Asymmetric hetero Diels-Alder as an access to carbacephams

Article abstract of DOI:10.1021/jo016186h

A short and efficient asymmetric synthesis of the (6R,7S)-7-tert-butoxycarbonylamino-2-ketocarbacepham is described. The key step involves the hetero Diels-Alder reaction of the benzylimine derived from the enantiomer of Garner's aldehyde with Danishefsky's diene.

Full text of DOI:10.1021/jo016186h

598
J . Org. Chem. 2002, 67, 598-601
ring onto a â-lactam, using different reactions.6 Never-
Asym m etr ic Heter o Diels-Ald er a s a n
theless, the construction of the six-membered ring fol-
lowed by the formation of the â-lactam ring has only been
found in a few examples of carbacepham synthesis.4e,5a,7
Using the above-mentioned strategy, we describe here
an efficient approach to asymmetric synthesis of the
carbacepham 1, using as key step the hetero Diels-Alder
reaction (HDA) of the benzylimine derived from the
enantiomer of Garner’s aldehyde with Danishefsky’s
diene.
Access to Ca r ba cep h a m s
Alberto Avenoza,* J esu´s H. Busto, Carlos Cativiela,†
Francisco Corzana, J esu´s M. Peregrina,* and
Mar´ıa M. Zurbano
Departamento de Quı´mica, Universidad de La Rioja
Grupo de S´ıntesis Quı´mica de La Rioja, U.A.-C.S.I.C.,
26006 Logron˜o, Spain
The piperidine ring formed in the HDA possesses the
appropriate stereochemistry at the stereogenic center,
which would allow the cis substitution at C-6 and C-7
required in the carbacepham system, according to the
literature, and directly related to the biological activity
of the carbacephems.2a Moreover, the carbonyl group at
C-2 can be conveniently used to prepare further carba-
cephem or carbacepham derivatives.
alberto.avenoza@dq.unirioja.es
Received October 9, 2001
Abstr a ct: A short and efficient asymmetric synthesis of the
(6R,7S)-7-tert-butoxycarbonylamino-2-ketocarbacepham is
described. The key step involves the hetero Diels-Alder
reaction of the benzylimine derived from the enantiomer of
Garner’s aldehyde with Danishefsky’s diene.
The bacterial resistance to cephalosporins (cephems),
caused by their widespread use during the past decades,1
has motivated a growing interest in the preparation and
biological evaluation of the new types of â-lactams. In
this sense, carbacephalosporins (carbacephems) are known
to exhibit antibiotic activity and increased chemical
stability compared to cephalosporins.2 In particular,
Loracarbef is the first example of this new class of
antibiotics that has been marketed.3
Carbacephems are generally obtained from function-
alized carbacephams.4 In this sense, the significance of
carbacephams is due not only to the role they play as
precursors of carbacephems but also to the fact that they
are interesting compounds to investigate the biological
behavior of â-lactam antibiotics.5
Because of the importance of functionalized pipe-
ridines, contained in numerous physiologically active
compounds,8 a considerable synthetic effort has been
made toward the preparation of these systems.9 In this
context, the HDA of C-N double bonds with carbon
dienes is probably one of the most efficient routes toward
substituted piperidines.9,10
However, the asymmetric version of this reaction has
been developed very lately, in the past decade, and has
been recently reviewed.11 In this sense, there are few
examples of asymmetric HDA with unactivated chiral
imines in which the chiral matrix is the carbonyl moiety;
therefore, to the best of our knowledge, we report here
the first example of an asymmetric HDA with an unac-
tivated imine derived from a chiral R-aminoaldehyde.
Imine 2 was prepared from the enantiomer of Garner’s
aldehyde12 and benzylamine in the presence of anhydrous
magnesium sulfate, conditions where enantiomerization
at the stereogenic center is not observed.13 This crude
imine 2 reacts with Danishefsky’s diene, in the presence
of a Lewis acid catalyst and dichloromethane as solvent,
Most synthetic approachs to carbacephem or the car-
bacepham ring system involve appending a six-membered
* Author to whom correspondence should be addressed. Fax: +34
941 299621.
† Departamento de Qu´ımica Orga´nica, Instituto de Ciencia de
Materiales de Arago´n, Universidad de Zaragoza-C.S.I.C., 50009 Zara-
goza, Spain.
(6) The Organic Chemistry of â-Lactams; George, G. I., Ed.; VCH
Press: New York, 1993.
(7) Berrien, J .-F.; Billion, M.-A.; Husson, H.-P.; Royer, J . J . Org.
Chem. 1995, 60, 2922.
(1) Neu, H. C. Science 1992, 257, 1064.
(2) (a) Cooper, R. D. G. In The Chemistry of â-Lactams; Page, M. I.,
Ed.; Blackie Academic & Professional: New York, 1992; chapter 8,
pages 273-305. (b) Cooper, R. D. G.; Preston, D. A. Exp. Opin. Invest.
Drugs 1994, 3, 831.
(3) Doern, G. V.; Vantour, R.; Parker, D.; Tubert, T.; Torre, B.
Antimicrob. Agents Chemother. 1991, 35, 1504.
(4) (a) Oumoch, S.; Rousseau, G. Bioorg. Med. Chem. Lett. 1994, 4,
2841. (b) Ciufolini, M. A.; Dong, Q. Chem. Commun. 1996, 881. (c)
Feigelson, G. B. Tetrahedron Lett. 1998, 39, 3387. (d) Crocker, P. J .;
Miller, M. J . J . Org. Chem. 1995, 60, 6176. (e) Folmer, J . J .; Acero, C.;
Thai, D. L.; Rapoport, H. J . Org. Chem. 1998, 63, 8170.
(5) (a) Maison, W.; Kosten, M.; Charpy, A.; Kintscher-Langenhagen,
J .; Schlemminger, I.; Lu¨tzen, A.; Westerhoff, O.; Martens, J . Eur. J .
Org. Chem. 1999, 2433. (b) Page, A. I.; Laws, A. P. Chem. Commun.
1998, 1609. (c) Toda, F.; Miyamoto, H.; Matsukawa, R. J . Chem. Soc.,
Perkin Trans. 1 1992, 1461.
(8) (a) Daly, J . W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1993; Vol. 43, p 185.
(b) Tietze, L. F.; Kettschau, G. In Topics in Current Chemistry; Metz,
P., Ed.; Springer-Verlag: Berlin, 1997; Vol. 189, pp 1-120. (c) Boger,
D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic
Synthesis; Wasserman, H. H., Ed.; Academic Press: San Diego, CA,
1987; Vol. 47.
(9) (a) Laschat, S.; Dickner, T. Synthesis 2000, 1781 and references
therein. (b) Comins, D. L.; Fulp, A. B. Tetrahedron Lett. 2001, 42, 6839.
(c) Comins, D. L.; Hiebel, A.-C.; Huang, S. Org. Lett. 2001, 3, 769.
(10) Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321.
(11) (a) Waldmann, H. Synthesis 1994, 535. (b) J orgensen, K. A.
Angew. Chem., Int. Ed. 2000, 39, 3558. (c) Buonora, P.; Olsen, J .-C.;
Oh, T. Tetrahedron 2001, 57, 6099.
(12) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J . M.;
Zurbano, M. M. Synthesis 1997, 1146.
10.1021/jo016186h CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/22/2001

Notes
Sch em e 1. HDA Rea ction of Im in e 2 w ith
J . Org. Chem., Vol. 67, No. 2, 2002 599
Sch em e 2. Syn th esis of Ca r ba cep h a m 1 fr om
Cycloa d d u ct 4a
Da n ish efsk y’s Dien e
a
Reagents and conditions: (a) (i) 4 N HCl, THF-H2O (3:1), 25
°C; (ii) (Boc)2O, Na2CO3‚10H2O, THF-H2O (5:1), 25 °C, 95%; (b)
(i) Raney Ni, MeOH, 50 °C; (ii) CbzCl, Na2CO3‚10H2O, THF-H2O
(5:1), 25 °C, 88%; (c) J ones oxidation, 90%; (d) H2, Pd-C, MeOH,
25 °C, 98%; (e) 2-chloro-N-methylpyridinium iodide, TEA, MeCN,
70 °C, 45%.
Ta ble 1. HDA Rea ction of Im in e 2 w ith Da n ish efsk y’s
Dien e
entry
LA (equiv)a
T (°C)
t (h)
yield (%)b
3/4c
1
2
3
4
5
6
7
8
9
ZnCl2 (0.7)
ZnCl2 (1.0)
ZnCl2 (1.2)
Et2AlCl (1.0)
Et2AlCl (1.0)
Et2AlCl (1.0)
Et2AlCl (1.5)
Et2AlCl (2.0)
EtAlCl2 (1.0)
EtAlCl2 (2.0)
0
-50
-40
0
-20
-40
-40
-40
-40
-40
6
28
48
72
24
26
72
17
48
15
28
20
29
38
41
57
34
65
55
57
38/62
36/64
21/79
41/59
26/74
25/75
24/76
17/83
19/81
20/80
The concomitant hydrogenation of the double bond and
the hydrogenolysis of the benzyl group in compound 5
were achieved in one step using Raney Ni in MeOH.
Under these conditions, the ketone group was also
reduced to the corresponding mixture of alcohols. Sub-
sequent protection of the amino group, carried out with
CbzCl in the presence of sodium carbonate, gave the
mixture of alcohols 6a /6b with an overall yield of 88%
10
a
b
LA (equiv): Lewis acid (equivalents). Determined after acid
hydrolysis and further purification by silica gel column chroma-
tography and calculated from enantiomer of Garner’s aldehyde.
c Measured by 1H NMR at the vinylic protons and corroborated
by HPLC. (Column: Hypersil ODS, 5 µm, 250 mm × 2.1 mm.
Detection: UV 198 nm. Flow: 0.35 mL/min. Eluent: MeOH-H2O
55/45).
1
from 5, in a ratio 3:1 determined by H NMR (Scheme
2).
The mixture of alcohols 6a /6b was treated with the
J ones reagent, and the sole product 7 was obtained, with
a yield of 90%, by oxidation of the primary alcohol to the
carboxylic acid and the secondary alcohols to the ketone
group. The direct precursor of the carbacepham 1, the
â-amino acid 8, was obtained after deprotection of the
benzyl carbamate group of compound 7 by hydrogenation
in the presence of palladium-carbon as catalyst (Scheme
2).
With the â-amino acid 8 in hand, the next step was
the cyclization of the amino acid to form the bicyclic
â-lactam 1. Although several methods to accomplish the
intramolecular cyclization of amino acids to lactams have
been described, in which either the carboxyl or the amino
group must be activated, really very few have given good
results in the case of â-lactams.4e,7 In this sense, a
common method for activating carboxylic acids toward
nucleophilic substitution is to use Mukaiyama’s reagent,16
2-chloro-N-methylpyridinium iodide, which has also been
successfully used to generate the â-lactam ring.4e,7,11,17
Therefore, in our case, applying to the â-amino acid 8
Mukaiyama’s reagent as coupling agent and triethy-
lamine (TEA) as base, we obtained the required carba-
cepham 1 with a 45% yield after column chromatography
(Scheme 2).
to give after acid hydrolysis the corresponding hetero
Diels-Alder adducts 3 and 4, in different proportions
depending on the temperature and the catalyst used, as
depicted in Scheme 1 and Table 1.
On the basis of preliminary results of hetero Diels-
Alder reactions between Danishefsky’s diene and various
chiral imines carried out by one of us to synthesize
pipecolic acid derivatives,14 we assayed the cycloaddition
with different proportions of BF3‚Et2O, ZnCl2, ZnI2, Et2-
AlCl, or EtAlCl2 as Lewis acids and a range of temper-
atures between -50 and 0 °C. With BF3‚Et2O or ZnX2 (2
equiv) the reaction did not progress. The best results of
diastereoselectivity and yield were achieved when 2 equiv
of Et2AlCl were used at -40 °C (entry 8, Table 1).
Once the major cycloadduct 4 in enantiomerically pure
form had been obtained, its absolute configuration was
determined by X-ray crystal structure analysis.15 Starting
from this compound 4 and using five steps, carbacepham
1 was achieved carrying out the following synthetic
strategy. Initially, we attempted the cleavage of the N,O-
acetal using various mild acid conditions but in all cases
the N-Boc group was hydrolyzed. Therefore, the treat-
ment of compound 4 with 4 N HCl in a mixture of THF-
H2O at 25 °C gave the corresponding 1,2-amino alcohol,
whose amino group was again protected by the action of
(Boc)2O in a basic medium to give compound 5 with an
overall yield of 95% from 4.
Azetidinone 1 was isolated as a stable crystalline solid,
and we could obtain a single crystal suitable for X-ray
analysis. Thus, the X-ray crystal structure of 1 confirms
the absolute configuration at the sterogenic centers.15
In summary, we have developed a brief and straight-
forward synthesis of the functionalized carbacepham 1,
which will be used as precursor of different carbaceph-
ems. The carbacepham core, the bicyclo[4.2.0]octane ring
(13) Palomo, C.; Coss´ıo, F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.;
Roma´n, P.; Luque, A.; Mart´ınez-Ripoll, M. J . Am. Chem. Soc. 1992,
114, 9360.
(14) (a) Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez,
J . A. Tetrahedron Lett. 1997, 38, 2547. (b) Badorrey, R.; Cativiela, C.;
D´ıaz-de-Villegas, M. D.; Ga´lvez, J . A. Tetrahedron 1999, 55, 7601.
(15) See Supporting Information.
(16) Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984,
1465.
(17) Amin, S. G.; Glazer, R. D.; Manhas, M. S. Synthesis 1979, 210.

600 J . Org. Chem., Vol. 67, No. 2, 2002
Notes
g, 4.6 mmol) and (Boc)2O (0.42 g, 2.0 mmol). After stirring for
12 h at 25 °C, the reaction mixture was washed with brine (10
mL), and the aqueous phase was extracted with ethyl acetate
(2 × 20 mL). The combined organic phases were dried (Na2SO4),
filtered, and evaporated to give a residue, which was purified
by a silica gel column chromatography (CH2Cl2-MeOH, 9:1),
yielding 0.43 g of compound 5 (95%) as an oil. Anal. Calcd for
C19H26N2O4: C, 65.87; H, 7.56; N, 8.09. Found: C, 65.73; H, 7.51;
system, has been prepared by an unusual synthetic route,
which first involves the generation of the six-membered
ring, followed by the construction of the â-lactam ring.
One of the stereogenic centers of the system comes from
the starting material, the chiral imine derived from the
enantiomer of Garner’s aldehyde, and the second one is
created in the asymmetric hetero Diels-Alder reaction
of this imine with Danishefsky’s diene.
N, 8.13. [R]25 (c 0.84, MeOH) +268.1. IR (CH2Cl2) ν (cm-1):
D
3621, 3433, 1707, 1637. ESI+ (m/z): 347. 1H NMR (CDCl3) δ:
1.46 (m, 9H), 2.46 (br d, 1H, J ) 17.4 Hz), 2.63-2.76 (m, 1H),
3.69-3.87 (m, 3H), 4.02-4.13 (m, 1H), 4.46 (d, 1H, J ) 15.0 Hz),
4.54 (d, 1H, J ) 15.0 Hz), 4.98 (d, 1H, J ) 7.2 Hz), 5.46 (d, 1H,
J ) 7.5 Hz), 7.13 (d, 1H, J ) 7.2 Hz), 7.25-7.45 (m, 5H). 13C
NMR (CDCl3) δ: 28.4, 36.3, 51.6, 56.5, 58.9, 61.1, 79.9, 97.2,
127.7, 128.3, 129.1, 136.6, 153.5, 155.8, 190.7.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. All
manipulations with air-sensitive reagents were carried out under
a dry argon atmosphere using standard Schlenk techniques.
Solvents were purified according to standard procedures. The
chemical reagents were purchased from the Aldrich Chemical
Co. Analytical TLC was performed using Polychrom SI F254
plates. Column chromatography was performed using Kieselgel
60 (230-400 mesh). Organic solutions were dried over anhy-
drous Na2SO4 and, when necessary, concentrated under reduced
pressure using a rotary evaporator. IR spectra υmax (cm-1) are
given for the main absorption bands. NMR spectra were recorded
at 300 (1H) and at 75 (13C) MHz and are reported in ppm
downfield from TMS. Mass spectra were obtained by electrospray
ionization (ESI).
(1S,2′R,4′R)-1-(1′-Ben zyloxyca r bon yl-4′-h yd r oxyp ip er i-
d in -2′-yl)-2-h yd r oxyeth ylca r ba m ic Acid ter t-Bu tyl Ester
(6a ) a n d (1S,2′R,4′S)-1-(1′-Ben zyloxyca r bon yl-4′-h yd r oxy-
p ip er id in -2′-yl)-2-h yd r oxyet h ylca r b a m ic Acid ter t-Bu t yl
Ester (6b). A solution of alcohol 5 (300 mg, 0.87 mmol) in MeOH
(50 mL) was hydrogenated, at atmospheric pressure and at 50
°C, in a suspension of Raney Ni and H2O 1:1 (10 mL). After
stirring for 48 h, the reaction was filtered through Celite, and
the solvent was evaporated. The white residue was dissolved in
a mixture of THF-H2O 5:1 (18 mL) and treated with Na2CO3‚
10H2O (324 mg, 1.13 mmol) and CbzCl (193 mg, 1.13 mmol).
After stirring for 12 h at 25 °C, the reaction was washed with
brine (10 mL), and the aqueous phase was extracted with ethyl
acetate (2 × 20 mL). The combined organic phases were dried
(Na2SO4), filtered, and evaporated to give a residue, which was
purified by a silica gel column chromatography (CH2Cl2-MeOH,
9:1), yielding 302 mg of a white solid corresponding to the
mixture of diols 6a and 6b (88%) in a ratio of 7:3. This mixture
of alcohols was used in the next step without purification. ESI+
(m/z): 394 + Na (NMR data, extracted from the mixture 6a /6b,
for the major product). 1H NMR (CDCl3) δ: 1.36 (m, 9H), 1.52-
1.84 (m, 3H), 1.94-2.17 (m, 1H), 3.25-3.52 (m, 1H), 3.61-3.80
(m, 2H), 3.82-4.32 (m, 5H), 4.39-4.58 (m, 1H), 5.11 (s, 2H),
5.19-5.35 (m, 1H), 7.34 (br s, 5H). 13C NMR (CDCl3) δ: 28.2,
31.3, 32.0, 34.6, 51.0, 52.9, 63.3, 63.5, 67.2, 79.3, 127.7, 128.0,
128.5, 136.5, 155.9, 156.5.
(4S,2′S)-4-(1′-Ben zyl-4′-oxo-1′,2′,3′,4′-tetr a h yd r op yr id in -
2′-yl)-3-ter t-bu toxycar bon yl-2,2-dim eth yloxazolidin e (3) an d
(4S,2′R)-4-(1′-Ben zyl-4′-oxo-1′,2′,3′,4′-tetr a h yd r op yr id in -2′-
yl)-3-ter t-bu toxyca r bon yl-2,2-d im eth yloxa zolid in e (4). To
a suspension of anhydrous MgSO4 (200 mg) in CH2Cl2 (10 mL)
was added, at 25 °C under an inert atmosphere of argon, a
solution of aldehyde (R)-3-tert-butoxycarbonyl-4-formyl-2,2-dim-
ethyloxazolidine (enantiomer of Garner’s aldehyde) (0.80 g, 3.5
mmol) and benzylamine (0.37 g, 3.5 mmol) in CH2Cl2 (40 mL).
After 2 h of stirring at the same temperature, the solution
corresponding to the crude imine 2 was filtered under an
atmosphere of argon over a Schlenk containing molecular sieves
(4 Å), which was then cooled to -40 °C, and a 1 M solution of
Et2AlCl in hexane (7.0 mL, 7.0 mmol) was added. After 5 min
of stirring at -40 °C, Danishefsky’s diene (0.90 g, 5.2 mmol) was
added, and the mixture was stirred for 17 h at the same
temperature. The reaction mixture was extracted with a 1 N
aqueous solution of HCl (10 mL), and the organic phase was
dried (Na2SO4), filtered, and concentrated to give an oily residue
corresponding to cycloadducts 3 and 4 (523 mg, 65% from
enantiomer of Garner’s aldehyde) in a ratio of 1:4, respectively.
These cycloadducts were separated by silica gel column chro-
matography (hexane-ethyl acetate, 3:7) to give 0.71 g of
compound 4 (52%) as a white solid and 0.17 g of compound 3
(13%) as an oil. Compound 3: Anal. Calcd for C22H30N2O4: C,
(2S,2′R)-ter t-Bu toxyca r bon yla m in o-(4′-oxop ip er id in -2′-
yl)-a cetic Acid (8). To a solution of diols 6a /6b (350 mg, 0.89
mmol) in acetone (15 mL), at 0 °C, was dropwise added (5 min)
the J ones reagent (2.22 mmol). After stirring at the same
temperature for 3 h, the reaction was allowed to stand at 25 °C
for another 3 h. The excess of the J ones reagent was destroyed
by treatment with 2-propanol. This mixture was diluted with
H2O and extracted with ethyl acetate (4 × 20 mL). The combined
organic phases were dried (Na2SO4), filtered, and concentrated
to give 325 mg (90%) of a colorless oil, corresponding to (2S,2′R)-
tert-butoxycarbonylamino-(1′-benzyloxycarbonyl-4′-oxopiperidin-
2′-yl)-acetic acid 7, which was used in the next step without
68.37; H, 7.82; N, 7.25. Found: C, 68.28; H, 7.77; N, 7.21. [R]25
D
(c 1.41, MeOH) -38.3. IR (CH2Cl2) ν (cm-1): 1691, 1641. 1H NMR
(CDCl3) δ: 1.25-1.75 (m, 15H), 2.11-2.43 (m, 1H), 2.55-2.73
(m, 1H), 3.61-4.21 (m, 4H), 4.45 (s, 2H), 4.47-4.95 (m, 1H),
7.01-7.14 (m, 1H), 7.15-7.35 (m, 5H). 13C NMR (CDCl3) δ: 22.4,
24.1, 26.2, 28.3, 36.5, 37.5, 55.4, 56.6, 59.0, 60.0, 64.4, 65.0, 80.6,
94.3, 97.2, 98.4, 127.1, 128.1, 128.8, 136.6, 152.0, 153.4, 154.4,
189.6. Compound 4: Anal. Calcd for C22H30N2O4: C, 68.37; H,
7.82; N, 7.25. Found: C, 68.30; H, 7.78; N, 7.23. Mp: 109-111
purification. [R]25 (c 0.84, MeOH) +16.0. IR (CH2Cl2) ν (cm-1):
D
3425, 1756, 1712. ESI- (m/z): 405. 1H NMR (CDCl3) δ: 1.40 (m,
9H), 2.37-2.51 (m, 2H), 2.52-2.87 (m, 2H), 3.31-3.62 (m, 1H),
4.09-4.54 (m, 2H), 4.75-4.95 (m, 1H), 5.15 (s, 2H), 7.34 (br s,
5H). 13C NMR (CDCl3) δ: 28.2, 39.6, 39.7, 41.8, 53.6, 56.0, 68.1,
80.7, 128.0, 128.3, 128.6, 135.5, 155.7, 156.2, 173.1, 206.6. A
solution of compound 7 (230 mg, 0.57 mmol) in MeOH (20 mL)
was hydrogenated at atmospheric pressure and at 25 °C, using
10% palladium-charcoal (40 mg). After stirring for 12 h, the
reaction mixture was filtered through Celite, and the solvent
was evaporated to obtain 152 mg of the â-amino acid 8 (98%),
°C. [R]25 (c 0.88, MeOH) +140.7. IR (CH2Cl2) ν (cm-1): 1694,
D
1639. ESI+ (m/z): 387. 1H NMR (CDCl3) δ: 1.30-1.78 (m, 15H),
2.27-2.48 (m, 1H), 2.74 (dd, 1H, J ) 17.1, 7.5 Hz), 3.52-3.80
(m, 1H), 3.83-3.98 (m, 2H), 4.38-4.65 (m, 3H), 5.05 (d, 1H, J )
7.2 Hz), 7.11 (d, 1H, J ) 7.2 Hz), 7.21-7.41 (m, 5H). 13C NMR
(CDCl3) δ: 22.7, 24.0, 27.0, 27.3, 28.4, 36.7, 54.9, 55.9, 56.8, 58.9,
64.6, 80.7, 94.0, 94.8, 97.7, 127.2, 127.6, 129.0, 136.8, 153.0,
154.2, 189.6.
which was used in the next step without purification. [R]25 (c
D
1.50, MeOH) +15.9. ESI- (m/z): 271. 1H NMR (CD3OD) δ: 1.46
(m, 9H), 1.55-1.72 (m, 1H), 1.74-1.95 (m, 1H), 2.02-2.35 (m,
2H), 2.95-3.50 (m, 4H), 3.54-3.72 (m, 1H), 4.31-4.43 (m, 1H).
13C NMR (CD3OD) δ: 31.2, 35.5, 35.9, 38.4, 39.0, 46.3, 46.5, 58.8,
59.4, 84.0, 97.1, 97.5, 160.3, 175.0, 205.3.
(1S,2′R)-1-(1′-Ben zyl-4′-oxo-1′,2′,3′,4′-tetr a h yd r op yr id in -
2′-yl)-2-h yd r oxyeth ylca r ba m ic Acid ter t-Bu tyl Ester (5). To
a solution of compound 4 (500 mg, 1.30 mmol) in THF (30 mL)
at 25 °C was added a 4 N aqueous solution of HCl (6 mL). After
2 h of stirring, the solvent and HCl were eliminated under
reduced pressure. The white residue was dissolved in a mixture
of THF-H2O 5:1 (36 mL) and treated with Na2CO3‚10H2O (1.30
(6R,7S)-7-ter t-Bu toxyca r bon yla m in o-1-a za bicyclo[4.2.0]-
octa -4,8-d ion e (1). To a solution of 2-chloro-1-methylpyridinium
iodide (250 mg, 0.95 mmol) in acetonitrile (20 mL) was added
Et3N (0.3 mL, 2.2 mmol), and the mixture was warmed to 70
°C. At this temperature, a solution of â-amino acid 8 (70 mg,

Notes
J . Org. Chem., Vol. 67, No. 2, 2002 601
0.26 mmol) in acetonitrile (20 mL) was dropwise added. After
stirring for 17 h at 25 °C, the mixture reaction was diluted with
H2O (20 mL) and extracted with ethyl acetate (3 × 40 mL). The
combined organic phases were dried (Na2SO4), filtered, and
concentrated to give a residue, which was purified by a silica
gel column chromatography (hexane-ethyl acetate, 3:7), yielding
30 mg of a white solid corresponding to carbacepham 1 (45%).
Anal. Calcd for C12H18N2O4: C, 56.68; H, 7.13; N, 11.02. Found:
Ack n ow led gm en t. We thank to Ministerio de Cien-
cia y Tecnolog´ıa (project PPQ2001-1305), to Gobierno
de La Rioja (project ACPI-2000) and to Universidad de
La Rioja (project API-01/B02). F.C. thanks Ministerio
de Educacio´n y Cultura for a grant.
1
Su p p or tin g In for m a tion Ava ila ble: A full listing of H
C, 56.63; H, 7.12; N, 11.03. Mp: 196-197 °C. [R]25 (c 0.45,
and 13C NMR data of all the new compounds with peak
D
CHCl3) +131.9. IR (CHCl3) ν (cm-1): 3436 (NH), 1759, 1715.
1
assignments, copies of H and 13C NMR spectra and 1H-1H
1
ESI+ (m/z) 255. H NMR (CDCl3) δ: 1.42 (s, 9H), 2.33-2.63 (m,
and 1H-13C correlations for 3, 4, 5 and 1, and the crystal
structure data for 4 and 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
4H), 3.12-3.28 (m, 1H), 3.91-4.01 (m, 1H), 4.22 (ddd, 1H, J )
13.5, 7.8, 2.1 Hz), 5.02-5.10 (m, 1H), 5.52 (d, 1H, J ) 6.6 Hz).
13C NMR (CDCl3) δ: 28.1, 38.7, 39.9, 40.7, 54.3, 61.8, 80.9, 155.0,
165.8, 205.9.
J O016186H