Rhodium-catalyzed synthesis of 3-hydroxy-β-lactams via oxonium ylide generation: Three-component reaction between azetidine-2,3-diones, ethyl diazoacetate, and alcohols

Article abstract of DOI:10.1021/jo9019013

(Chemical Equation Presented) 3-Substituted-3-hydroxy-β-lactams, with two new adjacent stereogenic centers, have been prepared in a single step by a rhodium-catalyzed, three-component reaction between azetidine-2,3-diones, ethyl diazoacetate, and alcohols

Full text of DOI:10.1021/jo9019013

pubs.acs.org/joc
and is present in several pharmacologically active mono-
Rhodium-Catalyzed Synthesis of 3-Hydroxy-
β-lactams via Oxonium Ylide Generation:
Three-Component Reaction between Azetidine-2,
3-diones, Ethyl Diazoacetate, and Alcohols
bactams such as sulfacezin and related products3 and in
enzyme inhibitors such as tabtoxin and its analogues.4 In
addition, these compounds are precursors of therapeutically
important compounds.5
On the other hand, the chemistry of diazo compounds is a
prolific area and a wide variety of literature has been
reported.6 In this context, the chemistry of carbonyl, phos-
phorus, sulfur, and ammonium ylides has been widely em-
ployed in organic synthesis.7
Benito Alcaide,*,† Pedro Almendros,‡ Cristina Aragoncillo,†
Ricardo Callejo,† M. Pilar Ruiz,† and M. Rosario Torres§
†
´
´
Departamento de Quımica Organica I, Facultad de Quımica,
ꢀ
Universidad Complutense, 28040-Madrid, Spain, ‡Instituto de
Multicomponent reactions (MCR) are a straightforward
synthetic tool to obtain structural complexity from three or
more reactants in a single reaction process, with greater
efficiency and atom economy.8 Recently, Hu has described
a novel reaction involving the Rh(II)-catalyzed aldol-type
three-component reaction of methyl phenyldiazoacetate
with an alcohol and an aldehyde(imine) providing a synthetic
route to access highly substituted hydroxy(amino) acid
skeletons with several quaternary centers in a single step
(Scheme 1).9 Of particular interest was the reaction with
isatins as the carbonyl component.9d
´
Quımica Organica General, CSIC, Juan de la Cierva 3, 28006-
Madrid, Spain, and Laboratorio de Difraccion de Rayos X.
ꢀ
§
ꢀ
´
Facultad de Quımica, Universidad Complutense, 28040-
Madrid, Spain
alcaideb@quim.ucm.es
Received September 11, 2009
Continuing with our work on the asymmetric synthesis of
nitrogenated compounds of biological interest,10 in this
contribution we report the synthesis of 3-substituted-3-hy-
droxy-β-lactams with two new adjacent stereogenic centers
in a single step via an efficient and stereoselective trapping of
oxonium ylide with azetidine-2,3-diones.
(6) (a) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577. (b) Wee, A. G. H.
Curr. Org. Synth. 2006, 3, 499.
3-Substituted-3-hydroxy-β-lactams, with two new adja-
cent stereogenic centers, have been prepared in a single
step by a rhodium-catalyzed, three-component reaction
between azetidine-2,3-diones, ethyl diazoacetate, and
alcohols. Good to moderate stereoselectivity was ob-
tained depending on the alcohol used. The stereochemis-
try of the new centers has been undoubtedly assigned by
single crystal X-ray diffraction.
(7) For carbonyl ylides, see: (a) Doyle, M. P.; Mckervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with Diazo Compounds;
Wiley: New York, 1998. (b) Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev.
1997, 97, 2341. (c) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(d) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. For phosphonium
ylides, see: (e) Aggarwal, V. K.; Fulton, J. R.; Sheldon, C. G.; Vicente, J. D. J. Am.
Chem. Soc. 2003, 125, 6034. (f) Maryanoff, B. E.; Retiz, A. B. Chem. Rev. 1989,
89, 863. For oxonium ylides, see: (g) Tester, R. W.; West, F. G. Tetrahedron Lett.
1998, 39, 4631. (h) West, F. G.; Eberlein, T. H.; Tester, R. W. J. Chem. Soc.,
Perkin Trans. 1 1993, 2857. (i) Pirrung, M. P.; Werner, J. A. J. Am. Chem. Soc.
1986, 108, 6060. (j) Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Stull, P. D.
J. Org. Chem. 1989, 54, 817. For ammonium ylides, see: (k) West, F. G.; Naidu,
B. N. J. Am. Chem. Soc. 1993, 115, 1177. (l) Doyle, M. P.; Bagheri, V.; Claxton,
E. E. J. Chem. Soc., Chem. Commun. 1990, 46. (m) Doyle, M. P.; Tamblyn, W.
H.; Bagheri, V. J. Org. Chem. 1981, 46, 5094.
The 3-substituted-3-hydroxy-β-lactam skeleton represents
an efficient carboxylate mimic,1 showing a promising acti-
vity in acyl CoA-cholesterol acyltransferase inhibition assays,2
ꢀ
(8) For reviews of multicomponent reaction, see: (a) Toure, B. B.; Hall,
D. G. Chem. Rev. 2009, 109, 4439. (b) Ganem, B. Acc. Chem. Res. 2009, 42,
ꢀ
463. (c) Guillena, G.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2007,
18, 693. (d) Domling, A. Chem. Rev. 2006, 106, 17. (e) Nair, V.; Rajesh, C.;
€
Vinod, A. U.; Bindu, S.; Streekenth, A. R.; Balagopal, L. Acc. Chem. Res.
ꢀ
*To whom correspondence should be addressed.
2003, 36, 899. (f) Multicomponent Reactions: Zhu, J., Bienayme, H., Eds.;
(1) (a) Unkefer, C. J.; London, R. E.; Durbin, R. D.; Uchytil, T. F.;
Langston-Unkefer, P. J. J. Biol. Chem. 1987, 262, 4993. (b) Meek, T. D.;
Villafranca, J. V. Biochemistry 1980, 19, 5513. (c) Sinden, S. L.; Durbin, R. D.
Nature 1968, 219, 379.
(2) Benfatti, F.; Cardillo, G.; Gentilucci, L.; Perciccante, R.; Tolomelli,
A.; Catapano, A. J. Org. Chem. 2006, 71, 9229.
(3) Imada, A.; Gitano, K.; Kintana, K.; Muroi, M.; Asai, M. Nature
1981, 289, 590.
(4) (a) Dolle, R. E.; Hughes, M. J.; Li, C.-S.; Kruse, L. I. J. Chem. Soc.,
Chem. Commun. 1989, 1448. (b) Greenlee, W. J.; Springer, J. P.; Patchett,
A. A. J. Med. Chem. 1989, 32, 165. (c) Baldwin, J. E.; Otsuka, M.; Wallce,
P. M. Tetrahedron 1986, 42, 3097.
(5) As an example, (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid
(norstatine) and (3R,4S)-4-amino-3-hydroxy-5-methylheptanoic acids (statine)
are residues for peptide inhibitors of enzymes such as rennin and HIV protease.
For rennin, see: Thaisrivongs, S.; Pals, D. T.; Kroll, L. T.; Turner, S. R.; Han,
F.-S. J. Med. Chem. 1987, 30, 976. For HIV protease, see: Huff, J. R. J. Med.
Chem. 1991, 34, 2305.
Wiley: Weinheim, Germany, 2005.
(9) (a) Zhu, Y.; Zhai, C.; Yue, Y.; Yang, L.; Hu, W. Chem. Commun.
2009, 1362. (b) Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang, H.; Hu, J.; Yang,
L.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 7782. (c) Huang, H.; Guo, X.;
Hu, W. Angew. Chem., Int. Ed. 2007, 46, 1337. (d) Guo, X.; Huang, H.; Yang,
L.; Hu, W. Org. Lett. 2007, 9, 4721. (e) Lu, C.; Liu, H.; Chen, Z.; Hu, W.; Mi,
A. Org. Lett. 2005, 7, 83. (f) Huang, H.; Wang, Y.; Chen, Z.; Hu, W. Adv.
Synth. Catal. 2005, 347, 531. (g) Wang, Y.; Chen, Z.; Mi, A.; Hu, W. Chem.
Commun. 2004, 2486. (h) Wang, Y.; Zhu, Y.; Chen, Z.; Mi, A.; Hu, W.;
Doyle, M. P. Org. Lett. 2003, 5, 3923.
(10) See, for instance: (a) Alcaide, B.; Almendros, P.; Martınez del
´
ꢀ
Campo, T.; Quiros, M. T. Chem.;Eur. J. 2009, 15, 3344. (b) Alcaide, B.;
Almendros, P.; Aragoncillo, C.; Cabrero, G.; Callejo, R.; Ruiz, M. P. Eur. J.
Org. Chem. 2008, 4434. (c) Alcaide, B.; Almendros, P.; Martı
T. Angew. Chem., Int. Ed. 2007, 46, 6684. (d) Alcaide, B.; Almendros, P.;
Martınez del Campo, T.; Rodrıguez-Acebes, R. Adv. Synth. Catal. 2007, 349,
´
nez del Campo,
´
´
749. (e) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Chem.
Commun. 2007, 4788.
DOI: 10.1021/jo9019013
r
Published on Web 10/15/2009
J. Org. Chem. 2009, 74, 8421–8424 8421
2009 American Chemical Society

Alcaide et al.
JOCNote
SCHEME 1. Trapping of Oxonium Ylides with Aldehydes and
Imines
reaction with methanol. Thus, reaction of azetidine-2,3-dione
1a in the presence of 1 equiv of ethyl diazoacetate and 1 equiv
of methanol under rhodium catalysis (1 mol %) cleanly
afforded 3-substituted-3-hydroxy-β-lactam 3a with good dia-
stereoselectivity (syn:anti, 90:10) in high yield (88%). Fortu-
natelly, both isomers were separated by flash chromatography.
When azetidine-2,3-diones (-)-1b and (()-1d were used in-
stead of the R-keto β-lactam (þ)-1a, the reactions proceeded in
a similar manner, giving the corresponding polysubstituted-
β-lactams 3 with a slight reduction in yield and selectivity
(entries 2 and 3, Table 1). Comparable yields and selectivities
were obtained when other primary alcohols were tested, as allyl
alcohol (see entry 4, Table 1); however, β-lactam 3d was
obtained as an inseparable mixture of syn:anti diastereomers
(85:15). Replacing Rh2(OAc)4 by affordable Cu(acac)2 did not
improve the reactivity of the azetidine-2,3-diones 1. In fact,
lower yield and selectivity were observed along with longer
reaction times (see entry 5, Table 1). Interestingly, reaction of
azetidine-2,3-diones (þ)-1a and (()-1d with a more hindered
alcohol (i-PrOH) in the conditions described above gave the
corresponding alcohols 3e and 3f in similar reaction times with
a slight decrease of the diastereoselectivity (see entries 6 and 7,
Table 1). However, when the three-component reaction of
azetidine-2,3-diones 1 was carried out with tert-butanol, addi-
tion of a second batch of ethyl diazoacetate and tert-butanol
was necessary to obtain full conversion with a slight decrease of
the diastereomeric excess in alcohols 3 (see entries 8 and 9,
Table 1). A dramatic reduction of the selectivity (57:43-56:44)
was observed when the reaction was carried out in ketones 1
with water (see entries 10, 11, and 12, Table 1). Probably, the
high reactivity of the oxonium ylide generated is responsible
for the low diastereoselectivity observed in these experiments.
When titanium(IV) isopropoxide was used instead alco-
hols,13 the corresponding 3-hydroxy-β-lactams 3 were obta-
ined, with a notable change in the selectivity being the anti-
isomer as the major product of the reaction (see entries 13
and 14, Table 1).
The stereoselectivity at the new stereogenic center C3 is
believed to be controlled by the bulky substituent at C4; one
face of the carbonyl group is blocked and thus the oxonium
ylide preferentially approaches the less hindered face.10c The
stereochemical outcome of the overall addition reaction of
oxonium ylides to azetidine-2,3-diones can be rationalized
by the five-membered cyclic transition states TS1 and TS2
(Scheme 4). Thus, interaction of the ethoxycarbonyl group of
the oxonium ylide with H4 of the β-lactam would determine
the reaction to take place mainly through TS1, affording the
syn-isomer. However, the opposite selectivity observed in the
reaction with titanium(IV) isopropoxide would be explained
via transition states TS3 and TS4. In this case, chelation of
the titanium atom to both carbonyl functionalities of azeti-
dine-2,3-dione and the ester group via TS4 would explain the
preferential formation of the anti-isomer.
The starting materials, azetidine-2,3-diones 1a-c, have
been efficiently prepared in optically pure form from aro-
matic or aliphatic (R)-2,3-O-isopropylideneglyceraldehyde-
derived imines by Staudinger reaction with acetoxyacetyl
chloride in the presence of Et3N, followed by sequential
transesterification and Swern oxidation, as we have pre-
viously reported.11 Racemic azetidine-2,3-dione 1d has been
prepared from a tolyl-derived imine following our previous
procedure.12 First, the nucleophilic addition of azetidine-2,3-
diones 1 with ethyl diazoacetate in the presence of catalytic
amounts of DBU affording the corresponding addition
products 2 in moderate to good yields has been investigated
(Scheme 2). Incorporation of the diazo functionality to
3-hydroxy-β-lactams 2 was confirmed by IR spectroscopy
(2100-2110 cm-1). Interestingly, under basic conditions, no
epimerization of the starting ketones was observed.
SCHEME 2. Nucleophilic Addition of Ethyl Diazoacetate to
Azetidine-2,3-diones 1 (PMP = 4-MeOC6H4)
Our initial aim was to explore the reactivity of diazo-
β-lactams 2 in the presence of alcohols and catalytic amounts
of Rh2(OAc)4 in order to obtain the corresponding insertion
products. Thus, treatment of diazo-β-lactam (-)-2a in metha-
nol with a catalytic amount of Rh2(OAc)4 at 0 °C gave 3a as a
mixture of syn/anti isomers in a 60:40 ratio in very low yield
(Scheme 3).
SCHEME 3. Insertion Reaction of Diazo-β-lactam 2a with
MeOH Catalyzed by Rh2(OAc)4
Due to the unsuccessful result obtained under the above
sequential conditions, we decided to test the reaction of
azetidine-2,3-diones 1 under the three-component conditions.9
For our first experiment we chose azetidine-2,3-dione (þ)-1a
as a model system for the study of the three-component
Configurational assignment for adducts syn- and anti-3 was
achieved by derivatization to the corresponding acetonides 4
(Scheme 5). Treatment of enantiomerically pure syn-3i, anti-3i,
syn-3j, and anti-3j in the presence of 2,2-dimethoxypropane and
catalytic amounts of pyridinium p-toluenesulfonate at reflux
temperature provided the expected acetonides syn- and anti-4 in
(11) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Rodrıguez-Acebes,
´
R. J. Org. Chem. 2001, 66, 5208. For a review on the chemistry of azetidine-
2,3-diones, see: (b) Alcaide, B.; Almendros, P. Org. Prep. Proced. Int. 2001,
33, 315.
(12) Alcaide, B.; Almendros, P.; Carrascosa, R.; Redondo, M. C.
Chem.;Eur. J. 2008, 14, 637.
(13) Lu, C.-D.; Liu, H.; Chen, Z.-Y.; Hu, W.-H.; Mi, A.-Q. Chem.
Commun. 2005, 2624.
8422 J. Org. Chem. Vol. 74, No. 21, 2009

Alcaide et al.
JOCNote
TABLE 1. Rh(II)-Catalyzed Three-Component Reaction of Azetidine-2,3-diones 1a-d, Ethyl Diazoacetate, and Alcohols
entry
substrate
R1
PMPa
Allyl
R2
R3
reagent
MeOH
catalysti
t (h)d
product
syn/anti
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(þ)-1a
(-)-1b
(()-1d
(þ)-1a
(þ)-1a
(þ)-1a
(()-1d
(þ)-1a
(()-1d
(þ)-1a
(()-1d
(-)-1c
(þ)-1a
(()-1d
Dioxb
Me
Me
Me
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
7
28
24
21
48
7
24
46
44
4
3a
3b
3c
3d
3a
3e
3f
3g
3h
3i
90:10e
86:14f
85:15e
85:15 f
67:33e
75:25e
81: 19e
75:25e
65:35e
56: 44 f
56:44 f
57:43 f
37:63e
40:60e
80:8g
Dioxb
MeOH
MeOH
Allyl alcohol
MeOH
i-PrOH
i-PrOH
t-BuOH
t-BuOH
H2O
H2O
H2O
Ti(i-PrO)4
Ti(i-PrO)4
46:8 g
60:11 g
67 h
PMPa
PMPa
PMPa
PMPa
PMPa
PMPa
PMPa
PMPa
PMPa
Bn
4-MeC6H4
Dioxb
2-propenyl
Me
Dioxb
Cu(acac)2
49:23 g
62:14
68:16
c
Dioxb
i-Pr
i-Pr
t-Bu
t-Bu
H
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
4-MeC6H4
Dioxb
4-MeC6H4
Dioxb
60 h
43:23 g
37:29 g
37:29 g
40:30 g
23:47 g
26:54 g
4-MeC6H4
Dioxb
H
H
i-Pr
i-Pr
7
7
2.5
6
3j
3k
3e
3f
PMPa
Dioxb
4-MeC6H4
PMPa
aPMP = 4-MeOC6H4. bDiox = 2,2-dimethyl-1,3-dioxolan-4-yl. cacac = acetylacetonate. dReaction progress was followed by TLC. eThe ratio was
determined by integration of well-resolved signals in the 1H NMR spectra (300 MHz) of the crude reaction mixtures before purification. fThe ratio was
determined by integration of well-resolved signals in the 1H NMR spectra (300 MHz) of the crude reaction mixtures after purification. gYield of pure,
isolated isomers with correct analytical and spectral data. hYield of pure, isolated mixture of isomers. iRh2(OAc)4 (1 mol %); Cu(acac)2 (10 mol %).
SCHEME 4. Rationalization of the Selectivity Observed in the Three-Component Reaction of Azetidine-2,3-diones 1 via TS1-TS4
excellent yields. The structures and configurations of com-
pounds 2-4 were established by one- and two-dimensional
NMR techniques. The configuration at C30 for isomers syn- and
anti-4a was deduced by comparison of NOE experiments.14
This structural and configurational assignment was confirmed
by X-ray diffraction analysis of compounds syn-(()-3f15
(Figure S1 in the SI) and syn-(-)-3k (Figure S3 in the SI).16
In conclusion, we have presented a new synthesis of den-
sely functionalized enantiopure 3-substituted-3-hydroxy-β-lactams
via a three-component reaction between azetidine-2,3-diones,
(14) Selected NOE enhancements are collected in the Supporting Informa-
tion. NOE irradiation of H30 in syn-(þ)-4aresulted in enhancement of the signal
corresponding to H4 (3%). Conversely, the same NOE enhancement was
observed for H30 upon irradiation of H4, which is consistent with a syn relative
stereochemistry between H4 and H30 and R configuration at C30. A NOE
enhancement of 0.2% for H4 in anti-(þ)-4a on irradiating the signal corre-
sponding to H30 is in good agreement with an anti relative disposition between
H30 and H4 in anti-(þ)-4a (S configuration at the new stereogenic center at C30).
(15) X-ray data of syn-(()-3f: crystallized from n-hexane/CH2Cl2 at 20 °C;
C
24H29NO6 (Mr = 427.48); triclinic; space group = P1; a = 9.2178(10) A,
(16) X-ray data of syn-(-)-3k: crystallized from n-hexane/CH2Cl2 at 20 °C;
C19H25NO7 (Mr = 379.40); orthorhombic; space group = P2(1)2(1)2(1)/n; a =
5.5776(7) A, b = 13.9511(17) A, c = 25.656(3) A; R = 90°, β = 90°, γ = 90°;
V = 1996.4(4) A3; Z = 4; Fcalcd = 1.262 mg m-3; μ = 0.096 mm-1; F(000) =
808. A transparent crystal of dimensions 0.45 ꢀ 0.07 ꢀ 0.04 mm3 was used; 3507
[R(int) = 0.1120] independent reflections were collected. Data were collected
[Mo KR radiation (λ = 0.71073 A)] over a hemisphere of the reciprocal space by
combination of three exposure sets. Each exposure of 20 and 30 s covered 0.3 in γ.
The structure was solved by direct methods and Fourier synthesis. It was refined
by full-matrix least-squares procedures on F2 (SHELXL-97). The non-hydrogen
atoms were refined anisotropically. The hydrogen atoms were refined only in
terms of their coordinates. CCDC-739824 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/deposit.
h
b = 10.9974(12) A, c = 12.3831(13) A; R = 79.964(2)°, β = 71.839(2)°, γ =
89.979(2)°; V = 1172.6(2) A3; Z = 2; Fcalcd = 1.211 mg m-3; μ = 0.087 mm-1
;
F(000) = 456. A transparent crystal of dimensions 0.35 ꢀ 0.17 ꢀ 0.17 mm3 was
used; 4016 [R(int) = 0.0425] independent reflections were collected. Data were
collected [Mo KR radiation (λ = 0.71073 A)] over a hemisphere of the
reciprocal space by combination of three exposure sets. Each exposure of
20 and 30 s covered 0.3 in γ. The structure was solved by direct methods and
Fourier synthesis. It was refined by full-matrix least-squares procedures on F2
(SHELXL-97). The non-hydrogen atoms were refined anisotropically. The
hydrogen atoms were refined only in terms of their coordinates. CCDC-739823
containsthe supplementary crystallographicdatafor thispaper. Thesedatacan
be obtained free of charge from the Cambridge Crystallographic Data Center
via www.ccdc.cam.ac.uk/deposit.
J. Org. Chem. Vol. 74, No. 21, 2009 8423

Alcaide et al.
JOCNote
SCHEME 5. Synthesis of Acetonides 4
chromatography (n-hexane/ethyl acetate 3:1) 56 mg (80%) of the
less polar compound syn-(þ)-3a and 6 mg (8%) of the more polar
compound anti-(þ)-3a were obtained. syn-(þ)-3a: Colorless oil.
1
[R]D þ108.4 (c 1.2, CHCl3). H NMR (300 MHz) δ 1.34, 1.44,
3.40, 3.79 (s, 3H each), 1.34 (t, 3H, J = 7.1 Hz), 3.80 (dd 1H, J =
8.6, 7.1 Hz), 4.12 (s, 1H), 4.18 (dd, 1H, J = 8.7, 6.6 Hz), 4.31
(m, 2H), 4.42 (q, 1H, J = 7.2 Hz), 4.58 (d, 1H, J = 6.6 Hz), 4.96
(br s, 1H), 6.85 (AA0XX0, 2H), 7.54 (AA0XX0, 2H). 13C NMR
(75 MHz) δ 170.1, 165.9, 156.8, 130.4, 120.4, 114.0, 109.7, 84.3,
79.8, 76.3, 66.4, 62.7, 61.8, 58.8, 55.4, 26.4, 25.3, 14.2. IR (CHCl3,
cm-1) ν 3314, 1731. EM-IE (m/z) 409 (Mþ•, 30), 149 ([PMP -
NdCdO]þ•, 100). HRMS (ESI) for C20H27NNaO8 (M þ Na)
calcd 432.1634, found 432.1629. anti-(þ)-3a: Colorless oil.
1
[R]D þ81.7 (c 0.2, CHCl3). H NMR (700 MHz) δ 1.18 (t, 3H,
ethyl diazoacetate, and alcohols in the presence of a catalytic
amount of Rh2(OAc)4.
J = 7.2 Hz), 1.34, 1.48, 3.55, 3.80 (s, 3H each), 3.76 (dd, 1H, J =
8.7, 6.4 Hz), 3.89 (br s, 1H), 4.10 (s, 1H), 4.12-4.23 (m, 3H), 4.30
(d, 1H, J = 7.2 Hz), 4.42 (q, 1H, J = 6.9 Hz), 6.86 (AA0XX0, 2H),
7.59 (AA0XX0, 2H). 13C NMR (175 MHz) δ 168.9, 164.2, 156.6,
130.7, 119.8, 114.0, 109.9, 84.2, 80.8, 76.6, 66.5, 63.5, 62.2, 59.5,
55.4, 26.5, 25.0, 14.0. IR (CHCl3, cm-1) ν 3350, 1747. HRMS
(ESI) for C20H28NO8 (M þ H) calcd 410.1815, found 410.1803.
Experimental Section
General. The same experimental techniques were used as
previously reported.10b
General Procedure for the Synthesis of 3-Hydroxy-3-substi-
tuted β-Lactams 5 via Multicomponent Reaction: Method A. To a
refluxed solution of azetidine-2,3-dione 1 (1 mmol) in anhy-
drous dichloromethane (10 mL) were added the corresponding
alcohol or water (1.2 mmol), Rh2(OAc)4 (0.01 mmol), and ethyl
diazoacetate (1.2 mmol). After 2 h, a second batch of alcohol or
water (1.2 mmol) and ethyl diazoacetate (1.2 mmol) were added.
Then, the reaction mixture was heated under reflux until com-
plete disappearance of the starting material (TLC). The reaction
mixture was allowed to cool to room temperature and filtered
off over a short path of Celite. The solvent was removed under
reduced pressure and the residue was purified by flash chroma-
tography.
ꢀ
Acknowledgment. We would like to thank the Direccion
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General de Investigacion, Ministerio de Educacion y Ciencia
(DGI-MEC) (Project CTQ2006-10292), and the Universi-
dad Complutense UCM-BSCH (Grant GR58/08) for finan-
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cial support. C.A. thanks the MEC for a Ramon y Cajal
contract cofinanced by the European Social Fund. R.C.
thanks the MEC for a predoctoral grant.
Supporting Information Available: Compound character-
ization data and experimental procedures for compounds 2a-c,
3b-k, 4a, and 4b, as well as X-ray data for compounds syn-(()-
3f and syn-(-)-3k. This material is available free of charge via
the Internet at http://pubs.acs.org.
3-Hydroxyazetidine-2-one 3a: Method A. From 50 mg (0.17 mmol)
of azetidine-2,3-dione (þ)-1a, compound 3a was obtained
as a mixture of isomers in a syn/anti ratio (90:10). After flash
8424 J. Org. Chem. Vol. 74, No. 21, 2009