Synthesis of enantiopure N-protected 4,5-disubstituted 3-pyrrolidinones and N-protected 2,5-disubstituted 3-pyrrolidinones via the Dieckmann reaction of dicarbonyl compounds derived from enantiopure β-amino esters

Article abstract of DOI:10.1016/S0957-4166(01)00115-X

Under the action of KHMDS in THF solvent the Dieckmann reaction of dicarbonyl compounds derived from enantiopure β-amino esters provides enantiopure N-protected 4,5-disubstituted 3-pyrrolidinones, whereas N-protected 2,5-disubstituted 3-pyrrolidinones formed in reactions mediated by tert-BuOK in DMF or toluene. Reduction of these pyrrolidinones afforded enantiopure polysubstituted pyrrolidines.

Full text of DOI:10.1016/S0957-4166(01)00115-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 725–730
Synthesis of enantiopure N-protected 4,5-disubstituted
3-pyrrolidinones and N-protected 2,5-disubstituted
3-pyrrolidinones via the Dieckmann reaction of dicarbonyl
compounds derived from enantiopure b-amino esters
Yue Wanga and Dawei Mab,*
aDepartment of Chemistry, Fudan University, Shanghai 200433, China
bState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 27 December 2000; accepted 2 March 2001
Abstract—Under the action of KHMDS in THF solvent the Dieckmann reaction of dicarbonyl compounds derived from
enantiopure b-amino esters provides enantiopure N-protected 4,5-disubstituted 3-pyrrolidinones, whereas N-protected 2,5-disub-
stituted 3-pyrrolidinones formed in reactions mediated by tert-BuOK in DMF or toluene. Reduction of these pyrrolidinones
afforded enantiopure polysubstituted pyrrolidines. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
In connection with our ongoing program into the syn-
thesis of enantiopure b-amino acid derivatives,1 we
became interested in the intramolecular Dieckmann
reaction of dicarbonyl compounds 3, which could be
prepared from N,N-disubstituted b-amino esters 12 in
three steps (Scheme 1). Depending on the regioselectiv-
ity of the Dieckmann reaction, enantiopure N-pro-
With this in mind, we examined the Dieckmann reac-
tion of diester 3a, which was prepared from 2a via
alkylation with methyl chloroacetate and subsequent
protection with (Boc)2O. Treatment of 3a with
KHMDS in THF at −78°C afforded the N-protected
4,5-disubstituted 3-pyrrolidinone 4a in moderate yield
(Scheme 2). Other bases such as tert-BuOK and NaH
were also applicable in this reaction. However, the
yields were not improved greatly.
tected 4,5-disubstituted 3-pyrrolidinones
4
or
N-protected 2,5-disubstituted 3-pyrrolidinones 5 could
be obtained from these unsymmetrical dicarbonyl com-
pounds. Both pyrrolidinones are obviously promising
intermediates for preparing various synthetically chal-
lenging and medicinally important agents. For example,
using 4 as starting materials we would be able to
synthesize pyrrolidine glycosidase inhibitors 63 and 7,4
and necine alkaloids such as (−)-petasinecine.5 It is
possible to transform products 5 to some natural pyrrol-
idine alkaloids like (−)-bulgecinine,6 (2R,3R,5R)-3-
hydroxy-5-methyl-2-pyrrolidinecarboxylic acid 8,7 as
well as (+)-preussin.8
Inspired by Sibi’s results,9 we investigated the use of
amides 9 as substrates in the Dieckmann reaction.
These were synthesized by following the alkylation
procedure used to form 3a except that N-methoxy-N-
methyl-chloroacetamide was used as the electrophile.
At this time the condensation reaction using KHMDS
in THF worked well to give the N-protected 4,5-disub-
stituted 3-pyrrolidinones 4 in good to excellent yields.
The results are summarized in Table 1. It was found
that both 5-alkyl-3-pyrrolidinones and 5-aryl-3-pyrrol-
idinones could be obtained by this method (entries
1–6). In addition, not only N-Boc but also N-alkyl
substrates were suitable in this reaction (compare
entries 2 and 3). Thus, this method is applicable to the
preparation of a variety of enantiopure 1,4,5-trisubsti-
tuted 3-pyrrolidinones.
* Corresponding author.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00115-X

726
Y. Wang, D. Ma / Tetrahedron: Asymmetry 12 (2001) 725–730
RO2C
Ph
OH
OH
CO2H HO2C
OH
HO
HO
OH
H
N
R
N
Me
Bn
1
OH
HO2C
N
H
N
H
CH3
N
H
6
(-)-petasinecine
OH
(-)-bulgecinine
8
HO
Ph
H2N
RO2C
R
N
H
C9H19-n
HO
N
H
7
NH2
2
(+)-preussin
1. ClCH2COY
2. X-Z
O
O
RO2C
R
RO2C
R
O
Y
base
base
N
X
4
N
X
3
R
N
X
5
COY
Scheme 1.
O
O
CO2Me
MeO
CO2Me
CO2Me
1. ClCH2CO2Me
KHMDS, THF
-78 oC, 50%
2. (Boc)2O/DMAP
~70%
N
N
H2N
Boc
Boc
2a
3a
4a
Scheme 2.
Table 1. Intramolecular Dieckmann reaction of 9a
Me
O
O
O
CO2R'
Me
Me
O
N
CO2R'
R
MeO
+
+
N
N
MeO
N
X
R
MeO
N
X
R
N
X
R
N
O
O
X
9
4
10
11
Entry
X/R/R%
Base
Solvent
T (°C)
t (min)
Yield (%)b
4
10
11
1
2
3
4
5
6
7
8
Boc/n-Bu/Me 9a
Ph(Me)CH/Me/Me 9b
Boc/Me/Me 9c
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
KOBu-t
THF
THF
THF
THF
THF
THF
Toluene
Toluene
Toluene
DMF
DMF
DMF
DMF
DMF
−78
−78
−78
−78
−78
−78
−20
−20
0
2
2
2
2
2
89
80
75
90
90
78
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
10
10
19
–
Bn/Ph/Et 9d
Boc/p-CH3OC6H4/Me 9e
Boc/BnO(CH2)3/Et 9f
Boc/n-Bu/Me 9a
Boc/n-Bu/Me 9a
Boc/n-Bu/Me 9a
2
–
25
25
5
2
2
2
2
2
25
20
30
40
43
37
–
9
10
11
12
13
14
Boc/n-Bu/Me 9a
Boc/BnO(CH2)3/Et 9f
−78c
−78c
−78c
−78c
−78c
Boc/n-C15
H31/Me 9g
–
72
60
Bn/Ph/Et 9d
Bn/Bu-n/Me 9h
–
–
a Reaction conditions: KHMDS (1 mmol), 9 (0.3 mmol) in THF (15 mL); or tert-BuOK (1 mmol), 9 (0.2 mmol) in DMF (15 mL).
b Isolated yield.
c Bath temperature.

Y. Wang, D. Ma / Tetrahedron: Asymmetry 12 (2001) 725–730
727
In order to change the regioselectivity of this Dieck-
mann reaction and gain access to different polysubsti-
tuted pyrrolidinones, other bases and solvents were
examined. When toluene was used as solvent the reac-
tion of 9a mediated by KHMDS at −20°C provided
2,5-disubstituted 3-pyrrolidinone 10a in lower yield,
together with some decomposition products (entry 7).
Replacement of KHMDS with tert-BuOK gave similar
results (entries 8 and 9). However, when the reaction of
9a was carried out in DMF at −78°C using tert-BuOK
as a base, it afforded 2,5-disubstituted 3-pyrrolidinones
10a and 11a in moderate yield. The major side products
were decomposition products. The ratio of 10a and 11a
was about 4:1 and their stereochemistry was assigned
by NOESY spectra. However, this regioselectivity was
restricted to the substrates in which R is an alkyl group
and the N-protecting group was Boc (entries 10–12 and
13, 14).
N-protected 2,5-disubstituted 3-pyrrolidinones in mod-
erate to good yields.10 Application of this method to
the synthesis of related natural alkaloids is currently
underway.
4. Experimental
4.1. General procedure for preparation of 9
A mixture of 1 (8 mmol) and Pd/C (10%, 0.3 g) in 60
mL methanol was stirred under an atmosphere of
hydrogen (70 atm) for one day. The catalyst was
filtered off and washed with methanol. The filtrate was
concentrated and the resulting residue was dissolved
with stirring in MeCN (20 mL). To this solution was
added NaHCO3 (8 mmol) followed by dropwise addi-
tion of a solution of BrCH2CONMe(OMe) (6 mmol) in
MeCN (10 mL). The reaction mixture was stirred for 10
h, then filtered and washed with ethyl acetate. The
filtrate was concentrated in vacuo and the residue was
chromatographed to afford the corresponding
monoalkylated product in 60–74% yield.
To further demonstrate the usage of the method pre-
sented, some pyrrolidinones were reduced to the corre-
sponding polysubstituted pyrrolidines under different
conditions. The stereochemistry of each product was
established by NOESY studies. As outlined in Scheme
3, hydrogenation of 4e catalyzed by Pd/C at 30°C and
atmospheric pressure for 3 days gave 12 in 70% yield.
However, reduction of 4e with NaBH4 gave 12 as a
minor product and its 3,4-epimer 13 as a major product
(ratio was about 1:2). Thus, different isomers could be
obtained by changing the reduction conditions. The
reduction of 10h or 11h with NaBH4 is shown in
Scheme 4. These reactions indicated that the stereo-
chemistry at the 3-position was completely controlled
by the 2-substituent.
4.1.1. (R)-3-N-(tert-Butyloxycarbonyl)-N-(N-methyl-N-
methoxycarboamido)methylaminoheptanoic acid, methyl
1
ester 9a. [h]2D0=−15.3 (c 1.2, CHCl3); H NMR (300
MHz, CDCl3) l 4.26 (m, 0.5 H), 4.06 (m, 0.5 H), 4.01
(s, 1H), 3.91 (s, 1H), 3.68 (s, 1.5 H), 3.66 (s, 1.5 H), 3.61
(s, 1.5 H), 3.59 (s, 1.5H), 3.12 (s, 3H), 2.85–2.63 (m,
1H), 2.47–2.38 (m, 1H), 1.62–1.48 (m, 2H), 1.43 (s,
4.5H), 1.34 (s, 4.5H), 1.25 (m, 4H), 0.85 (m, 3H); EIMS
m/z 361 (M++H+). Anal calcd for C17H32N2O6: C,
56.65; H, 8.95; N, 7.77. Found: C, 56.80; H, 8.47; N,
7.75%.
3. Conclusion
4.1.2. (R)-3-N-(R)-1-Phenylethyl)-N-(N-methyl-N-
methoxycarboamido)methylaminobutanoic acid, methyl
ester 9b. [h]2D0=−5.1 (c 2.1, CHCl3); 1H NMR (300
MHz, CDCl3) l 7.41–7.20 (m, 5H), 4.21 (q, J=6.7 Hz,
1H), 3.60 (s, 3H), 3.55 (s, 3H), 3.54–3.45 (m, 3H), 3.11
(s, 3H), 2.58 (dd, J=14.6, 5.8 Hz, 1H), 2.15 (dd,
J=14.6, 8.4 Hz, 1H), 1.35 (d, J=6.7 Hz, 3H), 1.08 (d,
In summary, we have discovered suitable reaction con-
ditions to control the regioselectivity of the Dieckmann
reaction of dicarbonyl compounds derived from enan-
tiopure b-amino esters, which allows the synthesis of
either N-protected 4,5-disubstituted 3-pyrrolidinones or
HO
O
HO
CO2Me
CO2Me
CO2Me
NaBH4, MeOH
Pd/C, H2, MeOH
30 oC, 3 d, 70%
12
+
aq NH4HCl, r.t.
86%
OMe
N
N
N
Boc
Boc
Boc
OMe
OMe
12
4e
13
Scheme 3.
Scheme 4.

728
Y. Wang, D. Ma / Tetrahedron: Asymmetry 12 (2001) 725–730
J=6.6 Hz, 3H); EIMS m/z 323 (M++H+). Anal calcd
for C17H26N2O4: C, 63.33; H, 8.13; N, 8.69. Found: C,
63.16; H, 8.20; N, 8.61%.
4.1.8. (R)-3-N-Benzyl-N-(N-methyl-N-methoxycar-
boamido)methylamino-3-heptanoic acid, methyl ester 9h.
[h]2D0=−5.4 (c 2.2, CHCl3); 1H NMR (300 MHz,
CDCl3) l 7.43 (d, J=7.4 Hz, 2H), 7.30 (t, J=7.5 Hz,
2H), 7.25 (m, 1H), 3.78 (m, 2H), 3.61 (s, 3H), 3.52 (s,
3H), 3.43 (s, 2H), 3.27 (m, 1H), 3.12 (s, 3H), 2.74 (dd,
J=14.4, 6.5 Hz, 1H), 2.34 (dd, J=14.3, 7.3 Hz, 1H),
1.67 (m, 1H), 1.47 (m, 1H), 1.36 (m, 4H), 0.90 (t, J=6.7
Hz, 3H); EIMS m/z 319 (M+−OMe). Anal calcd for
C19H30N2O4: C, 65.12; H, 8.63; N, 7.99. Found: C,
65.42; H, 8.31; N, 7.73%.
4.1.3. (R)-3-N-(tert-Butyloxycarbonyl)-N-(N-methyl-N-
methoxycarboamido)methylaminobutanoic acid, methyl
ester 9c. [h]2D0=−10.7 (c 1.2, CHCl3); 1H NMR (300
MHz, CDCl3) l 4.41 (q, J=6.9 Hz, 0.5H), 4.12 (q,
J=6.9 Hz, 0.5H), 4.08 (s, 1H), 3.92 (s, 1H), 3.68 (s,
1.5H), 3.66 (s, 1.5H), 3.62 (s, 1.5H), 3.60 (s, 1.5H), 3.12
(s, 3H), 2.79–2.61 (m, 1H), 2.43–2.36 (m, 1H), 1.43 (s,
4.5H), 1.34 (s, 4.5H), 1.21 (d, J=6.8 Hz, 1.5H), 1.17 (d,
J=6.8 Hz, 1.5H); EIMS m/z 319 (M++H+). Anal calcd
for C14H26N2O6: C, 52.82; H, 8.23; N, 8.80. Found: C,
52.62; H, 8.51; N, 8.72%.
4.2. General procedure for condensation of 9 catalyzed
by KHMDS
To a stirred solution of 9 (0.3 mmol) in dry THF (15
mL) was added dropwise KHMDS (0.5 M in THF, 2
mL) at −78°C. After the solution was stirred for 2 min
at the same temperature, HCl (1N, 1 mL) was added to
quench the reaction. The mixture was extracted with
ethyl acetate three times and the combined organic
layers were washed with brine and dried over MgSO4.
After removal of the solvent, the residue was chro-
matographed to afford 4.
4.1.4. (S) - 3 - N - Benzyl - N - (N - methyl - N - methoxycar-
boamido)methylamino-3-phenylpropanoic acid, ethyl
1
ester 9d. [h]2D0=−16.4 (c 2.8, CHCl3); H NMR (300
MHz, CDCl3) l 7.61–7.20 (m, 10H), 4.62 (t, J=6.9 Hz,
1H), 4.03 (q, J=6.7 Hz, 2H), 3.90 (d, J=13.8 Hz, 1H),
3.65 (m, 1H), 3.51–3.22 (m, 5H), 3.13–3.02 (m, 4H),
2.75 (dd, J=14.4, 8.8 Hz, 1H), 1.11 (t, J=7.1 Hz, 3H);
EIMS m/z 385 (M++H+). Anal calcd for C22H28N2O4:
C, 68.73; H, 7.34; N, 7.29. Found: C, 68.67; H, 7.19; N,
7.10%.
4.2.1. (4RS,5R)-1-(tert-Butyloxycarbonyl)-4-methoxy-
carbonyl-5-n-butyl-3-pyrrolidinone 4a. [h]2D0=+2.3 (c 1.3,
1
4.1.5. (S)-3-N-(tert-Butyloxycarbonyl)-N-(N-methyl-N-
methoxycarboamido)methylamino-3-(4%-methoxyphenyl)-
propanoic acid, methyl ester 9e. [h]2D0=−52.4 (c 2.7,
CHCl3); H NMR (300 MHz, CDCl3) l 4.80–4.51 (m,
1H), 4.30–4.02 (m, 2H), 3.88–3.60 (m, 3.5H), 3.18 (m,
0.5H), 1.95 (m, 1H), 1.67 (m, 1H), 1.45 (s, 9H), 1.25 (m,
4H), 0.85 (m, 3H); EIMS m/z 299 (M+); HRMS found
m/z 242.1043 (M+− Bu); C11H16NO5 requires 242.1031.
1
CHCl3); H NMR (300 MHz, CDCl3) l 7.24 (d, J=7.8
Hz, 2H), 6.84 (d, J=7.8 Hz, 2H), 5.81 (dd, J=9.5, 5.9
Hz, 0.5H), 5.54 (dd, J=9.5, 5.9 Hz, 0.5H), 4.11 (d,
J=17.8 Hz, 0.5H), 3.95 (d, J=17.8 Hz, 0.5H), 3.80 (s,
3H), 3.78–3.54 (m, 7H), 3.23–2.91 (m, 2H), 3.13 (s, 3H),
1.48 (s, 4.5H), 1.43 (s, 4.5H); EIMS m/z 354 (M+−Bu-t+
H+). Anal calcd for C20H30N2O7: C, 58.52; H, 7.37; N,
6.82. Found: C, 58.48; H, 7.42; N, 6.96%.
4.2.2. (4RS,5R)-1-((R)-1-Phenylethyl)-4-methoxycar-
bonyl-5-methyl-3-pyrrolidinone 4b. [h]2D0=−6.2 (c 8.0,
1
CHCl3); H NMR (300 MHz, CDCl3) l 7.35–7.22 (m,
5H), 4.17 (q, J=6.6 Hz, 1H), 3.75 (s, 3H), 3.61 (m, 1H),
3.11 (d, J=8.7 Hz, 1H), 3.03 (s, 2H), 1.37 (d, J=6.8
Hz, 3H), 1.27 (d, J=6.7 Hz, 3H); EIMS m/z 261 (M+);
HRMS found m/z 261.1387 (M+); C15H19NO3 requires
261.1367.
4.1.6. (R)-3-N-(tert-Butyloxycarbonyl)-N-(N-methyl-N-
methoxycarboamido)methylamino - 6 - benzoxyhexanoic
acid, ethyl ester 9f. [h]2D0=+1.6 (c 1.2, CHCl3); 1H NMR
(300 MHz, CDCl3) l 7.29 (m, 5H), 4.49 (s, 2H), 4.44
(m, 0.5H), 4.20–3.95 (m, 4.5H), 3.71 (s, 1.5H), 3.67 (s,
1.5H), 3.50 (s, 2H), 3.20 (s, 3H), 2.90–2.70 (m, 1H),
2.52–2.40 (m, 1H), 1.85–1.55 (m, 4H), 1.47 (s, 4.5H),
1.40 (s, 4.5H), 1.23 (m, 3H); EIMS m/z 467 (M++H+).
Anal calcd for C24H38N2O7: C, 61.78; H, 8.21; N, 6.00.
Found: C, 61.63; H, 7.97; N, 6.10%.
4.2.3. (4RS,5R)-1-(tert-Butyloxycarbonyl)-4-methoxy-
carbonyl-5-methyl-3-pyrrolidinone 4c. [h]2D0=−15.1 (c
1
6.7, CHCl3); H NMR (300 MHz, CDCl3) l 4.72–4.60
(m, 1H), 4.30–4.03 (m, 2H), 3.78–3.56 (m, 4H), 1.47 (s,
9H), 1.38–1.28 (m, 3H); EIMS m/z 258 (M++H+);
HRMS found m/z 226.1095 (M+−OMe); C11H16NO4
requires 226.1081.
4.1.7. (R)-3-N-(tert-Butyloxycarbonyl)-N-(N-methyl-
N-methoxycarboamido)methylaminooctadecanoic acid,
4.2.4. (4RS,5R)-1-Benzyl-4-methoxycarbonyl-5-phenyl-
3-pyrrolidinone 4d. [h]2D0=−32.4 (c 2.8, CHCl3); 1H
NMR (300 MHz, CDCl3) l 7.60 (d, J=7.5 Hz, 2H),
7.47–7.21 (m, 8H), 4.32 (d, J=10.6 Hz, 1H), 4.17 (m,
2H), 4.02 (d, J=13.1 Hz, 1H), 3.59 (d, J=17.6 Hz,
1H), 3.46 (d, J=10.5 Hz, 1H), 3.21 (d, J=13.1 Hz,
1H), 2.94 (d, J=17.6 Hz, 1H), 1.26 (t, J=7.3 Hz, 3H);
EIMS m/z 323 (M+); HRMS found m/z 323.1566 (M+);
C20H21NO3 requires 323.1523.
1
methyl ester 9g. [h]2D0=−1.2 (c 2.2, CHCl3); H NMR
(300 MHz, CDCl3) l 4.30 (m, 0.5H), 4.10 (m, 0.5H),
4.07 (s, 1H), 3.95 (s, 1H), 3.72 (s, 1.5H), 3.70 (s, 1.5H),
3.66 (s, 1.5H), 3.64 (s, 1.5H), 3.16 (s, 3H), 2.85 (dd,
J=15.7, 6.3 Hz, 0.5H), 2.78 (dd, J=15.5, 6.7 Hz,
0.5H), 2.49 (dd, J=7.5, 2.0 Hz, 0.5H), 2.43 (dd, J=7.2,
1.9 Hz, 0.5H), 1.64–1.49 (m, 2H), 1.47 (s, 4.5H), 1.38 (s,
4.5H), 1.26 (m, 26H), 0.85 (t, J=6.5 Hz, 3H); EIMS
m/z 413 (M+−Boc). Anal calcd for C28H54N2O6: C,
65.33; H, 10.57; N, 5.44. Found: C, 65.47; H, 10.61; N,
5.46%.
4.2.5. (4RS,5R)-1-(tert-Butyloxycarbonyl)-4-methoxy-
carbonyl-5-(4%-methoxyphenyl)-3-pyrrolidinone 4e. [h]2D0=
1
−13.2 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) l

Y. Wang, D. Ma / Tetrahedron: Asymmetry 12 (2001) 725–730
729
7.25–7.06 (m, 3H), 6.86–6.77 (m, 2H), 5.53 (m, 0.5H),
5.40 (m, 0.5H), 4.41–4.30 (m, 1H), 4.29–3.70 (m, 1H),
3.67 (s, 3H), 3.68–3.12 (m, 4H), 1.46–1.20 (m, 9H);
EIMS m/z 349 (M+); HRMS found m/z 349.1541 (M+);
C18H23NO6 requires 349.1526.
Hz, 1H), 1.78–1.28 (m, 13H); EIMS m/z 420 (M+);
HRMS found m/z 420.2298 (M+); C12H32N2O6 requires
420.2265.
4.3.5. (2R,5R)-1-(tert-Butyoxycarbonyl)-2-(N-methyl-N-
methoxycarboamido) - 5 - n - pentadecyl - 3 - pyrrolidinone
1
4.2.6. (4RS,5R)-1-(tert-Butyloxycarbonyl)-4-ethoxycar-
bonyl-5-(3%-benzoxypropanyl)-3-pyrrolidinone 4f. [h]2D0=
10g. [h]2D0=+44.0 (c 2.3, CHCl3); H NMR (300 MHz,
CDCl3) l 5.31 (m, 1H), 4.23 (m, 1H), 3.85 (s, 3H), 3.26
(s, 3H), 2.79 (m, 1H), 2.40 (d, J=17.9 Hz, 1H), 2.01–
1.25 (m, 38H), 0.88 (t, J=6.5 Hz, 3H); EIMS m/z 482
(M+); HRMS found m/z 381.3132 (M+−Boc);
C22H41N2O3 requires 381.3121.
1
+25.3 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) l
7.32 (m, 5H), 4.87–4.48 (m, 3H), 4.44–4.00 (m, 4H),
3.70–2.85 (m, 4H), 1.90–1.40 (m, 9H), 1.30 (m, 3H);
EIMS m/z 405 (M+); HRMS found m/z 405.2171 (M+);
C22H31NO6 requires 405.2151.
4.3.6. (2S,5R)-1-(tert-Butyoxycarbonyl)-2-(N-methyl-N-
methoxycarboamido) - 5 - n - pentadecyl - 3 - pyrrolidinone
4.3. General procedure for condensation of 9 catalyzed
by tert-BuOK
1
11g. [h]2D0=+16.9 (c 2.8, CHCl3); H NMR (300 MHz,
CDCl3) l 5.08 (m, 1H), 4.42 (m, 1H), 3.85 (s, 3H), 3.23
(s, 3H), 2.95 (m, 1H), 2.36 (d, J=17.9 Hz, 1H), 1.90–
1.28 (m, 38H), 0.88 (t, J=6.5 Hz, 3H); EIMS m/z 482
(M+); HRMS found m/z 381.3132 (M+−Boc);
C22H41N2O3 requires 381.3121.
To a dry flask containing tert-BuOK (110 mg, 0.982
mmol) was added a pre-cooled (−78°C) solution of 9
(0.2 mmol) in DMF (15 mL) under argon at −78°C.
The solution was stirred for 2 min at the same temper-
ature, then aqueous HCl (1N, 1 mL) was added to
quench the reaction. The mixture was neutralized with
NaHCO3 and extracted three times with ethyl acetate.
The combined organic extract was washed with brine,
dried over MgSO4 and filtered. After removal of the
solvent from the filtrate, the residue was chro-
matographed to afford 10 and 11.
4.3.7. (2R,3S,4S)-1-(tert-Butyloxycarbonyl)-4-hydroxy-
3-methoxycarbonyl-2-(4%-methoxyphenyl)-pyrrolidine 12.
A suspension of 4e (20 mg, 0.057 mmol) and 10% Pd/C
(5 mg) in of MeCN (1 mL) was stirred under hydrogen
(1 atm.) at 30°C for 3 days. The catalyst was removed
by filtration and the filtrate was concentrated. The
residue was chromatographed to afford 12 (14 mg,
1
4.3.1. (2R,5R)-1-(tert-Butyoxycarbonyl)-2-(N-methyl-
N-methoxycarboamido)-5-n-butyl-3-pyrrolidinone 10a.
[h]2D0=+41.5 (c 3.7, CHCl3); 1H NMR (300 MHz,
CDCl3) l 5.28 (m, 1H), 4.23 (m, 1H), 3.82 (s, 3H), 3.23
(s, 3H), 2.79 (m, 1H), 2.37 (d, J=18.5 Hz, 1H), 2.01 (m,
1H), 1.78–1.24 (m, 12H), 0.88 (t, J=6.7 Hz, 3H); EIMS
m/z 328 (M+); HRMS found m/z 328.2036 (M+);
C16H28N2O5 requires 328.2004.
70%). [h]2D0=−10.5 (c 0.5, CHCl3); H NMR (300 MHz,
CDCl3) l 7.27 (d, J=8.3 Hz, 2H), 6.78 (d, J=8.5 Hz,
2H), 5.08 (m, 1H), 4.61 (br s, 1H), 3.90 (m, 1H), 3.74 (s,
3H), 3.67 (m, 1H), 3.51 (s, 3H), 3.38 (m, 1H), 1.43–1.16
(m, 9H); EIMS m/z 351 (M+); HRMS found m/z
351.1649 (M+); C18H25NO6 requires 351.1683.
4.3.8. (2R,3R,4R)-1-(tert-Butyloxycarbonyl)-4-hydroxy-
3-methoxycarbonyl-2-(4%-methoxyphenyl)-pyrrolidine 13.
To a solution of 4e (28 mg, 0.08 mmol) in ethanol (3
mL) and saturated aqueous NH4Cl (1 mL) was added
sodium borohydride (10 mg, 0.26 mmol). The solution
was stirred at room temperature for 20 min, and parti-
tioned between ethyl acetate and water. The organic
layer was separated and the aqueous layer was
extracted further with ethyl acetate. The combined
organic extract was dried over MgSO4 and concen-
trated. The residue was chromatographed to afford 13
(16 mg, 59%) and 12 (8 mg, 29%). [h]2D0=+7.8 (c 1.8,
4.3.2. (2S,5R)-1-(tert-Butyoxycarbonyl)-2-(N-methyl-
N-methoxycarboamido)-5-n-butyl-3-pyrrolidinone 11a.
[h]2D0=+16.9 (c 2.8, CHCl3); 1H NMR (300 MHz,
CDCl3) l 5.10 (s, 0.4H), 5.06 (s, 0.6H), 4.45 (m, 0.6H),
4.42 (m, 0.4H), 3.85 (s, 3H), 3.27 (s, 3H), 2.97 (dd,
J=19.5, 9.5 H, 0.4H), 2.91 (dd, J=17.9, 9.4 Hz, 0.6H),
2.37 (d, J=17.8 Hz, 1H), 1.95–1.20 (m, 15H), 0.89 (m,
3H); EIMS m/z 328 (M+); HRMS found m/z 328.2035
(M+); C16H28N2O5 requires 328.2004.
1
4.3.3. (2R,5R)-1-(tert-Butyoxycarbonyl)-2-(N-methyl-N-
methoxycarboamido) - 5 - (3% - benzoxypropyl) - 3 - pyrroli-
CHCl3); H NMR (300 MHz, CDCl3) l 7.20 (d, J=8.1
Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.98 (br s, 1H), 4.53
(dd, J=14.8, 6.3 Hz, 1H), 4.11 (dd, J=11.0, 6.8 Hz,
1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.48 (dd, J=11.0, 7.7
Hz, 1H), 3.00 (t, J=7.8 Hz, 1H), 1.25–1.09 (m, 9H);
EIMS m/z 352 (M++H+); HRMS found m/z 351.1649
(M+); C18H25NO6 requires 351.1683.
1
none 10f. [h]2D0=+40.3 (c 1.0, CHCl3); H NMR (300
MHz, CDCl3) l 7.29 (m, 5H), 5.34 (m, 1H), 4.50 (s,
2H), 4.30 (m, 1H), 3.85 (s, 3H), 3.51 (m, 2H), 3.25 (s,
3H), 2.85 (m, 1H), 2.45 (d, J=18.8 Hz, 1H), 2.01–1.28
(m, 13H); EIMS m/z 420 (M+); HRMS found m/z
420.2298 (M+); C12H32N2O6 requires 420.2265.
4.3.9. (2R,3S,5R)-1-(tert-butyoxycarbonyl)-2-(N-methyl-
N-methoxycarboamido)-3-hydroxy-5-n-pentadecyl-pyrro-
lidine 14. To a solution of 10h (15 mg, 0.03 mmol) in
EtOH (1 mL) cooled with an ice-salt bath was added
sodium borohydride (4 mg, 0.1 mmol). The solution
was stirred for 20 min before it was partitioned between
ethyl acetate and water. The organic layer was sepa-
4.3.4. (2S,5R)-1-(tert-Butyoxycarbonyl)-2-(N-methyl-N-
methoxycarboamido)-5-(3%-benzoxypropyl)-3-pyrrolidi-
1
none 11f. [h]2D0=+10.4 (c 0.7, CHCl3); H NMR (300
MHz, CDCl3) l 7.28 (m, 5H), 5.12 (m, 1H), 4.48 (s,
2H), 4.26 (m, 1H), 3.83 (s, 3H), 3.47 (s, 2H), 3.21 (s,
3H), 2.92 (dd, J=17.6, 9.4 Hz, 1H), 2.36 (d, J=17.6

730
Y. Wang, D. Ma / Tetrahedron: Asymmetry 12 (2001) 725–730
References
rated and the aqueous layer was extracted with ethyl
acetate. The combined extracts were dried over MgSO4
and concentrated. The residue was chromatographed to
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1
afford 14 (15 mg, 98%). [h]2D0=−19.6 (c 1.9, CHCl3); H
NMR (300 MHz, CDCl3) l 4.94 (m, 1H), 4.55 (m, 1H),
3.85–3.73 (m 4H), 3.23 (s, 3H), 2.47–2.13 (m, 3H),
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C22H43N2O3 requires 383.3277.
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methyl-N-methoxycarboamido)-3-hydroxy-5-n-pentadecyl-
pyrrolidine 15. Following the procedure from 10h to 14,
pyrrolidine 15 was obtained from 11h in 98% yield.
[h]2D0=+3.1 (c 0.9, CHCl3); 1H NMR (300 MHz,
CDCl3) l 4.90 (d, J=8.0 Hz, 0.5H), 4.83 (d, J=8.0 Hz,
0.5H), 4.70 (m, 1H), 4.05 (m, 0.5H), 3.95 (m, 0.5H),
3.83 (s, 1.5H), 3.78 (s, 1.5H), 3.22 (s, 3H), 2.05 (m, 2H),
1.74 (m, 2H), 1.46 (s, 4.5H), 1.43 (s, 4.5H), 1.21 (m,
26H), 0.88 (t, J=6.7 Hz, 3H); EIMS m/z 383 (M+−
Boc); HRMS found m/z 383.3231 (M+−Boc);
C22H43N2O3 requires 383.3277.
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The authors are grateful to the Chinese Academy of
Sciences and National Natural Science Foundation of
China (grants 29725205 and 29972049), and Qiu Shi
Science
& Technologies Foundation for financial
support.
.