Chiral 3-hydroxypyrrolidin-2-ones. Part 2: Stereodivergent synthesis of conformationally restricted analogues of β-homoserine

Article abstract of DOI:10.1016/j.tetasy.2005.03.003

Starting from the homochiral 3-t-butyldimethylsilyloxypyrrolidin-2-one 2, a stereodivergent synthetic route was developed leading to both 3,4-trans- and 3,4-cis-3-amino-4-hydroxymethyl pyrrolidin-2-ones, 19 and 28, that are conformationally restricted ana

Full text of DOI:10.1016/j.tetasy.2005.03.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1779–1787
Chiral 3-hydroxypyrrolidin-2-ones. Part 2: Stereodivergent
synthesis of conformationally restricted analogues of
b-homoserineI
a
a
b
´
Roberta Galeazzi, Gianluca Martelli, Desire Natali,
Mario Orenaa,* and Samuele Rinaldia
a
`
Dipartimento di Scienze dei Materiali e della Terra, Universita Politecnica delle Marche, Via Brecce Bianche, I-60121 Ancona, Italy
b
`
Istituto di MorfologiaUmana Normale, Universta Politecnica delle Marche, Via Tronto 10/A, I-60131 Ancona, Italy
Received 18 February 2005; accepted 2 March 2005
Available online 23 March 2005
Abstract—Starting from the homochiral 3-t-butyldimethylsilyloxypyrrolidin-2-one 2, a stereodivergent synthetic route was devel-
oped leading to both 3,4-trans- and 3,4-cis-3-amino-4-hydroxymethyl pyrrolidin-2-ones, 19 and 28, that are conformationally
restricted analogues of b-homoserine 4. In addition, with a large number of 3,4-disubstituted pyrrolidin-2-ones in hand, a trend
was observed for both H-3 chemical shifts and J3,4 values, allowing the configuration to be assigned to either 3-hydroxy or 3-amino
derivatives.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
to homochiral 3-hydroxypyrrolidin-2-ones 2 and 3 start-
ing from the Baylis–Hillmans adduct 1 (Scheme 1).4
In recent years, the need to replace natural amino acids
in peptides with nonproteinogenic counterparts in order
to obtain new medicinal agents, exhibiting better bind-
ing to specific receptors and more potent inhibition of
target enzymes, has stimulated a great deal of innov-
ation in synthetic methods.1 In addition, developments
in new bioorganic methodologies, such as site-directed
mutagenesis using expanded genetic codes, total- or
semi-synthesis of enzymes, and protein splicing, have en-
abled incorporation of unnatural amino acids and their
constrained derivatives into the framework of native
proteins, with the aim of providing more drug-like pep-
tidomimetics, which have improved physiological and
physiochemical properties, such as binding affinity and
metabolic stability.2
RO
O
COOMe
OR
+
COOMe
N
+
EtOOC
2
1
ref. 4
Ph
Ph
RO
O
COOMe
(S)-Phenylethylamine
N
3
R = TBDMS
Scheme 1.
A closer inspection of the structure of compound 2 sug-
gested that it would constitute as a suitable precursor to
pyrrolidin-2-ones 7 and 8, the conformationally con-
strained isosteres of (S)-b-homoserine 4,5 an amino acid
involved in physiologically important biotransform-
ations.6 In fact, this compound has received particular
attention since N-acyl (S)-b-homoserine lactones 6, pre-
pared starting from (S)-b-homoserine lactone 5, are
effectors of prokaryotic gene expression and are cell-
density-dependent (quorum sensing) signal molecules.7
Over the course of a study directed at developing proce-
dures for the preparation of pyrrolidin-2-ones (c-lac-
tams) in high yield and a high degree of stereochemical
control,3 we recently reported a convenient approach
q Ref. 4 is considered to be Part 1.
*
Corresponding author. Tel.: +39 071 2204720; fax: +39 071
2204714; e-mail: m.orena@univpm.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.003

1780
R. Galeazzi et al. / Tetrahedron: Asymmetry 16 (2005) 1779–1787
Thus, the preparation of the heterocycles 7 and 8 is of
remarkable interest, due to their potential biological
activity in this field.8 Starting from 2 we report herein
the stereodivergent synthesis of these analogues for use
alone or in solid phase peptide synthesis (Scheme 2).
intramolecular nucleophilic displacement carried out
with sodium azide in DMSO led to the azido derivative
14 in 80% yield. In order to avoid amide formation as a
side reaction during the reduction of the azido group,
the benzoate ester was cleaved with anhydrous Na2CO3
in methanol, to give the alcohol 15. The next step of the
synthesis was the straightforward conversion of the azi-
do group at C-3 into a t-butoxycarbonylamino group.
Thus, 15 was treated with Zn and saturated aqueous
NH4Cl to give the corresponding amino derivative,
which was immediately converted into 16 by reaction
with Boc2O. Eventually, the hydroxy function was pro-
tected as THP ether to give 17, which was treated with
Li in liquid NH3 in order to remove the chiral phenyl-
ethyl group. The corresponding pyrrolidin-2-one 18
was recovered in very good yield and final removal of
the THP ether allowed us to obtain 19, the t-Boc pro-
tected form of 7, the constrained isostere of (S)-b-homo-
serine having a 3,4-trans-disubstitution pattern (Scheme
4).
H
H2N
R
N
H2N
OH
O
4
6
COOH
5
O
O
O
O
H2N
O
H2N
OH
OH
2
N
N
H
O
7
8
H
Scheme 2.
2. Results and discussion
MsO
O
RO
O
OBz
OBz
At first, the placement of an amino group at the 3-posi-
tion of 2 was investigated, but conversion of the alcohol
moiety into a nitrogen-containing functionality was not
trivial. In fact, owing to an elimination reaction, treat-
ment of compound 94 with diphenylphosphoryl azide
(DPPA)9 led to the exclusive formation of the a,b-unsat-
urated lactam 10, instead of the expected azido deriva-
tive. Similar results were obtained even upon heating
the methanesulfonyl derivative of 9 in DMSO in the
presence of sodium azide. In fact at rt, there was no
reaction at all, whereas at 80 ꢁC, fast elimination oc-
curred (Scheme 3).
c
a
d
2
N
N
94%
80%
80%
13
Ph
Ph
R = TBDMS, 11
b
R = H, 12
71%
H
N3
t-BocN
OR'
f
OR''
h
N
N
O
O
90%
75%
Ph
Ph
R'' = H, 16
R' = Bz, 14
e
g
R' = H, 15
R'' = THP, 17
RO
O
COOMe
HO
O
COOMe
74%
79%
H
H
ref. 4
a or b
t-BocN
t-BocN
N
N
OTHP
OH
2
9
i
Ph
R = TBDMS
Ph
85%
N
N
O
O
18
H
19
H
COOMe
Scheme 4. Reagents and conditions: (a) LiAlH4, THF, 0 ꢁC to rt; then
BzCl, TEA, DCM; (b) 6 M HCl, MeOH, rt; (c) methanesulfonyl
chloride, TEA, DCM, rt; (d) NaN3, DMSO, rt; (e) anhydrous
Na2CO3, MeOH, rt; (f) Zn, MeOH, NH4Cl, then (Boc)2O, MeOH;
(g) DHP, H 15, DCM, rt; (h) Li, NH3, ꢀ78 ꢁC; (i) H 15, MeOH, 40 ꢁC.
N
O
10
Ph
Scheme 3. Reagents and conditions: (a) DPPA, toluene, 67%; (b)
methanesulfonyl chloride, Et3N, DCM, 0 ꢁC; then NaN3, DMSO,
from rt to 80 ꢁC, 78%.
Having successfully demonstrated the feasibility of using
pyrrolidin-2-one 2 for the synthesis of 19, the N-t-Boc
derivative of the isostere 7, we turned our attention to
the preparation of an N-protected form of the 3,4-cis-
disubstituted isostere 8, once again starting from the
pyrrolidin-2-one 2. This latter compound was treated
with NaBH4 in anhydrous ethanol10 and the alcohol
acylated with benzoyl chloride under standard condi-
tions to give ester 20 in 75% overall yield. We were
pleased to observe that the reduction reaction led to
the 3,4-trans-disubstituted product exclusively, the
epimerization at C-4 prior to reduction probably being
Thus, by reaction with LiAlH4, compound 2 gave the
corresponding alcohol that was directly converted into
ester 11 in 80% overall yield by reaction with benzoyl
chloride. Through such a process the relative configur-
ation remained unchanged, as determined by NOE (irra-
diation of H-4 resulted in a 11% enhancement on H-3).
Subsequent removal of the TBDMS group, carried out
with 6 M HCl in methanol, afforded 12 in 71% yield.
After activation of the alcohol moiety as a mesylate,

R. Galeazzi et al. / Tetrahedron: Asymmetry 16 (2005) 1779–1787
1781
due to the presence of a small amount of sodium ethox-
RO
R'O
O
N3
O
OBz
OBz
d
OBz
ide in the reaction mixture. In fact, the configurational
assignment of 20 was established first by NOE difference
experiments (irradiation of H-3 resulted in a 10%
enhancement of CH2OBz), and then by comparison be-
tween the values for J3,4 of both diastereomers 11 and 20
(6.8 vs 8.0 Hz), that were reasonably explained by
inspection of molecular models. The subsequent trans-
formation of 20 to 28 was accomplished by the same
set of reactions used in the preparation of compound
19, a small change being exclusively introduced in the
conversion of the mesylate 22 into the azido derivative
23, that required heating and a longer reaction time,
clearly owing to the steric hindrance of the bulky group
at C-4 that lies on the same side of the incoming azide
ion (Scheme 5).
b
32
N
N
N
O
84%
73%
Ph
R = TBDMS, 29
Ph
R' = H, 30
R' = Ms, 31
Ph
c
75%
a
95%
3
e
75%
RO
O
R'O
O
N3
O
OBz
OBz
OBz
36
h
f
N
N
N
76%
72%
Ph
Ph
R' = H, 34
Ph
R = TBDMS, 33
g
R' = Ms, 35
MsO
O
RO
O
90%
OBz
d
OBz
a
c
Scheme 6. Reagents and conditions: (a) LiAlH4, THF, rt, then BzCl,
TEA, DCM; (b) 6 M HCl, MeOH; (c) methanesulfonyl chloride, TEA,
DCM, 0 ꢁC; (d) NaN3, DMSO, rt; (e) NaBH4, EtOH, rt, then BzCl,
TEA, DCM; (f) 6 M HCl, MeOH; (g) methanesulfonyl chloride, TEA,
DCM, 0 ꢁC; (h) NaN3, DMSO, 65 ꢁC.
2
N
N
75%
75%
95%
22
Ph
Ph
R = TBDMS, 20
b
R = H, 21
70%
H
the exception being mesylate 22 (J3,4-trans = 7.5 Hz).12,13
In addition, the signal of H-3 of the cis-isomers usually
appears somewhat shielded with respect to the analo-
gous signal of the trans-isomers, due to the effect of
the group at C-4 (Table 1).
N3
O
t-BocN
OR'
f
OR''
h
N
N
O
75%
92%
Ph
Ph
R' = Bz, 23
R'' = H, 25
R'' = THP, 26
e
g
R' = H, 24
80%
73%
Table 1. H-3 chemical shifts and J3,4 values for 3,4-disubstituted
pyrrolidin-2-ones
H
H
3,4-cis
d
J3,4
3,4-trans
d
J3,4
t-BocN
t-BocN
OTHP
OH
i
11
29
12
30
13
31
23
36
24
25
28
4.41
4.46
4.55
4.55
5.35
5.39
4.36
4.32
4.35
4.41
4.41
6.8
6.5
7.7
7.7
7.8
7.6
7.3
8.1
8.1
8.0
7.4
20
33
21
34
22
35
14
32
15
16
19
4.23
4.32
4.36
4.44
5.21
5.27
4.18
4.11
4.19
4.21
4.14
8.0
8.4
88%
N
N
O
O
27
H
28
8.6
9.2
H
7.5
8.2
Scheme 5. Reagents and conditions: (a) NaBH4, EtOH, rt; then BzCl,
TEA, DCM; (b) 6 M HCl, MeOH, rt; (c) methanesulfonyl chloride,
TEA, DCM, 0 ꢁC; (d) NaN3, DMSO, 65 ꢁC; (e) anhydrous Na2CO3,
MeOH, rt; (f) Zn, MeOH, NH4Cl, then (Boc)2O, MeOH; (g) DHP,
H 15, DCM, rt; (h) Li, NH3, ꢀ78 ꢁC; (i) H 15, MeOH, 40 ꢁC.
8.8
8.4
9.0
10.3
10.3
Eventually, the same reaction sequences reported above
were carried out starting from compound 3, with the
aim of preparing intermediates useful for the synthesis
of ent-19 and ent-28. In this case, azido derivatives 32
and 36 were obtained in comparable and reproducible
overall yields, with respect to compounds 14 and 23
(Scheme 6).
3. Conclusion
In summary, pyrrolidin-2-ones 2 and 3, with the appro-
priate choice of the reaction sequence, can lead in a
straightforward manner to all four stereoisomers of a
conformationally restricted analogue of b-homoserine,
7, 8, ent-7 and ent-8. Moreover it is worth mentioning
that, owing to the easy elaboration of the hydroxy-
methyl group at C-4, the latter compounds might return
a convenient access to a lot of conformationally con-
strained analogues of proteinogenic amino acids whose
synthesis is currently underway in our laboratory, direct-
ed towards the preparation of constrained, bioactive
oligopeptides.
Then, with a relatively large number of 3,4-disubstituted
pyrrolidin-2-ones in hand, by considering the trend of
the 1H NMR coupling constants and chemical shifts
of H-3, we were able to develop a concrete criterion
for the structural assignment of 3,4-cis and 3,4-trans
disubstituted pyrrolidin-2-ones.11 In fact, J3,4-cis are
significantly smaller than the corresponding J3,4-trans
(the difference in their values is about 1.0 Hz), with only

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R. Galeazzi et al. / Tetrahedron: Asymmetry 16 (2005) 1779–1787
4. Experimental
a colourless oil. MS: m/z 245 (9, M+), 149 (16), 129
(14), 105 (100), 69 (42), 43 (65). Anal. Calcd for
C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.51; H, 6.12; N, 5.75.
4.1. General
Melting points were measured on a hot stage apparatus
and are uncorrected. IR spectra were recorded in CHCl3
using NaCl cells. Diastereomeric purity was determined
by GC analysis using an instrument equipped with a
capillary column (50 m · 0.25 mm i.d.; stationary phase
4.3. (3R,4S,10S)-4-Benzoyloxymethyl-3-t-butyldimethyl-
silyloxy-1-(10-phenylethyl)pyrrolidin-2-one 11
To a solution containing compound 24 (2.3 g, 6.0 mmol)
in dry THF (15 mL), LiAlH4 (0.23 g, 6.0 mmol) was
added at 0 ꢁC. After 3 h methanol (1 mL) was added fol-
lowed by a saturated solution of Seignette salt (20 mL).
The mixture was then extracted with ethyl acetate
(3 · 50 mL), the organic layer dried over Na2SO4 and
eventually removed under reduced pressure. The residue
was dissolved in dry dichloromethane (15 mL) contain-
ing triethylamine (0.6 g, 6.0 mmol), and benzoyl chlo-
ride (0.84 g, 6.0 mmol) then added at 0 ꢁC. The
reaction mixture was stirred for 4 h and then concen-
trated. Water (15 mL) and ethyl acetate (70 mL) were
added and the resulting organic solution washed with
brine, dried and concentrated. Purification of the residue
by silica gel chromatography (cyclohexane–ethyl acetate
90:10 as eluent) afforded 11 (2.2 g, 80%) as a colourless
oil: IR (CHCl3) m 1735, 1668 cmꢀ1; 1H NMR (200 MHz,
CDCl3): d 0.18 (s, 3H), 0.22 (s, 3H), 0.92 (s, 9H), 1.52 (d,
J = 7.0 Hz, 3H), 2.63–2.80 (m, 1H), 3.10 (dd, J = 7.0,
9.9 Hz, 1H), 3.26 (dd, J = 5.1, 9.9 Hz, 1H), 4.34 (dd,
J = 7.7, 11.2 Hz, 1H), 4.41 (d, J = 6.8 Hz, 1H), 4.57
(dd, J = 5.9, J = 11.2 Hz, 1H), 5.48 (q, J = 7.0 Hz,
1H), 7.22–7.73 (m, 8ArH), 7.95–8.05 (m, 1ArH), 8.12–
8.19 (m, 1ArH); 13C NMR (50 MHz, CDCl3): d ꢀ5.4,
ꢀ4.5, 15.8, 18.3, 25.7, 37.4, 42.4, 49.3, 62.7, 71.9,
127.0, 127.5, 128.3, 128.5, 128.8, 129.5, 130.5, 133.0,
134.4, 139.8, 162.3, 166.4, 171.9; [a]D = ꢀ24.4 (c 1.03,
CHCl3); MS: m/z 396 (21 M+ꢀ57), 292 (10), 179 (17),
105 (100), 77 (19), 57 (12), 43 (15). Anal. Calcd for
C26H35NO4Si: C, 68.84; H, 7.78; N, 3.09. Found: C,
68.79; H, 7.81; N, 3.07.
1
CP-Sil-5 CB). H and 13C NMR spectra were recorded
at 200 and 50 MHz, respectively, using CDCl3 as a sol-
vent unless otherwise reported. Chemical shifts (d) are
reported in ppm relative to TMS and coupling constants
(J) in hertz. Assignments were aided by decoupling
and homonuclear two-dimensional experiments. Optical
rotations were measured using a 1 dm path length cell.
Mass spectra (MS) were obtained by electron impact
at 70 eV. Column chromatography was performed with
silica gel 60 (230–400 mesh). Compounds 2, 3 and 9 were
prepared as described in Ref. 4.
4.2. (10S)-4-Methoxycarbonyl-1,5-dihydro-1-(10-phenyl-
ethyl)-2H-pyrrol-2-one 10
4.2.1. Method A. To a solution containing 9 (1.2 g,
4.5 mmol) and diphenylphosphoryl azide (1.5 g,
5.5 mmol) in toluene (15 mL), DBU (0.84 g, 5.5 mmol)
was added at 0 ꢁC and the reaction stirred at room tem-
perature for 6 h. The mixture was poured in ethyl ace-
tate (50 mL) and the organic layer washed with 2 M
HCl (20 mL) and brine. After drying over Na2SO4 and
removal of the solvent, the residue was purified by silica
gel chromatography (cyclohexane–ethyl acetate 80:20 as
eluent), to give 10 (0.74 g, 67%) as a clear oil: IR
(CHCl3) m 1724, 1648 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): d 1.64 (d, J = 7.1 Hz, 3H), 3.36 (d, J = 1.9 Hz,
2H), 3.71 (s, 3H), 5.44 (q, J = 7.1 Hz, 1H), 7.26–7.43
(m, 5ArH + 1H); 13C NMR (50 MHz, CDCl3): d 19.1,
36.7, 50.1, 51.3, 108.9, 126.6, 128.1, 128.9, 139.9,
140.7, 163.4, 175.4; [a]D = ꢀ64.3 (c 1.0, CHCl3); MS:
m/z 245 (9, M+), 149 (16), 129 (14), 105 (100), 69 (42),
43 (65). Anal. Calcd for C14H15NO3: C, 68.56; H,
6.16; N, 5.71. Found: C, 68.51; H, 6.12; N, 5.75.
4.4. (3R,4S,10S)-4-Benzoyloxymethyl-3-hydroxy-1-(10-
phenylethyl)pyrrolidin-2-one 12
To a solution of compound 11 (1.36 g, 3.0 mmol) in
methanol (10 mL), 6 M HCl (7 mL) was added and the
solution stirred at room temperature for 2 h. Then water
(10 mL) was added, methanol removed under reduced
pressure and the mixture was extracted with ethyl ace-
tate (2 · 40 mL). After drying over Na2SO4 and evapo-
ration of the solvent, the residue was purified by silica
gel chromatography (cyclohexane–ethyl acetate 70:30
as eluent), to give compound 12 (0.72 g, 71%) as a
4.2.2. Method B. The alcohol 9 (1.1 g, 4.0 mmol) was
dissolved in dry dichloromethane (10 mL) containing
triethylamine (0.51 g, 5.0 mmol) and methanesulfonyl
chloride (0.57 g, 5.0 mmol) was added dropwise at
0 ꢁC. The reaction mixture was stirred at 0 ꢁC for 2 h
and subsequently poured onto crushed ice containing
1 M HCl (15 mL). After extraction with ethyl acetate
(2 · 30 mL), washing with dilute HCl, and drying
(Na2SO4), evaporation of the solvent under reduced
pressure gave the crude mesylate as an oil. To this
product DMSO (5 mL) and solid sodium azide (0.33 g,
5.0 mmol) were subsequently added and the mixture
was stirred first at 0 ꢁC for 3 h and then for 1 h at
80 ꢁC. Water (10 mL) was added to the reaction mixture
and, after extraction with ethyl acetate (2 · 40 mL), the
organic layers were combined and washed with brine,
dried (Na2SO4) and evaporated. Purification of the
residue by silica gel chromatography (cyclohexane–
ethyl acetate 80:20 as eluent) gave 10 (0.76 g, 78%) as
1
colourless oil: IR (CHCl3) m 3345, 1736, 1668 cmꢀ1; H
NMR (200 MHz, CDCl3): d 1.49 (d, J = 7.1 Hz, 3H),
2.55 (br s, 1H, OH), 2.77–2.94 (m, 1H), 3.08 (dd,
J = 6.7, 10.3 Hz, 1H), 3.32 (dd, J = 3.3, 10.3 Hz, 1H),
4.42 (dd, J = 7.4, 11.4 Hz, 1H), 4.55 (d, J = 7.7 Hz,
1H), 4.69 (dd, J = 4.8, 11.4 Hz, 1H), 5.48 (q,
J = 7.1 Hz, 1H), 7.21–7.62 (m, 8ArH), 7.97–8.05 (m,
2ArH); 13C NMR (50 MHz, CDCl3): d 15.6, 36.3,
42.7, 49.6, 62.6, 70.7, 127.0, 127.7, 128.3, 128.6, 129.5,
129.6, 129.9, 133.0, 139.4, 166.5, 173.5; [a]D = ꢀ97.5 (c
1.0, CHCl3); MS: m/z 219 (3, MH+ꢀ121), 188 (11),

R. Galeazzi et al. / Tetrahedron: Asymmetry 16 (2005) 1779–1787
1783
149 (6), 105 (32), 91 (24), 69 (25), 43 (67), 40 (100). Anal.
Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13.
Found: C, 70.72; H, 6.28; N, 4.08.
(d, J = 7.1 Hz, 3H), 2.09–2.28 (m, 1H), 2.85 (br s, 1H,
OH), 3.03 (dd, J = 8.4, 9.9 Hz, 1H), 3.18 (dd, J = 8.4,
9.9 Hz, 1H), 3.73 (dd, J = 6.6, 9.2 Hz, 1H), 3.76 (dd,
J = 5.2, 9.2 Hz, 1H), 4.19 (d, J = 9.0 Hz, 1H), 5.45 (q,
J = 7.1 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 16.0,
41.3, 41.7, 49.7, 60.8, 61.5, 126.9, 127.8, 128.6, 139.0,
170.1; [a]D = ꢀ373.8 (c 1.1, CHCl3); MS: m/z 218 (12,
M+ꢀ42), 201 (16), 146 (9), 132 (7), 105 (100), 77 (34).
Anal. Calcd for C13H16N4O2: C, 59.99; H, 6.20; N,
21.52. Found: C, 59.94; H, 6.15; N, 21.47.
4.5. (3S,4R,10S)-3-Azido-4-benzoyloxymethyl-1-(10-phen-
ylethyl)pyrrolidin-2-one 14
Alcohol 12 (1.2 g, 3.6 mmol) was dissolved in dry
dichloromethane (10 mL) containing triethylamine
(0.84 g, 5.4 mmol) after which methanesulfonyl chloride
(0.45 mL, 5.4 mmol) was added dropwise at 0 ꢁC. The
reaction mixture was stirred at 0 ꢁC for 2 h and subse-
quently poured onto crushed ice containing dilute
HCl. After extraction with ethyl acetate (2 · 30 mL),
washing with dilute HCl and drying over Na2SO4, evap-
oration of the solvent under reduced pressure gave the
crude (3R,4S,10S)-4-benzoyloxymethyl-3-methanesulfo-
nyloxy-1-(10-phenylethyl)pyrrolidin-2-one 13 (1.41 g,
94%) as a pale yellow oil that was used without further
4.7. (3S,4R,10S)-3-t-Butoxycarbonylamino-4-hydroxy-
methyl-1-(10-phenylethyl)pyrrolidin-2-one 16
To a solution of compound 15 (0.78 g, 3.0 mmol) in
MeOH (5 mL), Zn powder (0.39 g, 6.0 mmol) and an
aqueous saturated solution of NH4Cl (1 mL) were sub-
sequently added and the mixture was stirred for
15 min at rt. Then a saturated Na2CO3 solution
(15 mL) was added and the mixture extracted with
DCM (3 · 50 mL). After drying over Na2SO4 and re-
moval of the solvent under reduced pressure, the residue
was dissolved in methanol (10 mL) after which di-t-butyl
dicarbonate (0.78 g, 3.3 mmol) was added and the mix-
ture stirred at room temperature for 12 h. Removal of
the solvent and purification of the residue by chroma-
tography on silica gel (cyclohexane–ethyl acetate 70:30
as eluent) gave 16 (0.75 g, 75%) as a colourless oil: IR
1
purification: H NMR (200 MHz, CDCl3): d 1.53 (d,
J = 7.1 Hz, 3H), 2.89–3.04 (m, 1H), 3.14 (dd, J = 6.7,
10.3 Hz, 1H), 3.34 (dd, J = 5.3, 10.3 Hz, 1H), 3.35 (s,
3H), 4.49 (dd, J = 6.5, 11.4 Hz, 1H), 4.58 (dd, J = 5.8,
11.4 Hz, 1H), 5.35 (d, J = 7.8 Hz, 1H), 5.48 (q,
J = 7.1 Hz, 1H), 7.22 (m, 7ArH), 7.99–8.07 (m, 2ArH).
Then, the methanesulfonyl derivative 13 (0.84 g,
2.0 mmol) was taken up in DMSO (5 mL) and solid
sodium azide (0.38 g, 6.0 mmol) added. (Caution!:
Although these experiments have proceeded without
incident, extreme caution should be exercised in the han-
dling of organic azides, particularly with manipulations
that involve heating of neat liquids or solid residues).
The mixture was stirred at room temperature for 4 h
and then poured into water (10 mL)–ethyl acetate
(20 mL). After extraction with ethyl acetate
(2 · 40 mL), the organic layers were combined and
washed with brine, dried over Na2SO4 and evaporated.
Purification by silica gel chromatography (cyclohex-
ane–ethyl acetate 80:20 as eluent) gave 14 (0.58 g,
80%) as a colourless oil: IR (CHCl3) m 2107, 1728,
(CHCl3)
m
3345, 1730, 1668 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d 1.47 (s, 9H), 1.54 (d, J = 7.0 Hz,
3H), 2.07–2.21 (m, 1H), 2.98 (dd, J = 5.8, 7.2 Hz, 1H),
3.05 (dd, J = 7.2, 7.2 Hz, 1H), 3.63–3.76 (m,
1H + OH), 4.02–4.15 (m, 1H), 4.21 (dd, J = 5.4,
10.3 Hz, 1H), 5.41 (d, J = 5.4 Hz, 1H, NH), 5.49 (q,
J = 7.0 Hz, 1H), 7.22–7.43 (m, 5ArH); 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 = ꢀ141.3 (c 1.5, CHCl3); MS: m/z 335 (MH+, 2),
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.
1665 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.55 (d,
;
J = 7.2 Hz, 3H), 2.36–2.55 (m, 1H), 3.13–3.17 (m, 2H),
4.18 (d, J = 8.8 Hz, 1H), 4.44 (d, J = 5.5 Hz, 2H), 5.51
(q, J = 7.2 Hz, 1H), 7.24–7.65 (m, 8ArH), 7.96–8.05
(m, 2ArH); 13C NMR (50 MHz, CDCl3): d 16.0, 38.7,
42.0, 49.7, 61.9, 63.5, 126.9, 127.8, 128.5, 128.6, 128.7,
129.3, 129.6, 133.4, 138.9, 166.1, 169.4; [a]D = ꢀ271.2
(c 1.0, CHCl3); MS: m/z 365 (3, MH+), 322 (6), 214
(26), 146 (10), 105 (100), 77 (67), 51 (23). Anal. Calcd
for C20H20N4O3: C, 65.92; H, 5.53; N, 15.37. Found:
C, 65.88; H, 5.49; N, 15.41.
4.8. (3S,4R,10S)-3-t-Butoxycarbonylamino-4-tetrahydro-
pyranyloxymethyl-1-(10-phenylethyl)pyrrolidin-2-one 17
To a solution of compound 16 (1.0 g, 3.0 mmol) and
DHP (0.5 mL, 6.0 mmol) in DCM (20 mL), resin H 15
(1 g) was added and the mixture was stirred for 3 h at
rt. The resin was then filtered off and the solvent re-
moved under reduced pressure. The residue was purified
by silica gel chromatography (cyclohexane–ethyl acetate
70:30 as eluent), to give compound 17 (1.0 g, 79%) as a
4.6. (3S,4R,10S)-3-Azido-4-hydroxymethyl-1-(10-phenyl-
ethyl)pyrrolidin-2-one 15
1
colourless oil: IR (CHCl3) m 3341, 1728, 1666 cmꢀ1; H
NMR (200 MHz, CDCl3): d 1.36 (s, 9H), 1.41–1.79
(m, 6H), 1.45 (d, J = 7.0 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, J = 5.3, 10.1 Hz, 1H), 4.54 (m, 1H),
5.03 (d, 1H, NH, J = 5.3 Hz), 5.46 (q, J = 7.0 Hz, 1H),
7.21–7.36 (m, 5ArH); 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),
A mixture of 14 (1.29 g, 3.5 mmol) and anhydrous so-
dium carbonate (0.27 g, 2.5 mmol), in dry methanol
(7 mL) was stirred at room temperature for 5 h. After fil-
tration, methanol was removed under reduced pressure
and the residue purified by silica gel chromatography
(cyclohexane–ethyl acetate 60:40 as eluent) to give 15
(0.69 g, 74%) as a viscous oil: IR (CHCl3) m 2107,
1
1722, 1670 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.53

1784
R. Galeazzi et al. / Tetrahedron: Asymmetry 16 (2005) 1779–1787
99.4 (50), 126.7, 127.3, 128.3, 139.5, 155.6, 171.0 (50),
171.1 (50).
resulting organic solution washed with brine, dried over
Na2SO4 and concentrated. Purification of the residue by
silica gel chromatography (cyclohexane–ethyl acetate
90:10 as eluent) afforded 20 (2.0 g, 75%) as a colourless
oil: IR (CHCl3) m 1724, 1665 cmꢀ1; 1H NMR (200 MHz,
CDCl3): d 0.16 (s, 3H), 0.24 (s, 3H), 0.93 (s, 9H), 1.57 (d,
J = 7.3 Hz, 3H), 2.52–2.73 (m, 1H), 2.76 (dd, J = 8.1,
9.4 Hz, 1H), 3.46 (dd, J = 7.8, 9.4 Hz, 1H), 4.23 (d,
J = 8.0 Hz, 1H), 4.29 (dd, J = 6.6, 11.2 Hz, 1H), 4.42
(dd, J = 4.3, 11.2 Hz, 1H), 5.51 (q, J = 7.3 Hz, 1H),
7.22–7.72 (m, 6ArH), 7.87–7.95 (m, 2ArH), 8.08–8.21
(m, 2ArH); 13C NMR (50 MHz, CDCl3): d ꢀ5.2,
ꢀ4.1, 15.9, 18.2, 25.7, 41.5, 41.8, 49.5, 63.6, 73.1,
127.0, 127.6, 128.4, 128.6, 128.8, 129.5, 129.6, 130.1,
130.5, 133.1, 134.4, 139.6, 166.1, 172.0; [a]D = ꢀ29.8 (c
2.4, CHCl3); MS: m/z 396 (21, M+ꢀ57), 292 (10), 179
(17), 105 (100), 77 (19), 57 (12), 43 (15). Anal. Calcd
for C26H35NO4Si: C, 68.84; H, 7.78; N, 3.09. Found:
C, 68.81; H, 7.83; N, 3.04.
4.9. (3R,4S)-3-t-Butoxycarbonylamino-4-hydroxymethyl-
pyrrolidin-2-one 19
Ammonia (40 mL) was condensed in a three-necked
flask at ꢀ78 ꢁC, Li shots (140 mg, 20.0 mmol) were
added and the blue solution was stirred at this tempera-
ture for 20 min. Then compound 17 (1.25 g, 3.0 mmol)
was dissolved in a mixture of THF (9 mL) and t-BuOH
(1 mL), and the solution added in one portion. After
3 min, the reaction mixture was quenched by the addi-
tion of solid NH4Cl (2 g) and warmed to room temper-
ature. Then ammonia was removed, ethyl acetate
(40 mL) and water (10 mL) added, the mixture extracted
with ethyl acetate (2 · 50 mL) and the combined organic
layers dried over Na2SO4. After the solvent was re-
moved in vacuo, the crude product was purified by silica
gel chromatography (cyclohexane–ethyl acetate 40:60 as
eluent) to give (3S,4R)-3-t-butoxycarbonylamino-4-tet-
rahydropyranyloxymethylpyrrolidin-2-one 18 (0.85 g,
90%) as a colourless oil: IR (CHCl3) m 3341, 1728,
4.11. (3R,4R,10S)-4-Benzoyloxymethyl-3-hydroxy-1(10-
phenylethyl)pyrrolidin-2-one 21
1
1668 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.35–1.82
Starting from 11 (1.36 g, 3.0 mmol), the title compound
(0.71 g, 70%) was prepared as a colourless oil as de-
(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). This product was dissolved in methanol (20 mL),
H 15 (1 g) then added and the mixture heated to 45 ꢁC
for 1 h. The resin was filtered off, the solvent removed
under reduced pressure and the residue was purified by
silica gel chromatography (cyclohexane–ethyl acetate
30:70 as eluent) to give 19 (0.53 g, 85%) as a white solid:
scribed for 12: IR (CHCl3) m 3347, 1726, 1665 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 1.58 (d, J = 7.1 Hz,
3H), 2.64–2.81 (m, 1H), 2.82 (dd, J = 8.5, 8.9 Hz, 1H),
3.50 (dd, J = 7.7, 8.9 Hz, 1H), 4.36 (d, J = 8.6 Hz, 1H),
4.41 (dd, J = 6.2, 11.4 Hz, 1H), 4.53 (dd, J = 4.3,
11.4 Hz, 1H), 5.52 (q, J = 7.1 Hz, 1H), 7.23–7.61 (m,
8ArH), 7.91–7.98 (m, 2ArH); 13C NMR (50 MHz,
CDCl3): d 15.8, 40.6, 41.9, 49.6, 63.9, 71.9, 126.9,
127.6, 128.3, 128.5, 129.4, 129.6, 133.0, 139.1, 166.1,
173.8; [a]D = ꢀ71.1 (c 1.6, CHCl3); MS: m/z 219 (3,
MH+ꢀ121), 188 (11), 149 (6), 105 (32), 91 (24), 69
(25), 43 (67), 40 (100). Anal. Calcd for C20H21NO4: C,
70.68; H, 6.24; N, 4.13. Found: C, 70.61; H, 6.19; N,
4.17.
mp 128–130 ꢁC; IR (CHCl3) m 3345, 1728, 1671 cmꢀ1
;
1H 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, J = 6.1,
12.1 Hz, 1H), 3.77 (dd, J = 4.3, 12.1 Hz, 1H), 4.14 (dd,
J = 5.9, 10.3 Hz, 1H), 5.31 (d, J = 5.9 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 = ꢀ49.2 (c 0.6, MeOH); MS: m/z 230 (1, M+), 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, 12.14.
4.12. (3R,4R,10S)-4-Benzoyloxymethyl-3-methanesulfon-
yloxy-1-(10-phenylethyl)pyrrolidin-2-one 22
Starting from 21 (1.2 g, 3.0 mmol), the title compound
(1.44 g, 95%) was prepared as a colourless oil as de-
1
scribed for 13: H NMR (200 MHz, CDCl3): d 1.61 (d,
J = 7.1 Hz, 3H), 2.84 (dd, J = 8.5, 8.9 Hz, 1H), 2.86–
3.06 (m, 1H), 3.37 (s, 3H), 3.58 (dd, J = 7.7, 8.9 Hz,
1H), 4.44 (d, J = 4.2 Hz, 2H), 5.21 (d, J = 7.5 Hz, 1H),
5.49 (q, J = 7.1 Hz, 1H), 7.21–7.65 (m, 8ArH), 7.91–
7.99 (m, 2ArH).
4.10. (3R,4R,10S)-4-Benzoyloxymethyl-3-t-butyldimeth-
ylsilyloxy-1-(10-phenylethyl)pyrrolidin-2-one 20
To a solution containing compound 2 (2.3 g, 6.0 mmol)
in dry ethanol (15 mL), NaBH4 (0.96 g, 24.0 mmol) was
added at room temperature. After 6 h, the reaction mix-
ture was poured in water (30 mL) and extracted with
ethyl acetate (3 · 50 mL). After drying over Na2SO4,
the solvent was removed under reduced pressure. The
residue was dissolved in dry DCM (15 mL) containing
triethylamine (0.6 g, 6.0 mmol) and benzoyl chloride
(0.84 g, 6.0 mmol) was added at 0 ꢁC. The reaction mix-
ture was stirred for 4 h and then concentrated. Water
(15 mL) and ethyl acetate (70 mL) were added and the
4.13. (3S,4S,10S)-3-Azido-4-benzoyloxymethyl-1-(10-
phenylethyl)pyrrolidin-2-one 23
Starting from 22 (0.84 g, 2.0 mmol), the title compound
(0.55 g, 75%) was prepared as a colourless oil as de-
scribed for 14, but heating of the reaction mixture to
70 ꢁC for 4 h was required. (Caution!: Although these
experiments have proceeded without incident, extreme
caution should be exercised in the handling of organic
azides, particularly with manipulations that involve
heating of neat liquids or solid residues): IR (CHCl3) m

R. Galeazzi et al. / Tetrahedron: Asymmetry 16 (2005) 1779–1787
1785
1
2104, 1726, 1665 cmꢀ1; H NMR (200 MHz, CDCl3): d
(q, J = 7.2 Hz, 1H), 7.18–7.35 (m, 5ArH); 13C NMR
(50 MHz, CDCl3): d 15.9 (50), 16.1 (50), 19.0 (50), 19.2
(50), 25.0 (50), 25.1 (50), 26.7, 28.1, 30.0 (50), 30.1 (50),
35.0 (50), 35.1 (50), 41.1 (50), 42.4 (50), 49.5 (50), 50.0
(50), 53.8 (50), 54.3 (50), 61.7 (50), 62.0 (50), 65.0 (50),
65.2 (50), 79.6 (50), 79.8 (50), 98.6 (50), 99.4 (50),
127.0, 127.1, 127.3, 127.5, 129.4 (50), 132.8 (50), 139.5,
156.0 (50), 156.1 (50), 170.6 (50), 170.8 (50).
1.56 (d, J = 7.2 Hz, 3H), 2.79–2.96 (m, 2H), 3.40 (dd, J =
8.8, 11.8 Hz, 1H), 4.10 (dd, J = 7.4, 11.6 Hz, 1H), 4.36
(d, J = 7.3 Hz, 1H), 4.44 (dd, J = 5.8, 11.6 Hz, 1H),
5.50 (q, J = 7.2 Hz, 1H), 7.21–7.63 (m, 8ArH), 7.87–
7.96 (m, 2ArH); 13C NMR: 16.1, 35.1, 42.9, 49.8, 61.3,
62.2, 127.0, 127.8, 128.4, 128.7, 129.6, 133.1, 138.8,
166.0, 169.2; [a]D = ꢀ302.0 (c 0.5, CHCl3); MS: m/z
365 (3, MH+), 322 (6), 214 (26), 146 (10), 105 (100), 77
(67), 51 (23). Anal. Calcd for C20H20N4O3: C, 65.92;
H, 5.53; N, 15.37. Found: C, 65.96; H, 5.47; N, 15.34.
4.17. (3S,4S,10S)-3-t-Butoxycarbonylamino-4-tetra-
hydropyranyloxymethylpyrrolidin-2-one 27
4.14. (3R,4R,10S)-3-Azido-4-hydroxymethyl-1-(10-phen-
ylethyl)pyrrolidin-2-one 24
Starting from 26 (1.25 g, 3.0 mmol), the title compound
(0.87 g, 92%) was prepared as a colourless oil as
described for 18: IR (CHCl3) m 3350, 1725, 1668 cmꢀ1
;
Starting from 23 (1.29 g, 3.5 mmol), the title compound
(0.73 g, 80%) was prepared as a colourless oil as de-
1H NMR (200 MHz, CDCl3): d 1.38 (s, 9H), 1.41–1.82
(m, 6H), 2.74–2.99 (m, 1H), 3.21–3.53 (m, 4H), 3.60–
3.85 (m, 2H), 4.40 (dd, J = 7.2, 7.4 Hz, 1H), 5.09 (d,
J = 7.2 Hz, 1H, NH, 50%), 5.33 (d, J = 7.2 Hz, 1H,
NH, 50%), 4.45–4.58 (m, 1H), 6.82 (d, J = 6.5 Hz, 1H,
NH); 13C NMR (50 MHz, CDCl3): d 19.2 (50), 19.6
(50), 25.2 (50), 25.3 (50), 28.2, 30.4 (50), 30.5 (50),
37.6, 42.5 (50), 42.7 (50), 52.8 (50), 52.9 (50), 62.1 (50),
62.6 (50), 65.8, 79.8, 99.4, 156.1, 175.0.
scribed for 15: IR (CHCl3) m 3346, 2110, 1666 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 1.51 (d, J = 7.2 Hz,
3H), 2.49–2.78 (m, 1H), 2.80 (dd, J = 4.3, 10.2 Hz,
1H), 3.33 (dd, J = 7.4, 10.2 Hz, 1H), 3.45 (dd, J = 5.7,
11.4 Hz, 1H), 3.62 (dd, J = 6.8, 11.4 Hz, 1H), 4.35 (d,
J = 8.1 Hz, 1H), 5.46 (q, J = 7.2 Hz, 1H), 7.21–7.44
(m, 5ArH); 13C NMR (50 MHz, CDCl3): d 16.1, 36.9,
42.7, 49.7, 61.0, 61.6, 127.0, 127.8, 128.6, 139.0, 169.6;
[a]D = ꢀ278.0 (c 2.0, CHCl3); MS: m/z 218 (12,
M+ꢀ42), 201 (16), 146 (9), 132 (7), 105 (100), 77 (34).
Anal. Calcd for C13H16N4O2: C, 59.99; H, 6.20; N,
21.52. Found: C, 59.95; H, 6.17; N, 21.55.
4.18. (3S,4S,10S)-3-t-Butoxycarbonylamino-4-hydroxy-
methylpyrrolidin-2-one 28
Starting from 27 (0.85 g, 2.7 mmol), the title compound
(0.55 g, 88%) was prepared as a white solid as described
for 19: mp 150–152 ꢁC; IR (CHCl3) m 3347, 1721,
4.15. (3S,4S,10S)-3-t-Butoxycarbonylamino-4-hydroxy-
methyl-1-(10-phenylethyl)pyrrolidin-2-one 25
1665 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.46 (s,
;
9H), 2.15 (br s, 1H, OH), 2.81–2.89 (m, 1H), 3.40 (dd,
J = 10.2, 10.2 Hz, 1H), 3.53 (dd, J = 6.9, 10.2 Hz, 1H),
3.66 (dd, J = 4.0, 10.6 Hz, 1H), 3.73 (dd, J = 4.0,
10.6 Hz, 1H), 4.41 (dd, J = 5.6, 7.4 Hz, 1H), 5.30 (d,
J = 5.6 Hz, 1H, NH), 6.14 (br s, 1H, NH); 13C NMR
(50 MHz, CDCl3): d 28.3, 39.5, 42.8, 53.0, 61.1, 80.0,
156.5, 175.8; [a]D = +21.5 (c 1.4, MeOH); MS: m/z 230
(1, M+), 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, 52.13; H, 7.84; N, 12.20.
Starting from 24 (0.78 g, 3.0 mmol), the title compound
(0.75 g, 75%) was prepared as a colourless oil as de-
scribed for 16: IR (CHCl3) m 3455, 1722, 1665 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 1.43 (s, 9H), 1.52 (d,
J = 7.2 Hz, 3H), 1.93 (br s, 1H, OH), 2.62–2.77 (m,
1H), 2.93 (dd, J = 1.5, 10.3 Hz, 1H), 3.30 (dd, J = 6.1,
11.2 Hz, 1H), 3.38 (dd, J = 6.8, 10.3 Hz, 1H), 3.49 (dd,
J = 4.7, 11.2 Hz, 1H), 4.41 (dd, J = 5.6, 8.0 Hz, 1H),
5.24 (d, J = 5.6 Hz, 1H, NH), 5.46 (q, J = 7.2 Hz, 1H),
7.23–7.36 (m, 5ArH); 13C NMR (50 MHz, CDCl3): d
16.1, 28.3, 37.8, 42.6, 49.7, 54.4, 61.0, 80.1, 127.1,
127.7, 128.5, 139.5, 156.4, 171.0; [a]D = ꢀ83.0 (c 1.4,
CHCl3); MS: m/z 335 (2, MH+), 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, 64.58; H, 7.81; N, 8.34.
4.19. (3S,4R,10S)-4-Benzoyloxymethyl-3-t-butyldimeth-
ylsilyloxy-1-(10-phenylethyl)pyrrolidin-2-one 29
Starting from 3 (2.3 g, 6.0 mmol), the title compound
(2.0 g, 75%) was prepared as a colourless oil as described
for 11: IR (CHCl3) m 1718, 1667 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 0.18 (s, 3H), 0.23 (s, 3H), 0.93
(s, 9H), 1.55 (d, J = 7.1 Hz, 3H), 2.74–2.87 (m, 1H),
2.95 (dd, J = 5.3, 9.9 Hz, 1H), 3.33 (dd, J = 6.8,
9.9 Hz, 1H), 4.15 (dd, J = 8.3, 11.3 Hz, 1H), 4.46 (d,
J = 6.5 Hz, 1H), 4.52 (dd, J = 6.1, 11.3 Hz, 1H), 5.50
(q, J = 7.1 Hz, 1H), 7.20–7.65 (m, 8ArH), 7.89–8.18
(m, 2ArH); 13C NMR (50 MHz, CDCl3): d ꢀ5.4,
ꢀ4.5, 16.1, 18.3, 25.7, 37.5, 42.0, 49.0, 52.3, 72.1,
126.9, 127.5, 128.3, 128.4, 129.5, 129.9, 130.1, 133.0,
133.4, 139.4, 166.2, 172.0; [a]D = ꢀ77.8 (c 0.6, CHCl3);
MS: m/z 396 (21, M+ꢀ57), 292 (10), 179 (17), 105
(100), 77 (19), 57 (12), 43 (15). Anal. Calcd for
C26H35NO4Si: C, 68.84; H, 7.78; N, 3.09. Found: C,
68.78; H, 7.74; N, 3.06.
4.16. (3S,4S,10S)-3-t-Butoxycarbonylamino-4-tetrahy-
dropyranyloxymethyl-1-(10-phenylethyl)pyrrolidin-2-one
26
Starting from 25 (1.0 g, 3.0 mmol), the title compound
(0.92 g, 73%) was prepared as a colourless oil as de-
scribed for 17: IR (CHCl3) m 3344, 1721, 1668 cmꢀ1; H
1
NMR (200 MHz, CDCl3): d 1.28–1.55 (m, 6H), 1.38 (s,
9H, 50%), 1.40 (s, 9H, 50%), 1.48 (d, J = 7.2 Hz, 3H),
2.75–2.90 (m, 1H), 3.00 (dd, J = 8.3, 9.6 Hz, 1H) 3.12–
3.48 (m, 4H), 3.09–3.44 (m, 4H), 3.49–3.66 (m, 1H),
3.87 (m, 1H, 50%), 4.34 (m, 1H, 50%), 4.55 (dd,
J = 6.4, 7.2 Hz, 1H), 5.39 (d, J = 6.4 Hz, 1H, NH), 5.44

1786
R. Galeazzi et al. / Tetrahedron: Asymmetry 16 (2005) 1779–1787
4.20. (3S,4R,10S)-4-Benzoyloxymethyl-3-hydroxy-1-(10-
phenylethyl)pyrrolidin-2-one 30
(s, 9H), 1.51 (d, J = 7.1 Hz, 3H), 2.41–2.60 (m, 1H),
3.08 (dd, J = 9.7, 12.3 Hz, 1H), 3.12 (dd, J = 9.2,
12.3 Hz, 1H), 4.32 (d, J = 8.4 Hz, 1H), 4.8 (dd, J = 6.3,
11.4 Hz, 1H), 4.50 (dd, J = 4.2, 11.4 Hz, 1H), 5.49 (q,
J = 7.1 Hz, 1H), 7.28–7.72 (m, 8ArH), 7.95–8.21 (m,
2ArH); 13C NMR (50 MHz, CDCl3): d ꢀ5.1, ꢀ4.1,
16.1, 18.2, 25.7, 26.9, 41.3, 42.0, 49.2, 63.5, 73.0, 127.0,
127.6, 128.4, 128.5, 128.6, 129.5, 129.6, 130.1, 133.2,
139.5, 166.3, 172.0; [a]D = ꢀ230.7 (c 1.3, CHCl3); MS:
m/z 396 (21, M+ꢀ57), 292 (10), 179 (17), 105 (100), 77
(19), 57 (12), 43 (15). Anal. Calcd for C26H35NO4Si:
C, 68.84; H, 7.78; N, 3.09. Found: C, 68.79; H, 7.72;
N, 3.13.
Starting from 29 (1.36 g, 3.0 mmol), the title compound
(0.85 g, 84%) was prepared as a colourless oil as de-
scribed for 12: IR (CHCl3) m 3344, 1721, 1665 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 1.54 (d, J = 7.1 Hz,
3H), 2.85–3.04 (m, 2H + OH), 3.38 (dd, J = 6.7,
10.5 Hz, 1H), 4.05 (dd, J = 8.5, 11.5 Hz, 1H), 4.55 (d,
J = 7.7 Hz, 1H), 4.56 (dd, J = 4.8, 11.5 Hz, 1H), 5.47
(q, J = 7.1 Hz, 1H), 7.15–7.61 (m, 8ArH), 7.81–7.91
(m, 2ArH); 13C NMR (50 MHz, CDCl3): d 15.9, 36.2,
42.0, 49.5, 62.0, 72.8, 126.1, 127.6, 128.1, 128.4, 129.4,
129.8, 132.7, 138.7, 166.0, 173.6; [a]D = ꢀ112.3 (c 3.5,
CHCl3); MS: m/z 219 (3, MH+ꢀ121), 188 (11), 149
(6), 105 (32), 91 (24), 69 (25), 43 (67), 40 (100). Anal.
Calcd for C20H21NO4: C, 70.68; H, 6.24; N, 4.13.
Found: C, 70.63; H, 6.20; N, 4.09.
4.24. (3S,4S,10S)-4-Benzoyloxymethyl-3-hydroxy-1(10-
phenylethyl)pyrrolidin-2-one 34
Starting from 33 (1.36 g, 3.0 mmol), the title compound
(0.77 g, 76%) was prepared as a colourless oil as de-
4.21. (3S,4R,10S)-4-Benzoyloxymethyl-3-methanesulfon-
scribed for 12: IR (CHCl3) m 3347, 1724, 1670 cmꢀ1
;
yloxy-1-(10-phenylethyl)pyrrolidin-2-one 31
1H NMR (200 MHz, CDCl3): d 1.54 (d, J = 7.2 Hz,
3H), 2.49–2.71 (m, 1H), 2.98 (br s, 1H, OH), 3.12–3.24
(m, 2H), 4.44 (d, J = 9.2 Hz, 1H), 4.47 (dd, J = 6.3,
11.6 Hz, 1H), 4.57 (dd, J = 4.7, 11.6 Hz, 1H), 5.51 (q,
J = 7.2 Hz, 1H), 7.27–7.65 (m, 8ArH), 7.95–8.17 (m,
2ArH); 13C NMR (50 MHz, CDCl3): d 16.1, 41.1,
42.0, 49.7, 63.8, 72.0, 127.0, 127.9, 128.3, 128.7, 128.8,
129.6, 130.1, 133.2, 133.3, 138.9, 166.3, 174.0;
[a]D = ꢀ181.7 (c 1.2, CHCl3); MS: m/z 219 (3,
MH+ꢀ121), 188 (11), 149 (6), 105 (32), 91 (24), 69
(25), 43 (67), 40 (100). Anal. Calcd for C20H21NO4: C,
70.78; H, 6.24; N, 4.13. Found: C, 70.73; H, 6.19; N,
4.08.
Starting from 30 (1.2 g, 3.6 mmol), the title compound
(1.4 g, 95%) was prepared as a colourless oil as described
for 13: 1H NMR (200 MHz, CDCl3): d 1.57 (d,
J = 7.1 Hz, 3H), 2.95–3.15 (m, 2H), 3.32 (s, 3H), 3.46
(dd, J = 6.7, 10.5 Hz, 1H), 4.24 (dd, J = 7.1, 11.4 Hz,
1H), 4.45 (dd, J = 5.6, 11.4 Hz, 1H), 5.39 (d,
J = 7.6 Hz, 1H), 5.47 (q, J = 7.1 Hz, 1H), 7.18–7.29
(m, 5ArH), 7.38–7.49 (m, 2ArH), 7.51–7.63 (m, 1ArH),
7.89–7.95 (m, 2ArH).
4.22. (3R,4S,10S)-3-Azido-4-benzoyloxymethyl-1-(10-
phenylethyl)pyrrolidin-2-one 32
4.25. (3S,4S,10S)-4-Benzoyloxymethyl-3-methanesulfon-
yloxy-1-(10-phenylethyl)pyrrolidin-2-one 35
Starting from 31 (0.84 g, 2.0 mmol), the title compound
(0.53 g, 73%) was prepared as a colourless oil as de-
scribed for 14. (Caution!: Although these experiments
have proceeded without incident, extreme caution
should be exercised in the handling of organic azides,
particularly with manipulations that involve heating of
neat liquids or solid residues): IR (CHCl3) m 2109,
Starting from 34 (1.2 g, 3.6 mmol), the title compound
(1.35 g, 90%) was prepared as a colourless oil as de-
1
scribed for 13: H NMR (200 MHz, CDCl3): d 1.53 (d,
J = 7.2 Hz, 3H), 2.71–2.90 (m, 1H), 3.16 (dd, J = 7.9,
10.0 Hz, 1H), 3.23 (dd, J = 8.8, 10.0 Hz, 1H), 3.37 (s,
3H), 4.48 (dd, J = 5.6, 11.8 Hz, 1H), 4.54 (dd, J = 5.1,
11.8 Hz, 1H), 5.27 (d, J = 8.2 Hz, 1H), 5.47 (q,
J = 7.2 Hz, 1H), 7.24 (m, 8ArH), 7.96–8.07 (m, 2ArH).
1
1724, 1665 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.59
(d, J = 7.3 Hz, 3H), 2.47–2.65 (m, 1H), 2.81 (dd,
J = 7.8, 9.9 Hz, 1H), 3.48 (dd, J = 8.5, 9.9 Hz, 1H),
4.11 (d, J = 8.4 Hz, 1H), 4.35 (d, J = 5.5 Hz, 2H), 5.52
(q, J = 7.3 Hz, 1H), 7.23–7.54 (m, 5ArH), 7.38–7.51
(m, 2ArH), 7.53–7.64 (m, 1ArH), 7.87–7.95 (m, 2ArH);
13C NMR (50 MHz, CDCl3): d 18.9, 38.2, 42.0, 50.0,
61.8, 63.4, 126.9, 127.8, 128.4, 128.6, 129.3, 129.5,
133.2, 139.0, 165.9, 169.4; [a]D = ꢀ39.4 (c 2.0, CHCl3);
MS: m/z 365 (3, MH+), 322 (6), 214 (26), 146 (10), 105
(100), 77 (67), 51 (23). Anal. Calcd for C20H20N4O3:
C, 65.92; H, 5.53; N, 15.37. Found: C, 65.87; H, 5.48;
N, 15.32.
4.26. (3R,4R,10S)-3-Azido-4-benzoyloxymethyl-1-
(10-phenylethyl)pyrrolidin-2-one 36
Starting from 35 (0.84 g, 2.0 mmol), the title compound
(0.52 g, 72%) was prepared as a colourless oil as de-
scribed for 23. (Caution!: Although these experiments
have proceeded without incident, extreme caution
should be exercised in the handling of organic azides,
particularly with manipulations that involve heating of
neat liquids or solid residues): IR (CHCl3) m 2108,
1
4.23. (3S,4S,10S)-4-Benzoyloxymethyl-3-t-butyldimethyl-
1723, 1668 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.52
silyloxy-1(10-phenylethyl)pyrrolidin-2-one 33
(d, J = 7.1 Hz, 3H), 2.71–2.89 (m, 1H), 3.10 (dd,
J = 7.1, 10.1 Hz, 1H), 3.25 (dd, J = 5.1, 10.1 Hz, 1H),
4.32 (d, J = 8.1 Hz, 1H), 4.33 (dd, J = 6.8, 11.4 Hz,
1H), 4.53 (dd, J = 5.8, 11.4 Hz, 1H), 5.50 (q,
J = 7.1 Hz, 1H), 7.23–7.63 (m, 8ArH), 7.96–8.05 (m,
2ArH); 13C NMR (50 MHz, CDCl3): d 15.7, 34.8,
Starting from 3 (2.3 g, 6.0 mmol), the title compound
(2.0 g, 75%) was prepared as a colourless oil as described
for 20: IR (CHCl3) m 1724, 1668 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 0.17 (s, 3H), 0.24 (s, 3H), 0.94

R. Galeazzi et al. / Tetrahedron: Asymmetry 16 (2005) 1779–1787
1787
W.; Pritchard, D. I. Infect. Immun. 1998, 66, 36–42; (b)
Lawrence, R. N.; Dunn, W. R.; Bycroft, B. W.; Camara,
M.; Chhabra, S. R.; Williams, P.; Wilson, V. G. Br. J.
Pharmacol. 1999, 128, 845–848; (c) Chhabra, S. R.; Harty,
C.; Hooi, D. S. W.; Daykin, M.; Williams, P.; Telford, G.;
Pritchard, D. I.; Bycroft, B. W. J. Med. Chem. 2003, 46,
97–104.
42.9, 49.6, 61.0, 62.5, 126.8, 127.7, 128.3, 128.6, 129.5,
133.1, 139.1, 166.1, 169.1; [a]D = ꢀ21.7 (c 0.75, CHCl3);
MS: m/z 365 (3, MH+), 322 (6), 214 (26), 146 (10), 105
(100), 77 (67), 51 (23). Anal. Calcd for C20H20N4O3:
C, 65.92; H, 5.53; N, 15.37. Found: C, 65.85; H, 5.48;
N, 15.41.
8. (a) Olsen, J. A.; Severinsen, R.; Rasmussen, T. B.;
Hentzer, M.; Givskov, M.; Nielsen, J. Bioorg. Med. Chem.
Lett. 2002, 12, 325–328; (b) Reverchon, S.; Chantegrel, B.;
Deshayes, C.; Doutheau, A.; Cotte-Pattat, N. Bioorg.
Med. Chem. Lett. 2002, 12, 1153–1157; (c) Castang, S.;
Chantegrel, B.; Christian, D.; Dolmazon, R.; Gouet, P.;
Haser, R.; Reverchon, S.; Nasser, W.; Hugouvieux-Cotte-
Pattat, N.; Doutheau, A. Bioorg. Med. Chem. Lett. 2004,
14, 5145–5149.
Acknowledgements
This research was supported by MIUR (Rome, Italy,
`
PRIN 2004) and Universita Politecnica delle Marche
(Italy).
References
9. Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.;
Mathre, D. J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58,
5886–5888.
1. (a) Wilken, J.; Kent, S. B. H. Curr. Opin. Biotechnol. 1998,
9, 412–426; (b) Cotton, G. J.; Muir, T. W. Chem. Biol.
1999, 6, 247–256; (c) Hamachi, I.; Eboshi, R.; Watanabe,
J.; Shinkai, S. J. Am. Chem. Soc. 2000, 122, 4530–4531; (d)
Park, K.-H.; Kurth, M. J. Tetrahedron 2002, 58, 8629–
8659; (e) Suat, K. K.; Jois, S. D. S. Curr. Pharm. Des.
2003, 9, 1209–1224; (f) Kotha, S. Acc. Chem. Res. 2003,
36, 342–351.
2. (a) Marshall, G. R. Tetrahedron 1993, 49, 3547–3558; (b)
Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bos, M.; Cook,
C. M.; Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.;
Kahn, M.; Madison, V. S.; Rusiecki, V. K.; Sarabu, R.;
Sepinwall, J.; Vincent, G. P.; Voss, M. E. J. Med. Chem.
1993, 36, 3039–3049; (c) Adang, A. E. P.; Hermkens, P. H.
H.; Linders, J. T. M.; Ottenheijm, H. C. J.; van Staveren,
C. J. Rec. Trav. Chim. Pays Bas 1994, 113, 63–78; (d)
Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699–
1720; (e) Synthesis of Peptides and Peptidomimetics. In
Houben-Weyl, Methods in Organic Chemistry; Goodman,
M., Felix, A., Moroder, L., Toniolo, C., Eds.; Thieme:
Stuttgart, New York, 2003; Vol. E22c.
3. (a) Cardillo, B.; Galeazzi, R.; Mobbili, G.; Orena, M.
Synlett 1995, 1159–1160; (b) Galeazzi, R.; Mobbili, G.;
Orena, M. Tetrahedron 1996, 52, 1069–1084; (c) Galeazzi,
R.; Geremia, S.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1996, 7, 79–88; (d) Galeazzi, R.; Geremia, S.;
Mobbili, G.; Orena, M. Tetrahedron: Asymmetry 1996, 7,
3573–3584; (e) Galeazzi, R.; Mobbili, G.; Orena, M.
Tetrahedron: Asymmetry 1997, 8, 133–137; (f) Galeazzi,
R.; Mobbili, G.; Orena, M. Tetrahedron 1999, 55, 261–
270; (g) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron
1999, 55, 4029–4042; (h) Fava, C.; Galeazzi, R.; Mobbili,
G.; Orena, M. Tetrahedron: Asymmetry 2003, 14, 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.
4. Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.;
Rinaldi, S. Tetrahedron: Asymmetry 2004, 15, 3249–3256.
10. (a) Mandal, S. B.; Achari, B.; Chattopadhyay, S. Tetra-
hedron Lett. 1992, 33, 1647–1650; (b) Tsuboi, S.; Furutani,
H.; Ansari, M. H.; Sakai, T.; Utaka, M.; Takeda, A. J.
Org. Chem. 1993, 58, 486–492; (c) Bonini, B. F.; Carboni,
P.; Gottarelli, G.; Masiero, S.; Spada, G. P. J. Org. Chem.
1994, 59, 5930–5936; (d) Boger, D. L.; Honda, T.;
Menezes, R. F.; Colletti, S. L.; Dang, Q.; Yang, W. J.
Am. Chem. Soc. 1994, 116, 82–92.
11. For similar compounds, see: (a) Kametani, T.; Kigawa,
Y.; Ihara, M. Tetrahedron 1979, 35, 313–316; (b) Ma, D.;
Jiang, J. Tetrahedron: Asymmetry 1998, 9, 575–579; (c)
Alcaide, B.; Almendros, P.; Alonso, J. M. J. Org. Chem.
2004, 69, 993–996.
12. (a) Molecular mechanics calculations were carried out on
22 both using the implementation of an Amber all-atom
force field (AMBER*) and MM2* within the framework
of MACROMODEL version 5.5, both in vacuo and using the
implicit chloroform GB/SA solvation model and the
torsional space was randomly varied with the usage-
directed Monte Carlo conformational search. Six confor-
mations were found to lie between 0.0 and 0.46 kcal/mol:
Conformation 1: En = 0.0, torsion angle (H-3)–(C-3)–
(C-4)–(H-4) = ꢀ165.3ꢁ; Conformation 2: En = 0.1, torsion
angle (H-3)–(C-3)–(C-4)–(H-4) = ꢀ162.9ꢁ; Conformation
3: En = 0.13, torsion angle (H-3)–(C-3)–(C-4)–(H-
4) = ꢀ165.9ꢁ; Conformation 4: En = 0.21, torsion angle
(H-3)–(C-3)–(C-4)–(H-4) = ꢀ163.4ꢁ; Conformation 5:
En = 0.41, torsion angle (H-3)–(C-3)–(C-4)–(H-4) =
ꢀ163.4ꢁ; Conformation 6: En = 0.46, torsion angle (H-
3)–(C-3)–(C-4)–(H-4) = ꢀ164.1ꢁ. In the lowest energy
conformation the torsion angle (H-3)–(C-3)–(C-4)–(H-4)
was ꢀ165.3ꢁ, in agreement with the observed J3,4 value, so
that in 22 additional and specific interactions must occur
between the substituents altering the geometry. On the
other hand, it is worth noting that for all the other
pyrrolidin-2-ones, the calculated torsion angles were in
agreement with the observed J3,4 values. For references,
see: Weiner, S. J.; Kollman, P. A.; Nguyen, D. T.; Case, D.
A. J. Comput. Chem. 1986, 4, 230–252; (b) Allinger, N. L.
J. Am. Chem. Soc. 1977, 99, 8127–8134; (c) Mahamadi, F.;
Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton,
M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C.
J. Comput. Chem. 1990, 11, 440–452; (d) Still, W. C.;
Tempczyk, A.; Hawley, R.; Hendrickson, C. T. J. Am.
Chem. Soc. 1990, 112, 6127–6129; (e) Chang, G.; Guida,
W. C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379–
4386; (f) Goodman, J. M.; Still, W. C. J. Comput. Chem.
1991, 12, 1110–1116.
´
5. (a) Avenoza, A.; Cativiela, C.; Fernandez-Recio, M. A.;
Peregrina, J. M. Tetrahedron: Asymmetry 1996, 7, 721–
728; (b) Hammer, K.; Rømming, C.; Undheim, K.
Tetrahedron 1998, 54, 10837–10850; (c) Hammer, K.;
Undheim, K. Tetrahedron: Asymmetry 1998, 9, 2359–
2368; (d) Krikstolaityte, S.; Sackus, A.; Rømming, C.;
Undheim, K. Tetrahedron: Asymmetry 2001, 12, 393–398.
6. (a) Barclay, F.; Chrystal, E.; Gani, D. J. Chem. Soc.,
Chem. Commun. 1994, 815–816; (b) Barclay, F.; Chrystal,
E.; Gani, D. J. Chem. Soc., Perkin Trans. 1 1996, 683–690.
7. (a) Telford, G.; Wheeler, D.; Williams, P.; Tomkins, P. T.;
Appleby, P.; Sewell, H.; Stewart, G. S. A. B.; Bycroft, B.
13. Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783–2792.