A convenient synthesis of functionalized isoxazolines and related 5-hydroxyisoxazolidine-4-carboxylates

Article abstract of DOI:10.1016/j.tet.2009.01.071

The effectiveness of Sc(OTf)₃ as a Lewis acid catalyst for the 1,4-addition reaction of carbamates to appropriate 2-acetyl-2-pentenoic esters is herein reported. In particular, N-benzyl-(tert-butyldimethylsilyloxy)carbamate added efficiently to

Full text of DOI:10.1016/j.tet.2009.01.071

Tetrahedron 65 (2009) 2478–2483
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A convenient synthesis of functionalized isoxazolines and related
5-hydroxyisoxazolidine-4-carboxylates
,
a
a
a
Fides Benfatti a, Giuliana Cardillo a , Simone Contaldi , Luca Gentilucci , Elisa Mosconi ,
*
Alessandra Tolomelli a , Eusebio Juaristi , Gloria Reyes-Rangel
,
b
b
*
a
`
Dipartimento di Chimica ‘G. Ciamician’, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy
b Departamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional, Apartado Postal 14-740, 07000 Me´xico, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
The effectiveness of Sc(OTf)3 as a Lewis acid catalyst for the 1,4-addition reaction of carbamates to ap-
propriate 2-acetyl-2-pentenoic esters is herein reported. In particular, N-benzyl-(tert-butyldimethyl-
silyloxy)carbamate added efficiently to the title substrates to afford a new class of polyfunctionalized
isoxazolidines and isoxazolines.
Received 31 October 2008
Received in revised form 23 December 2008
Accepted 15 January 2009
Available online 21 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
regard, we have been active in the field of aza-Michael addition,
especially by means of metal catalyzed 1,4-addition of hydroxyl-
In the field of organic and medicinal chemistry, the preparation
of small heterocyclic rings by means of simple and efficient routes is
receiving ever-increasing attention. In this context, substituted
isoxazolidines constitute versatile synthetic intermediates as a re-
sult of the easy cleavage of the N–O bond under reducing
conditions.1 Indeed, various isoxazolidines are extensively used as
1,3-amino alcohol equivalents,2as masked amino acids3 or as
amino-sugar mimetics.4 Furthermore, substituted isoxazolidines,
isoxazolines, and isoxazoles are important substrates for mecha-
nistic studies of biologically interesting processes. For example,
isoxazolines have been incorporated as conformational constraint
element in avb3 and a5b1 integrin antagonists,5 as well as in several
transcriptional activators.6 In a similar way, combretastatin ana-
logues containing the isoxazoline or isoxazole ring have been
reported,7 and several AMPA (S-2-amino-3-(3-hydroxy-5-methyl-
4-isoxazolyl)-propionic acid) receptor agonists have been synthe-
sized and tested.8 Finally, the use of chiral isoxazolidines as
auxiliaries in asymmetric synthesis has been also reported.9 On the
other hand, the synthesis of unnatural nucleoside analogs3a,10
containing the isoxazolidinic and isoxazolinic ring is currently of
significant interest since it has been reported that the presence of
an isoxazoline ring increases the antibacterial activity of carbape-
nem derivatives.11 Although 1,3-dipolar cycloaddition1,12 is the
simplest method for the preparation of isoxazolidines, conjugate
addition of nitrogen containing nucleophiles to unsaturated car-
bonyl compounds represents a useful alternative approach.13 In this
amine derivatives to appropriate electrophilic acceptors.14 This
protocol has been applied to the synthesis of several biologically
active compounds.
Recently, we developed a practical and selective synthesis of 4-
carboxylated-5-hydroxyisoxazolidines.15 In this paper we report
a new approach to this class of compounds, using N-benzyl-(tert-
butyldimethylsilyloxy)carbamate16 as nucleophile and highly
reactive alkylidene acetoacetates as suitable acceptors. This pro-
cedure
directly furnished
N-Cbz-protected-5-hydroxyisox-
azolidines that can be easily transformed into the corresponding
dehydrated isoxazolines, which are useful precursors of aromatic
oxazoles.
The electrophilic substrates were prepared according to the
previously reported procedure,17 by condensation of ethyl acetoa-
cetate with aliphatic and aromatic aldehydes. Thus, compounds
1a–e were obtained in 70% yield, as ca. 4:1 mixtures of Z/E isomers,
which were easily separable by flash chromatography. With these
ketoesters in hand, we carried out the critical carbamate addition
under Lewis acid-catalyzed conditions (Scheme 1).
2. Results and discussion
2.1. Addition of N-benzyl-(tert-butyldimethylsilyloxy)-
carbamate to alkylidene acetoacetates 1a–e
Lewis acids have attracted much attention in organic synthesis
because of their strong influence on the rate, the regio-, and the
stereochemistry of numerous reactions.18 In this context,
carbamates have only recently been the subject of investigation
as nucleophilic reagents for conjugate addition.19 The low
* Corresponding authors. Fax: þ39 051 2099456.
E-mail addresses: giuliana.cardillo@unibo.it (G. Cardillo), alessandra.tolomelli@
unibo.it (A. Tolomelli).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.071

F. Benfatti et al. / Tetrahedron 65 (2009) 2478–2483
2479
Scheme 2. Lewis acid-induced dehydration of 2a–c.
Scheme 1. Conjugate addition of N-benzyl-(tert-butyldimethylsilyloxy)carbamate to
1a–e.
nucleophilicity of most carbamates compared with the pre-
cursor aromatic and aliphatic amines dictates the use of a suit-
able catalyst able to activate acceptor olefins via the lowering in
energy of LUMO orbitals to match the HOMO of the carbamate.
A survey of metal salts that have been used for the successful
Figure 1. ORTEP representation of 3a as obtained from X-ray crystallography.
addition of carbamates to
a,b-unsaturated ketones has been re-
cently reported by Kobayashi and co-workers.20 Furthermore, en-
hanced reaction rates and improved yields can also be achieved by
simply changing the nature of the nucleophile; in particular, use of
the more reactive benzyl-(tert-butyldimethylsilyloxy)carbamate,
recently introduced by MacMillan and co-workers,16 has led to
excellent results. Indeed, N-protected hydroxylamines react with
unsaturated aldehydes to give hydroxyisoxazolidines, in good
yields. Apparently, the intramolecular hemiacetal formation is an
important driving force of the reaction.21
To our knowledge, functionalized alkylidene acetoacetates 1a–e
have not been ever investigated in this kind of reaction. In our
hands, 1a–e were treated with benzyl-(tert-butyldimethylsilyloxy)-
carbamate in the presence of various Lewis acids in CH2Cl2 solvent,
to afford isoxazolidine hemiketals 2 and the corresponding dehy-
drated isoxazoline 3 in ratios that depend on the reaction condi-
tions (Table 1).17 It should be noted that the TBS protecting group
was removed during the usual work-up procedure.
reaction was run in the presence of Cu(OTf)2 at 0 ꢀC, the starting
material was recovered even after long reaction times (entry 3). On
the other hand, the reaction proceeded very slowly at room tem-
perature, so it was gently warmed to 40 ꢀC, affording the complete
conversion of the starting material to a mixture of trans-2a
(J3,4¼6.6 Hz) and 3a (entries 4 and 5 in Table 1). The cyclization to
2a led to the formation of a single epimer. Compounds 2a and 3a
were easily isolated by flash chromatography on silica gel, eluting
with cyclohexane/ethyl acetate 80:20 as eluant. Similar results
were observed using Yb(OTf)3 as catalyst (entries 6–8 in Table 1).
Scandium triflate showed an excellent efficiency for the activation
of the desired reaction. Indeed, at ambient temperature and in the
presence of Sc(OTf)3, complete conversion of the starting material
was observed in 5 h. A single epimer of the trans-isoxazolidine 2a
was obtained, accompanied by the corresponding product of de-
hydration 3a in 60:40 ratio (entry 10 in Table 1). Warming the re-
action to 40 ꢀC afforded an increased amount of 3a (Entry 11). On
the other hand, in a unique experiment carried out at room tem-
perature, a 46% conversion of (Z)-1a into trans-2a could be ob-
served after 1.5 h, while only traces of dehydrated 3a were detected
in the crude 1H NMR. After 3 h of reaction, the conversion reached
From Table 1 it can be appreciated that the reaction with (Z)-1a
Zn(OTf)2 as catalyst, at 0 ꢀC or at room temperature (entries 1 and
2) proceeded with unsatisfactory yields. Similarly, when the
Table 1
1,4-Addition of benzyl-(tert-butyldimethylsilyloxy)carbamate to 1a–ea
Entry
1 S.M.
L.A. (5%)
T (ꢀC)
t (h)
Conversionb 2þ3 (%)
d
trans-2/3
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
0
40
0
rt
40
0
40
16
40
20
5
40
20
5
5
5
5
5
d
23
d
>99:1
60:40
58:42
50:50
d
>95
>95
d
rt
44
>95
70
>95
>95
94
95
93
95
>99:1
63:37
80:20
60:40
30:70
62:38
60:40
60:40
58:42
40
10
rt
40
rt
rt
rt
rt
9
10
11
12
13
14
15
5
5
5
a
The reaction was performed in the presence of 1 equiv of nucleophile in CH2Cl2.
A 5% amount of catalyst was used in all reactions.
b
The rest being unreacted starting material. The conversion was established on
the basis of 1H NMR peak integration.
Scheme 3. Reactivity of isoxazolidine 3a.

2480
F. Benfatti et al. / Tetrahedron 65 (2009) 2478–2483
Table 2
Transformation of isoxazolidines 3a–e into isoxazoline 4a–e and oxazoles 5a–e
Entry
1
S.M.
Product 4
Yield (%)
Product 5
Yield (%)
O
O
N
HN
3a
>95
>95
COOEt
COOEt
O
O
HN
HN
N
N
2
3
4
3b
3c
3d
>95
>95
>95
>95
>95
>95
COOEt
O
COOEt
O
COOEt
O
COOEt
O
HN
N
COOEt
COOEt
O
O
HN
N
5
3e
>95
>95
COOEt
COOEt
90%, and trans-2a was present together with the corresponding
dehydrated product 3a, in 60:40 ratio.
Compound 4e resulted particularly unstable, being detected only in
the 1H NMR spectra of the crude product.
The experimental conditions selected for 1a were then explored
with substrates 1b–e. Thus, treatment of 1b–e with carbamate at
room temperature overnight in the presence of scandium catalyst,
afforded essentially quantitative conversion of the starting mate-
rials to 60:40 mixtures of 2b–e and 3b–e (entries 12–15 in Table 1).
Complete conversion of 2a–e to 3a–e was achieved upon addi-
tion of an additional half equivalent of Sc(OTf)2 or Zn(OTf)2 in tol-
uene to the reaction mixture, while simultaneously heating to
reflux for 3 h (Scheme 2).
The structures of compounds 2a and 3a were established by
NMR techniques (DEPT, HETCOR, and COSY). The formation of
a single epimer of isoxazolidine 2a was supported by the presence
of a single set of signals in the 1H NMR spectrum. The relative
stereochemistry of 2a was established by means of NOE experi-
ments that exhibited a strong enhancement (8%) of the isopropylic
side chain upon irradiation of the C(4) hydrogen. By contrast,
a weaker NOE effect (2%) was observed on the trans hydrogen at
C(3). Furthermore, a medium NOE effect on the anomeric methyl
substituent indicated a cis relationship between this group and the
hydrogen at C(4). X-ray analysis of 3a secured the configuration
assigned to this heterocycle (Fig. 1).22
3. Conclusion
In summary, the reactivity of carbamates as nucleophiles in the
conjugate addition to alkylidene acetoacetates has been in-
vestigated. Excellent results were also obtained with N-benzyl-
(tert-butyldimethylsilyloxy)carbamate as nucleophilic reagent. The
procedure described here affords new classes of polyfunctionalized
isoxazolidines and isoxazolines. The structure of these heterocycles
was established on the basis of NMR spectra, and further supported
by X-ray analysis of the dehydrated derivative.
4. Experimental
4.1. General
All chemicals were purchased from commercial suppliers and
used without further purification. Anhydrous solvents were pur-
chased in sure seal bottles over molecular sieves and used without
further drying. Flash chromatography was performed on silica gel
(230–400 mesh). NMR Spectra were recorded with Varian spec-
trometers Gemini 200 MHz, Inova 300 MHz or Mercury 600 MHz.
Chemical shifts were reported as
d values (ppm) relative to the
solvent peak of CDCl3 set at
d
¼7.27 (1H NMR) or
d
¼77.0 (13C NMR).
2.2. Reactivity of isozaxoline-4-carboxylates. Synthesis
of oxazoles
Infrared spectra were recorded with an FT-IR Nicolet 205 spec-
trometer. MS analyses were performed on a liquid chromatograph
coupled with an electrospray ionization-mass spectrometer
(LC–ESI-MS), using H2O/CH3CN as solvent at 25 ꢀC (positive scan
100–500 m/z, fragmentor 70 V). Elemental CHN analyses were
performed with a Fisons EA1108dEager 200 instrument, using K
factor calculation method. General procedure for the preparation of
acetoacetate 1 and complete characterization for 1a–d has been
already reported.14,17
In order to remove the CBz protecting group, 3a was stirred at
room temperature with an equimolar amount of NaBH4 in ethanol
under argon (method A) or LiOH in MeOH/H2O/THF (method B), until
the reaction was found to be complete by TLC. Following these pro-
tocols, isoxazoline 4a was isolated in almost quantitative yield. Iso-
xazoline 4a was characterized by spectroscopic analysis as well. This
compound was unstable and spontaneously converted to the corre-
sponding aromatic oxazole 5a, even under inert atmosphere (Scheme
3).23 Therefore, as soon as formed 4a was treated with the 3,5-dini-
trobenzoyl chloride to afford derivative 6a in quantitative yield.
Similar deprotection was carried out on 3b–e, affording 4b–e in
quantitative yield. Rapid oxidation of isoxazolines 4b–e took place
upon exposure to air, affording 5b–e in quantitative yield (Table 2).
4.2. General procedure for the 1,4-addition of benzyl-(tert-
butyldimethylsilyloxy)carbamate to 1a–e
To a stirred solution of 1a–e (0.5 mmol) and Lewis acid
(0.05 equiv, 0.025 mmol), in dry CH2Cl2 (5 mL) at the selected

F. Benfatti et al. / Tetrahedron 65 (2009) 2478–2483
2481
temperature under nitrogen atmosphere, the carbamate (1 equiv,
0.5 mmol, 140 mg) was added in one portion. The reaction was
followed by TLC and quenched with water. The residue was then
diluted with CH2Cl2 (10 mL) and washed twice with water
(2ꢁ10 mL). The organic layer was dried over Na2SO4 and solvent
was removed under reduced pressure. Compounds 2a–e and 3a–e
were purified by flash chromatography on silica gel (eluant cyclo-
hexane/EtOAc, 85:15).
IR nmax (film) 3374, 3089, 2983, 2554, 2254, 1955, 1714, 1604, 1496,
1243, 1089 cmꢂ1; 1H NMR (CDCl3, 300 MHz) dH 7.28–7.46 (10H, m,
Ph), 5.89 (1H, d, J¼7.8 Hz, NCH), 5.22 (2H, s, OCH2Ph), 4.42 (1H, br s,
OH), 4.23–4.31 (2H, m, OCH2CH3), 3.27 (1H, d, J¼7.8 Hz, CH3CCH),
1.88 (3H, s, OCCH3), 1.32 (3H, t, J¼7.2 Hz, OCH2CH3); 13C NMR
(CDCl3, 75 MHz) dC 14.0, 22.6, 61.5, 64.7, 65.2, 68.0, 105.9, 126.1,
127.6, 127.7, 128.1, 128.4, 128.7, 135.7, 140.6, 158.9, 167.3. LC–ESI-MS:
rt 9.8 min, m/z 408 (MþNa), 793 (2MþNa).
4.2.1. Compound 2a
4.2.6. Compound 3a
Colorless oil; [Found: C, 61.58; H, 7.14; N, 4.01. C18H25NO6 re-
quires: C, 61.52; H, 7.17; N, 3.99]; Rf (30% EtOAc/cyclohexane) 0.51;
White solid; [Found: C, 64.84; H, 6.94; N, 4.23. C18H23NO5 re-
quires: C, 64.85; H, 6.95; N, 4.20]; Rf (30% EtOAc/cyclohexane) 0.80;
IR nmax (film) 3332, 2963, 2925, 1709, 1465, 1393, 1242, 1020 cmꢂ1
;
IR nmax (film) 2961, 2926, 2851, 1728, 1667, 1457, 1264 cmꢂ1 1H
;
1H NMR (300 MHz, CDCl3): dH 7.27–7.34 (5H, m, Ph), 5.18 (1H, d,
J¼12.6 Hz, OCH2Ph), 5.10 (1H, d, J¼12.6 Hz, OCH2Ph), 4.60 (1H,
t, J¼6.6 Hz, NCH), 4.23 (2H, q, J¼7.2 Hz, OCH2CH3), 2.90 (1H, d,
J¼6.6 Hz, CH3CCH), 1.81 (1H, m, CH3CHCH3), 1.70 (3H, s, OCCH3),
1.22 (3H, t, J¼7.2 Hz, OCH2CH3), 0.89 (3H, d, J¼6.9 Hz, CH3CHCH3),
0.86 (3H, d, J¼6.6 Hz, CH3CHCH3); 13C NMR (CDCl3, 75 MHz): dC
14.0, 18.1, 18.7, 22.9, 32.7, 59.3, 61.3, 67.0, 68.0, 106.3, 127.9, 128.0,
128.4, 135.8, 159.9, 168.2. LC–ESI-MS: rt 9.6 min, m/z 352 (Mþ1),
725 (2MþNa).
NMR (CDCl3, 600 MHz) dH 7.26–7.30 (5H, m, Ph), 5.12 (2H, s,
OCH2Ph), 4.98 (1H, br d, J¼2.4 Hz, NCH), 4.04–4.13 (2H, m,
OCH2CH3), 2.18 (3H, s, OCCH3), 1.97–2.17 (1H, m, CH3CHCH3), 1.17
(3H, t, J¼7.2 Hz, OCH2CH3), 0.88 (3H, d, J¼6.6 Hz, CH3CHCH3), 0.71
(3H, d, J¼6.6 Hz, CH3CHCH3); 13C NMR (CDCl3, 75 MHz) dC 11.5, 14.2,
15.3, 19.5, 31.3, 60.0, 68.5, 70.3, 103.0, 128.1, 128.3, 128.5, 135.2,
158.5, 163.4, 163.7. LC–ESI-MS: rt 11.7 min, m/z 334 (Mþ1), 689
(2MþNa).
4.2.7. Compound 3b
4.2.2. Compound 2b
Sticky yellow oil; [Found: C, 65.70; H, 7.22; N, 4.01. C19H25NO5
requires: C, 65.69; H, 7.25; N, 4.03]; Rf (30% EtOAc/cyclohexane)
Pale yellow oil; [Found: C, 62.41; H, 7.47; N, 3.84. C19H27NO6
requires: C, 62.45; H, 7.45; N, 3.83]; Rf (30% EtOAc/cyclohexane)
0.77; IR nmax (film) 2955, 2925, 2857, 1712, 1444, 1260, 1109 cmꢂ1
;
0.49; IR nmax (film) 3299, 2969, 1961, 1734, 1476 cmꢂ1
;
1H NMR
1H NMR (CDCl3, 300 MHz) dH 7.30–7.37 (5H, m, Ph), 5.15–5.24 (2H,
m, OCH2Ph), 4.87 (1H, dd, J¼6.2, 7.8 Hz, NCH), 4.19 (2H, m,
OCH2CH3), 2.28 (3H, s, OCCH3), 1.77 (2H, m, CHCH2þCH3CHCH3),
1.56 (1H, m, CHCH2), 1.29 (3H, t, J¼7.2 Hz, OCH2CH3), 0.95 (3H, d,
J¼6.6 Hz, CH3CHCH3), 0.91 (3H, d, J¼6.6 Hz, CH3CHCH3); 13C NMR
(CDCl3, 75 MHz) dC 11.7, 14.2, 21.3, 23.6, 24.6, 43.8, 60.0, 64.1, 68.5,
105.1, 128.2, 128.3, 128.5, 135.3, 158.1, 163.3, 163.5. LC–ESI-MS: rt
12.3 min, m/z 348 (Mþ1).
(CDCl3, 300 MHz) dH 7.30–7.39 (5H, m, Ph), 5.15–5.24 (2H, m,
OCH2Ph), 4.87 (1H, dd, J¼6.2, 7.8 Hz, NCH), 4.17–4.28 (2H, m,
OCH2CH3), 2.82 (1H, d, J¼6.2 Hz, OCCH), 1.75 (3H, s, OCCH3), 1.64
(1H, m, CH3CHCH3), 1.23 (3H, t, J¼7.2 Hz, OCH2CH3), 1.07–1.44 (2H,
m, CHCH2), 0.80 (6H, d, J¼6.6 Hz, CH3CHCH3); 13C NMR (CDCl3,
75 MHz) dC 14.0, 21.9, 22.8, 23.0, 25.2, 26.9, 60.6, 61.4, 62.5, 68.0,
106.1, 127.8, 128.2, 128.5, 135.6, 159.8, 168.1. LC–ESI-MS: rt 10.3 min,
m/z 366 (Mþ1).
4.2.8. Compound 3c
4.2.3. Compound 2c
Pale yellow oil; [Found: C, 65.71; H, 7.28; N, 4.07. C19H25NO5
requires: C, 65.69; H, 7.25; N, 4.03]; Rf (30% EtOAc/cyclohexane)
Pale yellow oil; [Found: C, 62.48; H, 7.42; N, 3.86. C19H27NO6
requires: C, 62.45; H, 7.45; N, 3.83.]; Rf (30% EtOAc/cyclohexane)
0.45; IR nmax (film) 3385, 2952, 2921, 2850, 1712, 1644, 1463,
0.78; IR nmax (film) 2965, 1642, 1464, 1253, 1114 cmꢂ1 1H NMR
;
(CDCl3, 300 MHz) dH 7.34–7.40 (5H, m, Ph), 5.22 (1H, d, J¼12.3 Hz,
OCH2Ph), 5.26 (1H, d, J¼12.3 Hz, OCH2Ph), 5.12 (1H, br d, J¼2.7 Hz,
NCH), 4.16–4.22 (2H, m, OCH2CH3), 2.30 (3H, s, OCCH3), 1.75–1.81
(1H, m, CH3CHCH2CH3), 1.42–1.50 (2H, m, CH3CHCH2CH3), 1.29 (3H,
t, J¼7.2 Hz, OCH2CH3), 0.88 (3H, t, J¼7.2 Hz, CHCH2CH3), 0.80 (3H, d,
J¼6.9 Hz, CH3CHCH2CH3); 13C NMR (CDCl3, 75 MHz) dC 11.8, 12.7,
14.2, 16.0, 22.6, 38.5, 60.0, 68.5, 69.7, 103.1, 128.3, 128.5, 129.3, 135.2,
158.3, 163.7, 164.0. LC–ESI-MS: rt 12.18 min, m/z 348 (Mþ1).
1267 cmꢂ1 1H NMR (CDCl3, 300 MHz) dH 7.32–7.35 (5H, m, Ph),
;
5.15–5.24 (2H, m, OCH2Ph), 4.74 (1H, q, J¼7.2 Hz, NCH), 4.18–4.24
(2H, m, OCH2CH3), 3.97 (1H, br s, OH), 2.97 (1H, d, J¼6.3 Hz, OCCH),
1.74 (3H, s, OCCH3), 1.46–1.54 (1H, m, CH3CHCH2CH3), 1.28 (3H, t,
J¼7.2 Hz, OCH2CH3), 1.02–1.15 (2H, m, CH3CHCH2CH3), 0.86–0.91
(6H, m, CH3CHCH2CH3); 13C NMR (CDCl3, 75 MHz) dC 11.4, 14.1, 14.8,
23.0, 25.7, 39.2, 58.7, 61.4, 66.2, 68.0, 106.5,127.9, 128.4, 135.8,159.9,
168.3. LC–ESI-MS: rt 10.0 min, m/z 366 (Mþ1).
4.2.9. Compound 3d
4.2.4. Compound 2d
Colorless clear oil; [Found: C, 67.56; H, 7.32; N, 3.75. C21H27NO5
requires: C, 67.54; H, 7.29; N, 3.75]; Rf (30% EtOAc/cyclohexane)
Pale yellow oil; [Found: C, 64.40; H, 7.51; N, 3.56. C21H29NO6
requires: C, 64.43; H, 7.47; N, 3.58]; Rf (30% EtOAc/cyclohexane)
0.55; IR nmax (film) 3381, 3035, 2914, 2857, 1734, 1456, 1124; 1H
NMR (CDCl3, 200 MHz) dH 7.32–7.35 (5H, m, Ph), 5.25 (1H, d,
J¼18.2 Hz, OCH2Ph), 5.15 (1H, d, J¼18.2 Hz, OCH2Ph), 4.62 (t, 1H,
J¼6.8 Hz, NCH), 4.16–4.27 (2H, m, OCH2CH3), 3.81 (1H, br s, OH),
2.99 (1H, d, J¼6.6 Hz, CH3CCH), 1.74 (3H, s, OCCH3), 1.44–1.82 (6H,
m, cyclohexyl), 1.29 (3H, t, J¼7.0 Hz, OCH2CH3), 0.98–1.32 (5H, m,
cyclohexyl); 13C NMR (CDCl3, 50 MHz) dC 14.1, 23.1, 25.8, 26.2, 28.8,
29.3, 29.7, 42.5, 59.5, 61.4, 66.5, 68.0, 106.3, 127.9, 128.1, 128.4, 135.9,
160.0, 168.3. LC–ESI-MS: rt 11.2 min, m/z 414 (MþNa), 805
(2MþNa).
0.80; IR nmax (film) 2922, 2854, 1724, 1656, 1446, 1264, 1104 cmꢂ1
;
1H NMR (CDCl3, 600 MHz) dH 7.35–7.38 (5H, m, Ph), 5.23 (2H, s,
J¼2 Hz, OCH2Ph), 5.05 (1H, br d, J¼1.2 Hz, NCH), 4.16–4.24 (2H, m,
OCH2CH3), 2.28 (3H, s, OCCH3), 1.55–1.78 (6H, m, cyclohexyl), 1.28
(3H, t, J¼7.2 Hz, OCH2CH3), 1.01–1.27 (5H, m, cyclohexyl); 13C NMR
(CDCl3, 75 MHz) dC 11.4, 14.1, 25.4, 25.9, 26.1, 26.2, 30.1, 41.0, 60.0,
68.4, 69.9, 102.5, 128.1, 128.3, 128.4, 135.2, 158.4, 163.8, 163.9. LC–
ESI-MS: rt 13.6 min, m/z 396 (MþNa).
4.2.10. Compound 3e
Pale yellow oil; [Found: C, 68.62; H, 5.77; N, 3.84. C21H21NO5
requires: C, 68.65; H, 5.76; N, 3.81]; Rf (30% EtOAc/cyclohexane)
0.82; IR nmax (film) 3350, 2961, 2915, 2851, 1717, 1667, 1453, 1268,
4.2.5. Compound 2e
Yellow oil; [Found: C, 65.43; H, 5.99; N, 3.66. C21H23NO6 re-
quires: C, 65.44; H, 6.02; N, 3.63]; Rf (30% EtOAc/cyclohexane) 0.56;
1100 cmꢂ1 1H NMR (CDCl3, 300 MHz) dH 7.19–7.30 (10H, m, Ph),
;
6.00 (1H, br s, NCH), 5.18 (1H, d, J¼12.6 Hz, OCH2Ph), 5.10 (1H, d,

2482
F. Benfatti et al. / Tetrahedron 65 (2009) 2478–2483
J¼12.6 Hz, OCH2Ph), 3.93–4.05 (2H, m, OCH2CH3), 2.32 (3H, s,
OCCH3), 1.05 (3H, t, J¼7.0 Hz, OCH2CH3); 13C NMR (CDCl3, 300 MHz)
dC 11.6, 14.0, 60.0, 68.0, 68.5, 105.0, 127.2, 128.2, 128.3, 128.4, 128.5,
135.1, 139.9, 155.9, 162.5, 163.0. LC–ESI-MS: rt 11.2 min, m/z 390
(MþNa), 757 (2MþNa).
NCH), 4.24 (2H, q, J¼7.2 Hz, OCH2CH3), 2.21 (3H, s, OCCH3), 1.74 (1H,
m, CH3CHCH2CH3), 1.24 (3H, t, J¼7.2 Hz, OCH2CH3), 1.20–1.31 (2H,
m, CH3CHCH2CH3), 0.92 (3H, t, J¼7.2 Hz, CHCH2CH3), 0.81 (3H, d,
J¼6.9 Hz, CH3CHCH2CH3); 13C NMR (CDCl3, 75 MHz) dC 11.9, 12.4,
14.3, 16.0, 22.7, 38.3, 59.3, 68.5, 103.7, 164.7, 167.5. LC–ESI-MS: rt
9.7 min, m/z 214 (Mþ1).
4.3. General procedure for the conversion of 2a–e into 3a–e
4.4.4. Compound 4d
To the crude reaction mixture containing 2 and 3, toluene (5 mL)
and Sc(OTf)3 or Zn(OTf)2 (0.5 equiv) were added and the solution
was heated to reflux for 3 h. The reaction was followed by TLC and
quenched, after disappearance of compound 2, with water. The
residue was then diluted with CH2Cl2 (10 mL) and washed twice
with water (2ꢁ10 mL). The organic layer was dried over Na2SO4 and
solvent was removed under reduced pressure. Compounds 3a–e
were purified by flash chromatography on silica gel (eluant cyclo-
hexane/EtOAc, 85:15).
Colorless oil; [Found: C, 65.23; H, 8.87; N, 5.82. C13H21NO3 re-
quires: C, 65.25; H, 8.84; N, 5.85]; Rf (30% EtOAc/cyclohexane) 0.76; IR
nmax (film) 3401, 2955, 2843, 1710, 1653, 1418, 1167 cmꢂ1 1H NMR
;
(CDCl3, 600 MHz) dH 6.60–6.80 (1H, br s, NH), 5.05 (1H, br s, NCH),
4.21 (2H, q, J¼7.0 Hz, OCH2CH3), 2.22 (3H, s, OCCH3),1.45–1.80 (6H, m,
cyclohexyl), 1.30 (3H, t, J¼7.0 Hz, OCH2CH3), 1.10–1.39 (5H, m, cyclo-
hexyl); 13C NMR (CDCl3, 75 MHz) dC 11.6, 14.2, 26.1, 26.3, 26.5, 41.0,
59.6, 68.2, 102.6, 164.7, 167.1. LC–ESI-MS: rt 9.8 min, m/z 240 (Mþ1).
4.4.5. Compound 4e
4.4. General procedure for the conversion of 3a–e into 4a–e
Pale yellow oil; Rf (30% EtOAc/cyclohexane) 0.78; IR nmax (film)
3401, 3028, 2950, 2837, 1719, 1668, 1432, 1119 cmꢂ1 1H NMR
;
Method A. To a stirred solution of 3a–e (0.5 mmol) in ethanol
(5 mL) at 0 ꢀC under nitrogen atmosphere, NaBH4 (1 equiv,
0.5 mmol, 18 mg) was added in one portion. The reaction was
stirred at room temperature and followed by TLC. After quenching
with water, the residue was diluted with EtOAc (10 mL) and washed
twice with water (2ꢁ10 mL). The organic layer was dried over
Na2SO4 and solvent was removed under reduced pressure. Com-
pounds 4a–e were purified by flash chromatography on silica gel
(eluant cyclohexane/EtOAc, 75:25).
Method B. To a stirred solution of 3a–e (0.5 mmol) in THF/
methanol/water (4:1:1, 6 mL) at room temperature, LiOH (3 equiv,
1.5 mmol, 36 mg) was added in one portion. The reaction was fol-
lowed by TLC and quenched with water, the residue was diluted
with EtOAc (10 mL) and washed twice with water (2ꢁ10 mL). The
organic layer was dried over Na2SO4 and solvent was removed
under reduced pressure. Compounds 4a–e were purified by flash
chromatography on silica gel (eluant cyclohexane/EtOAc, 75:25).
(CDCl3, 300 MHz) d 7.20–7.45 (10H, m, Ph), 5.46 (1H, br s, NCH), 4.07
(2H, m, OCH2CH3), 2.34 (3H, s, OCCH3), 1.12 (3H, t, J¼7.0 Hz,
OCH2CH3); LC–ESI-MS: rt 7.6 min, m/z 234 (Mþ1).
4.4.6. Compound 5a
Yellow oil; [Found: C, 60.92; H, 7.69; N, 7.06. C10H15NO3 requires:
C, 60.90; H, 7.67; N, 7.10]; Rf (30% EtOAc/cyclohexane) 0.78; IR nmax
(film) 2954, 2919, 2847, 1720, 1660, 1460, 1264, 1114 cmꢂ1; 1H NMR
(CDCl3, 600 MHz) dH 4.30 (2H, m, OCH2CH3), 3.44 (1H, m,
CH3CHCH3), 2.64 (3H, s, OCCH3),1.39 (3H, t, J¼7.2 Hz, OCH2CH3), 0.96
(3H, d, J¼7.0 Hz, CH3CHCH3), 0.85 (3H, d, J¼7.0 Hz, CH3CHCH3); 13
C
NMR (CDCl3, 75 MHz) dC 14.2, 17.6, 18.2, 20.9, 26.8, 60.5, 107.7, 162.0,
168.1, 173.3. LC–ESI-MS: rt 3.2 min, m/z 198 (Mþ1), 417 (2MþNa).
4.4.7. Compound 5b
Pale yellow oil; [Found: C, 62.58; H, 8.09; N, 6.67. C11H17NO3
requires: C, 62.54; H, 8.11; N, 6.63]; Rf (30% EtOAc/cyclohexane)
0.75; IR nmax (film) 2960, 2919, 2848, 1721, 1455, 1380, 1260, 1091,
4.4.1. Compound 4a
1028 cmꢂ1 1H NMR (CDCl3, 300 MHz) dH 4.30 (2H, m, OCH2CH3),
;
Pale yellow oil; [Found: C, 60.30; H, 8.62; N, 7.06. C21H27NO5
requires: C, 60.28; H, 8.60; N, 7.03]; Rf (30% EtOAc/cyclohexane)
2.65 (3H, s, OCCH3), 2.05 (1H, m, CHCH2), 1.37 (3H, t, J¼7.0 Hz,
OCH2CH3), 1.18–1.40 (2H, m, CHCH2þCH3CHCH3), 0.96 (6H, d,
J¼6.6 Hz, CH3CHCH3); 13C NMR (CDCl3, 75 MHz) dC 13.4, 14.2, 22.9,
27.3, 34.5, 60.5, 108.4, 162.4, 162.5, 175.2. LC–ESI-MS: rt 10.6 min,
m/z 212 (Mþ1), 445 (2MþNa).
0.73; IR nmax (film) 3395, 2932, 2877, 1721, 1654, 1432, 1198 cmꢂ1
;
1H NMR (CDCl3, 600 MHz) dH 6.60–6.80 (1H, br s, NH), 4.31 (1H, br
s, NCH), 4.20 (2H, m, OCH2CH3), 2.24 (3H, s, OCCH3), 1.99 (1H, m,
CH3CHCH3), 1.30 (3H, t, J¼7.2 Hz, OCH2CH3), 0.97 (3H, d, J¼7.0 Hz,
CH3CHCH3), 0.87 (3H, d, J¼7.0 Hz, CH3CHCH3); 13C NMR (CDCl3,
75 MHz) dC 11.8, 14.3, 15.4, 19.7, 30.9, 59.6, 68.6, 103.9, 164.8, 167.2.
LC–ESI-MS: rt 9.3 min, m/z 200 (Mþ1), 222 (MþNa).
4.4.8. Compound 5c
Clear colorless oil; [Found: C, 62.51; H, 8.11; N, 6.58. C11H17NO3
requires: C, 62.54; H, 8.11; N, 6.63]; Rf (30% EtOAc/cyclohexane)
0.76; IR nmax (film) 2960, 2925, 2860, 1724, 1459, 1391, 1266,
4.4.2. Compound 4b
1102 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) dH 4.32 (2H, q, J¼7.2 Hz,
Yellow oil; [Found: C, 61.99; H, 9.00; N, 6.52. C11H19NO3 re-
quires: C, 61.95; H, 8.98; N, 6.57]; Rf (30% EtOAc/cyclohexane) 0.74;
OCH2CH3), 3.27 (1H, m, CH3CHCH2CH3), 2.65 (3H, s, OCCH3), 1.83
(1H, m, CH3CHCH2CH3), 1.57 (1H, m, CH3CHCH2CH3), 1.37 (3H, t,
J¼7.2 Hz, OCH2CH3), 1.30 (3H, d, J¼7.2 Hz, CH3CHCH2CH3), 0.93 (3H,
t, J¼7.5 Hz, CH3CHCH2CH3); 13C NMR (CDCl3, 75 MHz) dC 11.7, 13.5,
14.2, 18.2, 28.1, 33.0, 60.5, 108.0, 162.4, 167.3, 175.1. LC–ESI-MS: rt
10.1 min, m/z 212 (Mþ1).
IR nmax (film) 3390, 2918, 2873, 1738, 1662, 1444, 1187 cmꢂ1 1H
;
NMR (CDCl3, 300 MHz) dH 6.40–6.70 (1H, br s, NH), 4.37 (1H, br s,
NCH), 4.20 (2H, m, OCH2CH3), 2.22 (3H, s, OCCH3), 1.73 (1H, m,
CHCH2), 1.31 (3H, t, J¼7.0 Hz, OCH2CH3), 1.19–1.33 (2H, m,
CHCH2þCH3CHCH3), 0.95 (3H, d, J¼6.6 Hz, CH3CHCH3), 0.93 (3H, d,
J¼6.6 Hz, CH3CHCH3); 13C NMR (CDCl3, 75 MHz) dC 11.9, 14.2, 21.5,
23.6, 25.2, 43.6, 60.0, 62.2,106.2,164.5,167.0. LC–ESI-MS: rt 6.8 min,
m/z 214 (Mþ1).
4.4.9. Compound 5d
Pale yellow oil; [Found: C, 65.83; H, 8.04; N, 5.96. C13H19NO3
requires: C, 65.80; H, 8.07; N, 5.90]; Rf (30% EtOAc/cyclohexane)
0.77; IR nmax (film) 2930, 2850, 1728, 1612, 1452, 1314, 1103 cmꢂ1
;
4.4.3. Compound 4c
1H NMR (CDCl3, 600 MHz) dH 4.32 (2H, q, J¼7.0 Hz, OCH2CH3) 3.12
(1H, tt, J¼3.2,11.4 Hz, CHC), 2.64 (3H, s, OCCH3),1.38 (3H, t, J¼7.0 Hz,
OCH2CH3), 1.22–2.05 (10H, m, cyclohexyl); 13C NMR (CDCl3,
75 MHz) dC 13.3, 14.1, 25.9, 26.3, 31.2, 36.1, 60.4, 107.6, 162.3, 167.3,
175.0. LC–ESI-MS: rt 11.3 min, m/z 238 (Mþ1).
Colorless oil; [Found: C, 61.98; H, 8.95; N, 6.58. C11H19NO3 re-
quires: C, 61.95; H, 8.98; N, 6.57]; Rf (30% EtOAc/cyclohexane) 0.74;
IR nmax (film) 3388, 2924, 2855, 1715, 1658, 1442, 1898 cmꢂ1 1H
;
NMR (CDCl3, 300 MHz) dH 6.70–6.80 (1H, br s, NH), 4.42 (1H, br s,

F. Benfatti et al. / Tetrahedron 65 (2009) 2478–2483
2483
Sternativo, S.; Santi, C.; Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2001,
12, 3053–3059.
3. (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org. Chem. 2000, 65, 5575–
5589; (b) Li, X.; Takahashi, H.; Ohtake, H.; Ikegami, S. Heterocycles 2003, 59,
4.4.10. Compound 5e
Yellow oil; [Found: C, 67.55; H, 6.11; N, 6.07. C13H13NO3 requires:
C, 67.52; H, 5.67; N, 6.06]; Rf (30% EtOAc/cyclohexane) 0.79; IR nmax
(film) 2959, 2850, 1958, 1728, 1310, 1261, 1099 cmꢂ1 1H NMR
;
547–571; (c) Enantioselective Synthesis of
John Wiley & Sons: Hoboken, 1997; (d) Enantioselective Synthesis of
b
-Amino Acids, 1st ed.; Juaristi, E., Ed.;
-Amino
b
(CDCl3, 300 MHz) dH 7.63 (3H, m, Ph), 7.46 (3H, m, Ph), 4.25 (2H, q,
J¼7.2 Hz, OCH2CH3), 2.75 (3H, s, OCCH3), 1.23 (3H, t, J¼7.2 Hz,
OCH2CH3); 13C NMR (CDCl3, 75 MHz) dC 13.6, 13.9, 60.7, 108.5, 127.9,
128.2, 128.6, 129.6, 162.0, 162.6, 175.8. LC–ESI-MS: rt 9.2 min, m/z
232 (Mþ1).
Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; John Wiley & Sons: Hoboken,
2005.
4. Chiacchio, U.; Borrello, L.; Iannazzo, D.; Merino, P.; Piperno, A.; Rescifina, A.;
Richichi, B.; Romeo, G. Tetrahedron: Asymmetry 2003, 14, 2419–2425.
5. (a) Smallheer, J. M.; Weigelt, C. A.; Woerner, F. J.; Wells, J. S.; Daneker, W. F.;
Mousa, S. A.; Wexler, R. R.; Jadhav, P. K. Bioorg. Med. Chem. Lett. 2004, 14, 383–
387; (b) Marinelli, L.; Meyer, A.; Heckmann, D.; Lavecchia, A.; Novellino, E.;
Kessler, H. J. Med. Chem. 2005, 48, 4204–4207.
6. (a) Minter, A. R.; Fuller, A. A.; Mapp, A. K. J. Am. Chem. Soc. 2003, 125, 6846–
6847; (b) Rowe, S. P.; Casey, R. J.; Brennan, B. B.; Buhrlage, S. J.; Mapp, A. K. J. Am.
Chem. Soc. 2007, 129, 10654–10655.
7. (a) Kaffy, J.; Monneret, C.; Mailliet, P.; Commerçon, A.; Pontikis, R. Tetrahedron
Lett. 2004, 45, 3359–3362; (b) Simoni, D.; Grisolia, G.; Giannini, G.; Roberti, M.;
Rondanin, R.; Piccagli, L.; Baruchello, R.; Rossi, M.; Romagnoli, R.; Invidiata, F. P.;
Grimaudo, S.; Jung, M. K.; Hamel, E.; Gebbia, N.; Crosta, L.; Abbadessa, V.; Di
Cristina, A.; Dusonchet, L.; Meli, M.; Tolomeo, M. J. Med. Chem. 2005, 48, 723–
736; (c) Kaffy, J.; Pontikis, R.; Carrez, D.; Croisy, A.; Monneret, C.; Florent, J.-C.
Bioorg. Med. Chem. 2006, 14, 4067–4077.
8. (a) Osborne, H. B.; Egebjerg, J.; Nielsen, E. Ø.; Madsen, U.; Larsen, P. K. J. Med.
Chem. 2000, 43, 2609–2645; (b) Burkhart, D. J.; McKenzie, A. R.; Nelson, J. K.;
Myers, K. I.; Zhao, X.; Magnusson, K. R.; Natale, N. R. Org. Lett. 2004, 6, 1285–
1288.
4.5. Preparation of 6a starting from 4a
3,5-Dinitrobenzoyl chloride (1.2 equiv, 0.6 mmol, 138 mg) was
added in one portion to a stirred solution of 4a (0.5 mmol, 110 mg)
and Et3N (1.2 equiv, 84 m
l) in CH2Cl2 (5 mL) at 0 ꢀC. The reaction was
stirred at rt for 2 h and then quenched with water. The residue was
then diluted with CH2Cl2 (10 mL) and washed twice with water
(2ꢁ10 mL). The organic layer was dried over Na2SO4 and solvent
was removed under reduced pressure. Compound 6a was purified
by flash chromatography on silica gel (eluant cyclohexane/EtOAc,
98:2).
9. (a) Abiko, A.; Moriya, O.; Filla, S. A.; Masamune, S. Angew. Chem., Int. Ed. Engl.
1995, 34, 793–795; (b) Abiko, A.; Liu, J.-F.; Wang, G.; Masamune, S. Tetrahedron
Lett. 1997, 38, 3261–3264; (c) Sharma, G. V. M.; Reddy, I. S.; Reddy, V. G.; Rama
Rao, A. V. Tetrahedron: Asymmetry 1999, 10, 229–235.
10. For a review see: Pan, S.; Amankulor, N. M.; Zhao, K. Tetrahedron 1998, 54,
6587–6604.
11. Nishi, K.; Imuta, M.; Kimura, Y.; Miwa, H. J. Antibiot. 1995, 48, 1481–1487.
12. (a) DeShong, P.; Dicken, D. M.; Leginus, J. M.; Whittle, R. R. J. Am. Chem. Soc.
1984, 106, 5598–5602; (b) Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.;
Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, A. J. Org. Chem. 1999, 64, 9322–
9327; (c) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863–909; (d)
Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000, 1449–1458; (e) Gothelf, K.
V.; Jørgensen, K. A. Asymmetric Reactions. In Synthetic Application of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W., Eds.; John Wiley & Sons: New York, NY, 2002; Chapter 12, pp 817–
899.
4.5.1. Compound 6a
Yellow solid; [Found: C, 51.90; H, 4.89; N, 10.71. C17H19N3O8
requires: C, 51.91; H, 4.87; N, 10.68]; Rf (30% EtOAc/cyclohexane)
0.84; IR nmax (film) 2972, 2911, 2847, 1723, 1658, 1618, 1424, 1255,
1109 cmꢂ1; 1H NMR (CDCl3, 600 MHz) dH 9.10–9.17 (2H, m, Ph), 8.89
(1H, m, Ph), 5.64 (1H, br s, CHN), 4.24 (2H, m, OCH2CH3), 2.31 (1H,
m, CH3CHCH3), 2.24 (3H, s, OCCH3), 1.34 (3H, t, J¼7.2 Hz, OCH2CH3),
1.08 (3H, d, J¼7.0 Hz, CH3CHCH3), 0.96 (3H, d, J¼7.0 Hz, CH3CHCH3);
13C NMR (CDCl3, 75 MHz) dC 11.5, 14.2, 15.9, 19.8, 31.7, 56.9, 60.5,
104.5, 121.3, 128.8 (2), 136.0, 148.2 (2), 162.6, 168.9, 182.9. LC–ESI-
MS: rt 11.1 min, m/z 394 (Mþ1).
13. (a) Conjugate Addition Reaction in Organic Synthesis; Perlmutter, P., Ed.; Perga-
mon: Oxford, 1992; (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033–8061;
(c) Leonard, J.; Diez-Barra, E.; Merino, S. Eur. J. Org. Chem. 1998, 2051–2061; (d)
Davies, S. G.; Ichihara, O. J. Synth. Org. Chem. Jpn. 1997, 55, 26–34.
14. Benfatti, F.; Cardillo, G.; Gentilucci, L.; Mosconi, E.; Tolomelli, A. Synlett 2008,
2605–2608.
15. Benfatti, F.; Bottoni, A., Cardillo, G.; Gentilucci, L.; Monari, M.; Mosconi, E.;
Stenta, M.; Tolomelli, A. Eur. J. Org. Chem. 2008, 6119–6127.
16. Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328–
9329.
Acknowledgements
We thank MAE (Italian Minister for Foreign Affair) for financial
support to a bilateral projects between Italy and Mexico. MIUR
(PRIN 2006 prot.n. 2006030449_003) and University of Bologna
(Strategic project ID 450) are also acknowledged for financial
support. Mr. Andrea Garelli is gratefully acknowledged for the
LC–ESI-MS analysis.
17. Benfatti, F.; Cardillo, G.; Gentilucci, L.; Mosconi, E.; Tolomelli, A. Tetrahedron:
Asymmetry 2007, 18, 2227–2232.
18. (a) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim,
2000; Vol. 1 and 2; (b) Wang, C.; Xi, Z. Chem. Soc. Rev. 2007, 36, 1395–1406.
19. (a) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109–2114; (b) Wabnitz, T.
C.; Spencer, J. B. Org. Lett. 2003, 5, 2141–2144; (c) Xu, L.-W.; Xia, C.-G. Synthesis
2004, 2191–2195; (d) Menand, M.; Dalla, V. Synlett 2005, 95–98; (e) Yang, L.;
Xu, L.-W.; Xia, C.-G. Tetrahedron Lett. 2005, 46, 3279–3282; (f) For an enantio-
selective example see: Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Go´mez-
Bengoa, E.; Garcı´a, J. M. J. Am. Chem. Soc. 2004, 9188–9189.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.01.071.
References and notes
20. (a) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319–1322; (b)
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Int. Ed. 2007, 46, 7470–7472.
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849–851; (b) Lu, X.; Deng, L. Angew. Chem., Int. Ed. 2008, 47, 7710–7713.
22. The crystal structure has been deposited at the Cambridge Crystallographic
Data Centre and allocated the deposition number CCDC 696029.
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