Stereoselective NaN3-catalyzed halonitroaldol-type reaction of azetidine-2,3-diones in aqueous media

Article abstract of DOI:10.1039/b802011f

Azetidine-2,3-diones (α-oxo-β-lactams) and bromonitromethane undergo coupling in aqueous media in the presence of catalytic amounts of sodium azide. The stereoselectivity of the process was generally good, proceeding with reasonable anti: syn ratios under substrate control. On this basis, a simple and fast protocol for the synthesis of the potentially bioactive 3-substituted 3-hydroxy-β-lactam moiety has been developed. Besides, 2-azetidinone- tethered 1-halo-1-nitroalkan-2-ols are quite useful building blocks; for example, reactions of the above nitrobromohydrins provided spiranic and fused bicyclic-β-lactams. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b802011f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective NaN3-catalyzed halonitroaldol-type reaction of
azetidine-2,3-diones in aqueous media†
Benito Alcaide,*a Pedro Almendros,*b Amparo Lunaa and M. Rosario Torresc
Received 5th February 2008, Accepted 27th February 2008
First published as an Advance Article on the web 14th March 2008
DOI: 10.1039/b802011f
Azetidine-2,3-diones (a-oxo-b-lactams) and bromonitromethane undergo coupling in aqueous media in
the presence of catalytic amounts of sodium azide. The stereoselectivity of the process was generally
good, proceeding with reasonable anti : syn ratios under substrate control. On this basis, a simple and
fast protocol for the synthesis of the potentially bioactive 3-substituted 3-hydroxy-b-lactam moiety has
been developed. Besides, 2-azetidinone-tethered 1-halo-1-nitroalkan-2-ols are quite useful building
blocks; for example, reactions of the above nitrobromohydrins provided spiranic and fused
bicyclic-b-lactams.
aldehydes promoted by NaI in anhydrous medium.12 Continuing
Introduction
with our work on the synthesis of nitrogenated compounds
of biological interest,13 herein, we wish to report the efficient
NaN3-catalyzed coupling reaction between a-keto-lactams and
bromonitromethane in aqueous media, which resulted in the
corresponding 3-[bromonitromethyl]-3-hydroxy-b-lactams.
b-Lactams are among the most important pharmacophores for
treatment of diseases caused by bacterial infections.1 In addition,
there are many important nonantibiotic uses of 2-azetidinones in
fields ranging from enzyme inhibition2 to gene activation.3 These
biological activities, combined with the use of these products as
starting materials to prepare a- and b-amino acids, alkaloids,
heterocycles, taxoids, and other types of compounds of biological
and medicinal interest,4 provide the motivation to explore new
methodologies for the synthesis of substances based on the b-
lactam core. In particular, the 3-substituted 3-hydroxy-b-lactam
moiety represents an efficient carboxylate mimic,5 shows promis-
ing activity in acyl CoA-cholesterol acyltransferase inhibition
assays,6 and it is present in several pharmacologically active
monobactams such as sulfazecin and related products,7 and in
enzyme inhibitors such as tabtoxin and its analogues.8 Besides,
these compounds, with the correct absolute configurations, serve
as precursors to the corresponding a-hydroxy-b-amino acids
(isoserines), which are key components of a large number of
therapeutically important compounds.9
Nucleophilic carbonyl addition reactions can be ranked among
the premier transformations in organic synthesis for stereoselective
carbon–carbon bond formation. In particular, stereoselective
addition of nitroalkanes to carbonyls (Henry reaction) plays
an important role in organic synthesis.10 In contrast, the anal-
ogous reaction involving halonitroalkanes has remained unex-
plored despite its ability to provide useful intermediates, the
corresponding 1-halo-1-nitroalkan-2-ols;11 only Concello´n et al.
have recently reported the addition of bromonitromethane to
Results and discussion
Starting substrates, azetidine-2,3-diones 1a–d, were prepared
using our previously described procedure from the appropriate
imine, via Staudinger reaction with acetoxyacetyl chloride in
the presence of Et3N, followed by sequential transesterification
and Swern oxidation.14 First we studied the effect of different
catalysts (15 mol%) on the reaction of azetidine-2,3-dione 1a
with bromonitromethane (1 equiv.) in anhydrous THF as solvent.
Despite Concello´n’s statement that the NaI-catalyzed reaction did
not work with highly hindered aldehydes such as pivalaldehyde
or ketones,12 ketone 1a was found to be a good coupling partner
in the halonitroaldol-type reaction (Table 1). LiI, NaI, KI, and
NaN3 promoted the coupling with similar efficiency and selectivity.
However, the LiI- and KI-catalyzed processes proceeded more
slowly, whereas the NaI-induced reaction yielded appreciable
amounts of Henry adduct 3a. Consequently, we deemed NaN3 to
be the optimal catalyst for the synthesis of 3-[bromonitromethyl]-
3-hydroxy-b-lactams 2. The effect of altering the reaction solvent
was then explored (ethanol, acetonitrile, and DMF). Reactions
carried out in ethanol, acetonitrile, or N,N-dimethylformamide
yielded lower amounts of 2, together with considerable amounts
of Henry adducts 3.
The appealing properties of reactions in aqueous media include
their synthetic advantages (many reactive functional groups,
such as hydroxy and carboxylic functions, do not require the
protection–deprotection protocol in such reactions, and many
water-soluble compounds do not need to be converted into their
derivatives and can be reacted directly) and their potential as
environmentally benign chemical processes (the use of anhydrous
flammable solvents can be avoided and the burden of solvent
disposal may be reduced), as well as unique reactivity and
selectivity that are not often attained under dry conditions
aDepartamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, Universi-
dad Complutense de Madrid, 28040-Madrid, Spain. E-mail: alcaideb@
quim.ucm.es; Fax: +34-91-3944103
bInstituto de Qu´ımica Orga´nica General, Consejo Superior de Investigaciones
Cient´ıficas (CSIC), Juan de la Cierva 3, 28006-Madrid, Spain. E-mail:
Palmendros@iqog.csic.es; Fax: +34-91-5644853
cLaboratorio de Difraccio´n de Rayos X, Facultad de Qu´ımica, Universidad
Complutense de Madrid, 28040-Madrid, Spain
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures and characterization data for all compounds. CCDC
reference numbers 664893 and 664894. See DOI: 10.1039/b802011f
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Table 1 Reaction of azetidine-2,3-dione 1a with bromonitromethane
Functionalized 1-halo-1-nitroalkan-2-ols are quite useful build-
ing blocks in organic synthesis because the haloalkanol moiety can
easily be transformed into other functionalities. The usefulness of
the 3-[bromonitromethyl]-3-hydroxy-b-lactams 2 becomes much
higher by assuming that the 1-bromo-1-nitro-methanol moiety
is a placeholder for further conversions. As shown in Scheme 1,
water elimination proceeded by treating compound 2a with p-
nitrobenzoyl chloride in the presence of triethylamine, affording
the a-bromonitroethylene 4.17 Owing to the efficacy and functional
group tolerance of transition metal catalyzed cross-coupling
reactions in forming C–C bonds, we envisioned that such cou-
pling of bromoalkenyl adduct 4 with arylboronic acids (Suzuki–
Miyaura reaction) would provide polysubstituted 3-alkylidene-b-
lactams.17
under modified anhydrous conditions
Catalyst
(15 mol%)
2a,
2a,
3a,
Entry
t/h
yield (%)a
anti : synb
yield (%)a
1
2
3
4
NaI
LiI
KI
2
48
6
56
54
55
63
80 : 20
70 : 30
80 : 20
85 : 15
6
0
0
0
NaN3
3
a Yield of pure, isolated product with correct analytical and spectral data.
PMP = 4-MeOC6H4. b The ratio was determined by integration of well-
resolved signals in the 1H NMR spectra (300 MHz) of the crude reaction
mixtures before purification.
(the performance of organic reactions in aqueous conditions might
lead to different results as compared with those obtained in purely
organic solvents, regardless of whether the reactants are soluble
or not in water), making them profitable in many cases.15
Considering our experience in this field with the application of
“on-water chemistry” to the coupling of stabilized organometallic
species with carbonylic compounds,16 we envisaged that the
addition of bromonitromethane to carbonyls could be accom-
plished in the presence of water. To verify this hypothesis,
the bromonitroaldol-type reaction of azetidine-2,3-diones 1a–d
was performed in aqueous environment (Table 2). In all cases
the NaN3-catalyzed reactions proceeded well in aqueous media,
leading to reasonable yields of products 2a–d as a mixture of anti :
syn adducts, without the formation of any by-products, such as
Henry adducts. No significant difference was observed between
using THF–H2O (1 : 5) and THF–brine (1 : 5) mixtures, the yield
being slightly better for the former. When the catalyst loading
was lowered to 10% the yield did not change considerably, but
the reaction time was increased by 15h. A further decrease in the
amount of catalyst used led to a decrease in the yield, but did not
affect the degree of stereoselectivity.
Scheme 1 Preparation of b-lactams 4–7 from 2-azetidinone-tethered
bromonitroalcohols 2. Reagents and conditions: (i) PNPCOCl, Et3N,
CH2Cl2, −78 ◦C, 45 min. (ii) 2.5 mol% Pd(PPh3)4, 4-MeC6H4B(OH)2,
NaHCO3, toluene–EtOH-–H2O (18 : 1 : 1), reflux, 4 h. (iii) 5 mol% BiCl3,
MeCN–H2O (1 : 1), rt, 3 d. (iv) K2CO3, MeOH, rt, 5 h. PNP = 4-NO2C6H4.
Table 2 Reaction of azetidine-2,3-diones 1 with bromonitromethane under modified aqueous conditions
Entry
Ketone
R1
R2
Solvent
t/h
2, yield (%)a
2, anti : synb
1
2
3
4
5
1a
1a
1b
1c
1d
PMPc
PMP
Bn
Allyl
PMP
Dioxd
Dioxd
Dioxd
Dioxd
p-Tolyl
THF–brine (1 : 5)
THF–H2O (1 : 5)
THF–H2O (1 : 5)
THF–H2O (1 : 5)
THF–H2O (1 : 3)
2
2
5
3
5
2a, 68
2a, 77
2b, 70
2c, 72
2d, 80
2a, 85 : 15
2a, 85 : 15
2b, 80 : 20
2c, 80 : 20
2d, 85 : 15
1
a Yield of pure, isolated product with correct analytical and spectral data. b The ratio was determined by integration of well-resolved signals in the H
NMR spectra (300 MHz) of the crude reaction mixtures before purification. c PMP = 4-MeOC6H4. d (S)-2,2-dimethyl-1,3-dioxolan-4-yl.
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Indeed, the Pd-catalyzed coupling between electron-deficient
bromonitroalkene 4 and p-tolylboronic acid afforded product 5
(Scheme 1).
The (E)-stereochemistry for compound 5 was established by
selective NOE experiments. Surprisingly, treatment of adduct 2a
with aqueous BiCl3 furnished bicyclic b-lactam 6 (Scheme 1),
which probably arises from an initial acetonide cleavage fol-
lowed by a retroaldol-type reaction with concomitant selective
cyclization to the five-membered ring.18 The structure and relative
stereochemistry of fused-2-azetidinone 6 was established by X-
ray crystallography (Fig. 1).19† Next, we studied the reactivity
of 2-azetidinone-tethered bromonitroalcohol 2a with potassium
carbonate. Oxacyclopropane formation was observed to give
the highly strained oxiranyl-b-lactam 7 (Scheme 1), possessing
a spirocyclic structure.20 The relative stereochemistry of the
spirocyclic b-lactam 7 was determined by X-ray crystallography,21
as is shown in Fig. 2.
Scheme 2 Mechanistic explanation for the formation of 3-[bromo-
nitromethyl]-3-hydroxy-b-lactams 2.
substrate chirality control to afford adducts 2.22,23 From azetidine-
2,3-diones 1, full stereocontrol at the carbinolic stereocenter was
achieved due to the presence of a bulky group at C4, which was
able to control the stereochemistry of the new C3-substituted C3-
hydroxy quaternary center. One face of the carbonyl group is
blocked preferentially, thus the nucleophile species is delivered to
the less hindered face, and as a consequence the diastereoselectivity
was complete in all cases (Scheme 3). The observed stereochem-
istry for the second stereocenter can be explained by invoking
steric interactions between the bulky group at C4 and the bromine
atom of the bromonitronate (Scheme 3).
Fig. 1 ORTEP plot of fused b-lactam 6 with thermal ellipsoids with 35%
probability.
Scheme 3 Models to explain the observed stereochemistry for the
halonitroaldol-type reaction of ketones 1.
Fig. 2 ORTEP plot of spirocyclic b-lactam 7 with thermal ellipsoids with
25% probability.
Conclusions
We can conclude that new protocols for the synthesis of 3-
substituted 3-hydroxy-b-lactams from azetidine-2,3-diones and
bromonitromethane have been developed. This addition reaction
proceeds under mild conditions in aqueous media under the
presence of a cheap catalyst. Besides the observed reactivity, it
has been shown that the resulting 1-bromo-1-nitroalkan-2-ols are
not only important end points, but also key intermediates for
further manipulations, i.e. they are useful building blocks for the
preparation of diversely functionalized monocyclic, fused, and
spirocyclic 2-azetidinones.
The pathway proposed in Scheme 2 looks valid for the
formation of products 2. It involves the nucleophilic addition of
bromonitronate 8, a species generated in situ from the exposure
of bromonitromethane to the mild azide base, to an a-ketolactam
1. The addition product, alkoxide 9, would suffer a protonation
which produces the adduct 2 with concomitant liberation of the
catalyst. Despite the fact that halonitroaldol-type reaction of
ketone acceptors 1 with bromonitromethane generates two new
stereocenters, it proceeds with reasonable anti : syn ratios under
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Dehydration reaction of 2-azetidinone-tethered 1-bromo-1-
nitroalkan-2-ol 2a. Preparation of bromoalkenyl-b-lactam 4
Experimental
Melting points were taken using a Gallenkamp apparatus and
are uncorrected. IR spectra were recorded on a Perkin-Elmer
781 spectrophotometer. H NMR and 13C NMR spectra were
4-Nitrobenzoyl chloride (87 mg, 0.47 mmol) and triethylamine
(40 mg, 0.39 mmol) were sequentially added dropwise to a
stirred solution of bromonitroalcohol 2a (168 mg, 0.39 mmol) in
dichloromethane (4 mL) at −78 ◦C, and the mixture was stirred for
45 min at this temperature. Saturated aqueous sodium hydrogen
carbonate (2 mL) was added, and the mixture was allowed to
warm to room temperature, before being partitioned between
dichloromethane and water. The organic extract was washed with
water (2 × 1 mL), dried (MgSO4), and concentrated under reduced
pressure. Chromatography of the residue eluting with hexanes–
ethyl acetate (2 : 1) gave 121 mg (75%) of compound 4.
1
recorded on a Bruker Avance-300, Varian VRX-300S or Bruker
AC-200. NMR spectra were recorded in CDCl3 solutions, except
otherwise stated. Chemical shifts are given in ppm relative to
TMS (1H, 0.0 ppm), or CDCl3 (13C, 76.9 ppm). Low and high
resolution mass spectra were taken on a HP5989A spectrom-
eter using the electronic impact (EI) or electrospray modes
(ES) unless otherwise stated. Optical rotations were measured
using a Perkin-Elmer 241 polarimeter. Specific rotation [a]D is
given in deg cm2 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. THF was distilled
from Na–benzophenone. Dichloromethane and triethylamine
were distilled from CaH2. Flame-dried glassware and standard
Schlenk techniques were used for moisture sensitive reactions.
Flash chromatography was performed using Merck silica gel 60
(230–400 mesh).
3-[Bromonitromethylene]-2-azetidinone 4
Colorless solid; mp: 161–163 ◦C (hexanes–ethyl acetate); [a]D
=
−5.8 (c 0.6 in CH2Cl2); 1H NMR (300 MHz, CDCl3, 25 ◦C): d =
7.35 and 6.90 (d, J = 9.0 Hz, each 2H), 5.36 (d, J = 2.7 Hz, 1H),
4.74 (td, J = 6.4, 2.7 Hz, 1H), 4.07 (dd, J = 8.9, 6.6 Hz, 1H), 3.92
(dd, J = 8.9, 6.1 Hz, 1H), 3.81 (s, 3H), 1.29 (s, 6H); 13C NMR
(CDCl3): d = 157.7, 156.1, 144.1, 133.8, 129.8, 120.2, 114.6, 110.3,
73.6, 66.0, 64.8, 55.5, 26.0, 25.1; IR (CHCl3): m = 1746, 1550 cm−1;
MS (EI): m/z (%): 414 (100) [M + 2]+, 412 (98) [M]+.
General procedure for the halonitroaldol-type reaction of azetidine-
2,3-diones 1. Preparation of 3-[bromonitromethyl]-3-hydroxy-b-
lactams 2
Suzuki–Miyaura cross-coupling reaction of a-bromonitromethylene
b-lactam 4 with boronic acids. Preparation of 3-[nitro(p-tolyl)-
methylene]-2-azetidinone 5
Bromonitromethane (1.0 mmol) was added to a well stirred
solution of the corresponding azetidine-2,3-dione 1 (1.0 mmol)
and sodium azide (9.7 mg, 0.15 mmol) in THF–H2O (1 : 5,
12 mL) at room temperature. The mixture was stirred at the
same temperature until complete disappearance of the a-keto-b-
lactam (TLC). Saturated aqueous ammonium chloride (2.5 mL)
was added, before the product was extracted with ethyl acetate (3 ×
5 mL). The organic extract was washed with brine, dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue, eluting with hexanes–ethyl acetate mixtures, gave
analytically pure compounds 2.24
Compound 4 (45 mg, 0.11 mmol) was added under argon to a
stirred suspension of the p-tolylboronic acid (22.4 mg, 0.16 mmol),
sodium bicarbonate (28 mg, 0.33 mmol), in toluene–ethanol–
water (18 : 1 : 1) (2.24 mL), and the resulting mixture was
stirred for 15 min. Then, Pd(PPh3)4 (2.5 mol%) was added and
the reaction mixture was heated at reflux temperature for 4 h.
The reaction mixture was allowed to cool to ambient temperature,
before being partitioned between ethyl acetate and water. The
organic extract was washed with water (2 × 1 mL), dried (MgSO4),
and concentrated under reduced pressure. Chromatography of the
residue eluting with hexanes–ethyl acetate (3 : 1) gave 22 mg (48%)
of compound 5.
3-[Bromonitromethyl]-3-hydroxy-2-azetidinone 2a
3-[Nitro(p-tolyl)methylene]-2-azetidinone 5
From 185 mg (0.63 mmol) of azetidine-2,3-dione 1a, 209 mg
(77%) of compound anti-2a, containing ca. 15% of its syn-2a
epimer, were obtained as a colorless oil after purification by flash
chromatography (hexanes–ethyl acetate, 2 : 1); [a]D = +116.3 (c
0.8 in CH2Cl2); 1H NMR (300 MHz, CDCl3, 25 ◦C): d = 7.49 (m,
2H), 6.90 (d, J = 9.0 Hz, 2H), 6.34 (s, 0.15H), 6.21 (s, 0.85H),
4.98 (d, J = 4.6 Hz, 1H), 4.68 (m, 0.15H), 4.48 (m, 0.85H), 4.24
(dd, J = 9.0, 6.6 Hz, 0.15H), 4.20 (dd, J = 9.0, 6.6 Hz, 0.85H),
3.92 (dd, J = 9.0, 6.8 Hz, 1H), 3.80 (s, 3H), 1.41 and 1.36 (s, each
3H); 13C NMR (CDCl3): d = 162.5 (M + m), 157.6 (M + m), 129.0
(M + m), 120.8 (M), 120.0 (m), 114.5 (M + m), 114.4 (m), 110.4
(M + m), 85.5 (M + m), 76.1 (M + m), 74.9 (M + m), 66.1 (M),
65.5 (m), 61.8 (M + m), 55.4 (M + m), 26.4 (M), 26.1 (m), 25.4
(M), 25.2 (m) (M = major product; m = minor); IR (CHCl3): m =
3320, 1746, 1564 cm−1; MS (EI): m/z (%): 432 (100) [M + 2]+,
430 (98) [M]+.
Pale orange oil; [a]D = −1.4 (c 0.5 in CH2Cl2); 1H NMR (300 MHz,
CDCl3, 25 ◦C): d = 7.61 and 6.91 (d, J = 8.2 Hz, each 2H), 7.28
and 6.65 (d, J = 9.0 Hz, each 2H), 4.79 (d, J = 3.7 Hz, 1H), 4.35
(m, 1H), 3.68 (dd, J = 8.7, 7.0 Hz, 1H), 3.58 (dd, J = 8.7, 6.5 Hz,
1H), 3.22 (s, 3H), 1.95 (s, 3H), 1.31 and 1.14 (s, each 3H); 13C
NMR (CDCl3): d = 157.7, 157.5, 147.9, 142.1, 136.8, 131.5, 130.2,
129.8, 125.6, 120.2, 115.0, 110.6, 75.3, 66.3, 61.2, 55.3, 26.5, 25.8,
21.6; IR (CHCl3): m = 1745, 1552 cm−1; MS (EI): m/z (%): 424
(49) [M]+, 135 (100); elemental analysis calcd (%) for C23H24N2O6
(424.4): C 65.08, H 5.70, N 6.60; found C 64.70, H 5.36, N 6.35.
Retroaldol/cyclization reaction of 3-[bromonitromethyl]-3-
hydroxy-b-lactam 2a. Preparation of fused bicyclic b-lactam 6
Bismuth(III) chloride (6 mg, 0.02 mmol) was added to a stirred
solution of bromonitroalcohol 2a (168 mg, 0.39 mmol) in
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acetonitrile–water (1 : 1) (6 mL). The reaction mixture was stirred
at room temperature for 3 days, before being poured into a
saturated aqueous solution of NaHCO3. The aqueous layer was
extracted with ethyl acetate (3 × 5 mL), and the combined organic
extracts were dried (MgSO4), and concentrated under reduced
pressure. Recrystallization (ethyl acetate–hexanes) of the residue
gave 69 mg (70%) of compound 6.
(d) The Chemistry of b-Lactams, ed. M. I. Page, Chapman and Hall,
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Bergles, L. Jin, M. D. Hoberg, S. Vidensky, D. S. Chung, S. V. Toan,
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Med. Chem., 2004, 11, 1921; (c) A. R. A. S. Deshmukh, B. M. Bhawal,
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Fused bicyclic 2-azetidinone 6
Colorless solid; mp: 133–135 ◦C (hexanes–ethyl acetate); [a]D
=
+17.5 (c 1.0 in CH3OH); 1H NMR (300 MHz, acetone-d6, 25 ◦C):
d = 7.46 (d, J = 9.2 Hz, 2H), 6.98 (m, 2H), 4.59 (d, J = 3.9 Hz, 1H),
4.45 (t, J = 3.4 Hz, 1H), 4.22 (m, 2H), 3.90 (dd, J = 11.2, 3.4 Hz,
1H), 3.79 (s, 3H); 13C NMR (acetone-d6): d = 163.9, 157.0, 131.0,
118.6, 114.9, 113.2, 74.2, 70.3, 64.5, 55.3; IR (CHCl3): m = 3325,
1744 cm−1; MS (EI): m/z (%): 251 (29) [M]+, 134 (100); elemental
analysis calcd (%) for C12H13NO5 (251.1): C 57.37, H 5.22, N 5.58;
found C 56.95, H 5.06, N 5.25.
Dehydrobromination reaction of 3-[bromonitromethyl]-3-hydroxy-
b-lactam 2a. Preparation of spirocyclic b-lactam 7
5 (a) C. J. Unkefer, R. E. London, R. D. Durbin, T. F. Uchytil and P. J.
Langston-Unkefer, J. Biol. Chem., 1987, 262, 4993; (b) T. D. Meek and
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Potassium carbonate (65 mg, 0.47 mmol) was added to a stirred so-
lution of bromonitroalcohol 2a (168 mg, 0.39 mmol) in methanol
(5 mL). The reaction mixture was stirred at room temperature
for 5 h, before being poured into a saturated aqueous solution of
NH4Cl. The aqueous layer was extracted with ethyl acetate (3 ×
5 mL), and the combined organic extracts were dried (MgSO4),
and concentrated under reduced pressure. Chromatography of the
residue eluting with hexanes–ethyl acetate (3 : 1) gave 82 mg (60%)
of compound 7.
9 As an example, (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid
(norstatine) and (3R,4S)-4-amino-3-hydroxy-5-methylheptanoic acid
(statine) are residues for peptide inhibitors of enzymes, such as renin
and HIV-1 protease; see: (a) S. Thaisrivongs, D. T. Pals, L. T. Kroll,
S. R. Turner and F.-S. Han, J. Med. Chem., 1987, 30, 976; (b) J. R. Huff,
J. Med. Chem., 1991, 34, 2305; moreover, phenylisoserine analogues are
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Kuduk, P. Pera, J. M. Veith and R. J. Bernacki, J. Med. Chem., 1997,
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10 For selected reviews, see: (a) C. Palomo, M. Oiarbide and A. Laso,
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(d) F. A. Luzzio, Tetrahedron, 2001, 57, 915.
Spirocyclic 2-azetidinone 7
Colorless solid; mp: 71–73 ◦C (hexanes–ethylacetate);[a]D = +42.4
(c 0.5 in CH2Cl2); 1H NMR (300 MHz, CDCl3, 25 ◦C): d = 7.49
and 6.90 (d, J = 9.3 Hz, each 2H), 5.77 (s, 1H), 4.56 (m, 1H),
4.40 (d, J = 5.4 Hz, 1H), 4.25 and 4.00 (dd, J = 9.3, 6.5 Hz, each
1H), 3.81 (s, 3H), 1.40 and 1.37 (s, each 3H); 13C NMR (CDCl3):
d = 158.9, 157.4, 130.1, 120.0, 114.3, 110.2, 78.4, 75.4, 69.3, 66.1,
60.9, 55.4, 26.2, 25.3; IR (CHCl3): m = 1745, 1557 cm−1; MS (EI):
m/z (%): 350 (64) [M]+, 101 (100); elemental analysis calcd (%) for
C16H18N2O7 (350.3): C 54.86, H 5.18, N 8.00; found C 54.47, H
5.05, N 7.85.
11 For antibacterial or biocide activities, see: (a) N. G. Clark, B. Croshaw,
B. E. Leggetter and D. F. Spooner, J. Med. Chem., 1974, 17, 977;
(b) N. G. Clark, B. Croshaw, D. F. Spooner (Boots Pure Drug
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Abstr.198610599202; (e) S. Hirabayashi (Konishiroku Photo Industry
Co., Ltd., Japan), Japanese Patent Application, JP 07140620 A2, 1995;
Chem. Abstr.1995123241899.
12 J. M. Concello´n, H. Rodr´ıguez-Solla, C. Concello´n, S. Garc´ıa-Granda
and M. R. D´ıaz, Org. Lett., 2006, 8, 5979.
13 See, for instance: (a) B. Alcaide, P. Almendros and T. Mart´ınez del
Campo, Angew. Chem., Int. Ed., 2007, 46, 6684; (b) B. Alcaide,
P. Almendros, T. Mart´ınez del Campo and R. Rodr´ıguez-Acebes,
Adv. Synth. Catal., 2007, 349, 749; (c) B. Alcaide, P. Almendros, C.
Acknowledgements
Support for this work by the Direccio´n General de Investi-
gacio´n, Ministerio de Educacio´n y Ciencia (DGI-MEC) (Project
CTQ2006–10292), Comunidad Auto´noma de Madrid (CCG-
07-UCM/PPQ-2308 and Universidad Complutense de Madrid
(Grant GR74/07) are gratefully acknowledged.
References and notes
1 See, for example: (a) D. Niccolai, L. Tarsi and R. J. Thomas, Chem.
Commun., 1997, 2333; (b) R. Southgate, Contemp. Org. Synth., 1994,
1, 417; (c) R. Southgate, C. Branch, S. Coulton, E. Hunt, in Recent
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This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1635–1640 | 1639
©

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Aragoncillo and M. C. Redondo, J. Org. Chem., 2007, 72, 1604; (d) B.
Alcaide, P. Almendros, G. Cabrero and M. P. Ruiz, Chem. Commun.,
2007, 4788; (e) B. Alcaide, P. Almendros and T. Mart´ınez del Campo,
Angew. Chem., Int. Ed., 2006, 45, 4501.
refined riding on the respective carbon atoms. Final R(Rw) values were
R1 = 0.0308 and wR2 = 0.0636 [I > 2r(I)]. CCDC-664893 contains
the supplementary crystallographic data for this paper†.
20 The spirocyclic b-lactam framework is an important structural motif
in biologically relevant compounds as natural products and pharma-
ceuticals. Spiro-b-lactams behave as b-turn mimetics, as well as enzyme
inhibitors; they are precursors of a,a-disubstituted b-amino acids, and
the spiranic b-lactam moiety is present in chartellines, a family of
marine natural products. For selected references, see: (a) A. Mac´ıas,
A. Mora´n Ramallal, E. Alonso, C. del Pozo and J. Gonza´lez, J. Org.
Chem., 2006, 71, 7721; (b) H. Bittermann, F. Bo¨ckler, J. Einsiedel and
P. Gmeiner, Chem.–Eur. J., 2006, 12, 6315; (c) P. S. Baran and R. A.
Shenvi, J. Am. Chem. Soc., 2006, 128, 14028; (d) C. Sun, X. Lin and
S. M. Weinreb, J. Org. Chem., 2006, 71, 3159; (e) P. S. Baran, R. A.
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Mac´ıas, E. Alonso, C. del Pozo, A. Venturini and J. Gonza´lez, J. Org.
Chem., 2004, 69, 7004; (g) T. Kambara and K. Tomioka, J. Org. Chem.,
1999, 64, 9282.
14 (a) B. Alcaide, P. Almendros, C. Aragoncillo and R. Rodr´ıguez-Acebes,
J. Org. Chem., 2001, 66, 5208; (b) for a review on the chemistry of
azetidine-2,3-diones, see: B. Alcaide and P. Almendros, Org. Prep.
Proced. Int., 2001, 33, 315.
15 For reviews on organic reactions in aqueous media, see: (a) Or-
ganic Reactions in Water: Principles, Strategies and Applications, ed.
U. M. Lindstro¨m, Blackwell, Oxford, 2007; (b) C. J. Li and L. Chen,
Chem. Soc. Rev., 2006, 35, 68; (c) M. C. Pirrung, Chem.–Eur. J., 2006,
12, 1312; (d) C. J. Li, Chem. Rev., 2005, 105, 3095; (e) U. M. Lindstro¨m,
Chem. Rev., 2002, 102, 2751; (f) K. Manabe and S. Kobayashi, Chem.–
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Oxford University Press, New York, 1998.
21 X-Ray data of 7: crystallized from ethyl acetate–n-hexane at 20 ◦C;
C16H18N2O7 (Mr = 350.32); monoclinic; space group = P2(1); a =
16 (a) B. Alcaide, P. Almendros and C. Aragoncillo, Org. Lett., 2000, 2,
1411; (b) B. Alcaide, P. Almendros and R. Rodr´ıguez-Acebes, J. Org.
Chem., 2002, 67, 1925; (c) B. Alcaide, P. Almendros and C. Aragoncillo,
Chem.–Eur. J., 2002, 8, 1719.
◦
˚
˚
˚
11.0409(11) A, b = 6.1566(6) A; c = 12.5748(13) A; b = 90.669(2)
;
;
V = 854.71(15) A ; Z = 2; Dc = 1.361 mg m−1; l = 0.108 mm−1
3
˚
F(000) = 368. A transparent crystal of 0.45 × 0.09 × 0.08 mm3 was
used. 3333 [R(int) = 0.0405] independent reflections were collected on a
Bruker Smart CCD difractomer using graphite-monochromated Mo-
17 The 3-alkylidene-b-lactam subunit is present in an important class of
compounds which act as hydrolytic deactivators of b-lactamases or
as novel anticancer chemotherapeutic drugs. See: (a) D. K. Tiwari,
A. Y. Shaikh, L. S. Pavase, V. K. Gumaste and A. R. A. S. Deshmukh,
Tetrahedron, 2007, 63, 2524; (b) F. Broccolo, G. Cainelli, G. Caltabiano,
C. E. A. Cocuzza, C. G. Fortuna, P. Galletti, D. Giacomini, G.
Musumarra, R. Musumeci and A. Quintavalla, J. Med. Chem., 2006,
49, 2804; (c) M. Adinolfi, P. Galletti, D. Giacomini, A. Iadonisi, A.
Quintavalla and A. Ravida`, Eur. J. Org. Chem., 2006, 69; (d) D. Kuhn,
C. Coates, K. Daniel, D. Chen, M. Bhuiyan, A. Kazi, E. Turos and
Q. P. Dou, Front. Biosci., 2004, 9, 2605.
˚
Karadiation (k = 0.71073 A) operating at 50 kV and 30 mA. Data were
collected over a hemisphere of the reciprocal space by combination
of three exposure sets. Each exposure of 20 s covered 0.3 in x. The
cell parameters were determined and refined by a least-squares fit of
all reflections. The first 100 frames were recollected at the end of the
data collection to monitor crystal decay, and no appreciable decay was
observed. The structure was solved by direct methods and Fourier
synthesis. It was refined by full-matrix least-squares procedures on F2
(SHELXL-9725). All non-hydrogen atoms were refined anisotropically.
The hydrogen atoms H4, H5 and H10, bonded to C4, C5 and C10,
have been located in a Fourier synthesis, included and refined. The
rest of the hydrogen atoms were included in calculated positions and
refined riding on the respective carbon atoms. Final R(Rw) values were
R1 = 0.0410 and wR2 = 0.0864 [I > 2r(I)]. CCDC-664894 contains
the supplementary crystallographic data for this paper†.
18 For a review on the synthesis and biological properties of bicyclic b-
lactams with nonclassical structures, see: B. Alcaide and P. Almendros,
Curr. Org. Chem., 2002, 6, 245.
19 X-Ray data of 6: crystallized from ethyl acetate–n-hexane at 20 ◦C;
C12H13NO5 (Mr = 251.23); orthorhombic; space group = P2(1)2(1)2(1);
˚
˚
˚
a = 6.5660(5) A, b = 7.3847(6) A; c = 24.1727(19) A; V
=
1172.08(16) A ; Z = 4; Dc = 1.424 mg m−3; l = 0.112 mm−1; F(000) =
528. A transparent crystal of 0.43 × 0.31 × 0.07 mm3 was used.
2296 [R(int) = 0.0374] independent reflections were collected on a
Bruker Smart CCD difractomer using graphite-monochromated Mo-
22 Although we have tried to separate these diastereomers (anti-2a–d
and syn-2a–d), we failed to separate them. Therefore, we reported
1H and 13C NMR spectroscopic data for the mixture of diastere-
omers of 2a–d. Ratios of diastereomers of anti-2a–d and syn-2a–d
were determined on the basis of the integration ratio of separated
peaks.
23 Taking into account that 3-[bromonitromethyl]-3-hydroxy-b-lactam 2a
could be obtained and cyclized to spirocyclic oxiranyl-b-lactam 6,
the relative stereochemistry at the bromohydrin stereogenic centers
for major compounds 2 was immediately deduced because epoxide
formation requires an anti arrangement of the nucleophile and the
leaving group.
3
˚
˚
Karadiation (k = 0.71073 A) operating at 50 kV and 25 mA. Data were
collected over a hemisphere of the reciprocal space by combination
of three exposure sets. Each exposure of 20 s covered 0.3 in x. The
cell parameters were determined and refined by a least-squares fit of
all reflections. The first 100 frames were recollected at the end of the
data collection to monitor crystal decay, and no appreciable decay
was observed. The structure wassolved by direct methods and Fourier
synthesis. It was refined by full-matrix least-squares procedures on F2
(SHELXL-9725). All non-hydrogen atoms were refined anisotropically.
The hydrogen atoms H2, H3, H3a and H6, bonded to C2, O3, C3 and
O6, have been located in a Fourier synthesis, included and refined. The
rest of the hydrogen atoms were included in calculated positions and
24 Full spectroscopic and analytical data for all compounds are given in
the supporting information†.
25 G. M. Sheldrick, SHELXL-97, Program for refinement of crystal
structures, University of Go¨ttingen, Germany, 1997.
1640 | Org. Biomol. Chem., 2008, 6, 1635–1640
This journal is
The Royal Society of Chemistry 2008
©