Direct synthesis of protected enantiopure 5-cyano-3,4-dihydroxypyrrolidin- 2-ones from β-lactam aldehydes catalyzed by iodine

Article abstract of DOI:10.1055/s-2008-1067224

A single-step catalytic ring-expansion approach from 4-oxoazetidine-2- carbaldehydes to protected enantiopure 5-cyano-3,4-dihydroxypyrrolidin-2-ones has been achieved by the use of the commercially available and inexpensive reagent, molecular iodine, in the presence of tert-butyldimethyl cyanide. Interestingly, the catalyst directs the reaction toward the selective rearrangement reaction of the β-lactam nucleus rather than cyanohydrin formation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067224

PRACTICAL SYNTHETIC PROCEDURES
2835
Direct Synthesis of Protected Enantiopure 5-Cyano-3,4-dihydroxypyrrolidin-
2-ones from b-Lactam Aldehydes Catalyzed by Iodine
5
-Cyanopyrrolidi
e
n-2-ones nito Alcaide,*a Pedro Almendros,*b Gema Cabrero,a M. Pilar Ruiza
a
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3944103; E-mail: alcaideb@quim.ucm.es
Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Fax +34(91)5644853; E-mail: Palmendros@iqog.csic.es
PSP
b
Received 11 June 2008; revised 3 July 2008
Dedicated to Prof. Dr. Carmen Pardo on the occasion of her 65th birthday and retirement
No130
Abstract: A single-step catalytic ring-expansion approach from 4-oxoazetidine-2-carbaldehydes to protected enantiopure 5-cyano-3,4-di-
hydroxypyrrolidin-2-ones has been achieved by the use of the commercially available and inexpensive reagent, molecular iodine, in the
presence of tert-butyldimethyl cyanide. Interestingly, the catalyst directs the reaction toward the selective rearrangement reaction of the b-
lactam nucleus rather than cyanohydrin formation.
Key words: catalysis, iodine, b-lactams, pyrrolidines, ring expansion
MeO
O
OTBS
CN
MeO
O
O
I2 (10 mol%)
MeCN, r.t.
+
TBSCN
N
N
PMP
PMP
2a
1a
Scheme 1 Preparation of 5-cyanopyrrolidin-2-one 2a
Strecker reaction.7 We have recently described the cy-
anosilylation of 4-oxoazetidine-2-carbaldehydes 1 togeth-
Introduction
Iminosugars based on polyhydroxylated pyrrolidines have er with the manipulation of the corresponding b-lactam
attracted a great deal of attention due to the range of their cyanohydrins.8 On the basis of these principles, we decid-
biological activities, particularly exhibiting action as in- ed to test the mild Lewis acid nature of iodine for the
hibitors of the enzymes a-galactosidase, a-glucosidase, cyanosilylation of b-lactam aldehydes; however, we ob-
and glycosidase.1 Besides, the pyroglutamic acid core has tained instead protected enantiopure 5-cyano-3,4-dihy-
considerable chemical and medicinal importance as it is droxypyrrolidin-2-ones 2 (Scheme 1), which can be
involved in a wide range of relevant processes.2
regarded as hybrids of the pharmacologically relevant
subunits of iminosugar and pyroglutamic acid. Some re-
sults of this novel and practical methodology involving a
novel C3–C4 bond cleavage of the b-lactam nucleus by
using molecular iodine are presented herein.
On the other hand, in addition to the key role that b-lac-
tams have played in medicinal chemistry,3 the use of 2-
azetidinones as chiral building blocks for the synthesis of
a- and b-amino acids, alkaloids, heterocycles, taxoids,
and other types of compounds of biological and medicinal
interest is now well established.4 Although many efforts
have been made in these fields, the direct preparation of
the pyrrolidone core from b-lactam aldehydes was un-
known until we merged into this field.5
Scope and Limitations
Among the various solvents and conditions tested, it was
found that acetonitrile at room temperature gave the best
yields of pyrrolidinone-based products. Protected 5-cy-
ano-3,4-dihydroxy-pyrrolidin-2-ones 2 were efficiently
obtained under the optimized conditions: 10 mol% iodine,
acetonitrile, 0.3 M solution of b-lactam aldehyde 1, (1.5–
5:1) aldehyde/TBSCN ratio, room temperature (Table 1).
Lower catalyst loading slowed the reaction considerably.
This transformation tolerates different substituents and
functionalities at the 2-azetidinone nitrogen atom, such as
aryl (p-anisyl, p-tolyl, p-chlorophenyl), benzyl, allyl, pro-
pargyl and methoxycarbonylmethyl moieties. Besides,
Iodine-mediated reactions have captured much attention
recently because of the low cost, ready availability, envi-
ronmentally benign character, and high tolerance to air
and moisture of molecular iodine.6 Molecular iodine has
been identified as a mild catalyst to promote the addition
of trimethylsilyl cyanide to ketones as well as for the
SYNTHESIS 2008, No. 17, pp 2835–2839
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.08.2008
DOI: 10.1055/s-2008-1067224; Art ID: Z13708SS
© Georg Thieme Verlag Stuttgart · New York

2836
B. Alcaide et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 I2-Catalyzed Enantioselective Ring Expansion of b-Lac-
tams to g-Lactamsa (continued)
full chirality transfer of the C3 stereogenic centre was ob-
served. Furthermore, at the expense of loss of some dias-
tereoselectivity, sterically encumbered 4-oxoazetidine-2-
carbaldehydes 1i and 1j were also efficiently converted to
the pyrrolidinone derivatives 2i and 2j upon iodide catal-
ysis and TBSCN treatment.
Substrate
Product
Time (h) Yield (%)b
OMe
N
OTBS
CN
OMe
O
1
1
50j
N
O
Table 1 I2-Catalyzed Enantioselective Ring Expansion of b-Lac-
tams to g-Lactamsa
O
PMP
PMP
1i
2i
Substrate
Product
Time (h) Yield (%)b
O
O
OTBS
O
MeO
OTBS
CN
MeO
57k
O
N
CN
O
N
1.5
1.5
1.5
3
89
N
N
N
O
O
PMP
N
PMP
O
PMP
1j
PMP
2j
1a
2a
MeO
a PMP = 4-MeOC6H4; PMB = 4-MeOC6H4CH2.
OTBS
b Yield of pure, isolated product with correct analytical and spectral
data.
MeO
O
72c
63d
54e
54f
c In addition, a further 8% yield of the C5 anti-epimer was obtained.
d In addition, a further 7% yield of the C5 anti-epimer was obtained.
e In addition, a further 15% yield of a syn/anti mixture (73:27) of O-
silylated b-lactam cyanohydrin was obtained. TBSCN used: 2 equiv.
f In addition, a further 8% yield of the C5 anti-epimer was obtained.
TBSCN used: 2.5 equiv.
CN
O
N
O
PMB
PMB
1b
2b
MeO
OTBS
CN
MeO
O
O
g In addition, a further 9% yield of the C5 anti-epimer was obtained.
TBSCN used: 2.5 equiv.
N
O
Bn
Bn
h In addition, a further 7% yield of the C5 anti-epimer was obtained.
TBSCN used: 4 equiv.
1c
2c
BnO
OTBS
CN
i In addition, a further 13% yield of the C5 anti-epimer was obtained.
TBSCN used: 5 equiv.
BnO
O
j In addition, a further 17% yield of the C5 anti-epimer was obtained.
TBSCN used: 5 equiv.
N
O
N
O
PMP
PMP
k In addition, a further 18% yield of the C5 anti-epimer was obtained.
TBSCN used: 5 equiv.
1d
2d
BnO
OTBS
BnO
O
2.5
It was desirable to scale the procedure up to obtain gram
quantities of pyrrolidinone derivatives. Nicely, it quickly
became clear that scale-up was even convenient. Thus, an
improved 89% yield of adduct 2a was obtained when the
reaction was carried out on gram scale in comparison with
a 78% yield on milligram scale.
N
CN
O
N
O
PMB
PMB
1e
2e
MeO
OTBS
CN
MeO
O
1.5
56g
O
N
N
N
O
The limitations of the method arise from the fact that the
ring-expansion reaction is not compatible with C3 substit-
uents at the b-lactam ring different from alkoxy groups
(aldehydes 1k and 1l, see Scheme 2). When a three-fold
excess of TBSCN was used, the starting aldehyde was re-
covered as the main component together with small
amounts of the O-silylated cyanohydrin 3a. Besides, no
reaction was produced under standard reaction conditions
starting from the epimeric trans-b-lactam aldehyde epi-1a
(cis-b-lactam aldehyde 1a epimerized at C3). From all
these results it can be concluded that a cis-alkoxy group at
the C3 position of the 2-azetidinone ring is required for
the ring expansion.
1f
2f
MeO
OTBS
CN
MeO
O
1
50h
O
N
O
1g
2g
MeO
OTBS
MeO
O
1.5
46i
CN
O
N
N
O
CO2Me
CO2Me
1h
2h
We hope that the basic research work presented herein
will be of interest to synthetic chemists, and that it can be
applied to the chemical and pharmaceutical industry in the
near future.
Synthesis 2008, No. 17, 2835–2839 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
5-Cyanopyrrolidin-2-ones
2837
H), 5.07 (d, J = 14.7 Hz, 1 H), 6.90 (AA¢XX¢, 2 H), 7.20 (AA¢XX¢, 2
OTBS
CN
TBSCN
H
H
N
H).
R
R
O
O
I2 (10 mol%)
unreacted
13C NMR (50 MHz, CDCl3): d = –5.2, –4.9, 17.8, 25.5, 44.8, 50.7,
55.3, 59.5, 71.6, 82.7, 114.5, 125.7, 130.0, 159.7, 170.0.
MS (EI): m/z (%) = 390 (M+, 1), 333 (M – 57, 46), 131 (1), 121
(100).
+
aldehyde 1
N
MeCN, r.t.
6 h
O
PMP
PMP
1k R = i-Pr
1l R = Ph
1k (94%)
3a R = i-Pr (6%)
3b R = Ph (0%)
1l (100%)
Anal. Calcd for C20H30N2O4Si: C, 61.51; H, 7.74; N, 7.17. Found:
C, 61.63; H, 7.82; N, 7.21.
TBSCN
MeO
O
anti-2b
I2 (10 mol%)
[a]D20 –9.1 (c 1.2, CHCl3).
X
N
MeCN, r.t.
24 h
IR (CHCl3): 1721 cm–1.
O
PMP
1H NMR (300 MHz, CDCl3): d = 0.13 (s, 3 H), 0.15 (s, 3 H), 0.87
(s, 9 H), 3.68 (s, 3 H), 3.73 (d, J = 5.5 Hz, 1 H), 3.77 (d, J = 5.4 Hz,
1 H), 3.81 (s, 3 H), 3.91 (d, J = 14.8 Hz, 1 H), 4.43 (t, J = 5.4 Hz, 1
H), 5.19 (d, J = 14.8 Hz, 1 H), 6.89 (AA¢XX¢, 2 H), 7.22 (AA¢XX¢,
2 H).
epi-1a
Scheme 2 b-Lactam aldehydes bearing C3-alkyl, C3-aryl, and
trans-alkoxy substituents cannot be used in the ring expansion reac-
tion.
13C NMR (50 MHz, CDCl3): d = –5.0, –4.9, 17.8, 25.4, 44.5, 52.1,
1H NMR and 13C NMR spectra were obtained from spectrometers
operating at 200 MHz, 300 MHz, or 500 MHz for proton nucleus in
CDCl3 solutions, except otherwise stated. 1H chemical shifts are re-
55.3, 59.2, 75.1, 83.2, 114.5, 115.5, 126.1, 130.0, 159.7, 169.6.
MS (EI): m/z (%) = 390 (M+, 1), 333 (M–57, 47), 131 (5), 121
(100).
ported in ppm relative to TMS (0.0 ppm) as an internal standard. 13
C
Anal. Calcd for C20H30N2O4Si: C, 61.51; H, 7.74; N, 7.17. Found:
C, 61.43; H, 7.93; N, 7.02.
chemical shifts are reported relative to the central peak of CDCl3
(77.0 ppm). Low- and high-resolution mass spectra were taken on a
HP5989A spectrometer using the electronic impact (EI) or electro-
spray modes (ES) unless otherwise stated. Specific rotation [a]D is
given in 10–1 deg cm2 g–1 at 20 °C, and the concentration is ex-
pressed in g per 100 mL. All commercially available compounds
were used without further purification.
2c
[a]D20 +70.2 (c 0.5, CHCl3).
IR (CHCl3): 1721 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.10 (s, 3 H), 0.14 (s, 3 H), 0.92
(s, 9 H), 3.72 (s, 3 H), 3.98 (d, J = 7.0 Hz, 1 H), 3.99 (d, J = 14.6 Hz,
1 H), 4.15 (d, J = 7.3 Hz, 1 H), 4.23 (t, J = 7.1 Hz, 1 H), 5.14 (d,
J = 15.0 Hz, 1 H), 7.39–7.26 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = –5.1, –4.9, 17.9, 25.5, 45.4, 51.0,
59.5, 71.6, 82.6, 114.3, 128.5, 128.5, 129.1, 133.8, 170.1.
Rearrangement Reaction of 4-Oxoazetidine-2-carbaldehyde 1a;
Protected 5-Cyano-3,4-dihydroxypyrrolidin-2-one 2a; Typical
Procedure
A solution of TBSCN (902 mg, 6.38 mmol) in MeCN (14.3 mL)
was added dropwise to a stirred solution of the 4-oxoazetidine-2-
carbaldehyde 1a (1 g, 4.26 mmol) and molecular I2 (108 mg, 0.426
mmol) in MeCN (14.3 mL) at r.t. under argon. The mixture was
stirred for 1.5 h. Then, brine (40 mL) was added and the resulting
mixture was extracted with CH2Cl2 (5 × 80 mL). The combined or-
ganic layers were dried and the solvent was removed under reduced
pressure. Chromatography of the residue eluting with hexanes–
EtOAc (5:1) gave 1.42 g (89%) of analytically pure 2a as a colorless
oil; [a]D20 +44.9 (c 0.7, CHCl3).
MS (EI): m/z (%) = 345 (M+ – 15, 3), 303 (M – 57, 100), 275 (M –
57 – 28, 18), 131 (10), 91 (58).
Anal. Calcd for C19H28N2O3Si: C, 63.30; H, 7.83; N, 7.77. Found:
C, 63.35; H, 7.69; N, 7.58.
anti-2c
[a]D20 –1.8 (c 1.1, CHCl3).
IR (CHCl3): 1721 cm–1.
IR (CHCl3): 1727 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.13 (s, 3 H), 0.15 (s, 3H), 0.87 (s,
9 H), 3.69 (s, 3 H), 3.76 (d, J = 5.5 Hz, 1 H), 3.80 (d, J = 5.2 Hz, 1
H), 3.97 (d, J = 15.0 Hz, 1 H), 4.44 (t, J = 5.4 Hz, 1 H), 5.25 (d,
J = 15.0 Hz, 1 H), 7.38–7.27 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = –5.0, –4.9, 17.8, 25.4, 45.0, 52.3,
59.2, 75.1, 83.1, 115.4, 128.4, 128.5, 129.1, 134.1, 169.7.
1H NMR (300 MHz, CDCl3): d = 0.19 (s, 3 H), 0.20 (s, 3 H), 0.97
(s, 9 H), 3.75 (s, 3 H), 3.81 (s, 3 H), 4.11 (d, J = 7.9 Hz, 1 H), 4.47
(t, J = 7.6 Hz, 1 H), 4.68 (d, J = 7.3 Hz, 1 H), 6.94 (AA¢XX¢, 2 H),
7.43 (AA¢XX¢, 2 H).
13C NMR (50 MHz, CDCl3): d = –5.1, –4.8, 17.9, 25.5, 53.8, 55.5,
59.7, 71.9, 82.6, 114.6, 115.1, 124.1, 129.3, 158.4, 169.3.
MS (EI): m/z (%) = 345 (M+ – 15, 4), 303 (M – 57, 100), 275 (M –
57 – 28, 19), 131 (44), 91 (89).
MS (EI): m/z (%) = 376 (M+, 15), 319 (M – 57, 100), 291 (M – 57
– 28, 98).
Anal. Calcd for C19H28N2O3Si: C, 63.30; H, 7.83; N, 7.77. Found:
C, 63.21; H, 7.93; N, 7.92.
Anal. Calcd for C19H28N2O4Si: C, 60.61; H, 7.50; N, 7.44. Found:
C, 60.51; H, 7.42; N, 7.54.
2d
2b
[a]D20 +62.9 (c 1.2, CHCl3).
[a]D20 +58.5 (c 0.9, CHCl3).
IR (CHCl3): 1727 cm–1.
IR (CHCl3): 1719 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.18 (s, 6 H), 0.97 (s, 9 H), 3.83
(s, 3 H), 4.34 (d, J = 7.6 Hz, 1 H), 4.55 (t, J = 7.3 Hz, 1 H), 4.70 (d,
J = 7.1 Hz, 1 H), 4.87 (d, J = 11.2 Hz, 1 H), 5.19 (d, J = 11.2 Hz, 1
H), 6.95 (AA¢XX¢, 2 H), 7.35–7.47 (m, 7 H).
1H NMR (300 MHz, CDCl3): d = 0.10 (s, 3 H), 0.13 (s, 3 H), 0.92
(s, 9 H), 3.71 (s, 3 H), 3.81 (s, 3 H), 3.92 (d, J = 15.0 Hz, 1 H), 3.97
(d, J = 7.0 Hz, 1 H), 4.12 (d, J = 7.4 Hz, 1 H), 4.20 (t, J = 7.1 Hz, 1
Synthesis 2008, No. 17, 2835–2839 © Thieme Stuttgart · New York

2838
B. Alcaide et al.
PRACTICAL SYNTHETIC PROCEDURES
13C NMR (50 MHz, CDCl3): d = –5.0, –4.7, 17.9, 25.5, 54.1, 55.5,
71.9, 73.2, 80.0, 114.7, 115.1, 124.2, 128.1, 128.3, 128.5, 129.3,
137.0, 158.5, 169.5.
J = 5.4 Hz, 1 H), 4.04 (d, J = 5.4 Hz, 1 H), 4.44 (t, J = 5.2 Hz, 1 H),
4.53 (ddt, J = 15.4, 4.6, 1.4 Hz, 1 H), 5.33 (d, J = 10.5 Hz, 1 H), 5.35
(d, J = 17.6 Hz, 1 H), 5.72 (dddd, J = 17.6, 9.9, 7.8, 4.6 Hz, 1 H).
MS (EI): m/z (%) = 452 (M+, 6), 395 (M – 57, 30), 346 (13), 289
(10), 250 (68), 149 (12), 91 (100).
13C NMR (50 MHz, CDCl3): d = –4.95, –4.90, 17.8, 25.5, 43.8,
52.7, 59.2, 75.3, 83.1, 115.5, 120.5, 130.1, 169.6.
Anal. Calcd for C25H32N2O4Si: C, 66.34; H, 7.13; N, 6.19. Found:
C, 66.47; H, 7.23; N, 6.35.
MS (EI): m/z (%) = 295 (M+ – 15, 4), 253 (M – 57, 100), 225 (M –
57 – 28, 53), 131 (61).
Anal. Calcd for C15H26N2O3Si: C, 58.03; H, 8.44; N, 9.02. Found:
C, 57.95; H, 8.57; N, 9.21.
2e
[a]D20 +90.4 (c 1.1, CHCl3).
IR (CHCl3): 1718 cm–1.
2g
[a]D20 +38.7 (c 0.9, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.08 (s, 3 H), 0.10 (s, 3 H), 0.91
(s, 9 H), 3.82 (s, 3 H), 3.94 (d, J = 14.6 Hz, 1 H), 4.15 (d, J = 7.1 Hz,
1 H), 4.17 (d, J = 6.3 Hz, 1 H), 4.28 (t, J = 6.7 Hz, 1 H), 4.82 (d,
J = 11.2 Hz, 1 H), 5.10 (d, J = 15.1 Hz, 1 H), 5.16 (d, J = 11.2 Hz,
1 H), 6.90 (AA¢XX¢, 2 H), 7.21 (AA¢XX¢, 2 H), 7.34–7.41 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = –5.1, –4.8, 17.9, 25.5, 44.8, 51.0,
55.3, 71.7, 73.0, 80.1, 114.3, 114.5, 125.7, 128.1, 128.3, 128.5,
130.0, 137.0, 159.7, 170.2.
IR (CHCl3): 1726 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.18 (s, 6 H), 0.96 (s, 9 H), 2.38
(t, J = 2.6 Hz, 1 H), 3.69 (s, 3 H), 3.83 (dd, J = 17.8, 2.4 Hz, 1 H),
3.95 (d, J = 7.3 Hz, 1 H), 4.36 (t, J = 7.4 Hz, 1 H), 4.62 (d, J = 7.3
Hz, 1 H), 4.63 (dd, J = 17.6, 2.4 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = –5.1, –4.9, 17.9, 25.5, 31.2, 50.7,
59.5, 71.9, 74.6, 75.2, 82.3, 114.2, 169.4.
MS (EI): m/z (%) = 409 (M – 57, 17), 360 (M – 106, 7), 303 (M –
57 – 106, 1), 121 (100), 91 (44).
MS (EI): m/z (%) = 293 (M+ – 15, 3), 251 (M – 57, 100), 223 (M –
57 – 28, 90), 131 (70).
Anal. Calcd for C26H34N2O4Si: C, 66.92; H, 7.34; N, 6.00. Found:
C, 66.99; H, 7.29; N, 5.97.
Anal. Calcd for C15H24N2O3Si: C, 58.41; H, 7.84; N, 9.08. Found:
C, 58.53; H, 8.01; N, 8.99.
anti-2e
anti-2g
[a]D20 +15.0 (c 0.6, CHCl3).
[a]D20 +14.4 (c 0.6, CHCl3).
IR (CHCl3): 1721 cm–1.
IR (CHCl3): 1722 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.09 (s, 3 H), 0.10 (s, 3 H), 0.84
(s, 9 H), 3.79 (d, J = 5.1 Hz, 1 H), 3.82 (s, 3 H), 3.93 (d, J = 4.2 Hz,
1 H), 3.95 (d, J = 5.4 Hz, 1 H), 4.49 (t, J = 5.1 Hz, 1 H), 4.80 (d,
J = 11.2 Hz, 1 H), 5.13 (d, J = 11.5 Hz, 1 H), 5.21 (d, J = 14.9 Hz,
1 H), 6.89 (AA¢XX¢, 2 H), 7.23 (AA¢XX¢, 2 H), 7.34–7.40 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = –5.0, –4.9, 17.7, 25.4, 44.5, 52.4,
55.3, 72.7, 75.2, 80.5, 114.5, 115.5, 126.1, 128.0, 128.3, 128.4,
129.9, 136.9, 159.7, 169.8.
1H NMR (200 MHz, CDCl3): d = 0.18 (s, 3 H), 0.21 (s, 3 H), 0.93
(s, 9 H), 2.36 (t, J = 2.6 Hz, 1 H), 3.66 (s, 3 H), 3.74 (dd, J = 17.8,
2.4 Hz, 1 H), 3.78 (d, J = 5.9 Hz, 1 H), 4.24 (d, J = 5.6 Hz, 1 H),
4.47 (t, J = 5.7 Hz, 1 H), 4.76 (dd, J = 17.7, 2.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = –4.92, –4.89, 17.8, 25.5, 30.8,
52.1, 59.3, 74.2, 75.3, 75.4, 83.0, 115.2, 169.2.
MS (EI): m/z (%) = 308 (M+, 1), 293 (M+ – 15, 22), 251 (M – 57,
100), 223 (M – 57 – 28, 48), 131 (58).
MS (EI): m/z (%) = 409 (M – 57, 3), 360 (M – 106, 11), 303 (M –
57 – 106, 3), 121 (100), 91 (67).
Anal. Calcd for C15H24N2O3Si: C, 58.41; H, 7.84; N, 9.08. Found:
C, 58.33; H, 7.96; N, 9.11.
Anal. Calcd for C26H34N2O4Si: C, 66.92; H, 7.34; N, 6.00. Found:
C, 66.83; H, 7.22; N, 6.16.
2h
[a]D20 +20.7 (c 0.6, CHCl3)
2f
IR (CHCl3): 1750, 1730 cm–1.
[a]D20 +77.2 (c 1.1, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.17 (s, 6 H), 0.95 (s, 9 H), 3.68
(s, 3 H), 3.73 (m, 1 H), 3.78 (s, 3 H), 3.98 (d, J = 7.1 Hz, 1 H), 4.47
(t, J = 7.2 Hz, 1 H), 4.62 (d, J = 18.1 Hz, 1 H), 4.71 (d, J = 7.3 Hz,
1 H).
13C NMR (50 MHz, CDCl3): d = –5.1, –4.9, 17.9, 25.5, 42.1, 52.4,
52.6, 59.3, 71.7, 81.9, 114.4, 168.1, 170.4.
IR (CHCl3): 1721 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.16 (s, 3 H), 0.17 (s, 3 H), 0.95
(s, 9 H), 3.64 (dd, J = 15.1, 7.6 Hz, 1 H), 3.70 (s, 3 H), 3.96 (d,
J = 6.4 Hz, 1 H), 4.31 (t, J = 7.3 Hz, 1 H), 4.37 (d, J = 7.1 Hz, 1 H),
4.38 (ddt, J = 15.1, 5.0, 1.4 Hz, 1 H), 5.33 (dd, J = 16.8, 1.0 Hz, 1
H), 5.35 (dd, J = 10.5, 1.0 Hz, 1 H), 5.72 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = –5.1, –4.9, 17.9, 25.5, 44.3, 51.1,
59.5, 71.8, 82.6, 114.5, 120.8, 130.1, 169.9.
MS (EI): m/z (%) = 285 (M+ – 57, 100), 257 (M+· – 57 – 28, 53), 229
(43), 131 (48).
MS (EI): m/z (%) = 295 (M+ – 15, 4), 253 (M – 57, 100), 225 (M –
57 – 28, 56), 131 (21).
Anal. Calcd for C15H26N2O5Si: C, 52.61; H, 7.65; N, 8.18. Found:
C, 52.93; H, 7.82; N, 7.88.
Anal. Calcd for C15H26N2O3Si: C, 58.03; H, 8.44; N, 9.02. Found:
C, 58.12; H, 8.53; N, 8.97.
anti-2h
[a]D20 +10.2 (c 0.5, CHCl3)
IR (CHCl3): 1750, 1730 cm–1.
anti-2f
[a]D20 –3.2 (c 0.8, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.19 (s, 3 H), 0.20 (s, 3 H), 0.93
(s, 9 H), 3.68 (s, 3 H), 3.73 (m, 1 H), 3.79 (s, 3 H), 3.88 (d, J = 6.4
Hz, 1 ), 4.41 (d, J = 6.6 Hz, 1 H), 4.48 (t, J = 6.6 Hz, 1 H), 4.68 (d,
J = 18.1 Hz, 1 H).
IR (CHCl3): 1722 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.18 (s, 3 H), 0.19 (s, 3 H), 0.92
(s, 9 H), 3.56 (dd, J = 15.4, 7.8 Hz, 1 H), 3.66 (s, 3 H), 3.76 (d,
Synthesis 2008, No. 17, 2835–2839 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
5-Cyanopyrrolidin-2-ones
2839
13C NMR (50 MHz, CDCl3): d = –4.9, –4.8, 17.8, 25.5, 42.0, 52.6,
52.7, 59.4, 75.7, 82.6, 115.4, 168.1, 170.2.
Hz, 1 H), 4.48 (d, J = 2.2 Hz, 1 H), 4.52 (m, 1 H), 5.86 (m, 2 H),
6.96 (AA¢XX¢, 2 H), 7.38 (AA¢XX¢, 2 H).
MS (EI): m/z (%) = 285 (M+ – 57, 100), 257 (M+ – 57 – 28, 73), 229
(37), 131 (35).
13C NMR (50 MHz, CDCl3): d = –4.9, –4.9, 17.8, 23.6, 25.5, 55.5,
56.4, 63.1, 74.9, 78.0, 114.7, 115.9, 121.0, 124.8, 125.0, 129.2,
158.6, 170.5.
Anal. Calcd for C15H26N2O5Si: C, 52.61; H, 7.65; N, 8.18. Found:
C, 52.87; H, 7.31; N, 7.93.
MS (EI): m/z (%) = 414 (M+, 55), 386 (M – 28, 100), 357 (M – 57,
41), 329 (M – 57 – 28, 27), 302 (21), 222 (39).
2i
Anal. Calcd for C22H30N2O4Si: C, 63.74; H, 7.29; N, 6.76. Found:
C, 63.68; H, 7.33; N, 6.89.
[a]D20 –3.6 (c 1.8, CHCl3).
IR (CHCl3): 1719 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.22 (s, 6 H), 1.00 (s, 9 H), 2.68–
2.89 (m, 2 H), 3.42 (s, 3 H), 3.82 (s, 3 H), 4.74 (d, J = 7.8 Hz, 1 H),
4.84 (d, J = 7.6 Hz, 1 H), 5.18–5.28 (m, 2 H), 6.08 (ddt, J = 17.2,
10.1, 7.0 Hz, 1 H), 6.95 (AA¢XX¢, 2 H), 7.39 (AA¢XX¢, 2 H).
13C NMR (50 MHz, CDCl3): d = –4.7, –4.6, 18.0, 25.6, 34.4, 52.0,
54.4, 55.5, 70.0, 83.1, 114.7, 115.2, 119.2, 125.0, 128.9, 131.5,
158.7, 170.1.
Acknowledgment
Support of this work by the DGI-MEC (CTQ2006-10292), Comu-
nidad Autónoma de Madrid (CCG-07-UCM/PPQ-2308), and
Universidad Complutense de Madrid (Grant GR74/07) is acknow-
ledged. G.C. thanks the MEC for a predoctoral fellowship.
MS (EI): m/z (%) = 416 (M+, 27), 359 (M – 57, 75), 332 (M – 57 –
27, 62), 304 (73), 244 (73), 210 (85), 134 (80), 89 (100).
References
(1) (a) Compain, P.; Martin, O. R. Iminosugars: From Synthesis
to Therapeutic Applications; Wiley: Chichester, 2007.
(b) Curtis, K. L.; Evinson, E. L.; Handa, S.; Singh, K. Org.
Biomol. Chem. 2007, 5, 3544. (c) Asano, N. Glycobiology
2003, 13, 93R. (d) Nishimura, Y. Curr. Top. Med. Chem.
2003, 3, 575. (e) Asano, N.; Nash, R. J.; Molyneux, R. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645.
(f) Legler, G. In Iminosugars as Glycosidase Inhibitors:
Nojirimycin and Beyond; Stütz, A. E., Ed.; Wiley-VCH:
Weinheim, 1999.
Anal. Calcd for C22H32N2O4Si: C, 63.43; H, 7.74; N, 6.72. Found:
C, 63.52; H, 7.79; N, 6.84.
anti-2i
White solid; mp 108–110 °C (hexanes–EtOAc); [a]D20 +34.4 (c 0.8,
CHCl3).
IR (KBr): 1719 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.21 (s, 3 H), 0.22 (s, 3 H), 0.95
(s, 9 H), 2.56 (dd, J = 14.6, 7.1 Hz, 1 H), 2.79 (dd, J = 14.6, 7.1 Hz,
1 H), 3.45 (s, 3 H), 3.83 (s, 3 H), 4.36 (d, J = 3.9 Hz, 1 H), 4.60 (d,
J = 3.9 Hz, 1 H), 5.17–5.31 (m, 2 H), 5.86 (ddt, J = 17.2, 10.1, 7.1
Hz, 1 H), 6.96 (AA¢XX¢, 2 H), 7.31 (AA¢XX¢, 2 H).
13C NMR (50 MHz, CDCl3): d = –4.8, –4.7, 17.8, 25.6, 32.6, 52.1,
55.5, 56.1, 74.8, 83.4, 114.8, 116.2, 120.0, 125.5, 128.7, 130.8,
158.9, 170.0.
(2) For a seminal review, see: Nájera, C.; Yus, M. Tetrahedron:
Asymmetry 1999, 10, 2245.
(3) For antibiotic use, see: (a) Southgate, R.; Branch, C.;
Coulton, S.; Hunt, E. In Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products,
Vol. 2; Lukacs, G., Ed.; Springer: Berlin, 1993, 621.
(b) Chemistry and Biology of b-Lactam Antibiotics, Vol. 1–
3; Morin, R. B.; Gorman, M., Eds.; Academic: New York,
1982. For enzyme inhibition use, see: (c) Veinberg, G.;
Vorona, M.; Shestakova, I.; Kanepe, I.; Lukevics, E. Curr.
Med. Chem. 2003, 10, 1741. (d) Clader, J. W. J. Med. Chem.
2004, 47, 1. (e) Kvaerno, L.; Ritter, T.; Werder, M.; Hauser,
H.; Carreira, E. M. Angew. Chem. Int. Ed. 2004, 43, 4653.
For gene activation use, see: (f) Rothstein, J. D.; Patel, S.;
Regan, M. R.; Haenggeli, C.; Huang, Y. H.; Bergles, D. E.;
Jin, L.; Hoberg, M. D.; Vidensky, S.; Chung, D. S.; Toan, S.
V.; Bruijn, L. I.; Su, Z.-z.; Gupta, P.; Fisher, P. B. Nature
2005, 433, 73.
(4) For selected reviews, see: (a) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Rev. 2007, 107, 4437. (b) Alcaide,
B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921.
(c) Deshmukh, A. R. A. S.; Bhawal, B. M.; Krishnaswamy,
D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med.
Chem. 2004, 11, 1889. (d) Alcaide, B.; Almendros, P.
Synlett 2002, 381. (e) Palomo, C.; Aizpurua, J. M.; Ganboa,
I.; Oiarbide, M. Synlett 2001, 1813.
MS (EI): m/z (%) = 416 (M+, 55), 359 (M – 57, 41), 327 (M – 57 –
32, 77), 304 (16), 244 (90), 210 (14), 134 (59), 89 (100).
Anal. Calcd for C22H32N2O4Si: C, 63.43; H, 7.74; N, 6.72. Found:
C, 63.32; H, 7.83; N, 6.63.
2j
White solid; mp 106–108 °C (hexanes–EtOAc); [a]D20 +0.7 (c 1.0,
CHCl3).
IR (KBr): 1721 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.18 (s, 3 H), 0.21 (s, 3 H), 0.98
(s, 9 H), 2.35 (m, 1 H), 2.81 (m, 1 H), 3.82 (s, 3 H), 4.26 (m, 1 H),
4.53 (d, J = 7.1 Hz, 1 H), 4.78 (d, J = 7.1 Hz, 1 H), 4.83 (m, 1 H),
5.87 (m, 2 H), 6.94 (AA¢XX¢, 2 H), 7.43 (AA¢XX¢, 2 H).
13C NMR (50 MHz, CDCl3): d = –4.9, –4.5, 18.0, 24.2, 25.6, 54.0,
55.5, 63.3, 73.5, 76.3, 114.6, 115.5, 119.8, 124.5, 125.0, 129.3,
158.4, 171.5.
MS (EI): m/z (%) = 414 (M+, 29), 386 (M – 28, 100), 357 (M – 57,
(5) (a) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P.
Chem. Commun. 2008, 615. For a review on b-lactam
aldehydes, see: (b) Alcaide, B.; Almendros, P. Chem. Soc.
Rev. 2001, 30, 226.
67), 329 (M – 57 – 28, 20), 302 (52), 222 (96).
Anal. Calcd for C22H30N2O4Si: C, 63.74; H, 7.29; N, 6.76. Found:
C, 63.79; H, 7.12; N, 6.67.
(6) For a recent review, see: Togo, H.; Iida, S. Synlett 2006,
2159.
anti-2j
[a]D20 +11.2 (c 1.3, CHCl3).
(7) (a) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Prasad, A.
R. Tetrahedron Lett. 2002, 43, 9703. (b) Royer, L.; De S,
K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 4595.
(8) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. J. Org.
Chem. 2007, 72, 7980.
IR (KBr): 1723 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.18 (s, 3 H), 0.19 (s, 3 H), 0.92
(s, 9 H), 2.40 (m, 2 H), 3.83 (s, 3 H), 4.34 (m, 1 H), 4.34 (d, J = 2.2
Synthesis 2008, No. 17, 2835–2839 © Thieme Stuttgart · New York