Highly diastereoselective indium-mediated synthesis of β-lactam carbohydrates from imines

Article abstract of DOI:10.1016/j.tet.2011.02.006

A simple and very effective approach to versatile carbohydrate β-lactam synthons of predictable absolute configuration has been developed. The procedure, which is based on the indium-mediated reaction of imines and bromoesters, was applied to the enantios

Full text of DOI:10.1016/j.tet.2011.02.006

Tetrahedron 67 (2011) 2617e2622
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly diastereoselective indium-mediated synthesis of
from imines
b-lactam carbohydrates
*
ꢀ
Raquel G. Soengas , Yuri Segade, Carlos Jimenez, Jaime Rodríguez
~
~
Departamento de Química Fundamental, Facultad de Ciencias, Universidad de A Coruna, 15071 A Coruna, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and very effective approach to versatile carbohydrate b-lactam synthons of predictable absolute
Received 11 December 2010
Received in revised form 28 January 2011
Accepted 1 February 2011
Available online 1 March 2011
configuration has been developed. The procedure, which is based on the indium-mediated reaction of
imines and bromoesters, was applied to the enantioselective synthesis of 3-monosubstituted and 3-di-
substituted
to the corresponding sugar-derived
sponding azetidines was also achieved.
b
-lactams from readily available carbohydrates. The opening of the
b
-lactamic ring gave rise
b
-amino acids. Transformation of the
b-lactams into the corre-
ꢀ
In memoriam of Professor Jose M. Concellon
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
b
-Lactams
Indium
Reformatsky reaction
Azetidines
1. Introduction
biological interest of carbohydrates.8 In the search for carbohy-
drate mimetics, particular attention has been paid to the design
and development of hybrid molecules, including sugar amino
acids (SAA). These compounds represent a class of carbohydrate
derivatives bearing an amino and a carboxylic acid functionality
and they can be classified according to the position of the amino
acid moiety on the cyclic polyol.9 These compounds are present in
the post-translational modification of proteins where the attach-
ment of carbohydrates to the amino acids constitutes one of the
most important ways to modify the structure and activity of the
protein.10 In addition, the presence of several stereogenic centres
on these rings can be exploited to create chemical diversity
and the protection or deprotection of hydroxyl substituents
opens up opportunities to access hydrophobic or hydrophilic
peptidomimetics.
b
-Lactams are a very important class of compounds because of
their well-known biological activity.1 Since the advent of penicillin,
the
and investigation within both the scientific and public sectors.
-Lactam antibiotics have occupied a central role in the fight
b-lactam antibiotics have been the subject of much discussion
b
against pathogenic bacteria and the subsequent rise in the quality
of life for the world population as a whole.2 Additionally, these
compounds have been very useful as key intermediates in organic
synthesis3 and also provide ideal building blocks4 for the con-
struction of many nitrogen-containing organic molecules with
fundamental biological activities.5 Since
b-lactams may be regar-
ded as cyclized forms of b-amino acids, the most obvious applica-
tion is the synthesis of these interesting derivatives.6 The interest in
these compounds lies in the high propensity of their oligomers to
Although numerous synthetic methods have been developed for
fold into a range of secondary structures, such as
a
-helices,
b
-turns
the formation of the
b
-lactam ring, including [2þ2]-cycloadditions,
and
b
-sheets, which have proved to be resistant to peptidase deg-
cyclization reactions, carbene insertion reactions and rearrange-
radation.7 Moreover, the conformational stability of these systems
facilitates interactions with receptors and enzymes.
ment of heterocyclic compounds,11 the application of these pro-
cedures to the preparation of b-lactams linked to a carbohydrate,
Among the plethora of amino acids, those linked to a carbohy-
drate moiety are of particular interest. The structural diversity
found in sugarsdtogether with their biological role in molecular
recognition processesdjustifies the continued chemical and
which are precursors of sugar amino acids and aminosugars, is very
limited in the literature.12
As part of our continued interest in the synthetic usefulness of
indium in carbohydrate chemistry,13 we decided to investigate the
scope and limitations of the indium-mediated lactamization of
sugar-derived imines and the application of this approach to the
preparation of sugar b-amino acids.
* Corresponding author. E-mail address: rsoengas@udc.es (R.G. Soengas).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.006

2618
R.G. Soengas et al. / Tetrahedron 67 (2011) 2617e2622
Table 1
Some previous studies on metal-mediated lactamization of
imines have been reported. For example, the Reformatsky reactions
Sugar-
b
-lactams 6e10 from iminosugars 1e5
of an imine, 2-bromoesters and zinc dust in the synthesis of b-
Imine
b-Lactam
Yield (%)
lactams has been widely studied.14 However, the indium-mediated
lactamization of imines using haloesters is far less common.15 Thus,
Bn
O
N
the reported synthesis of 3-unsubstituted
b-lactams using ethyl
O
OTBS
O
N
OTBS
H
bromoacetate, indium and imines in THF under reflux was only
effective for imines derived from aryl aldehydes. Furthermore, the
yields were only moderate to low and stereospecific approaches
Bn
69
O
O
O
O
were not investigated. The enantiomeric synthesis of a-substituted
b
-lactams from imines derived from appropriately protected sugars
6
1
using acid chlorides by the Staudinger reaction has been reported.12
However, the indium-mediated reaction of 2-bromoesters with
carbohydrate imine derivatives has not been explored to date.
We wish to report here a simple and versatile method for the
Bn
O
N
O
O
N
O
H
O
Bn
70
stereoselective synthesis of carbohydrate-derived b-lactams based
on an indium-mediated reaction of bromoesters and imines.
O
O
BnO
BnO
7
2
2. Results and discussion
Bn
H
O
N
We started our investigation by focusing on the reaction of ethyl
O
a
-bromoisobutyrate with several sugar-derived imines. Iminosu-
gars 1e5 were reacted with ethyl -bromoisobutyrate and indium
powder in THF under sonication (Scheme 1) and this reaction
O
O
N
O
O
O
Bn
a
68
O
O
afforded the corresponding diastereoisomerically pure b-lactams
6e10 in good yields in all cases (Table 1).
O
O
8
3
Bn
*
O
Bn
H
In
N
*
N
O
O
+
R2
R2
O
THF
CO2Et
O
Br
*
72
TBDPSO
OR1
OR1
N
TBDPSO
syn
N
Bn
1-5
6-10
a-bromoisobutyrate with sugar-derived imines 1e5.
4
Bn
O
9
Scheme 1. Reaction of ethyl
O
O
Regarding the mechanism, as stated in previously reported in-
dium-mediated additions to imines,16 attack of the indium enolate
on a chelated intermediate in which a five-membered ring is cre-
ated by chelation between indium and the nitrogen and the oxygen
atoms in E-imine 1 would give the transition state model TS
depicted in Fig. 1. This situation could explain the highly stereo-
selective generation of syn isomers 6e10.
O
O
75
TBDPSO
N
TBDPSO
N
Bn
5
Bn
O
10
BrInCMe2CO2Et
O-
OEt
OR1
Taking into account these satisfactory results, and once the re-
action had proven to be of broad scope regarding the sugar imine
In
N
*
H
Bn
In
Bn
R2
N
structure, we decided to investigate the influence of the
a-sub-
Me
Me
R2
H
TS
stituent on the bromoester.
O
R1
Reaction of the sugar imine 1 with
(Scheme 2) under the same conditions as above afforded an epi-
meric mixture of sugar- -lactams 14e16 in all cases (Table 2).
a-bromoesters 11e13
Fig. 1. Proposed transition state leading exclusively to syn isomers.
b
The absolute configuration of isomer 14b was unequivocally
determined by X-ray diffraction (Fig. 2).
Once again the chelation of the indium to the nitrogen atom and
the oxygen atom in the proposed transition states TS1 and TS2
depicted in Fig. 3 might explain the diastereoselectivity observed in
the case of 2-monosubstituted-2-bromoesters 11e13. Thus, the steric
O
R
Bn
H
N
O
O
R
N
OTBS
OTBS
In
Bn
+
THF
CO2Et
Br
O
O
O
O
interaction between the a-substituent of the bromoester and the
sugar ring of the imine in the transition state TS1 (which is absent in
TS2) could explain the preference for the formation of the 6S isomer.
14a-16a: 6S
14b-16b: 6R
11-13
1
Scheme 2. Reaction of sugar imine 1 with ethyl 2-bromoesters 11e13.
The
these studies because the resulting
rivatives are precursors of the corresponding
a
-bromoisobutyrate addition product was chosen to initiate
-disubstituted -lactam de-
-disubstituted
a,
a
b
Another very useful application of these sugar-derived lactams
is the preparation of azetidines. Azetidines constitute an important
class of azaheterocycles, exhibiting a wide range of biological ac-
tivities, such as antihypertensive, anti-inflammatory, antiarrhyth-
mic, antidepressant, and monoamine oxidase inhibitory activities.18
a,a
b
-amino acids, which are of great interest in the preparation of
conformationally restricted peptidomimetics.17
b-Lactam 7 was
heated with sodium methoxyde in methanol (Scheme 3) to give,
after aqueous work-up, the pure -amino acids 17.
b

R.G. Soengas et al. / Tetrahedron 67 (2011) 2617e2622
2619
Table 2
Influence of the
the yield of the
a-substituent of the bromoester on the diastereoisomeric ratio and
O
O
O 2
O
b-lactams
i
1
3'
4'
2'
3
TBDPSO
TBDPSO
a
-Bromoester
R
b
-Lactams
Ratio R/S
Yield (%)
N
N
11
12
13
ePh
eMe
ePr
14aþ14b
15aþ15b
16aþ16b
1:3
2:3
1:3
61
39a
47a
1'
Bn
Bn
O
18: 2'R
19: 2'S
9: 2'R
10: 2'S
a
Some of the open-chain ester was obtained as a side product.
ii
OH
OAc
iii
HO
AcO
OH
Bn
20: 2'R
21: 2'S
N
OAc
N
Bn
22: 2'R
23: 2'S
Scheme 4. Reagents and conditions: (i) LAH, THF, reflux, 24 h, 47% for 18 and 45% for
19; (ii) TFA/H2O, 12 h; (iii) Ac2O, DMAP, Py, 12 h, 65% for 22 and 65% for 23.
3. Conclusions
A very simple and highly effective approach to versatile carbo-
hydrate
applicable to the preparation 3-monosubstituted and 3-di-
substituted -lactams. The -lactam formation is stereoselective at
b-lactam derivatives has been developed. The procedure is
Fig. 2. ORTEP diagram for 14b.
b
b
the new nitrogenated stereocentre. Furthermore, the configuration
at this centre can be predicted based solely on the absolute con-
figuration of the chiral centre next to the imino group. On using 2-
monosubstituted-2-bromoesters, an additional stereocentre is
formed at C-3. A mixture of epimeric b-lactams at C-3, in which
presumably the kinetically controlled product is the major isomer,
is obtained in all cases.
OEt
O-
OEt
R
O-
In
In
OTBS
O
OTBS
O
N
N
Bn
Bn
R
H
H
O
O
O
O
H
H
Moreover, the novel carbohydrate-derived 3,3-disubstituted
lactams reported here were used in the straightforward synthesis
of -disubstituted- -amino acids and azetidines.
Work is in progress in our laboratory aimed at the preparation of
peptidomimetics based on these novel highly substituted -amino
b-
TS2
TS1
Fig. 3. Proposed transition states leading to the epimeric mixture of
a,
a
b
b-lactams.
b
acids as well as for the biological evaluation of the novel azetidine
derivatives obtained.
4. Experimental section
O
HO2C
BnHN
NaOMe
4.1. General experimental procedure for the reaction of ethyl
2-bromoisobutyrate and imines 1e5
O
O
N
O
O
Bn
MeOH
80 ºC
O
O
BnO
BnO
To a suspension of indium powder (0.5 mmol) and ethyl 2-
bromoisobutyrate (0.75 mmol) in THF (1 mL) was added the cor-
responding imine (0.5 mmol) and the mixture was sonicated for
6 h. The reaction mixture was quenched with saturated aqueous
sodium hydrogen carbonate (10 mL) and extracted with ether
(3ꢀ25 mL). The combined organic layers were dried over magne-
sium sulfate, filtered and evaporated in vacuo. The residue was
purified by flash column chromatography in mixtures of ethyl ac-
etate/hexane to give the compounds shown in Table 1.
7
17
Scheme 3. Preparation of b-amino acid 17 from b-lactam 7.
However, the azetidine skeleton has been one of the most difficult
amines to synthesize because of the ring strain.
A powerful method is reduction of b-lactams by nucleophilic
hydrides to afford the corresponding azetidines.
However, this transformation cannot be generalized because
many reactions of
do not lead to azetidines but instead give rise to
b
-lactams with reducing agents, e.g., diborane,
4.1.1. 4-(1-Benzyl-3,3-dimethyl-4-oxoazetidin-2-yl)-1-O-tert-bu-
g
-amino alcohols.19
tyldimethylsilyl-2,3-O-isopropyliden-
b-L -erytrofuranose
Interestingly, treatment of lactams 9 and 10 with LAH in
refluxing THF afforded the corresponding azetidine derivatives
(Scheme 4). In these conditions, the silyl protecting group was also
cleaved. Azetidines 18 and 19 were then submitted to acidic hy-
drolysis of the isopropylidene group to afford the corresponding
triols 20 and 21, which were then polyacetylated with acetic an-
hydride and pyridine in the presence of DMAP, to yield the pro-
tected azetidines 22 and 23.
(6). Purification by flash column chromatography (ethyl acetate/
25
hexane 1:8) to obtain lactam 6 (0.16 g, 69%) as a yellow oil. [a]
þ52.5 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): 0.11, 0.14 (2ꢀDs,
6H, eSi(CH3)2); 0.98 (s, 9H, eSiC(CH3)3); 1.22, 1.26, 1.29, 1.31
(4ꢀ s, 12H, 4ꢀ eCH3); 3.36 (d, 1H, J2 4¼9.1 Hz, H-20); 4.05 (d, 1H,
0
0
J¼14.8 Hz, eCHPh); 4.11 (dd, 1H, J42 ¼9.1 Hz, J43¼4.1 Hz, H-4);
4.52 (d, 1H, J23¼5.6 Hz, H-2); 4.76e4.81 (m, 2H, eCHPh, H-3);
5.38 (s, 1H, H-1); 7.26e7.31 (m, 5H, 5ꢀHAr). 13C NMR (125 MHz,

2620
R.G. Soengas et al. / Tetrahedron 67 (2011) 2617e2622
CDCl3): ꢁ5.3, ꢁ4.4 (eSi(CH3)2); 17.3, 21.9, 24.8, 25.8 (4ꢀ eCH3);
18.0 (eSiC(CH3)3); 25.6 (eSiC(CH3)3); 44.9 (eCH2Ph); 53.3 (C-
30); 62.1 (C-20); 80.0, 81.6, 86.7 (C-2, C-3, C-4); 101.1 (C-1); 112.5
(eCe); 127.3, 128.4, 128.5 (5ꢀ CHAr); 136.6 (CAr), 173.7 (C]O).
LRMS (ESI, m/z, %): 923.53 (100, [2MþH]þ); 462.27 (89,
[MþH]þ). HRMS for C25H40NO5Si ([MþH]þ) calculated 462.2670.
Found: 462.2663.
(eCe). LRMS (ESI, m/z, %): 558.30 (52, [MþH]þ). HRMS for
C34H44NO4Si ([MþH]þ) calculated 558.3034. Found: 558.3021.
4.2. General experimental procedure for the reaction of imine
1 and ethyl 2-bromo-alkanoates 11e13
To a suspension of indium powder (0.5 mmol) and the corre-
sponding ethyl 2-bromo-alkanoate (0.75 mmol) in THF (1 mL) was
added imine 1 (0.5 mmol) and the mixture was sonicated for 6 h.
The reaction mixture was quenched with saturated aqueous so-
dium hydrogen carbonate (10 mL) and extracted with ether
(3ꢀ25 mL). The combined organic layers were dried over magne-
sium sulfate, filtered and evaporated in vacuo. The residue was
purified by flash column chromatography in mixtures of ethyl ac-
etate/hexane to give the compounds shown in Table 2.
4.1.2. 4-(1-Benzyl-3,3-dimethyl-4-oxoazetidin-2-yl)-3-O-benzyl-1,2-
O-isopropyliden-b-L-threofuranose (7). Purification by flash column
chromatography (ethyl acetate/hexane 2:3) to obtain lactam 7
25
(0.15 g, 70%) as a yellow oil. [
a
]
þ2.8 (c 0.5, CHCl3). 1H NMR
D
(300 MHz, CDCl3): 1.06, 1.11, 1.33, 1.46 (4ꢀ s, 12H, 4ꢀ eCH3);
3.47e3.49 (m, 1H, H-20); 3.99 (d, 1H, J12¼6.1 Hz, H-2); 4.12 (d, 1H,
J¼11.4 Hz, eCHPh); 4.18e4.24 (m, 1H, H-3); 4.39 (d, 1H, J¼16.0 Hz,
eCHPh); 4.59e4.70 (m, 3H, 2ꢀ eCHPh, H-4); 5.94 (d, 1H,
J12¼5.9 Hz, H-1); 7.24e7.31 (m, 10H, 10ꢀ HAr). 13C NMR (125 MHz,
CDCl3): 17.2, 22.2, 26.3, 26.8 (4ꢀ eCH3); 44.9 (eCH2Ph); 51.9 (C-30);
61.3 (C-20); 71.5 (eCH2Ph); 81.6, 81.8, 82.3 (C-2, C-3, C-4); 104.8 (C-
1); 111.6 (eCe); 127.2, 128.3, 128.4, 128.5 (5ꢀ CHAr); 136.5, 130.7
(2ꢀ CAr), 173.2 (C]O). LRMS (ESI, m/z, %): 875.45 (80, [2MþH]þ);
438.23 (100, [MþH]þ). HRMS for C26H32NO5 ([MþH]þ) calculated
438.2274. Found: 438.2284.
4.2.1. 4-[(2R,3S)-1-Benzyl-3-phenyl-4-oxoazetidin-2-yl]-1-O-tert-bu-
tyldimethylsilyl-2,3-O-isopropyliden-
[(2R,3R)-1-benzyl-3-phenyl-4-oxoazetidin-2-yl]-1-O-tert-butyldime-
thylsilyl-2,3-O-isopropyliden- -erytrofuranose (14b). Purification by
b-L-erytrofuranose (14a) and 4-
b-L
flash column chromatography (ethyl acetate/hexane 1:8) to obtain
lactam 14a (0.10 g, 42%) as a yellow oil and lactam 14b (0.05 g, 19%)
as a yellow oil which was crystallized from diethyl ether/hexane.
25
Data for 14a: [
a]
ꢁ11.0 (c 0.6, CHCl3). 1H NMR (300 MHz,
D
4.1.3. 5-(1-Benzyl-3,3-dimethyl-4-oxoazetidin-2-yl)-1,2:3,4-di-O-
CDCl3): 0.15, 0.16 (2ꢀ s, 6H, eSi(CH3)2); 0.92 (s, 9H, eSiC(CH3)3);
0
0
0
isopropyliden-
b
-L
-arabinopyranose (8). Purification by flash col-
1.25,1.34 (2ꢀ s, 6H, 2ꢀ eCH3); 3.85 (dd,1H, J2 3 ¼2.2 Hz, J2 4¼7.0 Hz,
H-20); 4.11 (dd, 1H, J43¼3.5 Hz, J2 4¼7.0 Hz, H-4); 4.32e4.40 (m, 3H,
0
umn chromatography (ethyl acetate/hexane 2:5) to obtain lac-
25
tam 8 (0.14 g, 68%) as a yellow oil. [
a
]
ꢁ20.9 (c 1.1, CHCl3). 1H
eCHPh, H-3, H-30); 4.52 (d, 1H, J23¼5.9 Hz, H-2); 4.68 (d, 1H,
J¼15.3 Hz, eCHPh); 5.34 (s,1H, H-1); 7.28e7.37 (m, 5H, 5ꢀ HAr). 13C
NMR (125 MHz, CDCl3): ꢁ5.2, ꢁ4.2 (eSi(CH3)2); 24.5, 25.9 (2ꢀ
eCH3); 18.0 (eSiC(CH3)3); 25.7 (eSiC(CH3)3); 45.2 (eCH2Ph); 58.6,
58.9 (C-20, C-30); 79.7, 80.5, 87.5 (C-2, C-3, C-4); 101.4 (C-1); 112.7
(eCe); 127.3, 127.7, 128.4, 128.6, 128.7 (10ꢀ CHAr); 135.4, 136.9 (2ꢀ
CAr), 168.9 (C]O). LRMS (ESI, m/z, %): 510.27 (100, [MþH]þ). HRMS
for C29H40NO5Si ([MþH]þ) calculated 510.2670. Found: 510.2675.
Data for 14b: 1H NMR (300 MHz, CDCl3): 0.17, 0.18 (2ꢀ s, 6H, eSi
(CH3)2); 0.94 (s, 9H, eSiC(CH3)3); 1.23 (s, 6H, 2ꢀ eCH3); 3.86 (dd,
D
NMR (300 MHz, CDCl3): 1.20, 1.25, 1.28, 1.31, 1.33, 1.49 (6ꢀs, 18H,
6ꢀeCH3); 3.40 (d, 1H, J2 4¼9.0 Hz, H-20); 3.90 (dd, 1H,
0
0
J52 ¼9.0 Hz, J53¼3.1 Hz, H-5); 3.88e3.92 (m, 2H, H-3, eCHPh);
4.33 (dd, 1H, J21¼6.2 Hz, J23¼3.1 Hz, H-2); 4.33 (dd, 1H, J¼8.9,
2.9 Hz, H-4); 4.76 (d, 1H, J¼14.3 Hz, eCHPh); 5.57 (d, 1H,
J12¼6.2 Hz, H-1); 7.22e7.29 (m, 5H, 5ꢀHAr). 13C NMR (125 MHz,
CDCl3): 17.9, 21.7, 24.7, 24.8, 25.8, 25.9 (6ꢀ eCH3); 45.0
(eCH2Ph); 51.6 (C-30); 60.7 (C-20); 69.2, 69.9, 70.6, 71.2 (C-2, C-
3, C-4, C-5); 96.0 (C-1); 108.7, 109.7 (2ꢀ eCe); 127.0, 128.2,
128.5 (5ꢀ CHAr); 136.8 (CAr), 173.6 (C]O). LRMS (ESI, m/z, %):
418.22 (100, [MþH]þ). HRMS for C23H32NO6 ([MþH]þ) calcu-
lated 418.2224. Found: 418.2231.
1H, J2 3 ¼2.3 Hz, J2 4¼8.6 Hz, H-20); 4.12e4.27 (m, 3H, eCHPh, H-4,
H-30); 4.57 (d, 1H, J23¼5.8 Hz, H-2); 4.87 (dd, 1H, J34¼3.8 Hz,
J23¼5.8 Hz, H-3); 4.94 (d, 1H, J¼14.8 Hz, eCHPh); 5.42 (s, 1H, H-1);
7.24e7.35 (m, 5H, 5ꢀ HAr). 13C NMR (125 MHz, CDCl3): ꢁ5.1, ꢁ4.2
(eSi(CH3)2); 25.0, 25.9 (2ꢀ eCH3); 18.2 (eSiC(CH3)3); 25.8 (eSiC
(CH3)3); 45.6 (eCH2Ph); 57.5, 57.9 (C-20, C-30); 80.3, 83.6, 87.0 (C-2,
C-3, C-4); 102.2 (C-1); 112.9 (eCe); 127.3, 127.7, 127.8, 128.6, 128.7,
128.8 (10ꢀ CHAr); 134.9,136.6 (2ꢀ CAr),167.7 (C]O). LRMS (ESI, m/
z, %): 1019.53 (100, [2MþH]þ); 510.27 (88, [MþH]þ). HRMS for
C29H40NO5Si [MþH]þ calculated 510.2670. Found: 510.2686.
0
0
0
4.1.4. 1-(1-Benzyl-3,3-dimethyl-4-oxoazetidin-2-yl)-3-O-terc-bu-
tyldiphenylsilyl-1,2-O-isopropyliden-
D
-glycerol (9). Purification by
flash column chromatography (ethyl acetate/hexane 1:5) to ob-
25
tain lactam 9 (0.20 g, 73%) as a yellow oil. [
a
]
ꢁ27.8 (c 1.1,
D
CHCl3). 1H NMR (300 MHz, CDCl3): 0.94 (s, 3H); 0.98 (s, 9H); 1.51
(s, 3H); 3.38 (d, 1H); 3.45 (dd, 1H); 3.57 (dd, 1H); 4.18 (m, 3H);
4.65 (d, 1H); 7.37 (m, 10H); 7.64 (m, 5H). 13C NMR (125 MHz,
CDCl3): 16.8 (eCH3); 19.0 (eCH3); 22.0 (eCH3); 25.2 (eCH3); 26.8
e(CH3); 27.4 (eCH3); 45.1 (eCH2); 51.6 (eCHe); 61.5 (eCHe);
63.5 (eCH2); 78.6; 108.6 (eCe); 127.4 (eCHe); 127.8 (eCHe);
128.6 (eCHe); 129.8; 135.0; 135.7 (eCHe). LRMS (ESI, m/z, %):
558.30 (61, [MþH]þ). HRMS for C34H44NO4Si ([MþH]þ) calculated
558.3034. Found: 558.3023.
4.2.2. 4-[(2R,3S)-1-Benzyl-3-methyl-4-oxoazetidin-2-yl]-1-O-tert-
butyldimethylsilyl-2,3-O-isopropyliden-b-L -erytrofuranose
(15aþ15b). Purification by flash column chromatography (ethyl
acetate/hexane 1:8) to obtain a mixture of lactams 15aþ15b (0.11 g,
47%) as a yellow oil. Further purification afforded pure lactam 15a
(0.03 g). Data for 15a: 1H NMR (300 MHz, CDCl3): 0.09, 0.10, 0.12,
0.14 (4ꢀ s, 12H, 2ꢀ eSi(CH3)2); 0.87, 0.92 (2ꢀ s, 18H, 2ꢀ eSiC
(CH3)3); 1.19e1.39 (m, 15H, 5ꢀ eCH3); 3.05e3.12 (m, 1H, H-30);
3.50e3.55 (m, 1H, H-20); 3.92e3.95 (m, 1H); 4.28e4.39 (m, 3H);
4.75e4.82 (m, 2H); 5.35 (s, 1H, H-1); 7.28e7.32 (m, 5H, 5ꢀ HAr). 13C
NMR (125 MHz, CDCl3): ꢁ5.2, ꢁ4.3 (eSi(CH3)2); 13.9 (eCH3); 14.8
(C-30); 18.0 (eSiC(CH3)3); 24.6, 25.7, 25.9, 26.2 (4ꢀ eCH3); 45.2
(eCH2Ph); 51.9, 54.5 (C-20, C-30); 79.9, 81.3, 87.2 (C-2, C-3, C-4);
101.4 (C-1); 112.7 (eCe); 127.5, 128.4, 128.7 (5ꢀ CHAr); 136.8 (2ꢀ
CAr), 171.2 (C]O). LRMS (ESI, m/z, %): 448.25 (100, [MþH]þ).
4.1.5. 1-(1-Benzyl-3,3-dimethyl-4-oxoazetidin-2-yl)-3-O-tert-butyldi-
phenylsilyl-1,2-O-isopropyliden- -glycerol (10). Purification by flash
L
column chromatography (ethyl acetate/hexane 1:5) to obtain lactam
25
1
10 (0.21 g, 76%) as a yellow oil. [
a
]
ꢁ30.2 (c 1.1, CHCl3). H NMR
D
(300 MHz, CDCl3): 0.99 (s, 9H); 1.19 (s, 3H); 1.23 (s, 3H); 1.33 (d, 3H);
3.32 (d, 1H); 3.65 (m, 2H); 3.78 (ddd, 1H); 4.05 (d, 1H); 4.17 (dd, 1H);
4.94 (d, 1H); 7.34 (m, 10H); 7.59 (m, 5H). 13C NMR (125 MHz, CDCl3)
ppm: 15.3 (eCH3); 17.4 (eCH3); 19.1 (eCH3); 22.6 (eCH3); 26.8
(eCH3); 27.2 (eCH3); 27.(eCH3); 44.9 (eCH2e); 52.9 (eCH)e; 62.5
(eCHe); 63.1 (eCHe); 64.2 (eCH2e); 79.5 (eCHe); 109.9 (eCe);
127.5 (eCHe); 127.8 (eCHe); 128.5 (eCHe); 129.6 (eCHe); 174.1
4.2.3. 4-[(2R,3R,S)-1-Benzyl-3-propyl-4-oxoazetidin-2-yl]-1-O-tert-
butyldimethylsilyl-2,3-O-isopropyliden-b-l-erytrofuranose

R.G. Soengas et al. / Tetrahedron 67 (2011) 2617e2622
2621
25
(16aþ16b). Purification by flash column chromatography (ethyl
(0.10 g, 65%) as a yellow oil. [
a
]
ꢁ28.3 (c 1.1, CHCl3). 1H NMR
D
acetate/hexane 1:8) to obtain a mixture of lactams 16aþ16b (0.11 g,
(300 MHz, CDCl3): 1.15 (s, 3H); 1.37 (s, 3H); 1.98 (s, 3H); 2.09 (s, 6H);
2.5 (d,1H); 2.97 (m, 2H); 3.32 (d,1H); 3.92 (d,1H); 4.16 (dd,1H); 4.42
(dd, 1H); 5.04 (ddd, 1H); 5.54 (dd, 1H); 7.25 (m, 5H). 13C NMR
(125 MHz, CDCl3): 20.6 (eCH3); 20.8 (eCH3); 20.9 (eCH3); 22.7
(eCH3); 27.8(eCH3); 34.2 (eCH3); 61.9 (eCH2e); 63.3 (eCH2e); 64.7
(eCH2e); 70.3 (eCHe); 71.5 (eCHe); 73.6 (eCHe); 128.3 (eCHe);
138.2 (eCe); 169.8 (eCe); 170.2 (eCe); 170.6 (-Ce). LRMS (ESI, m/z,
%): 392.21 (100, [MþH]þ). HRMS for C21H30NO6 [MþH]þ calculated
392.2073. Found: 392.2063.
25
47%) as a yellow oil. [
a
]
þ35.3 (c 2.0, CHCl3). 1H NMR (300 MHz,
D
CDCl3): 0.09, 0.10, 0.12, 0.15 (4ꢀ s,12H, 2ꢀ eSi(CH3)2); 0.88, 0.92 (2ꢀ
s, 18H, 2ꢀ eSiC(CH3)3); 1.26, 1.28, 1.33, 1.38 (4ꢀ s, 12H, 4ꢀ eCH3);
1.41e1.81 (m,14H); 3.08e3.13 (m, 1H, H-30); 3.17e3.24 (m, 1H, H-30);
3.44 (dd, 1H, J¼2.8, 6.1 Hz, H-20); 3.77 (dd, 1H, J¼9.0, 6.2 Hz, H-20);
3.92e3.95 (m, 1H); 4.08e4.19 (m, 3H); 4.36e4.38 (m,1H); 4.47e4.63
(m, 3H); 4.77e4.82 (m, 2H); 5.27 (s, 1H, H-1); 5.38 (s, 1H, H-1);
7.29e7.32 (m, 10H, 10ꢀ HAr). 13C NMR (125 MHz, CDCl3): ꢁ5.3, ꢁ5.2,
ꢁ4.3 (2ꢀ eSi(CH3)2); 14.1, 14.3 (C-30); 18.0, 18.1 (2ꢀ eSiC(CH3)3);
20.3, 21.3 (2ꢀ eCH2e); 24.6, 24.9, 25.7, 25.8, 25.9, 26.0 (10ꢀ eCH3);
28.2, 29.8 (2ꢀ eCH2e); 45.0, 45.3 (2ꢀ eCH2Ph); 51.3, 53.6, 54.4, 56.4
(2ꢀ C-20, 2ꢀ C-30); 79.8, 80.0, 80.4, 81.4, 87.1, 87.5 (2ꢀ C-2, 2ꢀ C-3,
2ꢀ C-4); 101.3, 101.4 (C-1); 112.5, 112.8 (eCe); 127.4, 127.5, 128.3,
128.5, 128.6, 128.7 (10ꢀ CHAr); 136.7,137.2 (2ꢀ CAr),170.5,171.4 (C]
O). LRMS (ESI, m/z, %): 476.28 (100, [MþH]þ). HRMS for C26H42NO5Si
[MþH]þ calculated 476.2826. Found: 476.2845.
4.2.7. 1-(1-Benzyl-3,3-dimethyl-azetidin-2-yl)-3-O-tert-butyldiphe-
nylsilyl-1,2-O-isopropyliden- -glycerol (19). Lactam 10 (0.10 g,
L
0.2 mmol) was reduced following the same procedure described for
7 to obtain azetidine 19 (0.025 g, 45%) as a clear oil. 1H NMR
(300 MHz, CDCl3): 1.09 (s, 3H); 1.27 (s, 3H); 1.39 (s, 3H); 1.48 (s, 3H);
2.56 (d, 1H); 3.01 (m, 2H); 3.39 (d, 1H); 3.66 (d, 2H); 4.01 (m, 2H);
4.12 (d, 1H); 7.27(m, 5H). 13C NMR (125 MHz, CDCl3): 23.5 (CH3);
27.3 (CH3); 27.7 (CH3); 28.7 (CH3); 34.8 (eCH3); 62.4 (eCH2e); 62.8
(eCH2e); 64.8(eCH2e); 79.6 (eCHe); 108.7 (eCe); 126.9 e(CHe);
128.2 (eCHe); 128.9 (eCHe); 137.8 (eCe). LRMS (ESI, m/z, %):
543.32 (100, [MþH]þ).
4.2.4. 5-Benzylamino-3-O-benzyl-5-deoxy-6,6-dimethyl-1,2-O-iso-
propyliden-a-L-idofuranuronic acid (17). A solution of sodium
methoxide (35% in MeOH, 5 mL) was added to lactam 7 (0.20 g,
0.46 mmol) and the resulting mixture was refluxed for 16 h. After
cooling at rt, water was added (10 mL) and the mixture was stirred
for 30 min and then extracted with ethyl acetate (3ꢀ15 mL), which
was then washed with water until neutral, dried, filtered and
4.2.8. 1-(1-Benzyl-3,3-dimethyl-azetidin-2-yl)-1,2,3-O-acetyl-L-glyc-
erol (23). Azetidine 19 (0.025 g, 0.08 mmol) was acetylated fol-
lowing the same procedure described for 18 to obtain protected
amino alditol 23 (0.04 g, 65%) as a yellow oil. [
25
evaporated under reduced pressure to obtain amino acid 17 (0.21 g,
a
]
þ9.2 (c, 0.4,
D
25
quant.) as clear oil. [
a
]
ꢁ31.6 (c 0.7, CHCl3). 1H NMR (300 MHz,
CHCl3). 1H NMR (300 MHz, CDCl3): 0.95 (s, 3H); 1.23 (s, 3H); 1.96 (s,
3H); 1.97 (s, 3H); 2.41 (d, 1H); 3.07 (m, 2H); 3.26 (d, 1H); 3.96 (m,
2H); 4.3 (dd, 1H); 5.15 (ddd, 1H); 5.49 (dd, 1H); 7.26 (m, 5H). 13C
NMR (125 MHz, CDCl3): 20.7 (eCH3); 20.8 (eCH3); 20.8 (eCH3);
22.7 (eCH3); 27.7 (eCH3); 33.7 (eCH3); 62.5 (eCH2e); 63.4
(eCH2e); 64.6 (eCH2e); 69.3 (eCHe); 70.4 (eCHe); 128.2 (eCHe);
170.1 (eCe); 170.5 (eCe); 170.8 (eCe). LRMS (ESI, m/z, %): 392.21
(100, [MþH]þ). HRMS for C21H30NO6 [MþH]þ calculated 392.2073.
Found: 392.2065.
D
CDCl3): 1.23, 1.27, 1.42, 1.56 (4ꢀ s, 12H, 4ꢀ eCH3); 3.21 (d, 1H,
J54¼6.1 Hz, H-5); 3.85 (d, 1H, J¼14.9 Hz, eCHPh); 3.97e4.10 (m, 2H,
eCHPh, H-3); 4.36e4.39 (m, 1H, H-4); 4.59 (d, 1H, J¼15.0 Hz,
eCHPh); 4.79e4.85 (m, 2H, eCHPh, H-2); 6.00 (d, 1H, J12¼6.1 Hz, H-
1); 7.26e7.31 (m, 10H, 10ꢀ HAr). 13C NMR (125 MHz, CDCl3): 21.2,
24.5, 26.6, 27.2 (4ꢀ eCH3); 43.9 (C-6); 54.2 (eCH2Ph); 60.2 (C-5);
72.5 (eCH2Ph); 77.8, 82.3, 83.4 (C-2, C-3, C-4); 104.5 (C-1); 112.5
(-C-); 128.3, 128.6, 128.9, 129.0, 129.1 (10ꢀ CHAr); 136.7, 137.2 (2ꢀ
CAr), 178.8 (C]O). LRMS (ESI, m/z, %): 456.24 (100, [MþH]þ). HRMS
for C26H34NO6 [MþH]þ calculated 456.2380. Found: 456.2401.
Acknowledgements
4.2.5. 1-(1-Benzyl-3,3-dimethyl-oxoazetidin-2-yl)-3-O-tert-butyldi-
This work was supported by the Spanish Ministry of Science and
Innovation (CTQ2008-06493). R.G.S. thanks the Xunta de Galicia for
financial support (Isidro Parga Pondal program).
phenylsilyl-1,2-O-isopropyliden- -glycerol (18). To a solution of lac-
D
tam 9 (0.53 g, 1.1 mmol) in THF (17 mL) LAH was added (0.08 g,
2.2 mmol) and the suspension was refluxed for 24 h. The reaction
mixture was cooled to rt, quenched with water and filtered through
Celite. The filtrate was extracted with EtOAc and the combined
organic extracts were washed with aqueous NaOH (5%, 15 mL) and
H2O (20 mL), dried (MgSO4), filtered and evaporated to dryness.
The residue was purified by flash column chromatography (ethyl
Supplementary data
13C NMR of compounds 6e10, 14e17, 22 and 23 and cif archive
for 14b. Supplementary data associated with this article can be
found in online version at doi:10.1016/j.tet.2011.02.006. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
acetate/hexane 2:1) to obtain azetidine 18 (0.16 g, 45%) as a clear
25
oil. [a
]
ꢁ41.8 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): 0.99 (s,
D
3H); 1.02 (s, 3H); 1.41 (s, 3H); 3.04 (s, 3H); 3.51 (d, 2H); 3.71 (d, 2H);
3.90 (dd, 2H); 4.15 (m, 1H); 4.33 (dd, 1H); 7.30 (m, 5H). 13C NMR
(125 MHz, CDCl3): 20.8 (eCH3); 24.4 (eCH3); 25.1 (eCH3); 27.2
(eCH3); 38.9 (eCH)e; 54.9 (eCH2e); 62.2 (eCHe); 62.7 (eCH2e);
72.5 (eCH2e); 107.9 (eCe); 127.4 (eCHe); 128.5 (eCHe); 128.6
(eCHe); 139.5 (eCe). LRMS (ESI, m/z, %): 543.32 (100, [MþH]þ).
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