Indium-promoted acyloxyallylation reaction of azetidine-2,3-diones in aqueous media: A new route to densely functionalized 3-substituted 3-hydroxy-β-lactams

Article abstract of DOI:10.1002/ejoc.200800521

Densely functionalized 3-substituted 3-hydroxy-β-lactams have been obtained by acyloxyallylation reaction of azetidine-2,3-diones with 3-bromopropenyl acetate or benzoate in aqueous media promoted by indium under Barbier conditions. Two new stereocenters were formed; the stereochemistry at the new C-3 quaternary center was fully controlled by placing a bulky chiral substituent at C-4. However, poor diastereoselectivities were observed in the new allylic stereocenter formed (up to 58% de). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800521

FULL PAPER
DOI: 10.1002/ejoc.200800521
Indium-Promoted Acyloxyallylation Reaction of Azetidine-2,3-diones in
Aqueous Media: A New Route to Densely Functionalized 3-Substituted
3-Hydroxy-β-lactams
Benito Alcaide,*[a] Pedro Almendros,[b] Cristina Aragoncillo,[a] Gema Cabrero,[a]
Ricardo Callejo,[a] and M. Pilar Ruiz[a]
Dedicated to Professor Dr. Carmen Pardo on the occasion of her 65th birthday and retirement
Keywords: Addition reactions / Ketones / C–C coupling / Heterocycles / Indium / Synthetic methods
Densely functionalized 3-substituted 3-hydroxy-β-lactams
have been obtained by acyloxyallylation reaction of azetid-
ine-2,3-diones with 3-bromopropenyl acetate or benzoate in
aqueous media promoted by indium under Barbier condi-
tions. Two new stereocenters were formed; the stereochemis-
try at the new C-3 quaternary center was fully controlled by
placing a bulky chiral substituent at C-4. However, poor dia-
stereoselectivities were observed in the new allylic
stereocenter formed (up to 58% de).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
HIV-1 protease.[6] Moreover, phenylisoserine analogues are
used to synthesize new taxoids.[7] On the other hand, the
development of new carbon–carbon bond-forming reac-
tions is of particular interest in organic synthesis, especially
in the context of creating quaternary chiral centers in a ster-
eoselective reaction.[8] In this context, the α-hydroxyal-
lylation reaction of carbonyl compounds has been de-
scribed[9,10] as a synthetic tool for the preparation of carbo-
hydrates and related bioactive compounds containing a
polyhydroxylated chain in their structural framework.[11]
Continuing with our work on the asymmetric synthesis of
nitrogenated compounds of biological interest,[12] we wish
to report the acyloxyallylation reactions of enantiopure az-
etidine-2,3-diones in aqueous media,[13] which results in the
corresponding 3-functionalized 3-hydroxy-β-lactams.
Introduction
3-Substituted 3-hydroxy-β-lactams are important sub-
strates both for studies of biological activity and as versatile
building blocks for β-amino acid synthesis, so the develop-
ment of practical methods for their preparation is of much
interest. In addition, the 3-substituted 3-hydroxy-β-lactam
moiety represents an efficient carboxylate mimic,[1] shows
promising activity in acyl CoA-cholesterol acyltransferase
inhibition assays,[2] and is present in several pharmacologi-
cally active monobactams such as sulfacezin and related
products[3] and in enzyme inhibitors such as tabtoxin and
its analogues.[4] In addition, these compounds with the cor-
rect absolute configurations serve as precursors to the cor-
responding α-hydroxy-β-amino acids (isoserins), which are
key components of a large number of therapeutically im-
portant compounds. As an example, (2R,3S)-3-amino-2-hy-
droxy-5-methylhexanoic acid (norstatine) and (3R,4S)-4-
amino-3-hydroxy-5-methylheptanoic acid (statine) are resi-
dues for peptide inhibitors of enzymes such as rennin[5] and
Results and Discussion
The starting materials, azetidine-2,3-diones 1a–c, were
[a] Departamento de Química Orgánica I, Facultad de Química, efficiently prepared in optically pure form from aromatic or
Universidad Complutense de Madrid,
aliphatic (R)-2,3-O-isopropylideneglyceraldehyde-derived
E-28040 Madrid, Spain
imines by Staundinger reaction with acetoxyacetyl chloride
in the presence of Et3N, followed by sequential transesterifi-
cation and Swern oxidation, as we have previously reported
(Scheme 1).[14]
3-Bromopropenyl acetate and benzoate were prepared
following the experimental procedures described by Lom-
bardo et al.[15]
Fax: (+34)-91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Instituto de Química Orgánica General, Consejo Superior de
Investigaciones Científicas, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: (+34)-91-5644853
E-mail: Palmendros@iqog.csic.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
4434
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4434–4439

Acyloxyallylation of Azetidine-2,3-diones in Aqueous Media
To obtain better diastereoselectivity in the acyloxyallyl-
ation reaction, the next stage was to treat the azetidine-2,3-
diones with 3-bromopropenyl benzoate (Table 2). We rea-
soned that by introducing a sterically more hindered group,
the benzoyl group, the diastereoselectivity of the acyloxyal-
lylation products could be improved. For this purpose, azet-
idine-2,3-dione 1a was treated with 3-bromopropenyl ben-
zoate (E/Z = 75:25) under the conditions described above,
giving the corresponding addition product 2d with better
syn/anti diastereoselectivity (79:21) in 68% yield (Table 2,
entry 1). Similar results were obtained when the reaction of
1a was carried out with a catalytic amount of Lewis acid
InCl3 (Table 2, entry 2) or HfCl4 (Table 2, entry 3), whereas
with azetidine-2,3-diones 1b and 1c worse results in terms
of selectivity were achieved (Table 2, entries 4 and 5). When
the reaction was performed with (E)-3-bromopropenyl ben-
zoate instead of the E/Z (75:25) mixture the same diastereo-
selectivities were obtained for compounds 2d–f.
Scheme 1. Preparation of azetidine-2,3-diones 1. Reagents and con-
ditions: i) Et3N, AcOCH2COCl, CH2Cl2, room temp., overnight;
ii) MeONa, MeOH, 0 °C to room temp., 30 min; iii) ClCOCOCl,
DMSO, CH2Cl2, –78 °C, 1 h, then Et3N, to room temp.
Having obtained the ketones, the next stage was set to
carry out the key coupling reactions. As indium in aqueous
solution has shown considerable promise in the addition of
unsaturated halides to azetidine-2,3-diones 1,[16] we decided
to study the acyloxyallylation reaction with substrates 1. We
first investigated the reaction of azetidine-2,3-dione 1a with
3-bromopropenyl acetate promoted by indium in aqueous
media (in aqueous saturated THF/NH4Cl; Table 1) using
the same optimum conditions that we described previously
for allylation and propagylation/allenylation reactions of
the same substrates.[17] In the event, the corresponding ad-
dition product 2a was obtained in a good yield (66%;
Table 1, entry 1) with full control of the regiochemistry and
total diastereoselectivity at the new quaternary stereocenter
C-3, but with poor diastereoselectivity at the new allylic ste-
reogenic center formed. Fortunately, both isomers were iso-
lated after flash chromatography. In addition, it is impor-
tant to note that the formation of byproducts associated
with the transesterification processes were not observed.[18]
Table 2. Benzoyloxyallylation reactions of azetidine-2,3-diones 1
under aqueous conditions.
Entry
Ketone
R1
Additive t [h] Prod- syn/anti[a] Yield[b]
uct
[%]
1
2
3
4
5
(+)-1a
(+)-1a
(+)-1a
(–)-1b
(+)-1c
PMP[c]
PMP
PMP
Bn
2-Propynyl
–
InCl3
HfCl4
–
0.5
0.5
1
1.2
1.2
2d
2d
2d
2e
2f
79:21
78:22
76:24
70:30
65:35
68
66
63
64
45
–
Table 1. Acetoxyallylation reactions of azetidine-2,3-diones 1 under
aqueous conditions.
[a] The ratio was determined by integration of well-resolved signals
in the 1H NMR spectra of the crude reaction mixtures before puri-
fication. [b] Yield of the pure isolated product from appropriate
analytical and spectroscopic data. [c] PMP = 4-MeOC6H4.
Configurational assignment for adducts syn- and anti-2a
was achieved by derivatization to the corresponding bis-
acetonides 4a (Scheme 2). Thus, treatment of enantiomer-
ically pure syn- and anti-2a in the presence of sodium meth-
oxide at room temperature gave diols syn- and anti-3a in
good yields, respectively. The reactions of compounds 3
with 2,2-dimethoxypropane and catalytic amounts of pyr-
Entry
Ketone
R1
Additive t [h] Prod- syn/anti[a] Yield[b]
uct
[%]
1
2
3
4
5
(+)-1a
(+)-1a
(+)-1a
(–)-1b
PMP[c]
PMP
PMP
Bn
–
InCl3
HfCl4
–
1
1
1
1.2
1.2
2a
2a
2a
2b
2c
55:45
55:45
54:46
45:55
50:50
66
48
55
54
72
(+)-1c 2-Propynyl
–
[a] The ratio was determined by integration of well-resolved signals
in the 1H NMR spectra of the crude reaction mixtures before puri-
fication. [b] Yield of the pure isolated product from appropriate
analytical and spectroscopic data. [c] PMP = 4-MeOC6H4.
The acetoxyallylation reaction of ketones 1b and 1c pro-
vided inseparable mixtures of the corresponding syn/anti
isomers of 2b and 2c (Table 1, entries 4 and 5). No better
diastereoselectivity was observed when the reaction was
carried out with a catalytic amount of the Lewis acid InCl3
(Table 1, entry 2) or HfCl4 (Table 1, entry 3).
Scheme 2. Synthesis of bis-acetonides 4. Reagents and conditions:
i) MeONa, MeOH, 0 °C to room temp., 30 min; ii) 2,2-dimeth-
oxypropane, PPTS, ∆.
Eur. J. Org. Chem. 2008, 4434–4439
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4435

B. Alcaide et al.
FULL PAPER
idinium p-toluensulfonate at reflux temperature provided pounds 2–4 appears as a ddd in the range 5.87–6.11 ppm.
the expected bis-acetonides syn- and anti-4a in excellent However, for the anti compounds, this signal is shifted up-
yields (90 and 76% respectively).
field by 0.08–0.20 ppm. The opposite effect was observed
The structures (by DEPT, HETCOR, and COSY) and for the signal corresponding to the allylic proton 3Ј-H. This
stereochemistries (by vicinal proton couplings and NOESY signal appears in the range 4.28–5.83 ppm for the syn iso-
experiments) of compounds 2a, 3a, and 4a were established mers, whereas for the anti isomers, this signal is shifted
by mono- and two-dimensional NMR techniques. The ste- downfield by 0.01–0.28 ppm.
reochemistries of the new allylic stereogenic center were de-
Furthermore, it has been observed that the vicinal coup-
duced by comparison with NOE results for the isomers syn- ling constant between the allylic and vinylic protons of the
and anti-4a (Figure 1). NOE irradiation of 4-H in syn-4a syn isomers of 2 and 3 is 0.4–1.6 Hz smaller than for the
resulted in enhancement of the signal corresponding to 3Ј- anti isomers. The 13C NMR spectroscopic data show some
H (4%). Conversely, the same NOE enhancement was ob- trends in the signals of the syn and anti isomers as well. As
served for 4-H upon irradiation of 3Ј-H, which is consistent an example, for the syn compounds 2 and 3, the signals
with a syn relative stereochemistry between 4-H and 3Ј-H corresponding to carbon C-4 resonate in the range 61.7–
and an S configuration at C-3Ј. A NOE enhancement of 64.3 ppm, however, for the anti isomers, this signal is shifted
0.4% for 4-H in anti-4a on irradiating the signal corre- upfield by 0.5–1.2 ppm. In contrast, the signals correspond-
sponding to 3Ј-H is in good agreement with an anti relative ing to C-3Ј and the terminal olefinic carbon (=CH2) in the
disposition between 3Ј-H and 4-H in anti-4a (R configura- syn isomers of 2 and 3 resonate upfield with respect to those
tion at the stereogenic center C3Ј).
of the anti isomers. However, we did not observe this
pattern for the bis-acetonides 4, probably due to conforma-
tional restrictions of the vinyl moiety.
Nucleophilic addition of the organometallic reagent can
occur from two different positions due to unsymmetrical
substitution of the allylic reagent. A priori, two different
products can be formed (types I and II, Scheme 3).[19] How-
ever, full regiochemical control in the reactions of our sub-
strates 1 was observed. Compounds of type II were formed
exclusively when the reactions were performed with indium
as the metal promoter.
Figure 1. Selected NOE effects and configurations for adducts 4a.
The transesterification reaction of the inseparable mix-
tures of acetates and benzoates syn/anti-2b–f under the
above conditions provided the corresponding β-lactam diols
3 in good yields. The syn and anti isomers of compounds 3
were separated by flash chromatography (Table 3).
The absolute configurations of the new stereogenic cen-
ters in adducts 2b–f and their corresponding diols 3 were
determined by correlation of their spectroscopic pattern
with those of 2a and 3a and by considering the results ob-
Scheme 3. Regiochemistry observed for the addition of 3-haloprop-
enyl esters to aldehydes.
On the other hand, the stereoselectivity at the new
tained in the NOE experiments on bis-acetonides syn- and stereogenic center C-3 is believed to be controlled by the
anti-4a. Some spectroscopic correlations have been ob- bulky substituent at C-4; one face of the carbonyl group is
1
served in the analysis of the H and 13C NMR spectra of blocked and thus the allylmetal species preferentially ap-
the syn and anti compounds. For example, the signal corre- proaches the less hindered face (Figure 2). However, the
sponding to the olefinic proton H2C=CH in the syn com- syn/anti ratio observed at the allylic stereogenic center
Table 3. Preparation of diols 3.
Entry Compound (syn/anti)
R1
R2
t [h]
Products
Yield of syn-/anti-3[a] [%]
1
2
3
4
5
2b (45:55)
2c (50:50)
2d (79:21)
2e (70:30)
2f (65:35)
Bn
Ac
Ac
Bz
Bz
Bz
1
1
5.5
8.5
7.5
syn-3b/anti-3b
syn-3c/anti-3c
syn-3a/anti-3a
syn-3b/anti-3b
syn-3c/anti-3c
37/45
31/32
62/17
66/28
24/14
2-Propynyl
PMP[b]
Bn
2-Propynyl
[a] Yield of pure isolated isomers after chromatography from appropriate analytical and spectroscopic data. [b] PMP = 4-MeOC6H4.
4436 Eur. J. Org. Chem. 2008, 4434–4439
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Acyloxyallylation of Azetidine-2,3-diones in Aqueous Media
were isolated after purification by flash chromatography (hexanes/
ethyl acetate, 10:1–7:1).
formed in the acyloxyallylation reaction is governed by the
steric size of the substituent attached to the organometallic
reagent. Thus, better selectivities were obtained when the
reaction was carried out with 3-bromopropenyl benzoate (R
= Ph) than by using 3-bromopropenyl acetate (R = Ac).
syn-2a: Colorless oil. [α]D = +38.5 (c = 0.9, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.58 (AAЈXXЈ, 2 H, C6H4), 6.85
(AAЈXXЈ, 2 H, C6H4), 6.01 (ddd, 3J = 17.3, 10.8, 5.4 Hz, 1 H,
3
3
=CH-), 5.62 (d, J = 5.4 Hz, 1 H, 3Ј-H), 5.43 (d, J = 17.6 Hz, 1
3
H, =CHH), 5.42 (d, J = 10.4 Hz, 1 H, =CHH), 4.80 (br. s, 1 H,
OH), 4.44 (q, 3J = 6.9 Hz, 1 H, 4’-H), 4.28 (dd, 2J = 9.0, 3J =
3
2
6.8 Hz, 1 H, OCHH), 4.12 (d, J = 7.6 Hz, 1 H, 4-H), 3.81 (dd, J
= 9.1, J = 6.6 Hz, 1 H, OCHH), 3.79 (s, 3 H, MeO), 2.05 (s, 3 H,
3
MeCO), 1.49 and 1.35 (s, each 3 H, Me2C) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 169.3 (COO), 165.8 (CON), 156.9
(CAr ipso-O), 130.8 (=CH-), 130.4 (CAr ipso-N), 120.1 (2 CHAr),
119.6 (=CH2), 114.1 (2 CHAr), 109.8 (Me2C), 84.6 (C-3), 76.5 (C-
4Ј), 73.8 (C-3Ј), 66.8 (CH2O), 64.3 (C-4), 55.4 (MeO), 26.6 and 25.1
Figure 2. Model to explain the observed stereoselectivity for the
acyloxyallylation reaction of azetidine-2,3-diones 1.
(Me2C), 20.8 (MeCO) ppm. IR (CHCl3):
ν = 3332, 1751,
˜
1729 cm–1. MS (EI): m/z (%) = 391 (36) [M]+, 149 (100).
C20H25NO7 (391.2): calcd. C 61.37, H 6.44, N 3.58; found C 61.69,
H 6.65, N 3.42.
Conclusions
A new protocol for the preparation of densely function-
alized 3-substituted 3-hydroxy-β-lactams from enantiopure
azetidine-2,3-diones and 3-bromopropenyl acetate or ben-
zoate has been developed. The reaction proceeds in an
aqueous environment under mild conditions promoted by
indium.
anti-2a: Colorless oil. [α]D = +60.3 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.56 (AAЈXXЈ, 2 H, C6H4), 6.87
(AAЈXXЈ, 2 H, C6H4), 5.87 (ddd, 3J = 17.0, 10.6, 6.4 Hz, 1 H,
3
3
=CH-), 5.63 (d, J = 6.4 Hz, 1 H, 3’-H), 5.49 (d, J = 17.1 Hz, 1
H, =CHH), 5.37 (d, 3J = 10.3 Hz, 1 H, =CHH), 4.43 (q, 3J =
2
3
6.8 Hz, 1 H, 4’-H), 4.25 (dd, J = 8.8, J = 6.8 Hz, 1 H, OCHH),
3
4.09 (br. s, 1 H, OH), 4.09 (d, J = 7.1 Hz, 1 H, 4-H), 3.80 (s, 3 H,
2
3
MeO), 3.78 (dd, J = 8.5, J = 6.8 Hz, 1 H, OCHH), 2.14 (s, 3 H,
MeCO), 1.49 and 1.35 (s, each 3 H, Me2C) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 170.1 (COO), 165.5 (CON), 156.8
(CAr ipso-O), 130.3 (CAr ipso-N), 130.2 (=CH-), 120.8 (=CH2),
120.1 (2 CHAr), 114.1 (2 CHAr), 109.8 (Me2C), 84.7 (C-3), 76.6 (C-
4Ј), 75.2 (C-3Ј), 66.7 (CH2O), 63.3 (C-4), 55.4 (MeO), 26.5 and
Experimental Section
General Methods: Melting points were measured by using a Gallen-
kamp apparatus and are uncorrected. IR spectra were recorded
with a Perkin–Elmer 781 spectrophotometer. 1H and 13C NMR
spectra were recorded with a Bruker Avance-300, Varian VRX-
300S or Bruker AC-200 spectrometer. NMR spectra were recorded
in CDCl3 solutions unless otherwise stated. Chemical shifts are
given in ppm relative to TMS (1H, 0.0 ppm) or CDCl3 (13C,
77.0 ppm). Mass spectra were recorded with a HP5989A spectrom-
eter using the electronic impact (EI) method. Optical rotations were
measured by using a Perkin–Elmer 241 polarimeter. Specific rota-
tions [α]D are given in degcm2 g–1 at 25 °C and the concentration
(c) is expressed in g per 100 mL. All commercially available com-
pounds were used without further purification. Dichloromethane
and triethylamine were distilled from CaH2. Flame-dried glassware
and standard Schlenk techniques were used for moisture-sensitive
reactions. Flash chromatography was performed by using Merck
silica gel 60 (230–400 mesh). Products were identified by TLC (Kie-
selgel 60F-254). UV light (λ = 254nm) and a solution of phos-
phomolybdic acid in EtOH (1 g of phosphomolybdic acid hydrate,
100 mL EtOH) were used to develop the plates.
25.0 (Me C), 20.9 (MeCO) ppm. IR (CHCl ): ν = 3356, 1748,
˜
2
3
1730 cm–1. MS (EI): m/z (%) = 391 (39) [M]+, 149 (100).
C20H25NO7 (391.2): calcd. C 61.37, H 6.44, N 3.58; found C 61.59,
H 6.22, N 3.73.
General Procedure for the Preparation of Diols 3a: Sodium meth-
oxide (0.11 mmol) was added dropwise to a well-stirred solution of
3-substituted 3-hydroxy-β-lactam
2 (0.11 mmol) in methanol
(1.05 mL) at 0 °C. After 50 min, a saturated aqueous sodium chlo-
ride solution was added (0.21 mL) and methanol was removed un-
der reduced pressure. The mixture was extracted with ethyl acetate
(4ϫ5 mL), dried (MgSO4), and concentrated under reduced pres-
sure.
Diol syn-3a: From 3-substituted 3-hydroxy-β-lactam syn-2a (41 mg,
0.11 mmol), 30 mg (82%) of diol syn-3a was obtained as a white
solid after purification by flash chromatography (hexanes/ethyl ace-
tate, 3:1). M.p. 143–145 °C (hexanes/ethyl acetate). [α]D = +59.2 (c
= 1.0, CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.56
General Procedure for the Acyloxyallylation of Azetidine-2,3-diones
1. Preparation of 3-Substituted 3-Hydroxy-β-lactams 2: 3-Bromo-
propenyl acetate or benzoate (2 mmol) was added to a well-stirred
suspension of the α-keto lactam 1a–c (1 mmol) and indium powder
(2 mmol) in aq. saturated THF/NH4Cl (1:5, 7.2 mL) at room tem-
perature. After disappearance of the starting material (TLC), satu-
rated aqueous sodium hydrogen carbonate (10 mL) was added at
0 °C and the mixture was warmed to room temperature before be-
ing extracted with ethyl acetate (4ϫ15mL). The organic extract
was washed with brine (30 mL), dried (MgSO4), and concentrated
under reduced pressure.
3
(AAЈXXЈ, 2 H, C6H4), 6.87 (AAЈXXЈ, 2 H, C6H4), 6.05 (ddd, J =
17.2, 10.7, 5.3 Hz, =CH-), 5.52 (d, 3J = 17.2 Hz, 1 H, =CHH), 5.38
(d, 3J = 10.6 Hz, 1 H, =CHH), 4.43 (q, 3J = 6.7 Hz, 1 H, 4’-H),
3
2
3
4.41 (d, J = 5.3 Hz, 1 H, 3’-H), 4.24 (dd, J = 8.9, J = 6.8 Hz, 1
3
H, OCHH), 4.19 (d, J = 6.7 Hz, 1 H, 4-H), 4.18 (br. s, 1 H, OH),
2
3
3.84 (dd, J = 8.9, J = 6.7 Hz, 1 H, OCHH), 3.79 (s, 3 H, MeO),
2.51 (br. s, 1 H, OH), 1.46 and 1.36 (s, each 3 H, Me2C) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 167.1 (CON), 156.8 (CAr ipso-
O), 134.6 (=CH-), 130.5 (CAr ipso-N), 120.2 (2 CHAr), 118.5
(=CH2), 114.0 (2 CHAr), 109.8 (Me2C), 85.6 (C-3), 76.6 (C-4Ј), 73.4
(C-3Ј), 66.8 (CH2O), 63.8 (C-4), 55.4 (MeO), 26.5 and 25.1
3-Hydroxyazetidin-2-one 2a: From azetidine-2,3-dione 1a (99 mg,
0.34 mmol), 48 mg (36%) of syn-2a and 40 mg (30%) of anti-2a
(Me C) ppm. IR (CHCl ): ν = 3317, 1726 cm–1. MS (EI): m/z (%)
˜
2
3
Eur. J. Org. Chem. 2008, 4434–4439
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4437

B. Alcaide et al.
= 349 (46) [M]+, 149 (100). C18H23NO6 (349.1): calcd. C 61.88, H 3Ј), 77.0 (C-4Ј), 67.1 (CH2O), 64.9 (C-4), 55.4 (MeO), 26.5 and 24.6
FULL PAPER
6.64, N 4.01; found C 61.59, H 6.72, N 3.98.
(s, each 3 H, Me2C), 26.0 and 25.1 (s, each 3 H, Me2C) ppm. IR
(CHCl ): ν = 1752 cm–1. MS (EI): m/z (%) = 389 (93) [M]+ , 149
˜
3
Diol anti-3a: From 3-substituted 3-hydroxy-β-lactam anti-2a
(40 mg, 0.10 mmol), 20 mg (56%) of diol anti-3a was obtained as
a colorless oil after purification by flash chromatography (hexanes/
ethyl acetate, 3:1). [α]D = +74.3 (c = 1.2, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.52 (AAЈXXЈ, 2 H, C6H4), 6.87
(AAЈXXЈ, 2 H, C6H4), 5.90 (ddd, 3J = 17.0, 10.8, 6.0 Hz, 1 H,
(100). C21H27NO6 (389.2): calcd. C 64.77, H 6.99, N 3.60; found C
64.69, H 7.01, N 3.72.
Supporting Information (see also the footnote on the first page of
this article): Full spectroscopic and analytical data for previously
unreported compounds not included in the Exp. Sect. are described
in the Supporting Information. It contains compound characteriza-
tion data and experimental procedures for compounds 2b–f and
3
3
=CH-), 5.54 (d, J = 17.2 Hz, 1 H, =CHH), 5.35 (d, J = 10.6 Hz,
1 H, =CHH), 4.50 (br. d, 3J = 6.0 Hz, 1 H, 3’-H), 4.44 (q, 3J =
2
3
1
3b,c, as well as H and 13C NMR chemical shifts of representative
6.6 Hz, 1 H, 4’-H), 4.22 (dd, J = 8.9, J = 6.8 Hz, 1 H, OCHH),
3
2
4.17 (d, J = 6.4 Hz, 1 H, 4-H), 4.05 (br. s, 1 H, OH), 3.82 (dd, J
hydrogen and carbon atoms of compounds 2, 3, and 4.
3
= 8.9, J = 6.9 Hz, 1 H, OCHH), 3.80 (s, 3 H, MeO), 2.57 (br. s, 1
H, OH), 1.45 and 1.36 (s, each 3 H, Me2C) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 167.2 (CON), 156.8 (CAr ipso-O),
133.6 (=CH-), 130.4 (CAr ipso-N), 120.1 (2 CHAr), 119.2 (=CH2),
Acknowledgments
114.0 (2 CHAr), 109.8 (Me2C), 85.4 (C-3), 76.7 (C-4Ј), 74.2 (C-3Ј), We would like to thank the Dirección General de Investigación,
66.8 (CH2O), 63.2 (C-4), 55.4 (MeO), 26.5 and 25.1 (Me2C) ppm. Ministerio de Educación Ciencia (DGI-MEC) (Project
y
IR (CHCl ): ν = 3385, 1735 cm–1. MS (EI): m/z (%) = 349 (45) CTQ2006-10292), the Comunidad Autónoma de Madrid (CCG-
˜
3
[M]+, 149 (100). C18H23NO6 (349.1): calcd. C 61.88, H 6.64, N
4.01; found C 61.65, H 6.79, N 4.11.
07-UCM/PPQ-2308) and the Universidad Complutense de Madrid
(Grant GR74/07) for financial support. C. A. thanks the MEC for
a Ramón y Cajal contract. G. C. and R. C. thank the MEC and
UCM, respectively, for predoctoral grants.
General Procedure for the Preparation of β-Lactams 4: A solution
of diol 3a (45 mg, 0.13 mmol) and pyridinium p-toluensulfonate
(0.03 mmol) in dimethoxypropane (4.5 mL) was heated at reflux
temperature until complete disappearance of the starting material
(TLC). The reaction mixture was cooled to room temperature and
the solvent removed under reduced pressure. The crude product
was purified by flash chromatography.
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β-Lactam syn-4a: From diol syn-3a (20 mg, 0.06 mmol), 20 mg
(90%) of compound syn-4a was obtained as a white solid after
flash chromatography (hexanes/ethyl acetate, 3:1). M.p. 147–149 °C
(hexanes/ethyl acetate). [α]D = +64.4 (c = 1.4, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.63 (AAЈXXЈ, 2H, C6H4), 6.86
(AAЈXXЈ, 2 H, C6H4), 5.93 (ddd, 3J = 17.1, 10.1, 8.1 Hz, 1 H,
3
3
=CH-), 5.49 (d, J = 17.0 Hz, 1 H, =CHH), 5.33 (d, J = 10.6 Hz,
3
3
1 H, =CHH), 4.61 (d, J = 8.1 Hz, 1 H, 3’-H), 4.44 (dt, J = 8.5,
6.7 Hz, 1 H, 4’-H), 4.33 (dd, J = 8.6, J = 7.0 Hz, 1 H, OCHH),
3.99 (d, J = 8.6 Hz, 1 H, 4-H), 3.79 (s, 3 H, MeO), 3.76 (dd, J =
8.6, J = 6.3 Hz, 1 H, OCHH), 1.65 and 1.34 (s, each 3 H, Me2C),
2
3
3
2
3
1.54 and 1.47 (s, each 3 H, Me2C) ppm. 13C NMR (75 MHz
CDCl3, 25 °C): δ = 164.7 (CON), 156.5 (CAr ipso-O), 131.1
(=CH-), 130.7 (CAr ipso-N), 122.0 (=CH2), 119.6 (2 CHAr), 113.9
(2 CHAr), 112.1 (Me2C), 109.8 (Me2C), 90.5 (C-3), 81.7 (C-3Ј), 77.1
(C-4Ј), 66.6 (CH2O), 63.2 (C-4), 55.4 (MeO), 27.7 and 24.7 (Me2C),
26.6 and 26.1 (Me C) ppm. IR (CHCl ): ν = 1754 cm–1. MS (EI):
˜
2
3
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3
3
=CH-), 5.43 (d, J = 17.0 Hz, 1 H, =CHH), 5.39 (d, J = 9.5 Hz,
3
3
1 H, =CHH), 4.89 (d, J = 7.1 Hz, 1 H, 3’-H), 4.38 (dt, J = 8.6,
3J = 6.6 Hz, 1 H, 4’-H), 4.29 (dd, 2J = 8.5, 3J = 7.0 Hz, 1 H,
3
OCHH), 4.19 (d, J = 8.6 Hz, 1 H, 4-H), 3.79 (s, 3 H, MeO), 3.66
2
3
(dd, J = 8.6, J = 6.1 Hz, 1 H, OCHH), 1.58 and 1.33 (s, each 3
H, Me2C), 1.55 and 1.53 (s, each 3 H, Me2C) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 166.1 (CON), 156.5 (CAr ipso-O),
132.6 (=CH-), 130.8 (CAr ipso-N), 120.4 (=CH2), 119.7 (2 CHAr),
113.9 (2 CHAr), 111.0 (Me2C), 109.8 (Me2C), 89.9 (C-3), 79.0 (C-
4438
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4434–4439

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Received: May 29, 2008
Published Online: July 29, 2008
Eur. J. Org. Chem. 2008, 4434–4439
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4439