
mixture was purified by chromatography to give the (52% yield,
1
246 mg) of the product. H NMR (acetone-d6, 400 MHz); δ 1.41
(s, 9H), 3.43 (s, 3H), 3.80 (s, 3H), 3.99 (d, J ) 10.0 Hz, 1H), 5.23
(t, J ) 10.0 Hz, 1H), 6.74 (d, J ) 10.0 Hz, 1H), 6.82-7.25 (m,
9H). Methyl (N-Boc-N-(4-methoxyphenyl)-2(R)-phenyl-4-amino-
3-butenoate (200 mg, 0.503 mmol) was dissolved in 9 mL of
ethanol, 10% palladium on activated carbon (20 mg) was added,
and the mixture was hydrogenated under 20 psi hydrogen for 1
h. The resulting mixture was filtered through Celite and washed
with ethanol (5 mL) five times. The filtrate was evaporated
under reduced pressure, and the product was purified by flash
chromatography with 9:1 petroleum ether/ethyl acetate to give
1
195 mg of the (87% yield) of product as a colorless oil. H NMR
(CDCl3, 400 MHz) δ 1.39 (br, 9H), 2.02 (m, 1H), 2.29 (m, 1H),
3.52 (m, 1H), 3.57 (m, 2H), 3.61 (s, 3H), 3.79 (s, 3H), 6.83 (d, J
) 9.0 Hz, 2H), 7.05 (bs, 2H), 7.21-7.28 (m, 5H); 13C NMR
(CDCl3, 125.5 MHz) δ 28.3, 31.9, 48.0, 48.9, 52.0, 55.4, 80.3,
114.0, 127.3, 127.8, 128.2, 128.7, 135.1, 138.5, 157.6, 173.9; mass
spectrum (70 eV) m/e (relative intensity) 399 (M+, 16), 299 (100),
238 (60), 136 (90).
Methyl N-Boc-N-(4-methoxyphenyl)-2(R)-phenyl-4-aminobu-
tanoate (113 mg, 0.28 m mol) was dissolved in methylene
chloride (3.7 mL) in ice bath, and trifluoroacetic acid (0.32 mL,
4.2 mmol) was added. The reaction mixture was stirred for 2 h
at room temperature. The resulting solution was concentrated
under reduced pressure, 8 mL of water was added, and the pH
of the solution was adjusted to 8-9 with saturated sodium
bicarbonate solution in an ice bath and then extracted with ethyl
acetate. The organic layer was then dried over anhydrous
magnesium sulfate, and the solvent was evaporated in vacuo.
The product was purified by silica gel chromatography with 20%
ethyl acetate in petroleum ether to give 78 mg (93% yield) of
(R)-5 as a pale yellow oil. 1H NMR (CDCl3, 500 MHz) δ 2.06-
2.09 (m, 1H), 2.38-2.42 (m, 1H), 3.06 (t, J ) 6.6 Hz, 2H), 3.66
(s, 3H), 3.74 (s, 3H), 3.73 (t, J ) 7.5 Hz, 1H), 6.53 (d, J ) 9.0
Hz), 6.72 (d, J ) 9.0 Hz, 2H), 7.26-7.36 (m, 5H); 13C NMR
(CDCl3, 125.5 MHz) δ 33.1, 42.9, 49.2, 52.1, 55.8, 114.2, 114.9,
127.4, 127.9, 138.6, 142.2, 152.2, 174.3.
The enantiomeric ratio of (R)-5 was determined to be 92:8 in
favor of the R-enantiomer by chiral HPLC analysis using racemic
material as a standard (Chiralpak AD: 5% v/v 2-propanol in
hexane; a flow rate of 2.0 mL/min; a detection wavelenth of 254
nm). The R-enantiomer (major) had a retention time of 11.6 min,
and the S-enantiomer (minor) had a retention time of 9.34 min.
(14) Clark, R. D.; J ahanger, Tetrahedron 1993, 49, 1351.

1708 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
racemic material as a standard (Chiakpak AD: 30% v/v 2-pro-
panol in hexane; a flow rate of 1.0 mL/min; a detection wavelenth
of 254 nm. The S-enantiomer (major) had a retention time of
14.7 min, and the R-enantiomer (minor) had a retention time of
27.4 min.
From 79 mg (0.30 mmol) of N-(4-methoxylphenyl)-3(R)-phenyl-
2-pyrrolidone was obtained 40 mg (84%) of 3(R)-phenyl-2-
pyrrolidone as a solid. mp 104-105 °C; 1H NMR (CDCl3, 500
MHz) δ 2.25 (m, 1H), 2.60 (m, 1H), 3.46 (t, J ) 9.0 Hz), 6.9 (br,
1H), 7.25-7.36 (m, 5H); 13C NMR (CDCl3, 125.5 MHz) δ 30.7,
40.6, 127.1, 128.0, 139.3, 179.0.
allowed to slowly warm to room temperature. Workup consisted
of addition of water, extraction of the aqueous layer with diethyl
ether, extraction of the combined diethyl ether extracts with sat.
NH4Cl solution, drying over anhydrous MgSO4, filtration, and
concentration in vacuo. The crude mixture was purified by
chromatography to give of (S)-8 as a colorless oil in (389 mg 85%
yield). 1H NMR (CDCl3, 400 MHz) δ 1.38 (m, 12H), 3.75 (s, 3H),
3.79 (s, 3H), 5.65 (br, 1H), 7.15-6.70 (m, 8H); 13C NMR (CHCl3,
100.5 MHz) δ 18.0, 28.2, 55.05, 55.12, 79.8, 113.1, 128.6, 130.8,
131.2, 134.3, 155.3, 157.9, 158.5; HRMS calcd for C21H27NO4:
357.1940; found: 357.1940.
For determination of the absolute configuration, 6 was
converted to N-[(S)-1-(naphthyl)ethyl]-3(S)-phenyl-2-pyrrolidone-
1-carboxamide. From 40 mg (0.25 mmol) of 3(R)-phenyl-2-
pyrrolidone was obtained N-[(S)-1-(naphthyl)ethyl]-3(R)-phenyl-
2-pyrrolidone-1-carboxamide as 76 mg of a colorless oil (86%
N-Boc-a la n in e Meth yl Ester ((S)-9). To 8 (283 mg, 0.79
mmol) dissolved in CH3CN-H2O (4:1; ca.0.05 M) was added CAN
(ceric ammonium nitrate, 954 mg, 2.2 equiv) at 0 °C. After
stirring at 0 °C for 0.5 h, the mixture was diluted with diethyl
ether, poured into water, and extracted with diethyl ether. The
extracts were combined, dried over MgSO4, filtered through a
pad of Celite, and concentrated in vacuo. The crude mixture was
further purified by chromatography to give the product, 111 mg,
56% yield. 1H NMR (CDCl3, 400 MHz) δ 1.41 (s, 12H), 3.79 (s,
3H), 4.73 (br, 2H), 6.85 (d, J ) 9.2 Hz, 2H), 7.22 (d, J ) 9.2 Hz,
2H). To a solution of above product (30 mg, 0.12 mmol) in 0.5
mL of CCl4, 1.1 mL of MeCN, and 1.1 mL of H2O were added
NaIO4 (387 mg, 15 equiv) and RuCl3 H2O (2.5 mg). After stirring
for 48 h at room temperature, the reaction mixture was diluted
with CH2Cl2/H2O mixture and extracted twice with CH2Cl2. The
extract was dried and concentrated in vacuo. The resulting crude
product was treated with SOCl2/MeOH for 2 h and concentrated
in vacuo, and then excess (Boc)2O in CH2Cl2 was added. Washing
of the solution with sat. NaHCO3 solution and brine, drying,
evaporation, and flash column chromatography gave (S)-9 (10
1
yield). H NMR (CDCl3, 500 MHz) δ 1.66 (d, J ) 7.0 Hz), 2.15-
2.24 (m, 1H), 2.47-2.53 (m, 1H), 3.79-3.91 (m, 2H), 4.03-4.08
(m, 1H), 5.79-5.94 (overlapping quartets, 1H), 7.11-8.11 (m,
12H), 8.89 (d, J ) 7.0 Hz, 1H); mass spectrum (70 eV) m/e
(relative intensity) 358 (M+, 38), 343 (22), 270 (20), 197 (29),
182 (14), 171 (14), 170 (100), 163 (21), 161 (12), 118 (12), 107
(49). Anal. Calcd for C23H22N2O2: C, 77.09; H, 6.15; N, 7.82.
Found: C, 76.84; H, 6.38; N, 7.46. The absolute configuration
was assigned comparism of preparative HPLC retention time
to reference data. The second eluted diastereomer was reported
to have (R)-configuration.7
N-Boc-N-(4-m eth oxyp h en yl)-p-m eth oxyben zyla m in e (7).
From the reaction of N-Boc-p-anisidine (1.92 g, 8.6 mmol) and
p-methoxybenzyl chloride (1.28 mL, 1.1 equiv) with NaH (1.1
equiv) in THF (25 mL) was obtained 7: 2.95 g, 86% yield. 1H
NMR(CDCl3, 400 MHz) δ 1.42 (s, 9H), 3.76 (s, 3H), 3.78 (s, 3H),
4.69(s, 2H), 7.14-6.76 (m, 8H); 13C NMR (CDCl3, 100.5 MHz) δ
28.2, 53.3, 55.1, 55.2, 80.0, 113.5, 113.6, 128.1, 129.0, 130.6,
135.3, 155.0, 157.4, 158.5; HRMS calcd for C20H25NO4: 343.1784;
found: 343.1777.
1
mg) in 42% overall yield. H NMR (CDCl3, 400 MHz) δ 1.37 (d,
J ) 7.2 Hz, 3H), 1.44 (s, 9H), 3.74 (s, 3H), 4.30 (s, 1H), 5.02 (br,
1H). The absolute configuration was assigned by comparison of
CSP-HPLC retention time with authentic material prepared
from commercially available (S)-alanine.
N-Boc-N-(4-m et h oxyp h en yl)-r-m et h yl-p -m et h oxyb en -
zyla m in e ((S)-8). To a solution of (-)-sparteine (0.33 mL, 1.2
equiv) in toluene (14 mL) at -78 °C was added n-BuLi (1.1
equiv). The reaction mixture was stirred for 30 min at -78 °C,
and a solution of 7 (440 mg, 1.0 equiv) in toluene (7 mL) was
transferred to the above solution at -78 °C. The resulting
reaction mixture was stirred at -78 °C for 4 h, and methyl
triflate (0.18 mL, 1.2 equiv) in toluene (14 mL) was added after
precooling. After stirring for 3 h at -78 °C, this mixture was
Ack n ow led gm en t. We are grateful to the National
Institute of Health (GM-18874) and the National Sci-
ence Foundation (CHE-9526355) for support of this
work. B.J .K. thanks KRICT, and Y.S.P. thanks Konkuk
University, for the support of this work.
J O9817568