Conformationally restricted analogues of both (S)-β-homoserine and (S)-aspartic acid from chiral 3-acylamino pyrrolidin-2-ones

Article abstract of DOI:10.1016/j.tet.2005.03.129

Starting from chiral 3,4-trans-disubstituted pyrrolidin-2-ones 11a and 11b, obtained from a Baylis-Hillman adduct, conformationally restricted analogues of both (S)-β-homoserine, 17, and (S)-aspartic acid, 21, were synthesized, respectively, and these com

Full text of DOI:10.1016/j.tet.2005.03.129

Tetrahedron 61 (2005) 5465–5473
Conformationally restricted analogues of both (S)-b-homoserine
and (S)-aspartic acid from chiral 3-acylamino pyrrolidin-2-ones
a
b
Roberta Galeazzi,a Gianluca Martelli,a Mario Orena,a, Samuele Rinaldi and Piera Sabatino
*
a
`
Dipartimento di Scienze dei Materiali e della Terra, Universita Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
b
`
Dipartimento di Chimica “G. Ciamician”, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 19 January 2005; revised 16 March 2005; accepted 31 March 2005
Available online 29 April 2005
Abstract—Starting from chiral 3,4-trans-disubstituted pyrrolidin-2-ones 11a and 11b, obtained from a Baylis–Hillman adduct,
conformationally restricted analogues of both (S)-b-homoserine, 17, and (S)-aspartic acid, 21, were synthesized, respectively, and these
compounds are suitable either for introduction in peptidomimetics or for synthesis of novel b-foldamers.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
addition/ring closure sequence starting from the Baylis–
Hillman adduct 5 and (S)-phenylethylamine, leading to
formation of both (N-1)–(C-5) and (N-1)–(C-2) bonds of the
g-lactam ring, and this synthetic approach was directed
toward the synthesis of chiral 3-hydroxypyrrolidin-2-ones,
intermediates for the preparation of an inhibitor of
glycosidases.6 Our previous investigations concerning the
chemistry of Baylis–Hillman adducts disclosed a straight-
forward general procedure for the preparation of 3-
acylamino-2-methylene alkanoates, by exploiting the cor-
responding acyl carbamates.7 In this report, the acyl
carbamates 7a,b were prepared in quantitative yield by
reaction of the adduct 5 and the appropriate acyl isocyanate
6a,b (Scheme 2).8 However, whereas treating the 1-
naphthoyl carbamate 7b with DABCO in DCM gave the
corresponding 1-naphthoylamino derivative 8b in good
yield, the trichloroacetylamino derivative 8a was obtained
only in a disappointing 20% yield from 7a under the same
reaction conditions. The other products of this reaction were
a complex, inseparable mixture of polar products. To
overcome this problem, an alternative approach to com-
pound 8a was devised, starting from the trichloroacetimi-
date 9. The preparation of this compound, however, turned
Properly substituted pyrrolidin-2-ones (g-lactams) can be
isosteres of natural amino acids. Thus, they can give rise to
conformational constrictions useful to both restrict the
flexibility of the peptide molecules and to provide
informations on the topographical requirements of recep-
tors,1 when they are introduced in bioactive peptides.
Moreover, the incorporation of these units in a peptide lead
to analogues that display a lot of advantages such as
increased biostability and bioselectivity against the natural
biological target of the parent peptide. Therefore, they are
interesting target compounds,2 useful for the synthesis of
both terminally constrained or internally constrained
peptidomimetics3 and their availability in an enantiomeri-
cally pure form is important for applications in medicinal
chemistry.4 In this field, our attention was focused to the
pyrrolidin-2-ones 3 and 4, that are constrained analogues of
(S)-b-homoserine 1 and (S)-aspartic acid, 2, respectively
(Scheme 1).
2. Results and discussion
We already demonstrated the viability of the approach
involving (C-3)–(C-4) bond formation for construction of
the pyrrolidin-2-one ring, leading to conformationally
restricted amino acids in the enantiomerically pure form.5
As a further development, we recently, devised a conjugate
Keywords: Amino acids; Analogues; Baylis–Hillman; Peptidomimetics;
Conformational constrictions.
*
Corresponding author. Tel.: C39 071 2204720; fax: C39 071 2204714;
e-mail: m.orena@univpm.it
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.129

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R. Galeazzi et al. / Tetrahedron 61 (2005) 5465–5473
Scheme 2. Reagents and conditions: (a) DCM, rt (b) 10% DABCO, DCM,
0 8C; 8a, R1ZCCl3; 8b, R1Z1-naphthyl.
Scheme 4. Reagents and conditions: (a) MeOH, rt to 60 8C, then DBU,
toluene at rt. a R1ZCCl3, R2ZC6H5; b R1ZCCl3, R2Z4-CH3OC6H4;
c R1Z1-naphthyl, R2ZC6H5.
evidenced by the shielding effects on H-5 and H-50 due to
both the phenyl group and the substituent at C-4 (Table 1).
Scheme 3. Reagents and conditions: (a) CCl3CN, DBU, K15 8C. (b) 10%
DABCO, DCM, 0 8C, 2 min.
1
The configuration at C-3 was also assigned by H NMR
analysis, being significantly supported by the quite large J3,4
coupling constant values (J3,4O9.0 Hz) (Table 1), and
further, confirmed by NOE difference data. In fact, by
irradiation of H-3 only a very small enhancement (!1%)
was observed to H-4, consistent with the trans relative
stereochemistry. Eventually, compound 11a was crystal-
lized from methanol and from the single-crystal X-ray data
its absolute configuration was definitely ascertained as
out to be far from routine. In fact, only traces of the desired
product 9 were obtained by following the standard
procedures.9
On the other hand, when the reaction was carried out by
using CCl3CN as the solvent and DBU as the base, the
trichloroacetimidate 9 was obtained in moderate yield.
Subsequent treatment with DABCO in DCM afforded the
trichloroacetylamino derivative 8a in quantitative yield
(Scheme 3).10
1
(3S,4R,10S), in full agreement with H NMR spectral data
(Fig. 1).12,13
Our first goal was to find a simple and straightforward
access to the constrained b-homoserine derivative 3,14 but
some difficulties arose in the removal of the naphthoyl
group in both 11c and 12c. Therefore, since the trichloro-
acetyl group can be more easily cleaved, we considered as
starting materials for further transformations the trichloro-
acetylamino derivatives 11a,b, that are homochiral at C-3
with the same absolute configuration as the natural amino
acids.
By analogy with the synthesis of chiral hydroxypyrrolidin-
2-ones from the Baylis–Hillman adduct 5,6 condensation of
N-acylamino derivatives 8a,b with (S)-phenylethylamine,
10a, or (S)-4-MeO-phenylethylamine, 10b, was carried out
in MeOH from rt to 60 8C. Although a diastereomeric
mixture of four 3,4-disubstituted pyrrolidin-2-ones was
formed at first, as evidenced by the corresponding peaks for
1
the methyl esters in the H NMR spectrum of the crude
reaction, direct treatment of the diastereomeric mixture with
DBU in toluene at rt afforded in good yield the 3,4-trans-
disubstituted derivatives 11a–c and 12a–c, exclusively,
which were easily separated by flash chromatography on
silica gel (Scheme 4).11 The determination of the absolute
configurations of 4-monosubstituted pyrrolidin-2-ones with
nitrogen bearing a chiral phenylethyl group was described
elsewhere.5 Thus, 1H NMR analysis was diagnostic for
structural assignment at C-4 of 11a–c and 12a–c, as
In fact, we treated the pyrrolidin-2-one 11a with NaBH4 in
dry ethanol and we were pleased to obtain in good yield the
corresponding trans-3-amino-4-hydroxymethyl derivative
13, the reaction proceeding through simultaneous reduction
of the methoxycarbonyl group and removal of the
trichloroacetamido moiety (Scheme 5).
Prior to the removal of the phenylethyl group, both the
Table 1. Selected 1H NMR data for compounds 11 and 12
d H-50 (ppm)
Entry
d H-3 (ppm)
d H-5 (ppm)
J3,4 (Hz)
J4,5 (Hz)
J4,5’ (Hz)
11a
12a
11b
12b
11c
12c
4.65
4.58
4.65
4.71
4.84
4.71
3.45
3.05
3.43
3.13
—
3.13
3.28
3.60
3.28
3.62
—
3.62
9.5
9.4
9.6
9.2
9.2
9.2
9.1
8.8
9.2
8.9
—
8.8
8.7
9.2
8.7
9.4
—
9.4
a
a
a
a
a H-5 and H-50 give rise to a complex pattern, in agreement with a single shielding for each proton.

R. Galeazzi et al. / Tetrahedron 61 (2005) 5465–5473
5467
Scheme 7. Reagents and conditions: (a) CAN, CH3CN–H2O; (b) 6 M
NaOH; then t-Boc2O, TEA, MeOH; then CH2N2, diethyl ether; (c) CAN,
CH3CN–H2O.
removed from 11b and the amino functionality at C-3 was
protected as t-Boc derivative to give 20. Eventually, by
treatment with CAN in acetonitrile–water, the protected
constrained analogue 21 was obtained in good yield.19
Figure 1. ORTEP drawing of compound 11a.
3. Conclusion
In summary, by reaction of either (S)-phenylethylamine 10a
or (S)-(4-methoxyphenyl)ethylamine 10b and the acyl-
amino derivatives 8a,b, obtained from the Baylis–Hillman
adduct 5, the chiral 3,4-trans-disubstituted pyrrolidin-2-
ones 11a,b and 12a,b were produced in good yield. Then, 17
and 21, conformationally restricted analogues of (S)-b-
homoserine and (S)-aspartic acid, were obtained starting
from compounds 11a and 11b, respectively, and it is worth
mentioning that both ent-17 and ent-21 can be accessible
starting from 12a,b. In addition, 21 and ent-21 will be
employed as units for the preparation of novel b-
foldamers20,21 having a constriction due to the sp2 carbon
of the pyrrolidin-2-one and work along this line is currently
in progress in our laboratory.
Scheme 5. Reagents and conditions: (a) NaBH4 (4 equiv), dry EtOH, rt;
(b) t-Boc2O, MeOH, rt; (c) DHP, DCM, H 15, rt, (d) Li, NH3, K78 8C;
(e) Amberlyst H 15, MeOH, 40 8C.
derivatives 14 and 15 were subsequently prepared. Cleavage
of the phenylethyl group was easily performed by treating
15 with Li in liquid ammonia at K78 8C, leading to the
unsubstituted pyrrolidin-2-one 16 in good yield. Eventually,
removal of the THP group afforded 17, the N-protected
derivative of 3, the analogue of b-homoserine (Scheme
5).15,16
Then, we started the synthesis of the analogue of the aspartic
acid, 4, but when compound 17 was treated with the Jones’
reagent in order to obtain a carboxy group at C-5, only a
complex mixture of products resulted from the reaction. In
addition, when the compound 18, easily prepared starting
from 14, underwent cleavage of the phenylethyl group with
Li in liquid ammonia, compound 17 was exclusively
obtained in moderate yield (Scheme 6).17
4. Experimental
4.1. General
Melting points were measured on an Electrothermal IA
9000 apparatus and are uncorrected. IR spectra were
recorded in CHCl3 on a Nicolet Fourier Transform Infrared
1
20-SX spectrophotometer. H and 13C NMR spectra were
recorded at 200 and 50 MHz, respectively, on a Varian
Gemini 200 spectrometer, using CDCl3 as a solvent.
Chemical shifts (d) are reported in ppm relative to TMS
and coupling constants (J) in Hz. Assignments were aided
by decoupling and homonuclear two-dimensional exper-
iments. Optical rotations were measured on a Perkin Elmer
241 polarimeter. Mass spectra (MS) were obtained by
electron impact on a Hewlett-Packard spectrometer 5890,
series II. Column chromatography was performed with
silica gel 60 (230–400 mesh). Compound 5 was synthesized
as reported the literature.22 Trichloroacetyl isocyanate 6a
was purchased from Aldrich, whereas 1-naphthoyl isocya-
nate 6b was prepared according to a literature method
starting from 1-naphthoyl chloride8b and used without
purification.
Thus, an alternative starting substrate to the compound 4
was pyrrolidin-2-one 11b. In fact, by treatment with CAN in
acetonitrile–water18 this compound underwent rapid clea-
vage of the 4-methoxyphenylethyl group, to give in good
yield the enantiomeric 3,4-trans-disubstituted pyrrolidin-2-
one 19, a diprotected form of the constrained analogue 4
(Scheme 7). In addition, the trichloroacetyl group was
Scheme 6. Reagents and conditions: (a) Jones’ reagent, acetone, then
CH2N2; (b) Li, NH3, K78 8C.

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R. Galeazzi et al. / Tetrahedron 61 (2005) 5465–5473
4.2. General procedure for the preparation of acyl
carbamates (7a,b)
(50 MHz, CDCl3) d 13.9, 52.3, 56.0, 62.5, 92.0, 131.7,
134.1, 161.2, 165.3, 168.2; MS: m/z 334–332 (4, MHC),
318–316 (12), 260 (22), 198 (18), 158 (44), 99 (100). Anal.
Calcd for C10H12Cl3NO5: C, 36.12; H, 3.64; N, 4.21. Found:
C, 36.16; H, 3.57; N, 4.16.
To a solution containing the adduct 5 (1.9 g, 10 mmol) in
dry DCM (50 mL), the appropriate acyl isocyanate 6
(12 mmol) dissolved in dry DCM (10 mL) was added at
0 8C and the mixture was stirred at rt for 2 h. The solvent
was removed under reduced pressure and the residue was
chromatographed on silica gel (cyclohexane–ethyl acetate
80:20 as eluent) to give in quantitative yield the acyl
carbamates 7a,b.
4.3.2. 1-Ethyl 4-methyl 2-(1-naphthoylamino)-3-meth-
ylenebutanedioate (8b). According to the above reported
procedure and starting from 7b, the title compound was
obtained as a colorless oil (4.0 g, 78%): IR (CHCl3) n 3350,
1
1735, 1720, 1668 cmK1; H NMR (200 MHz, CDCl3) d
1.27 (t, JZ7.4 Hz, 3H), 3.75 (s, 3H), 4.25 (q, JZ7.4 Hz,
2H), 5.72 (d, JZ8.5 Hz, 1H), 6.19 (s, 1H), 6.48 (s, 1H), 7.14
(d, JZ8.5 Hz, 1H, NH), 7.40–7.94 (m, 6 ArH), 8.31–8.42
(m, 1 ArH); 13C NMR (50 MHz, CDCl3) d 14.0, 52.2, 51.8,
62.2, 124.7, 125.4, 125.5, 126.4, 127.2, 128.3, 128.5, 130.2,
130.8, 131.0, 133.5, 136.0, 165.9, 168.7, 169.6; MS: m/z 341
(3, MC), 268 (20), 155 (100), 127 (56), 43 (12). Anal. Calcd
for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C, 66.79;
H, 5.57; N, 4.14.
4.2.1. 1-Ethyl 4-methyl 2-(1-trichloroacetylaminocarbo-
nyloxy)-3-methylenebutanedioate (7a). According to the
above reported procedure and starting from 5 and
commercially available trichloroacetyl isocyanate 6a, the
compound 7a was obtained as a viscous oil: IR (CHCl3) n
3355, 1741, 1724, 1665 cmK1; 1H NMR (200 MHz, CDCl3)
d 1.24 (t, JZ7.2 Hz, 3H), 3.79 (s, 3H), 4.22 (q, JZ7.2 Hz,
2H), 5.98 (s, 1H), 6.11 (s, 1H), 6.55 (s, 1H), 8.78 (s, 1H,
NH); 13C NMR (50 MHz, CDCl3) d 13.9, 52.4, 62.3, 72.4,
91.4, 132.3, 133.7, 148.5, 157.5, 164.5, 166.7; MS: m/z 377–
375 (2, MC), 143 (22), 116 (40), 84 (100). Anal. Calcd for
C11H12Cl3NO7: C, 35.08; H, 3.21; N, 3.72. Found: C, 35.02;
H, 3.15; N, 3.64.
4.3.3. 1-Ethyl 4-methyl 2-trichloroacetiminoxy-3-methy-
lenebutanedioate (9). To a solution of the adduct 5 (2.8 g,
15 mmol) in CCl3CN (7.5 g, 75.0 mmol), DBU (0.63 mL,
4.5 mmol) was directly added in three portions (every
15 min) at K15 8C under vigorous stirring. After 1 h the
mixture was directly purified by silica gel chromatography
(cyclohexane–ethyl acetate 95:5 as eluent) to give the
trichloroacetimidate 9 (2.9 g; 58% yield) as a colorless oil:
4.2.2. 1-Ethyl 4-methyl 2-(1-naphthoylaminocarbonyl-
oxy)-3-methylenebutanedioate (7b). According to the
above reported procedure and starting from 5 and 1-
naphthoyl isocyanate 6b, the compound 7b was obtained as
IR (CHCl3) n 3339, 1732, 1720, 1671 cmK1 1H NMR
;
a viscous oil: IR (CHCl3) n 3350, 1734, 1724, 1668 cmK1
;
(200 MHz, CDCl3) d 1.27 (t, JZ7.3 Hz, 3H), 3.82 (s, 3H),
4.25 (q, JZ7.3 Hz, 2H), 6.12 (s, 1H), 6.13 (s, 1H), 6.55 (s,
1H), 8.53 (br s, 1H, ]NH); 13C NMR (50 MHz, CDCl3) d
13.7, 53.0, 61.5, 73.4, 90.3, 129.7, 134.1, 160.8, 164.5,
166.8; MS: m/z 334 (MHC, 5), 332 (MHC, 5), 318 (6), 316
(6), 170 (32), 161 (24), 144 (100). Anal. Calcd for
C10H12Cl3NO5: C, 36.12; H, 3.64; N, 4.21. Found: C,
36.06; H, 3.58; N, 4.27.
1H NMR (200 MHz, CDCl3) d 1.22 (t, JZ7.3 Hz, 3H), 3.74
(s, 3H), 4.18 (q, JZ7.3 Hz, 2H), 5.97 (s, 1H), 6.04 (s, 1H),
6.48 (s, 1H), 7.36–7.94 (m, 6 ArH), 8.21–8.29 (m, 1 ArH),
8.64 (s, 1H, NH); 13C NMR (50 MHz, CDCl3) d 13.8, 52.2,
62.0, 71.5, 124.3, 124.8, 125.9, 126.6, 127.6, 128.3, 128.4,
129.9, 131.7, 132.1, 133.5, 134.1, 149.5, 164.6, 166.9,
167.2; MS: m/z 385 (3, MC), 197 (29), 155 (100), 127 (76),
83 (88), 43 (70). Anal. Calcd for C20H19NO7: C, 62.33; H,
4.97; N, 3.63. Found: C, 62.27; H, 5.03; N, 3.59.
4.3.4. 1-Ethyl 4-methyl 2-trichloroacetylamino-3-meth-
ylenebutanedioate (8a). To a solution containing the
trichloroacetimidate 9 (1.7 g, 5.0 mmol) in DCM (20 mL)
at 0 8C, DABCO (65 mg, 0.5 mmol) was added and the
mixture was stirred for 2 min at 0 8C. After dilution with
ethyl acetate (150 mL), the organic layer was washed with
1 M HCl (30 mL) and brine (100 mL) and dried (Na2SO4).
The solvents were removed under reduced pressure to give
the pure trichloroacetylamino derivative 8a (1.7 g; quanti-
tative yield) as a colorless oil.
4.3. General procedure for the preparation of acylamino
derivatives (8a,b)
To a solution containing 7 (15.0 mmol) in DCM (20 mL) at
0 8C, DABCO (0.2 g, 1.5 mmol) was added and the mixture
was stirred for 15 min at 0 8C. The mixture was then diluted
with ethyl acetate (150 mL) and the organic layer washed
with 1 M HCl (30 mL) and brine (100 mL). After drying
(Na2SO4), the solvents were removed under reduced
pressure and the residue was purified by silica gel
chromatography (cyclohexane–ethyl acetate 80:20 as elu-
ent), to give pure compounds 8a,b.
4.4. General procedure for the preparation of
pyrrolidin-2-ones (11) and (12)
To a solution containing compound 8 (15 mmol) in
methanol (20 mL), (S)-phenylethylamine 10a or (S)-4-
methoxyphenylethylamine 10b (16 mmol) was added and
the mixture was stirred for 12 h at rt and then for 2 h at
60 8C. Methanol was evaporated under reduced pressure,
the residue was dissolved ethyl acetate (50 mL) and the
organic layer washed with 1 M HCl (20 mL) and brine.
After drying (Na2SO4) and removal of the solvent under
reduced pressure, the residue was dissolved in toluene
(20 mL), DBU (2.28 g, 15 mmol) was added and the
4.3.1. 1-Ethyl 4-methyl 2-trichloroacetylamino-3-meth-
ylenebutanedioate (8a). According to the above reported
procedure and starting from 7a, the title compound was
obtained as a colorless oil (1.0 g; 20%), followed by a
substantial amount of trichloroacetamide (1.8 g): IR
(CHCl3) n 3351, 1732, 1722, 1668 cmK1 1H NMR
;
(200 MHz, CDCl3) d 1.26 (t, JZ7.1 Hz, 3H), 3.80 (s, 3H),
4.25 (q, JZ7.1 Hz, 2H), 5.25 (d, JZ7.9 Hz, 1H), 6.10 (s,
3H), 6.47 (s, 1H), 7.81 (d, JZ7.9 Hz, 1H, NH); 13C NMR

R. Galeazzi et al. / Tetrahedron 61 (2005) 5465–5473
5469
solution was stirred at rt for 12 h. After removal of the
solvent, the residue was dissolved in ethyl acetate (40 mL)
and the organic layer was washed with 2 M HCl (10 mL).
After drying (Na2SO4) and removal of the solvent, the
residue was purified by silica gel chromatography (cyclo-
hexane–ethyl acetate 90:10), to give in equimolar amount
pure separated diastereomers 11 and 12 as white crystalline
solids.
(200 MHz, CDCl3) d 1.58 (d, JZ7.2 Hz, 3H), 3.05 (dd,
JZ8.8, 9.4 Hz, 1H), 3.20–3.56 (m, 1H), 3.60 (dd, JZ9.2,
9.4 Hz, 1H), 3.74 (s, 3H), 3.82 (s, 3H), 4.58 (dd, JZ5.8,
9.4 Hz, 1H), 5.47 (q, JZ7.2 Hz, 1H), 6.87 (d, JZ8.6 Hz, 2
ArH), 7.21 (d, JZ8.6 Hz, 2 ArH), 7.42 (d, 1H, NH, JZ
5.8 Hz); 13C NMR (50 MHz, CDCl3) d 16.0, 42.1, 43.1,
49.8, 52.6, 55.2, 56.2, 91.7, 114.0, 128.2, 130.6. 159.2,
162.3, 167.7, 171.6; [a]D K65.0 (c 2.0, CHCl3); MS: m/z
436 (3, MC), 434 (3, MC), 301 (7), 299 (7), 216 (23), 162
(22), 135 (100), 77 (24).
4.4.1. (3S,4R,10S)-4-Methoxycarbonyl-1-(10-phenyl-
ethyl)-3-trichloroacetylaminopyrrolidin-2-one (11a)
and its (3R,4S,10S)-isomer (12a). Starting from 8a and
10a, the diastereomers 11a and 12a were obtained after
chromatographic separation in 78% overall yield according
to the above reported procedure: IR (CHCl3) n 3347, 1725,
1670 cmK1. Anal. Calcd for C16H17Cl3N2O4: C, 47.14; H,
4.20; N, 6.87. Found: C, 47.06; H, 4.16; N, 6.82.
(3S,4R,10S)-4-Methoxycarbonyl-1-(10-phenylethyl)-3-tri-
chloroacetylaminopyrrolidin-2-one (11a). Colorless crys-
4.4.3. (3S,4R,10S)-4-Methoxycarbonyl-3-(100-naphthoyl-
amino)-1-(10-phenylethyl)pyrrolidin-2-one (11c) and its
(3R,4S,10S)-isomer (12c). Starting from 8b and 10a, the
diastereomers 11c and 12c were obtained after chromato-
graphic separation in 76% overall yield according to the
above reported procedure: IR (CHCl3) n 3351, 1722,
1658 cmK1. Anal. Calcd for C25H24N2O4: C, 72.10; H,
5.81; N, 6.73. Found: C, 72.04;00 H, 5.87; N, 6.68.
(3S,4R,10S)-4-Methoxycarbonyl-3-(1 -naphthoylamino)-1-
(10-phenylethyl)pyrrolidin-2-one (11c). Colorless crystals:
mp 132–134 8C; 1H NMR (200 MHz, CDCl3) d 1.56 (d, JZ
7.0 Hz, 3H), 3.12–3.59 (m, 3H), 3.76 (s, 3H), 4.84 (dd, JZ
5.9, 9.2 Hz, 1H), 5.56 (q, JZ7.0 Hz, 1H), 6.82 (d, JZ
5.9 Hz, 1H, NH), 7.21–7.73 (m, 9 ArH), 7.81–7.96 (m, 2
ArH), 8.31–8.48 (m, 1 ArH); 13C NMR (50 MHz, CDCl3) d
16.2, 42.2, 45.0, 50.0, 52.6, 56.1, 124.6, 125.4, 125.5, 125.6,
126.4, 127.0, 127.1, 127.8, 128.2, 128.3, 128.4, 128.8,
131.0, 133.2, 133.7, 139.1, 169.2, 170.1, 172.4; [a]D
K177.8 (c 0.6, MeOH); MS: m/z 416 (11, MC), 261 (8),
245 (9), 186 (13), 172 (16), 155 (100), 127 (74), 105 (67).
(3R,4S,10S)-4-Methoxycarbonyl-3-(100-naphthoylamino)-1-
(10-phenylethyl)pyrrolidin-2-one (12c). Colorless crystals:
mp 176–178 8C; 1H NMR (200 MHz, CDCl3) d 1.58 (d, JZ
7.0 Hz, 3H), 3.13 (dd, JZ8.8, 8.9 Hz, 1H), 3.35–3.51 (m,
1H), 3.62 (dd, JZ9.4, 8.9 Hz, 1H), 3.73 (s, 3H), 4.71 (dd,
JZ6.2, 9.2 Hz, 1H), 5.50 (q, JZ7.0 Hz, 1H), 6.89 (d, JZ
6.2 Hz, 1H), 7.22–7.72 (m, 9 ArH), 7.78–7.95 (m, 2 ArH),
8.34–8.44 (m, 1 ArH); 13C NMR (50 MHz, CDCl3) d 15.9,
42.3, 44.5, 50.2, 52.5, 55.9, 124.5, 125.3, 126.3, 127.0,
127.2, 127.8, 128.1, 128.7, 130.1, 130.9, 133.1, 133.5,
138.9, 169.2, 170.0, 172.2; [a]D K115.2 (c 0.4, CHCl3);
MS: m/z 416 (15, MC), 261 (8), 245 (7), 186 (10), 172 (18),
155 (100), 127 (75), 105 (67).
1
tals: mp 196–198 8C (dec); H NMR (200 MHz, CDCl3) d
1.57 (d, JZ7.3 Hz, 3H), 3.09–3.21 (m, 1H), 3.28 (dd, JZ
8.7, 8.7 Hz, 1H), 3.45 (dd, JZ8.7, 9.0 Hz, 1H), 3.75 (s, 3H),
4.65 (dd, JZ5.6, 9.6 Hz, 1H), 5.50 (q, JZ7.3 Hz, 1H),
7.25–7.48 (m, 6H, 5 ArHCNH); 13C NMR (50 MHz,
CDCl3) d 16.2, 42.2, 44.0, 50.2, 52.7, 56.4, 127.0, 128.0,
128.8, 138.6, 162.3, 167.7, 171.6; [a]D K75.0 (c 0.5,
CHCl3). MS: m/z 408 (4, MC), 406 (4, MC), 269 (4), 271
(4), 2460 (8), 186 (18), 132 (21), 105 (100), 77 (25).
(3R,4S,1 S)-4-Methoxycarbonyl-3-trichloroacetylamino-1-
(10-phenylethyl)pyrrolidin-2-one (12a). Colorless crystals:
mp 138–140 8C; 1H NMR (200 MHz, CDCl3) d 1.57 (d, JZ
7.0 Hz, 3H), 3.06 (dd, JZ8.8, 9.2 Hz, 1H), 3.22–3.41 (m,
1H), 3.63 (dd, JZ9.2, 9.2 Hz, 1H), 3.69 (s, 3H), 4.57 (dd,
JZ5.9, 9.1 Hz, 1H), 5.48 (q, JZ7.0 Hz, 1H), 7.21–7.39 (m,
5 ArH), 7.84 (d, JZ5.9 Hz, 1H, NH); 13C NMR (50 MHz,
CDCl3) d 15.9, 42.2, 43.2, 50.3, 52.6, 56.2, 91.7, 126.8,
127.0, 128.0, 128.7, 138.6, 162.4, 167.9, 171.6; [a]D K82.5
(c 1.06, CHCl3); MS: m/z 408 (4, MC), 406 (4, MC), 269
(5), 271 (5), 246 (11), 186 (16), 132 (24), 105 (100), 77 (25).
4.4.2. (3S,4R,10S)-4-Methoxycarbonyl-3-trichloroace-
tylamino-1-[10-(400-methoxyphenyl)ethyl]pyrrolidin-2-
one (11b) and its (3R,4S,10S)-isomer (12b). Starting from
8a and 10b, the diastereomers 11b and 12b were obtained
after chromatographic separation in 78% overall yield
according to the above reported procedure: IR (CHCl3) n
3345, 1724, 1668 cmK1. Anal. Calcd for C17H19Cl3N2O5:
C, 46.65; H, 4.38; N, 6.40. Found: C, 46.61; H, 4.34; N,
6.44. (3S,4R,1000S)-4-Methoxycarbonyl-3-trichloroacetyl-
amino-1-[10-(4 -methoxyphenyl)ethyl]pyrrolidin-2-one
(11b). Colorless crystals: mp 178–180 8C; 1H NMR
(200 MHz, CDCl3) d 1.52 (d, JZ7.2 Hz, 3H), 3.06–3.31
(m, 1H), 3.28 (dd, JZ8.7, 9.2 Hz, 1H), 3.43 (dd, JZ9.2,
9.2 Hz, 1H), 3.76 (s, 3H), 3.81 (s, 3H), 4.65 (dd, JZ4.5,
9.6 Hz, 1H), 5.47 (q, JZ7.2 Hz, 1H), 6.90 (d, JZ8.7 Hz, 2
ArH), 7.26 (d, JZ8.7 Hz, 2 ArH), 7.41 (d, JZ4.5 Hz, 1H,
NH); 13C NMR (50 MHz, CDCl3) d 16.3, 42.0, 43.9, 49.7,
52.7, 55.3, 56.5, 114.1, 128.2, 130.6, 159.2, 162.3, 167.6,
171.7; [a]D K73.0 (c 0.6, CHCl3); MS: m/z 436 (3, MC),
434 (3, MC), 301 (5), 299 (5), 216 (20), 162 (23), 135 (100),
77 (24). (3R,4S0,010S)-4-Methoxycarbonyl-3-trichloroacetyl-
amino-1-[10-(4 -methoxyphenyl)ethyl]pyrrolidin-2-one
(12b). Colorless crystals: mp 46–48 8C; 1H NMR
4.4.4. (3S,4R,10S)-3-Amino-4-hydroxymethyl-1-(10-phe-
nylethyl)pyrrolidin-2-one (13). To a solution of 11a
(2.0 g; 5.0 mmol) in dry ethanol (10 mL) sodium borohy-
dride (0.76 g; 20.0 mmol) was added at 0 8C. Then the ice-
bath was removed and the reaction was stirred for 12 h at rt.
Water (10 mL) was added, ethanol was removed under
reduced pressure and the reaction mixture was extracted
with ethyl acetate (2!70 mL). The combined organic
phases were dried over sodium sulphate and filtered. After
removal of the solvent under reduced pressure, the residue
was chromatographed on silica gel (ethyl acetate as eluent)
to give 13 (0.94 g, 80%) as a viscous oil: IR (CHCl3) n 3350,
1
1671 cmK1; H NMR (200 MHz, CDCl3) d 1.47 (d, JZ
7.0 Hz, 3H), 1.90–2.08 (m, 1H), 2.82 (br s, 3H, OHCNH2),
2.97–3.02 (m, 2H), 3.38 (d, JZ9.9 Hz, 1H), 3.70 (d, JZ
5.5 Hz, 2H), 5.40 (q, JZ7.0 Hz, 1H), 7.17–7.38 (m, 5 ArH);
13C NMR (50 MHz, CDCl3) d 16.1, 41.6, 44.3, 49.3, 56.0,
62.3, 126.7, 126.8, 127.5, 128.5, 128.6, 139.6, 174.6; [a]D

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R. Galeazzi et al. / Tetrahedron 61 (2005) 5465–5473
K160.9 (c 0.5, CHCl3). MS: m/z 218 (2, MCKNH2), 217
(4), 203 (4), 187 (5), 122 (11), 106 (13), 85 (18), 82 (48) 70
(100). Anal. Calcd for C13H18N2O2: C, 66.64; H, 7.74; N,
11.96. Found: C, 66.59; H, 7.69; N, 12.02.
oil: IR (CHCl3) n 3341, 1728, 1668 cmK1 1H NMR
;
(200 MHz, CDCl3) d 1.35–1.82 (m, 6H), 1.41 (s, 9H), 2.47–
2.71 (m, 1H), 3.15–3.29 (m, 1H), 3.38–3.71 (m, 3H), 3.74–
4.16 (m, 3H), 4.59 (m, 1H), 5.10 (br s, 1H, NH), 6.65 (br s,
1H, NH); 13C NMR (50 MHz, CDCl3) d 19.0 (50%), 19.2
(50%), 25.1, 28.0, 30.2, 42.0 (50%), 42.5 (50%), 42.8
(50%), 43.1 (50%), 53.2 (50%), 53.6 (50%), 61.8 (50%),
62.2 (50%), 66.6 (50%), 66.9 (50%), 79.3, 98.4 (50%), 99.1
(50%), 155.6, 175.4 (50%), 175.5 (50%).
4.4.5. (3S,4R,10S)-3-t-Butoxycarbonylamino-4-hydroxy-
methyl-1-(10-phenylethyl)pyrrolidin-2-one (14). To the
compound 13 (0.94 g, 4.0 mmol) dissolved in methanol
(10 mL), di-tert-butyl dicarbonate (0.96 g, 4.4 mmol) was
added and the mixture was stirred at rt for 12 h. Removal of
the solvent and purification of the residue by chromato-
graphy on silica gel (cyclohexane–ethyl acetate 50:50 as
eluent) gave the product 14 (0.95 g, 71%) as a colorless oil:
IR (CHCl3) n 3345, 1730, 1668 cmK1; 1H NMR (200 MHz,
CDCl3) d 1.47 (s, 9H), 1.54 (d, JZ7.0 Hz, 3H), 2.07–2.25
(m, 1H), 2.98 (dd, JZ5.8, 7.2 Hz, 1H), 3.05 (dd, JZ7.2,
7.2 Hz, 1H), 3.63–3.76 (m, 2H, 1HCOH), 4.02–4.15 (m,
1H), 4.21 (dd, JZ5.4, 10.3 Hz, 1H), 5.41 (d, JZ5.4 Hz, 1H,
NH), 5.49 (q, JZ7.0 Hz, 1H), 7.22–7.43 (m, 5 ArH); 13C
NMR (50 MHz, CDCl3) d 16.2, 28.2, 41.4, 45.8, 49.7, 55.4,
61.6, 80.7, 126.8, 127.7, 128.6, 139.4, 157.5, 171.0; [a]D
K141.3 (c 1.5, CHCl3); MS: m/z 335 (2, MHC), 279 (48),
218 (15), 187 (46), 156 (32), 134 (30), 106 (100), 70 (44), 58
(87). Anal. Calcd for C18H26N2O4: C, 64.65; H, 7.84; N,
8.38. Found: C, 64.59; H, 7.79; N, 8.42.
4.4.8. (3S,4R)-3-t-Butoxycarbonylamino-4-hydroxy-
methylpyrrolidin-2-one (17). Compound from 16 (0.79 g,
2.5 mmol) was dissolved in MeOH (20 mL), acidic resin
Amberlyst H 15 (1.0 g) was added and the mixture was
heated at 45 8C for 3 h.23 After filtration, the solvent was
removed under reduced pressure and the residue was
purified by silica gel chromatography (cyclohexane–ethyl
acetate 30:70 as eluent) to give title compound (0.49 g, 85%
yield) as a white solid: mp 128–130 8C: IR (CHCl3) n 3345,
1
1728, 1671 cmK1; H NMR (200 MHz, CDCl3) d 1.45 (s,
9H), 2.32–2.52 (m, 1H), 3.13 (m, 1H), 3.36 (m, 1H), 3.65
(dd, JZ6.1, 12.1 Hz, 1H), 3.77 (dd, JZ4.3, 12.1 Hz, 1H),
4.14 (dd, JZ5.9, 10.3 Hz, 1H), 5.31 (d, JZ5.9 Hz, 1H,
NH), 6.36 (br s, 1H, NH); 13C NMR (50 MHz, CDCl3) d
28.2, 41.1, 47.5, 54.3, 61.7, 80.8, 157.4, 175.0; [a]D K49.2
(c 0.6, MeOH); MS: m/z 230 (1, MC), 203 (3), 174 (5), 149
(17), 81 (45), 69 (88), 57 (51), 43 (100). Anal. Calcd for
C10H18N2O4: C, 52.16; H, 7.88; N, 12.17. Found: C, 52.11;
H, 7.85; N, 12.21.
4.4.6. (3S,4R,10S)-3-t-Butoxycarbonylamino-1-(10-phe-
nyl-ethyl)-4-tetrahydropyranyloxymethylpyrrolidin-2-
one (15). To a solution of 14 (1.0 g; 3.0 mmol) and DHP
(0.5 g; 6.0 mmol) in DCM (20 mL), acidic resin H 15 (1.0 g)
was added at 0 8C.23 After 3 h at 0 8C, the resin was filtered
off, the solvent was removed under reduced pressure and the
residue was purified by silica gel chromatography (cyclo-
hexane–ethyl acetate 70:30 as eluent) to give the title
compound (1.12 g, 89%) as a colorless oil: IR (CHCl3) n
4.4.9. (3S,4R,10S)-3-t-Butoxycarbonylamino-4-methoxy-
carbonyl-1-(10-phenylethyl)pyrrolidin-2-one (18). To a
solution containing compound 14 (1.0 g, 3.0 mmol) in
acetone (10 mL), the Jones’ reagent (1.5 mL) was added at
0 8C and the mixture was stirred for 5 min. Then ethyl
acetate (20 mL) and subsequently saturated aqueous
Na2CO3 solution (15 mL) were added at 0 8C. After
extraction of the aqueous phase with ethyl acetate
(50 mL), organics were discarded and pH of the aqueous
layer raised to 2 by slow addition of 1 M HCl under stirring.
Then, extraction with ethyl acetate (2!50 mL) followed by
drying (Na2SO4) and removal of the solvent under reduced
pressure gave a residue which was dissolved in methanol
(5 mL). This solution was treated with an ethereal solution
of CH2N2 in ether [CAUTION: Diazomethane is an
explosive and a highly toxic gas. Explosions may occur if
the substance is dry and undiluted. All operations involving
diazomethane should be carried out in an efficient fumehood
following appropriate precautions] until nitrogen evolution
ceased. Then, the solvent was evaporated under reduced
pressure, to give a residue which was purified by silica gel
chromatography (cyclohexane–acetate 70:30 as eluent)
affording the ester 18 (0.84 g, 77% yield) as a colorless
1
3341, 1728, 1666 cmK1; H NMR (200 MHz, CDCl3) d
1.36 (s, 9H), 1.41–1.79 (m, 6H), 1.45 (d, JZ7.0 Hz, 3H),
2.18–2.39 (m, 1H), 3.01–3.22 (m, 2H), 3.38–3.56 (m, 2H),
3.62–4.02 (m, 2H), 4.16 (dd, JZ5.3, 10.1 Hz, 1H), 4.54 (m,
1H), 5.03 (d, JZ5.3 Hz, 1H, NH), 5.46 (q, JZ7.0 Hz, 1H),
7.21–7.36 (m, 5 ArH); 13C NMR (50 MHz, CDCl3) d 16.0,
19.4 (50%), 19.5 (50%), 25.1, 28.1, 30.3, 41.2 (50%), 41.5
(50%), 42.3 (50%), 42.8 (50%), 49.3, 54.4 (50%), 54.7
(50%), 62.2 (50%), 62.4 (50%), 66.9 (50%), 67.5 (50%),
79.4, 98.8 (50%), 99.4 (50%), 126.7, 127.3, 128.3, 139.5,
155.6, 171.0 (50%), 171.1 (50%).
4.4.7. (3S,4R)-3-t-Butoxycarbonylamino-4-tetrahydro-
pyranyloxymethylpyrrolidin-2-one (16). After NH3
(40 mL) was condensed in a three-necked flask at
K78 8C, Li shots (140 mg, 20.0 mmol) were added and
the blue solution was stirred at this temperature for 20 min.
Then compound 15 (1.25 g, 3.0 mmol) was dissolved in a
mixture of THF (9 mL) and t-BuOH (1 mL), and the
solution was added in one portion. After 3 min, the reaction
mixture was quenched by addition of solid NH4Cl (2 g) and
warmed to rt. Ammonia was removed, ethyl acetate (40 mL)
and water (10 mL) were added, the mixture was extracted
with ethyl acetate (2!50 mL) and the combined organic
layers were dried over Na2SO4. The solvent was removed in
vacuo and the crude product was purified by silica gel
chromatography (cyclohexane–ethyl acetate 40:60 as elu-
ent) to give the compound 16 (0.87 g; 92%) as a colorless
1
oil: IR (CHCl3) n 3341, 1733, 1725, 1664 cmK1; H NMR
(200 MHz, CDCl3): 1.40 (s, 9H), 1.51 (d, JZ7.2 Hz, 3H),
2.93–3.12 (m, 1H), 3.15 (dd, JZ8.8, 9.3 Hz, 1H), 3.39 (dd,
JZ9.2, 9.3 Hz, 1H), 3.69 (s, 3H), 4.43 (dd, JZ6.5, 9.5 Hz,
1H), 5.31 (d, JZ6.5 Hz 1H, NH), 5.46 (q, JZ7.2 Hz, 1H),
7.21–7.35 (m, 5 ArH); 13C NMR (50 MHz, CDCl3) d 16.0,
28.1, 41.6, 45.3, 49.7, 52.2, 56.3, 80.0, 126.9, 127.6, 128.5,
139.0, 155.2, 169.3, 172.3; [a]D K53.8 (c 1.0, CHCl3); MS:
m/z 363 (2, MHC), 306 (26, MHCK57), 245 (6), 186 (25),
133 (20), 105 (93), 69 (57), 57 (100). Anal. Calcd for

R. Galeazzi et al. / Tetrahedron 61 (2005) 5465–5473
5471
C19H26N2O5: C, 62.97; H, 7.23; N, 7.73. Found: C, 62.94;
H, 7.19; N, 7.69.
taken off in methanol (5 mL). Subsequent esterification by
excess diazomethane in ethyl ether [CAUTION: Diazo-
methane is an explosive and a highly toxic gas. Explosions
may occur if the substance is dry and undiluted. All
operations involving diazomethane should be carried out in
an efficient fumehood following appropriate precautions]
followed by removal of the solvent and purification of the
residue by silica gel chromatography (cyclohexane–ethyl
acetate 70:30 as eluent) gave compound 20 (0.36 g, 79%) as
4.4.10. (3S,4R)-3-t-Butoxycarbonylamino-4-hydroxy-
methylpyrrolidin-2-one (17). After NH3 (30 mL) was
condensed in a three-necked flask at K78 8C, Li shots
(70 mg, 10.0 mmol) were added and the blue solution was
stirred at this temperature for 20 min. Then compound 18
(0.38 g, 1.0 mmol) was dissolved in a mixture of THF
(4 mL) and t-BuOH (1 mL), and the solution was added in
one portion. After 3 min, the reaction mixture was quenched
by addition of solid NH4Cl (2 g) and warmed to rt. After
removal of ammonia, ethyl acetate (40 mL) and water
(10 mL) were added, the mixture was extracted with ethyl
acetate (2!50 mL) and the combined organic layers were
dried over Na2SO4. After the solvent was removed in vacuo,
the crude product was purified by silica gel chromatography
(cyclohexane–ethyl acetate 30:70 as eluent) to give the
compound 17 (0.18 g; 69%) as a white solid: mp 128–
130 8C; [a]D K49.2 (c 0.6, MeOH); MS: m/z 230 (1, MC),
203 (3), 174 (5), 149 (17), 81 (45), 69 (88), 57 (51), 43
(100). Anal. Calcd for C10H18N2O4: C, 52.16; H, 7.88; N,
12.17. Found: C, 52.11; H, 7.85; N, 12.21.
a viscous oil: IR (CHCl3) n 3341, 1731, 1725, 1668 cmK1
;
1H NMR (200 MHz, CDCl3) d 1.42 (s, 9H), 1.50 (d, JZ
7.2 Hz, 3H), 2.91–3.10 (m, 1H), 3.16 (dd, JZ8.8, 9.5 Hz,
1H), 3.38 (dd, JZ9.3, 9.5 Hz, 1H), 3.71 (s, 3H), 3.79 (s,
3H), 4.43 (dd, JZ6.3, 9.6 Hz, 1H), 5.20 (d, JZ6.3 Hz, 1H,
NH), 5.44 (q, JZ7.2 Hz, 1H), 6.86 (d, JZ8.8 Hz, 2 ArH),
7.22 (d, JZ8.8 Hz, 2 ArH); 13C NMR (50 MHz, CDCl3) d
16.1, 28.1, 41.5, 45.2, 49.2, 52.2, 55.1, 56.3, 79.9, 113.8,
128.1, 131.0, 155.2, 160.0, 169.2, 172.3; [a]D K117.1 (c
1.9, CHCl3); MS: m/z 393 (1, MHC), 336 (19, MHCK57),
321 (10), 275 (7), 216 (33), 135 (100), 69 (42), 57 (67).
Anal. Calcd for C20H28N2O6: C 61.21; H 7.19; N 7.14.
Found: C, 61.24; H, 7.16; N, 7.09.
4.4.13. (3S,4R)-3-t-Butoxycarbonylamino-4-methoxycar-
bonylpyrrolidin-2-one (21). A solution of 20 (0.39 g,
1.0 mmol) in CH3CN (5 mL) was treated at rt with cerium
ammonium nitrate (CAN) (1.1 g, 2.0 mmol) dissolved in
H2O (5 mL), and the reaction mixture was stirred for 3 h.
The aqueous layer was extracted with ethyl acetate (3!
25 mL), the organic layers were combined, washed with
brine and dried (Na2SO4). Removal of the solvent under
reduced pressure provided a crude residue, which was
purified by silica gel chromatography (cyclohexane–ethyl
acetate 30:70) to give 21 (0.21 g, 82%) as white solid: mp
4.4.11. (3S,4R)-3-Trichloroacetylamino-4-methoxycar-
bonylpyrrolidin-2-one (19). A solution of 11b (1.31 g,
3.0 mmol) in CH3CN (5 mL) was treated at rt with cerium
ammonium nitrate (CAN) (3.3 g, 6.0 mmol) dissolved in
water (10 mL), and the reaction mixture was stirred for 3 h.
The aqueous layer was extracted with ethyl acetate (3!
25 mL), the organic layers were combined, washed with
brine and dried (Na2SO4). Removal of the solvent under
reduced pressure provided a crude residue, which was
purified by silica gel chromatography (cyclohexane–EtOAc
80:20 as eluent) on silica gel to give 19 (0.7 g, 76%) as a
white solid: mp 73–75 8C: IR (CHCl3) n 3347, 1728,
131–133 8C: IR (CHCl3) n 3340, 1733, 1725, 1665 cmK1
;
1H NMR (200 MHz, CDCl3) d 1.40 (s, 9H), 3.24–3.65 (m,
3H), 3.75 (s, 3H), 4.31 (dd, JZ7.3, 9.2 Hz, 1H), 5.44 (d, JZ
7.3 Hz, 1H, NH), 7.12 (br s, 1H, NH); 13C NMR (50 MHz,
CDCl3) d 28.2, 31.3, 46.6, 52.4, 55.1, 80.3, 155.4, 172.2,
173.5; [a]D K36.7 (c 0.6, CHCl3); MS: m/z 258 (1, MC),
202 (16, MHCK57), 185 (10), 143 (13), 81 (28), 69 (56), 57
(100), 43 (98). Anal. Calcd for C11H18N2O5: C, 51.16; H,
7.02; N, 10.85. Found: C, 51.12; H, 6.97; N, 10.79.
1
1668 cmK1; H NMR (200 MHz, CDCl3) d 3.39–3.57 (m,
2H), 3.59–3.71 (m, 1H), 3.76 (s, 3H), 4.62 (dd, JZ7.3,
9.1 Hz, 1H), 7.43 (s, 1H, NH), 8.12 (d, JZ7.3 Hz 1H, NH);
13C NMR (50 MHz, CDCl3) d 41.7, 45.1, 52.8, 55.0, 91.7,
162.6, 171.6, 172.2; [a]D K46.1 (c 1.9, CHCl3); MS: m/z
302 (3, MC), 304 (3, MC), 269 (34), 267 (34), 185 (45), 141
(56), 110 (82), 82 (100), 55 (80). Anal. Calcd for
C8H9Cl3N2O4: C, 31.66; H, 2.99%; N, 9.23. Found: C,
31.63; H, 2.26; N, 9.18.
4.5. Crystal data for 11a
4.4.12. (3S,4R,10S)-3-t-Butoxycarbonylamino-4-meth-
oxy-carbonyl-1-[10-(4-methoxyphenyl)ethyl]pyrrolidin-
2-one (20). In a flask containing compound 11b (0.5 g,
1.14 mmol), 6 M NaOH (5 mL) was added at rt and the
resulting mixture was stirred for 24 h. The pH of the
homogeneous solution was adjusted to 7 by addition of 6 M
HCl, then water was removed under reduced pressure and
methanol (10 mL) was added in order to precipitate the salts
that were removed by filtration and filter was washed with
methanol (5 mL). The combined filtrates were partially
evaporated under reduced pressure and Boc2O (0.33 g,
1.5 mmol) and TEA (0.4 mL, 3.0 mmol) were added at rt.
After 12 h water (5 mL) was added, methanol was removed
in vacuo and the solution was acidified with 1 M HCl
(0.3 mL). After extraction with ethyl acetate (3!10 mL),
the organic layer was dried (Na2SO4) and removal of the
solvent under reduced pressure gave a residue that was
C16H17Cl3N2O4: MwZ407.67, colorless crystal 0.35!
0.28!0.15 mm, aZ8.594(4) A, bZ8.188(3) A, cZ
˚
˚
˚
19.262(6) A, aZ90.00(3)8, bZ90.00(3)8, gZ90.00(3)8,
VZ1841.5(11) A , DcalcZ1.470 mg/m3, aZ0.095 mmK1
,
3
˚
˚
ZZ4, Orthorhombic, space group P212121, lZ0.71069 A,
TZ223 K, u and f scans, 11413 reflections collected, 2245
independent (RintZ0.0251), 242 refined parameters,
R1/wR2 [IR2s(I)]Z0.0499/0.1308 and R1/wR2 (all
data)Z0.0516/0.1329, maximum (minimum) residual elec-
K3
˚
tron density 0.497 (K0.392) e A
.
Acknowledgements
`
We thank MIUR, Rome (PRIN 2004), and Universita
Politecnica delle Marche (Ancona, Italy) for financial
support.

5472
R. Galeazzi et al. / Tetrahedron 61 (2005) 5465–5473
Mobbili, G.; Orena, M. Tetrahedron: Asymmetry 2003, 14,
Supplementary data
3697–3703. (i) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena,
M.; Rinaldi, S. Tetrahedron: Asymmetry 2003, 14, 3353–3358.
(j) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.;
Panagiotaki, M. Heterocycles 2003, 60, 2485–2498.
6. Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.; Rinaldi, S.
Tetrahedron: Asymmetry 2004, 15, 3249–3256.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.03.
129
Crystallographic data for the structural analysis of com-
pound 11a have been deposited at the Cambridge Crystal-
lographic Data Centre. The CCDC no. 261070 has been
assigned for the compound 11a. Copies of the information
may be obtained free of charge from The Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: C44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://
www.ccdc.cam.ac.uk).
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1H and 13C NMR spectra of compounds 11a–c, 12a–c, 17,
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10. Galeazzi, R.; Martelli, G.; Orena, M.; Rinaldi, S. Synthesis
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