Halide-terminated N-acyliminium ion-alkyne cyclizations: A new construction of carbacephem antibiotics

Article abstract of DOI:10.1021/jo971433w

A series of 4-(3-alkynyl)azetidinones 13 was prepared from 4- (phenylsulfonyl)azetidine-2-one (9) and isopropyl glyoxylate hydrate. The 3- pentynyl (13a) and 4-phenyl-3-butynyl (13b) azetidinone acetates underwent 6- exo cyclization when treated with 3 equity of SnCl₄ at 0 °C to provide 3- (1-chloroalkylidene)carbacephems 15a (65%) and 15b (33%) respectively. In contrast, the 3-butynyl (13d) and 4-(trimethylsilyl)-3-butynyl (13c) azetidinone acetates underwent 7-endo cyclization under similar conditions to give 1-azabicyclo[5.2.0]nonenes 14a (11%) and 14b (71%), respectively. Beginning with penicillin degradation product 18, the more elaborate 3- pentynyl azetidinone cyclization substrate 27 was prepared in seven steps. Exposure to 27 to 3 equiv of SnCl₄ in CH₂Cl₂ at 0 °C for 6 h, followed by allowing the reaction mixture to warm to rt, provided the desired 3-(1- chloroethylidene)carbacephem 28 in 60% yield and high (>99%) enantiometric purity. Cleavage of the chloroethylidene group of 28 with ozone gave 3- hydroxy carbacephem 29 in 77% yield. Since this intermediate has been converted in three steps to loracarbef (3), a new formal total synthesis of this carbacephem antibiotic was concluded.

Full text of DOI:10.1021/jo971433w

9210
J . Org. Chem. 1997, 62, 9210-9216
Ha lid e-Ter m in a ted N-Acylim in iu m Ion -Alk yn e Cycliza tion s: A
New Con str u ction of Ca r ba cep h em An tibiotics
Eric Metais,1a Larry E. Overman,* Maria Ine´s Rodriguez,1b and Brian A. Stearns
Department of Chemistry, 516 Physical Sciences 1, University of California, Irvine,
Irvine, California 92697-2025
Received August 1, 1997X
A series of 4-(3-alkynyl)azetidinones 13 was prepared from 4-(phenylsulfonyl)azetidine-2-one (9)
and isopropyl glyoxylate hydrate. The 3-pentynyl (13a ) and 4-phenyl-3-butynyl (13b) azetidinone
acetates underwent 6-exo cyclization when treated with 3 equiv of SnCl4 at 0 °C to provide 3-(1-
chloroalkylidene)carbacephems 15a (65%) and 15b (33%) respectively. In contrast, the 3-butynyl
(13d ) and 4-(trimethylsilyl)-3-butynyl (13c) azetidinone acetates underwent 7-endo cyclization under
similar conditions to give 1-azabicyclo[5.2.0]nonenes 14a (11%) and 14b (71%), respectively.
Beginning with penicillin degradation product 18, the more elaborate 3-pentynyl azetidinone
cyclization substrate 27 was prepared in seven steps. Exposure to 27 to 3 equiv of SnCl4 in CH2Cl2
at 0 °C for 6 h, followed by allowing the reaction mixture to warm to rt, provided the desired 3-(1-
chloroethylidene)carbacephem 28 in 60% yield and high (>99%) enantiometric purity. Cleavage
of the chloroethylidene group of 28 with ozone gave 3-hydroxy carbacephem 29 in 77% yield. Since
this intermediate has been converted in three steps to loracarbef (3), a new formal total synthesis
of this carbacephem antiboitic was concluded.
In tr od u ction
bacephems have been reported4,5 since the original total
synthesis was disclosed in 19722a and the first enanti-
oselective synthesis in 1985.6 Most syntheses of carba-
cephems assemble the six-membered ring last, with
formation of the N-C(4) and C(3)-C(4) σ bonds being
the most common.4
For over 50 years, â-lactam antibiotics have been
indispensable in man’s war against bacterial pathogens.
One recent development in this area was the introduction
of carbocyclic analogues of natural penicillins and cepha-
losporins. Christensen and colleagues at Merck were the
first to describe carbacephem analogues 1 of the widely
employed cephalosporin class of antibiotics 2.2 In 1992
loracarbef (Lorabid, 3), the carbacephem analogue of one
of the most widely prescribed cephalosporin antibiotics
cefaclor (Ceclor, 4), was introduced by Eli Lilly & Co.
Loracarbef, the first carbacephem antibiotic to be mar-
keted in the United States, is an orally active, broad
spectrum antibiotic that is approved for treatment of
infections of the upper and lower respiratory and urinary
tracts and skin infections.3 It has a similar pharmaco-
logical profile to cefaclor and, as is typical of carbaceph-
ems, displays greater chemical stability than the parent
cephem.
Numerous disclosures from our laboratories have
demonstrated the utility of nucleophile-promoted imi-
nium ion-alkyne cyclizations for the synthesis of nitro-
gen heterocycles.7 Nucleophile participation in Mannich
cyclizations can regulate regio- and stereochemistry,
allowing simple alkynes to be employed as cyclization
components rather than more elaborate π-nucleophiles
such as unsaturated silanes or stannanes. To develop
fully this chemistry, we have recently been examining
the role that external nucleophiles can play in related
cyclization reactions initiated by N-acyliminium ions.8 As
a further development of this theme, a new route to
carbacephems is suggested in Scheme 1. Involvement
of an external nucleophile in the pivotal cyclization of
glyoxylate-derived N-acyliminium ion 6 would yield a
3-alkylidenecarbacepham 7.9,10 Oxidative cleavage of the
alkylidene unit of 7 would provide a 3-hydroxycarba-
cephem,11 an intermediate that has been widely employed
(4) For reviews, see: (a) Kant, J .; Walker, D. G. In The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993; pp
121-196. (b) Cooper, R. D. G. In The Chemistry of â-Lactams; Page,
M. I., Ed.; Chapman & Hall: London, 1992; pp 272-305.
(5) For recent contributions, see: (a) Lotz, B. T.; Miller, M. J . J .
Org. Chem. 1993, 58, 618. (b) Saito, S.; Ishikawa, T.; Moriwake, T.
Synlett 1993, 139. (c) Bachi, M. D.; Bar-Ner, N. Biomed. Chem. 1993,
3, 2439. (d) Teng, M.; Gasparski, C. M.; Williams, M. A.; Miller, M. J .
Biomed. Chem. 1993, 3, 2431. (e) Guzzo, P. R.; Miller, M. J . J . Org.
Chem. 1994, 59, 4862.
To date, carbacephems are available only by total or
semi synthesis. Numerous methods for constructing car-
(6) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 26, 3787.
(7) See, inter alia: (a) Overman, L. E.; Sharp, M. J . J . Am. Chem.
Soc. 1988, 110, 612. (b) Lin, N.-H.; Overman, L. E.; Rabinowitz, M.
H.; Robinson, L. A.; Sharp, M. J .; Zablocki, J . J . Am. Chem. Soc. 1996,
118, 9062. (c) Caderas, C.; Lett, R.; Overman, L. E.; Rabinowitz, M.
H.; Sharp, M. J .; Zablocki, J . J . Am. Chem. Soc. 1996, 118, 9073.
(8) Brosius, A. D.; Overman, L. E. J . Org. Chem. 1997, 62, 440.
(9) The synthesis of bicyclic â-lactams by related free-radical cy-
clizations has been extensively developed by Bachi and co-workers,
see: Bachi, M. D. In Recent Advances in the Chemistry of â-Lactam
Antibiotics; Bentley, P. H., Southgate, R., Eds.; Royal Society of
Chemistry: London, 1990; pp 91-105.
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) (a) Rotary Club Postdoctoral Fellow, 1995-96. Current ad-
dress: Rhone-Poulenc Industrialisation, BP 62, 85 Ave. Des Freres
Perret, Lyon, France. (b) Fonds National Suisse de la Recherche
Scientifique Postdoctoral fellow, 1993-94.
(2) (a) Christensen, B. G.; Guthikonda, R. N.; Cama, L. D. J . Am.
Chem. Soc. 1974, 96, 7584. (b) Firestone, R. A.; Fahey, J . L.; Macie-
jiwicz, N. S.; Christensen, B. G. J . Med. Chem. 1977, 20, 551.
(3) Force, R. W.; Nahata, M. C. Ann. Pharmacotherapy 1993, 27,
321.
S0022-3263(97)01433-3 CCC: $14.00 © 1997 American Chemical Society

A New Construction of Carbacephem Antibiotics
J . Org. Chem., Vol. 62, No. 26, 1997 9211
Sch em e 1
Sch em e 2
to prepare other 3-substituted carbacephems.12 Alter-
natively, the alkylidene functionality might be elaborated
to provide access to less common carbacephem analogues.
In this paper, we report the successful development of
this new route to carbacephems and illustrate its poten-
tial utility by a short enantioselective formal total
synthesis of loracarbef (3).13
Resu lts a n d Discu ssion
In itia l Mod el Stu d ies. Our first objective was to
determine which structural features were required for
the alkyne to cyclize in the desired 6-exo mode (6 f 7).
With this aim, a representative set of 4-(3-alkynyl)-
azetidinones was prepared from 4-(phenylsulfonyl)aze-
tidin-2-one (9),14 an intermediate that has been employed
extensively as a precursor of 4-substituted azetidin-2-
ones.15 Thienyl cyano cuprates (R2CuLi‚LiCN)16 derived
from homopropargyl iodides 8a -c17 coupled efficiently
with 9 to give alkynyl azetidinones 10a -c in high yields
(Scheme 2). Subsequent desilylation of 10c with TBAF
efficiently provided 3-butynylazetidinone 10d . Condensa-
tion of 10a -d with isopropyl glyoxylate hydrate 1118
yielded hemiaminals 12a -d , which were acetylated with
acetic anhydride to afford 13a -d in 63-69% yield for
Sch em e 3
(10) For other examples of cyclizations of N-acyliminium cations
derived from glyoxylates with tethered alkynes, see: Mooiweer, H. H.;
Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N. Tetrahedron Lett.
1987, 28, 3285.
(11) (a) Scartazinni, R.; Bickel, H. Helv. Chim. Acta 1974, 57, 1919.
(b) Chauvette, R. R.; Pennington, P. A. J . Am. Chem. Soc. 1974, 96,
4986.
(12) For a recent review of functional group transformations on the
â-lactam nucleus see: Wild, H. In The Organic Chemistry of â-Lactams;
Georg, G. I., Ed.; VCH: New York, 1993; pp 49-119.
(13) For previous asymmetric total syntheses of loracarbef: (a)
Bodurow, C. C.; Boyer, B. D.; Brennan, J .; Bunnell, C. A.; Burks, J .
E.; Carr, M. A.; Doecke, C. W.; Eckrich, T. M.; Fisher, J . W.; Gardner,
J . P.; Graves, B. J .; Hines, P.; Hoying, R. C.; J ackson, B. G.; Kinnick,
M. D.; Kochert, C. D.; Lewis, J . S.; Luke, W. D.; Moore, L. L.; Morin,
J . M., J r.; Nist, R. L.; Prather, D. L.; Sparks, D. E.; Vladuchick, W. C.
Tetrahedron Lett. 1989, 30, 2321. (b) Frazier, J . W.; Staszak, M. A.;
Weigel, L. O. Tetrahedron Lett. 1992, 33, 857.
(14) Clauss, K.; Grimm, D.; Prossel, G. Liebigs Ann. Chem. 1974,
539.
(15) (a) Mickel, S. Aldrichimica Acta 1985, 18, 95. (b) Koller, W.;
Linkies, A.; Pietsch, H., Rehling, H.; Reuschling, D. Tetrahedron Lett.
1982, 23, 1545. (c) Bevilacqua, P.; Roberts, J . L. Synth. Commun. 1983,
10, 797.
(16) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett.
1987, 28, 945.
(17) Iodoalkynes 8 have been previously described. 8a : Hewson, A.
T.; MacPherson, D. T. J . Chem. Soc., Perkin Trans. 1 1985, 2625. 8b:
Fisher, M. J .; Overman, L. E. J . Org. Chem. 1990, 55, 1447. 8c:
Negishi, E.; Boardman, L. D.; Sawada, H.; Bagheri, V.; Stoll, A. T.;
Tour, J . M.; Rand, C. L. J . Am. Chem. Soc. 1988, 110, 5383.
(18) Kelly, T. R.; Schmidt, T. E.; Haggerty, J . C. Synthesis 1972,
544.
the two steps. The related R-methoxy ester 13e was
readily obtained by exposure of 12d to methanolic HCl.
Our initial attempts to cyclize the 4-(3-butynyl)azeti-
din-2-one derivatives 12d , 13d , or 13e in CH2Cl2 at low
temperature with 1 equiv of typical Lewis acids were
unsuccessful (Scheme 3). Under more forcing conditions
(3 equiv of SnCl4, 0 °C, 6 h), acetate precursor 13d was
transformed to a single bicyclic product (14a ) in low (11%)
yield. The addition of external nucleophiles, such as NaI,

9212 J . Org. Chem., Vol. 62, No. 26, 1997
Metais et al.
Sch em e 4a
derivative 17 in ∼45% yield after reaction with Tf2O and
i-Pr2EtN. Definitive evidence that the isomers of 15a
differed only in stereochemistry of the 1-chloroethylidene
unit was obtained by treatment of the separated isomers
of 15a with RuO4.19 From each isomer, an identical 9:1
mixture of R-hydroxy ketones 16a and 16b was obtained.
The major isomer 16a provided single crystals, thus
allowing structural assignments to be unambiguously
secured by X-ray analysis.20 Beckmann fragmentation
of the oxime derivatives of 16 with Tf2O provided a
second, less conventional, way to secure triflate 17.21
Syn th esis of Ca r ba cep h em 29 a n d F or m a l Asym -
m etr ic Tota l Syn th esis of Lor a ca r bef. The next
challenge was to see if this new construction of carba-
cephems would also succeed with more relevant sub-
strates containing a 3-acylamino side chain and a car-
boxylic acid protecting group that could be removed
without damaging the carbacephem skeleton. These
studies began with (3R,4R)-3-(phenoxyacetamido)-4-ac-
etoxyazetidin-2-one (18), which is readily available by the
chemical degradation of penicillin V.22 Not surprisingly,
condensation of the homopropargyl cuprate derived from
iodide 8a with sulfone derivative 1923 provided the 3,4-
anti product 20 (eq 1).
a
V ) PhOCH2CONH. PNB ) p-nitrobenzyl.
We turned to an alkylation-reduction sequence intro-
duced by Morin and co-workers for incorporating the
3-pentynyl substituent at C(4).23 Alkylation was first
attempted by generating the dianion of N-silyl sulfone
21 with 2.2 equiv of LDA in THF at -78 °C (Scheme 4),
followed by addition of 1-iodo-3-pentyne (8a ) or 1-bromo-
3-pentyne (22a ). The homopropargyl bromide was com-
pletely unreactive toward this dianion. Iodide 8a , while
unreactive at -78 °C, produced trace amounts of alky-
lation product 23 when the reaction mixture was allowed
to warm to -20 °C for 2 h. When the more reactive
3-pentynyl triflate (22b)24 was employed, alkylation
occurred smoothly at -78 °C to deliver 23 in a 60% yield.
Although the relative stereochemistry of this product was
not determined, a single stereoisomer was formed and
is presumed, on the basis of literature precedent,23 to be
as depicted in 23. Desilylation of 23 by brief treatment
with concentrated HCl, followed by reductive removal of
the phenyl sulfone with lithium tri-tert-butoxyaluminum
hydride provided the desired cis-disubstituted â-lactam
24 (J 3,4 ) 5 Hz) in good yield.
n-Bu4NBr, or n-Bu4NI, had no beneficial effect. That 14a
had the 1-azabicyclo[5.2.0]nonene skeleton resulting from
7-endo cyclization was apparent from the magnitude of
the 1H NMR coupling constant of the vinylic hydro-
gen (δ 5.94, J ) 6 Hz). Not surprisingly, silyl alkyne
analogue 13c also underwent 7-endo cyclization when
exposed to SnCl4 or SnBr4 under similar conditions.
Cyclization of the silyl derivative was cleaner and
provided azabicyclo[5.2.0]nonenes 14b and 14c in yields
of 71 and 39%, respectively. The structure of 14c was
secured by treatment with n-Bu3SnH to give 14d , which
showed a diagnostic doublet of doublets for the vinylic
1
hydrogen in the H NMR spectrum at δ 5.05 (J ) 8.2,
5.0 Hz).
In marked contrast, the 3-pentynyl (13a ) and 4-phenyl-
3-butynyl (13b) azetidinone acetates underwent 6-exo
cyclization when treated with 3 equiv of SnCl4 at 0 °C to
provide the desired 3-(1-chloroalkylidene)carbacephems
15a (65%) and 15b (33%). In each case, a 4:1 mixture of
isomers was produced. Exposure of 13a to 2 equiv of
TiCl4 delivered 15a in similar yield (59%), while the
corresponding bromo derivative 15c was obtained in 51%
yield (a 6.5:2.5:1 mixture of isomers) when 13a was
treated at 0 °C with 4 equiv of SnBr4. The isomers of
15a could be separated by column chromatography, and
(19) Carlsen, P. H.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936.
(20) The authors have deposited atomic coordinates for this com-
pound with the Cambridge Crystallographic Data Centre. The coor-
dinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(21) Olah, G. A.; Vankar, Y. D.; Berrier, A. L. Synthesis 1980, 45
and references therein.
(22) Blaszczak, L. C. U.S. Patent No. 4,771,135, 1988.
(23) Deeter, J . B.; Hall, D. A.; J ordan, C. L.; J ustice, R. M.; Kinnick,
M. D.; Morin, J . M., J r.; Paschal, J . W.; Ternansky, R. J . Tetrahedron
Lett. 1993, 34, 3051.
1
each showed a diagnostic H NMR singlet for a vinylic
methyl group at ∼δ 2.1, although only the major isomer
showed a NOE enhancement between this signal and the
C(4) methine hydrogen. That at least the major isomers
of 15a and 15c had the carbacepham skeleton was first
confirmed by ozonolysis of the isomer mixtures to yield
an unstable enolic â-keto ester, which provided triflate
(24) Hanack, M.; Collins, C. J .; Stutz, H.; Benjamin, B. M. J . Am.
Chem. Soc. 1981, 103, 2356.

A New Construction of Carbacephem Antibiotics
J . Org. Chem., Vol. 62, No. 26, 1997 9213
Sch em e 5a
Lilly synthesis of loracarbef (3) was prepared in high
enantiomeric purity in seven steps, and 19% overall yield,
from readily available (3R,4S)-3-(phenoxyacetamido)-4-
(benzenesulfonyl)-azetidin-2-one (19). The success of the
key cyclization reaction with a substrate as highly
functionalized as 27 suggests that chloride-terminated
N-acyliminium ion-alkyne cyclizations could find wide
application in the construction of complex azacyclic
molecules.
Exp er im en ta l Section 28
4-(3-P en tyn yl)a zetid in -2-on e (10a ). A solution of 1-iodo-
3-pentyne (8a ) (9.2 g, 47 mmol) in dry ether (50 mL) was added
dropwise to a solution of tert-butyllithium (54 mL, 92 mmol,
1.7 M solution in pentane) and dry ether (50 mL) at -78 °C.
The solution was stirred for 2 h and then added by cannula to
a solution of lithium 2-thienylcyanocuprate (200 mL, 50 mmol,
0.25 M solution in THF) at -78 °C and the resulting brown
solution was warmed to 0 °C, and maintained at this temper-
ature for 1 h. The resulting cuprate solution was cooled to
-78 °C, and a solution of 4-(phenylsulfonyl)azetidinone (4.00
g, 18.9 mmol) in dry THF (50 mL) was added. The solution
was stirred at 0 °C for 3 h and then quenched with saturated
aqueous NH4Cl (200 mL). The precipitate was removed by
filtration and washed with EtOAc (100 mL). The combined
filtrates were washed with brine (100 mL), dried (MgSO4), and
concentrated to give 2.81 g of a light brown oil. Purification
by flash chromatography on silica gel (1:1 hexanes-EtOAc)
gave azetidinone 10a as a light yellow oil (2.3 g, 88%): 1H
NMR (CDCl3, 300 MHz) δ 6.35 (br s, 1H), 3.68-3.78 (m, 1H),
3.08 (ddd, J ) 14.8, 5.0, 2.1 Hz, 1H), 2.61 (ddd, J ) 14.8, 2.3,
1.3 Hz, 1H,), 2.16-2.26 (m, 2H), 1.70-1.80 (m, 5H); 13C NMR
(CDCl3,125 MHz) δ167.9, 77.4, 76.9, 47,6, 43.5, 34.1, 16.1, 3.4;
IR (film) 3420, 3246, 1750 cm-1; MS (CI) m/e 138.0913
(138.0919 calcd for C8H12NO, MH).
Isop r op yl 2-Hyd r oxy-2-[4-(3-p en tyn yl)-2-oxoa zetid in -
1-yl]a ceta te (12a ). A mixture of isopropyl glyoxylate hydrate
(11, 1.5 g, 11 mmol) and toluene (100 mL) was heated at reflux
in a Dean-Stark apparatus for 1 h. A solution of azetidinone
10a (1.0 g, 7.3 mmol) and toluene (10 mL) was then added,
and the resulting solution was heated at reflux for 3 h.
Toluene was removed by rotary evaporation, and the residue
was dissolved in ether (150 mL) and washed with H2O (5 ×
20 mL) and brine (3 × 20 mL). The combined aqueous
washings were extracted with ether (2 × 40 mL), and the
combined ether extracts were dried (MgSO4) and concentrated.
Purification of the residue by flash chromatography on silica
gel (1:1 hexanes-EtOAc) gave 12a (1.49 g, 80%), a 1.2:1
mixture of stereoisomers (1H NMR analysis), as a colorless oil
that was contaminated with a small amount of glyoxylate 11.
12a : 1H NMR (CDCl3, 500 MHz) (major isomer) δ 5.34 (s, 1H),
5.14 (septet, J ) 6.3 Hz, 1H), 4.23 (br s, 1H), 3.80-3.88 (m,
1H), 3.00-3.12 (m, 1H), 2.73 (dd, J ) 4.0, 2.6 Hz, 1H), 2.11-
2.27 (m, 2H), 1.88-2.10 (m, 1H), 1.55-1.80 (m, 4H), 1.25-
1.34 (m, 6H); (minor isomer) δ 5.29 (s, 1H), 5.12 (septet, J )
6.8 Hz, 1H), 3.91-3.40 (m, 1H), 2.68 (dd, J ) 4.0, 2.6 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ 169.4, 168.3, 167.3, 166.9, 77.4,
77.2, 76.9, 72.1, 71.7, 71.4, 71.3, 51.4, 50.2, 42.8, 42.6, 33.0,
32.4, 25.5, 21.7, 21.6, 15.4, 15.3, 3.4; IR (film) 3390, 1750, 1738
cm-1; MS (CI) m/e 254.1398 (254.1391 calcd for C13H20NO4,
MH).
a
V ) PhOCH2CONH. PNB ) p-nitrobenzyl.
Condensation of freshly prepared p-nitrobenzyl (PNB)
glyoxylate hydrate (25)25 with azetidinone 24 provided a
mixture of hemiaminals 26, which were acetylated to
provide acetates 27 (a 4:1 mixture of diastereomers) in
70% overall yield from 24. Exposure of 27 to 3 equiv of
SnCl4 in CH2Cl2 at 0 °C for 6 h, followed by allowing the
reaction mixture to warm to rt, provided the desired 3-(1-
chloroethylidene)carbacephem 28 in 60% yield. We were
delighted to find that this key conversion proceeded as
efficiently with the more elaborate substrate 27 as it did
in the less-functionalized model series. The stereostruc-
ture of 28 was assigned in analogy with our earlier model
studies. Cleavage of the chloroethylidene group by
exposure of 28 to an excess of ozone in MeOH-CH2Cl2
at -78 °C followed by treatment with Me2S gave the
known 3-hydroxy carbacephem 29 in 77% yield after flash
chromatography. Since this intermediate has been con-
verted in three steps to loracarbef (3),13a a new formal
total synthesis of this carbacephem antibiotic was con-
cluded.
The high enantiomeric purity of 29 was confirmed as
shown in Scheme 5. Reaction of 29 with 1.1 equiv of Tf2O
and excess i-Pr2EtN in CH2Cl2 at -40 °C formed the
known enol triflate 30.26 Carbacephem 3-triflates have
proven to be useful intermediates for synthesis of a wide
variety of 3-substituted carbacephems, owing to their
ready participation in transition metal-mediated cross-
couplings and direct nucleophilic substitution reactions.12
Condensation of 30 with the individual enantiomers of
protected cysteine 3127 provided the diastereomeric vi-
nylogous cysteine thioesters 32a and 32b in near quan-
titative yield. These products were readily resolved by
reverse-phase HPLC and each showed a diastereomeric
purity of >99%.
Isop r op yl 2-Acetoxy-2-[4-(3-p en tyn yl)-2-oxoa zetid in -1-
yl]a ceta te (13d ). Acetic anhydride (670 µL, 7.1 mmol) and a
few milligrams of DMAP were added to a solution of 12d (1.2
g, 4.7 mmol), pyridine (2 mL), and CH2Cl2 (10 mL) at 0 °C.
Con clu sion s
A new method for constructing carbacephems has been
developed in which the C(3)-C(4) σ-bond is formed by a
chloride-terminated N-acyliminium-alkyne cyclization.
Using this approach, late intermediate 29 of an earlier
(28) The procedure we employed to purify THF, CH2Cl2 and toluene
has been described: Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.;
Rosen, R. K.; Timmers, F. J . Organometallics 1996, 15, 1518. Triethy-
lamine-pyridine, diisopropylethylamine, diisopropylamine, and ac-
etonitrile were distilled from CaH2 at atmospheric pressure. Tin
tetrachloride was purchased from Aldrich Chemical Co. and was
distilled from P2O5 at atmospheric pressure. Other general experi-
mental details have been described: Deng, W.; Overman, L. E. J . Am.
Chem. Soc. 1994, 116, 11241.
(25) Brain, E. G.; Eglington, J .; Nayler, J . H. C.; Osborne, N. F.;
Southgate, R.; Tolliday, P. J . Chem. Soc., Perkin Trans. 1 1977, 2479.
(26) Crowell, T. A.; Halliday, B. H.; McDonald, J . H., III; Indelicato,
J . M.; Pasini, C. E.; Wu, E. C. Y. J . Med. Chem. 1989, 32, 2436.
(27) Shinkai, I.; Liu, T.; Reamer, R.; Sletzinger, M. Synthesis 1980,
924.

9214 J . Org. Chem., Vol. 62, No. 26, 1997
Metais et al.
The reaction was maintained at rt overnight. The solution
was diluted with ether (50 mL), washed with 1 M HCl (2 × 10
mL) and brine (10 mL), dried (MgSO4), and concentrated.
Purification of the residue by flash chromatography on silica
gel (3:1 hexanes-EtOAc) gave acetate 13d (1.2 g, 86%), a 1.2:1
mixture of stereoisomers (1H NMR analysis), as a colorless
oil: 1H NMR (CDCl3, 500 MHz) (major isomer) δ 6.24 (s, 1H),
4.98-5.10 (m, 1H), 3.78-3.85 (m, 1H), 3.05 (t, J ) 15.4 Hz,
1H), 2.69 (dd, J ) 15.2, 2.8 Hz, 1H), 1.90-2.10 (m, 6H), 1.50-
1.70 (m, 4H), 1.15-1.25 (m, 6H); (minor isomer) δ 6.07 (s, 1H),
3.88-3.93 (m, 1H), 3.08 (t, J ) 5.4 Hz, 1H), 2.75 (dd, J ) 15.3,
2.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 169.3, 167.2, 166.4,
164.6, 163.9, 76.9, 72.3, 72.1, 70.7, 51.9, 51.7, 42.9, 32.7, 31.8,
21.5, 21.4, 20.5, 20.4, 15.1, 14.9, 3.3; IR (film) 1780, 1745, 1736
cm-1; MS (CI) m/e 296.1502 (296.1496 calcd for C15H22NO5,
MH).
mixture of stereoisomers (signals at δ 4.79 and 4.48), as a
1
colorless solid. The H NMR spectrum showed a third minor
component.
An analytical sample of the major isomer 16a was prepared
by flash chromatography (1:1 hexanes-EtOAc) and recrystal-
lization from CH2Cl2-hexane: mp 103-104 °C; 1H NMR
(CDCl3, 500 MHz) δ 4.95 (septet, J ) 6.3 Hz, 1H), 4.90 (br s,
1H), 4.49 (s, 1H), 3.83-3.89 (m, 1H), 3.16 (dd, J ) 14.7, 4.6
Hz, 1H), 2.71 (dd, J ) 14.7, 1.3 Hz, 1H), 2.33 (s, 3H), 2.20 (td,
J ) 13.6, 4.2 Hz, 1H), 1.85-2.20 (m, 2H), 1.75-1.80 (m, 1H),
1.25 (d, J ) 6.2 Hz, 3H), 1.22 (d, J ) 6.2 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 209.4, 168.2, 167.1, 77.2, 69.9, 58.5, 45.9,
44.4, 27.2, 25.6, 23.9, 21.7, 21.4; IR (CHCl3) 1737 cm-1; MS
(EI) m/e 269.1258 (269.1263 calcd for C13H19NO5, M).
Isop r op yl 3-[[(tr iflu or om eth yl)su lfon yl]oxy]-1-ca r ba -
1-d eth ia -3-cep h em -4-ca r boxyla te (17). A solution of 15a
(80 mg, 0.29 mmol) and CH2Cl2-MeOH (1:1, 10 mL) was
saturated with ozone at 78 °C. After the observation of a deep
blue color, excess ozone was flushed from the solution with
nitrogen, and Me2S (150 µL, 2.0 mmol) was added. The
reaction was warmed to rt and conentrated to give 39 mg of a
yellow oil. The crude enol was dissolved in CH2Cl2 (5 mL) and
i-Pr2EtN (150 µL, 0.86 mmol) and trifluoromethanesulfonic
anhydride (50 µL, 0.30 mmol) were added at 0 °C. The reaction
was allowed to warm to rt, and after 1 h, the reaction was
quenched with saturated aqueous NaHCO3 (2 mL). The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL), and
the combined organic extracts were dried (MgSO4) and con-
centrated. Purification of the residue by flash chromatography
on silica (1:2 EtOAc-hexanes) gave 47 mg (45%) of triflate 17
as a pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ 5.22 (septet,
J ) 6.3 Hz, 1H), 3.64-3.74 (m, 1H), 3.35 (dd, J ) 15.7, 5.3
Hz, 1H), 2.71 (dd, J ) 15.7, 2.4 Hz, 1H), 2.58-2.65 (m, 2H),
2.30-2.40 (m, 1H), 1.62-1.80 (m, 1H), 1.33 (t, J ) 6.1, 6H);
13C NMR (CDCl3, 75 MHz) δ 165.2, 158.8, 141.3, 123.8, 120.4,
71.1, 46.1, 43.4, 26.3, 26.2, 21.5, 21.3; IR (film) 1789, 1770,
1728 cm-1; MS (EI) m/e 357.0481 (357.0481 calcd for C12H14F3-
NO6S, M).
Isop r op yl 4-ch lor o-9-oxo-1-a za bicyclo[5.2.0]n on -3-en e-
3-ca r boxyla te (14a ). Tin tetrachloride (320 µL, 2.7 mmol)
was added dropwise to a solution of acetate 13d (250 mg, 0.8
mmol) and CH2Cl2 (9 mL) at 0 °C, and the reaction was
maintained at this temperature for 6 h. The reaction was then
poured into a mixture of saturated aqueous NaHCO3 (15 mL)
and ether (50 mL) and stirred for 15 min. The layers were
separated, the aqueous slurry was extracted with ether (2 ×
10 mL), and the combined organic layers were dried (MgSO4)
and concentrated. Purification of the residue by flash chro-
matography on silica gel (2:1 hexanes-EtOAc) gave recovered
13d (63 mg, 29%) and azabicyclo[5.2.0]non-3-ene 14a (25 mg,
12%) as a single stereoisomer (13C NMR analysis): 1H NMR
(CDCl3, 500 MHz) δ 5.94 (d, J ) 6.0 Hz, 1H), 5.07 (d, J ) 6.0
Hz, 1H), 5.03 (septet, J ) 6.2 Hz, 1H,), 4.24-4.30 (m, 1H),
3.17 (dd, J ) 14.8, 4.9 Hz, 1H), 2.32-2.40 (m, 2H), 2.67 (dd, J
) 14.8, 2.2 Hz, 1H), 2.18-2.25 (m, 1H), 1.78-1.86 (m, 1H),
1.27 (d, J ) 6.2 Hz, 3H), 1.26 (d, J ) 6.2 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 167.4, 165.7, 137.7, 122.2, 69.9, 52.5, 51.9,
43.1, 34.2, 31.2, 21.7, 21.6; IR (film) 1750, 1736 cm-1; MS (CI)
m/e 258.0890 (258.0896 calcd for C12H17ClNO3, MH).
Isop r op yl 3-(1-Ch lor oet h ylid en e)-1-ca r b a -1-d et h ia -
cep h a m -4-ca r boxyla te (15a ). Tin tetrachloride (900 µL, 7.7
mmol) was added dropwise to a solution of acetate 13d (1.0 g,
3.4 mmol) and CH2Cl2 (30 mL) at 0 °C, and the reaction was
maintained at this temperature for 6 h. Workup as described
for 14a and purification of the residue by flash chromatogra-
phy on silica gel (2:1 hexanes-EtOAc) gave 15a (597 mg, 65%),
a 4:1 mixture of stereoisomers (integration of 1H NMR signals
at 5.6 and 5.2 ppm), as a colorless oil. The isomers were
separated by flash chromatography on silica gel (6:1 hexanes-
EtOAc) for characterization. Major isomer: 1H NMR (CDCl3,
500 MHz) δ 5.22 (s, 1H), 4.98 (septet, J ) 6.4 Hz, 1H), 3.82-
3.90 (m, 1H), 3.10-3.19 (m, 2H), 2.55 (dd, J ) 14.9, 1.6 Hz,
1H), 2.22 (s, 3H), 2.15-2.20 (m, 1H), 2.00-2.10 (m, 1H), 1.28-
1.38 (m, 1H), 1.24 (d, J ) 6.2 Hz, 3H), 1.20 (d, J ) 6.2 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 167.8, 166.2, 129.3, 124.9,
69.5, 52.6, 46.8, 43.9, 30.5, 25.2, 23.0, 21.6, 21.5; IR (film) 1750,
3-P en tyn yl Tr iflu or om eth a n esu lfon a te (22b). Follow-
ing the general procedure of Hanack,29 a solution of 3-pentyn-
1-ol (4.21 g, 50.0 mmol), 2,6-lutidine (7.0 mL, 60 mmol), and
dry CH2Cl2 was cooled to 0 °C. Trifluoromethanesulfonic
anhydride (freshly distilled from P2O5, 10 mL, 60 mmol) was
added dropwise by syringe over 10 min, and after 30 min, the
reaction mixture was concentrated and the resulting red syrup
was partitioned between pentane (250 mL) and water (50 mL).
The organic layer was separated, washed with water (2 × 50
mL) and brine (2 × 50 mL), dried (MgSO4), and concentrated
to afford a red oil. Filtration through a short column of basic
alumina (pentane) gave 9.90 g (91%) of the known30 triflate
22b as a somewhat unstable orange oil: 1H NMR (CDCl3, 300
MHz) δ 4.52 (t, J ) 6.8 Hz, 2H), 2.63-2.70 (m, 2H), 1.78 (t, J
) 2.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 118.6 (q), 79.3,
74.5, 71.7, 22.3, 3.3; IR (film) 1208, 947 cm-1; MS (EI) m/e
216.0075 (216.0068 calcd for C6H7F3O3S, M), 133, 105, 99, 66.
Anal. Calcd for C6H7F3O3S: C, 33.34; H. 3.26; Found: C,
33.29; H, 3.31.
(3R,4S)-1-(ter t-Bu t yld im et h ylsilyl)-3-(p h en oxya cet a -
m id o)-4-(b e n ze n e su lfon yl)-4-(3-p e n t yn yl)a ze t id in -2-
on e (23). A THF solution of LDA (1.7 mL, 0.89 mmol, 0.52
M solution in THF) was added dropwise by syringe over 15
min to a solution of 21 (190 mg, 0.400 mmol, 0.1 M) and dry
THF (4 mL) at -78 °C. After 30 min, a solution of freshly
prepared triflate 22b (96.0 mg, 0.44 mmol) and THF (0.5 mL)
was added dropwise by cannula. After 30 min at -78 °C, the
reaction was quenched by adding saturated aqueous NH4Cl
(1 mL) and the resulting mixture was allowed to warm to rt.
Concentration gave a reddish oil, which was dissolved in
EtOAc (200 mL) and washed with H2O (3 × 10 mL) and brine
(2 × 10 mL). After drying (MgSO4), concentration afforded
230 mg of a red foamy solid, which was chromatographed on
1655 cm-1; MS (EI) m/e 271.0965 (271.0975 calcd for C13H18
-
ClNO3, M). Anal. Calcd. for C13H18ClNO3: C, 57.45; H, 6.76;
N, 5.15. Found: C, 57.32; H, 6.60; N, 5.05. Minor isomer: 1H
NMR (CDCl3, 500 MHz) δ 5.60 (s, 1H), 4.98 (septet, J ) 6.2
Hz, 1H), 3.75-3.83 (m, 1H), 3.15 (dd, J ) 14.7, 4.7 Hz, 1H),
2.67-2.78 (m, 1H), 2.55 (d, J ) 14.7 Hz, 1H), 2.10-2.20 (m,
5H), 1.25-1.40 (m, 1H), 1.25 (d, J ) 6.4 Hz, 3H), 1.21 (d, J )
6.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 168.1, 165.8, 128.3,
125.4, 69.4, 53.9, 46.6, 44.0, 30.9, 24.9, 22.2, 21.6; MS (CI) m/e
272.1054 (272.1053 calcd for C13H19ClNO3, MH).
Isopr opyl 3-Eth an oyl-3-h ydr oxyl-1-car ba-1-deth iaceph -
a m -4-ca r boxyla te (16a a n d 16b). Following the general
procedure of Sharpless, a solution of RuCl3‚H2O (8 mg, 0.4
mmol) and H2O (2 mL) was added to the stereoisomeric
mixture of vinyl chlorides 15a (500 mg, 1.8 mmol), NaIO4 (1.6
g, 6.9 mmol), CCl4 (4 mL), and MeCN (4 mL) at rt. After 5
min, the mixture was diluted with CH2Cl2 (50 mL) and washed
with a 5% aqueous solution of Na2S2O3 (2 × 10 mL). The
combined aqueous extracts were extracted with CH2Cl2 (10
mL), and the combined organic layers were dried (MgSO4) and
concentrated to give hydroxy ketones 16 (451 mg, 94%), a 9:1
(29) Stang, P. J .; Hanack, M.; Subramanian, L. R. Synthesis. 1982,
85.
(30) Hanack, M.; Collins, C. J .; Stutz, H.; Benjamin, B. M. J . Am.
Chem. Soc. 1981, 103, 2356.

A New Construction of Carbacephem Antibiotics
J . Org. Chem., Vol. 62, No. 26, 1997 9215
silica gel (2:1:0.02 hexanes-EtOAc-Et3N) to afford 23 (130
mg, 60%) as a colorless solid: mp 142-143 °C; [R]24D +100.7°,
7.60 (d, J ) 8.8 Hz, 1H), 7.55 (d, J ) 8.5 Hz, 2H), 7.29 (t, J )
7.8 Hz, 2H), 7.01 (t, J ) 7.3 Hz, 1H), 6.89 (d, J ) 8.2 Hz, 2H),
5.33 (s, 1H), 5.32 (s, 2H), 5.27-5.31 (m 1H), 4.50 (s, 2H), 4.18
(dd, J ) 12.2, 6.5 Hz, 1H), 2.11-2.20 (m, 2H), 1.57-1.89 (m,
5H); (minor isomer) 8.22 (d, J ) 8.6 Hz, 2H), 7.56 (d, J ) 8.07
Hz, 2H), 5.65 (s, 1H), 4.09 (dd, J ) 12.1, 6.3 Hz, 1H); 13C NMR
(CD2Cl2, 125 MHz) (major isomer) 169.2, 169.0, 166.5, 157.5,
148.3, 142.0, 130.1, 129.4, 124.1, 122.5, 115.0, 77.5, 77.1, 73.4,
67.4, 67.6, 58.4, 57.9, 28.8, 15.9, 3.94 ppm; (minor isomer) δ
169.1, 167.9, 167.1, 142.2, 124.2, 129.0, 77.0, 72.6, 67.5, 58.1,
29.0, 15.7 ppm; IR (film) 3333, 1756, 1682 cm-1; MS (FAB)
m/e 518.1541 (518.1539 calcd for C25H25N3O8Na, MNa).
p-Nitr oben zyl 2-Acetoxy-2-[(3R,4R)-3-(p h en oxya ceta -
m id o)-4-(3-p en t yn yl)-2-oxoa zet id in on -1-yl]a cet a t e (27).
Acetic anhydride (660 µL, 7.0 mmol) was added rapidly to a
solution of the crude hemiaminal 26 (1.40 g, ca. 1.4 mmol),
pyridine (570 µL, 7.0 mmol), and CH2Cl2 (50 mL) at rt. After
30 min, the reaction was diluted with EtOAc (200 mL), washed
with water (2 × 20 mL) and brine (2 × 20 mL), dried (MgSO4),
and concentrated to give 750 mg of a yellow oil. Flash
chromatography on silica gel (2:1 hexanes-EtOAc) gave 581
mg (77% over two steps) of 27, a 2:1 mixture of diastereomers
(1H NMR analysis), as an off-white foam: 1H NMR (CDCl3,
500 MHz) (major isomer) δ 8.23 (d, J ) 8.7 Hz, 2H), 7.53 (d, J
) 8.6 Hz, 2H), 7.32 (t, J ) 7.6 Hz, 2H), 7.12 (d, J ) 8.3 Hz,
1H), 7.06 (t, J ) 7.2 Hz, 1H), 6.91 (d, J ) 7.8 Hz, 2H), 6.24 (s,
1H), 5.40 (dd, J ) 8.4, 5.6 Hz, 1H), 5.33 (s, 2H), 4.55 (s, 2H),
4.19 (dd, J ) 6.0, 1.4 Hz, 1H), 2.19 (s, 3H), 2.00-2.11 (m, 2H),
1.74 (s, 3H), 1.51-1.71 (m, 2H); (minor isomer) δ 6.50 (s, 1H),
4.14 (dd, J ) 5.7, 1.5 Hz, 1H), 2.17 (s, 3H); 13C NMR (CD2Cl2,
125 MHz) (major isomer) δ 169.7, 169.1, 166.6, 165.0, 157.5,
148.3, 142.2, 130.1, 129.2, 124.1, 122.6, 115.0, 77.2, 77.1, 72.8,
67.6, 67.1, 58.7, 58.6, 28.3, 20.6, 15.6, 3.54; (minor isomer)
169.6, 169.0, 166.4, 164.5, 142.1, 129.0, 124.2, 77.5, 77.1, 72.2,
[R]24
+103.1°, [R]24
+119.6°, [R]24
+222.7°, [R]24
577
546
1
435
405
+275.6° (c 0.6, CHCl3); H NMR (CDCl3, 500 MHz) δ 8.02 (d,
J ) 11 Hz, 1H), 8.00 (d, J ) 7.6 Hz, 2H), 7.71 (t, J ) 7.5 Hz,
1H), 7.59 (t, J ) 7.9 Hz, 2H), 7.13 (t, J ) 8.0 Hz, 2H), 6.92 (t,
J ) 7.5 Hz, 1H), 6.65 (d, J ) 8.0 Hz, 2H), 6.29 (d, J ) 11 Hz,
1H), 4.54 (d, J ) 15.5 Hz, 1H), 4.31 (d, J ) 15.0 Hz, 1H), 2.16-
2.28 (m, 3H), 1.18-1.28 (m, 1H), 1.73 (s, 3H), 1.09 (s, 9H), 0.46
(s, 3H), 0.41 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.6, 167.8,
156.7, 136.1, 134.3, 130.4, 129.6, 129.2, 122.0, 114.1, 83.3, 80.8,
77.2, 66.8, 60.8, 26.6, 25.5, 19.8, 15.0, 3.4, -4.6, -4.7; IR (KBr)
3681, 1770, 1698 cm-1; MS (FAB) m/e 541.2183 (541.2192 calcd
for C28H37N2O5SSi, MH). Anal. Calcd for C28H36N2O5SSi: C,
58.20; H, 6.38; 5.90; Found: C, 58.07; H, 6.33; N, 5.98.
(3R,4R)-3-(P h en oxya ceta m id o)-4-(3-p en tyn yl)a zetid in -
2-on e (24). Concentrated HCl (3.4 mL, 41 mmol) was added
to a solution of 23 (2.21 g, 4.09 mmol) and THF (5 mL) at rt.
After 30 min, saturated aqueous NaHCO3 solution (10 mL)
was carefully added and the resulting mixture was extracted
with EtOAc (4 × 50 mL). The organic extracts were washed
with brine (2 × 20 mL), dried (MgSO4) and concentrated to
give 1.7 g of the corresponding 1-unsubstituted azetidinone
as an unstable yellow solid, which was used immediately
without further purification: 1H NMR (CDCl3, 300 MHz) δ 8.05
(d, J ) 7.5 Hz, 2H), 7.87 (d, J ) 10.0 Hz, 1H), 7.73 (t, J ) 7.3
Hz, 1H), 7.63 (t, J ) 7.5 Hz, 2H), 7.37 (s, 1H), 7.23 (t, J ) 8.3
Hz, 2H), 6.98 (t, J ) 7.3 Hz, 1H), 6.83 (d, J ) 7.9 Hz, 2H),
5.76 (d, J ) 10.0 Hz, 1H), 4.56 (d, J ) 15.3 Hz, 1H), 4.49 (d,
J ) 15.9 Hz, 1H), 2.36-2.37 (m, 2H), 2.20 (dt, J ) 15.0, 5.3
Hz, 1H), 1.72 (t, J ) 1.9 Hz, 3H), 1.61-1.64 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 168.7, 164.7, 156.7, 134.8, 133.4, 130.4,
129.7, 129.4, 122.2, 114.4, 79.1, 78.8, 70.6, 66.9, 61.7, 26.4, 25.1,
14.7; IR (CH2Cl2) 3666, 3394, 1798, 1699 cm-1; MS (FAB) m/e
449.1150 (449.1147 calcd for C22H22N2O5SNa, MNa).
67.0, 58.5, 29.0, 20.7, 15.7; IR (film) 3356, 1766, 1682 cm-1
;
MS (FAB) m/e 560.1661 (560.1645 calcd for C27H27N3O9Na,
MNa). Anal. Calcd for C27H27N3O9: C, 60.33; H, 5.06; N, 7.57;
Found: C, 60.07; H, 5.07; N, 7.57.
A THF solution of lithium tri-tert-butoxyaluminum hydride
(4.1 mL, 1 M, 4.1 mmol) was added dropwise by syringe over
15 min to a solution of this product (1.7 g) and dry THF (40
mL) at 0 °C. After 45 min, the reaction was quenched with
saturated aqueous sodium potassium tartrate (10 mL). The
resulting aluminum salts were removed by filtration and
washed with CH2Cl2 (4 × 40 mL). The combined organic
extracts were washed with brine (2 × 15 mL), dried (MgSO4),
and concentrated to give 1.6 g of a crude yellow solid.
Recrystallization of this product from 10:1 hexanes-CH2Cl2
gave 24 (1.05 g, 90% over two steps) as a colorless crystalline
solid: mp 159-160 °C; [R]24 +73.2°, [R]24 +73.5°, [R]24
p-Nitr oben zyl (7R,8R)-3-(1-Ch lor oeth ylid en e)-7â-(p h e-
n oxya ce t a m id o)-1-ca r b a -1-d e t h ia ce p h a m -4-ca r b oxy-
la te (28). A CH2Cl2 solution of SnCl4 (2.3 mL, 1.0 M, 2.3
mmol) was added dropwise to a solution of 27 (403 mg, 0.750
mmol) and dry CH2Cl2 (3 mL) at 0 °C. After 6 h, the cooling
bath was removed and after 15 min the reaction was quenched
by addition of saturated aqueous NaHCO3 (5 mL). The
resulting emulsion was diluted with EtOAc (20 mL) and stirred
vigorously for 30 min. The organic layer was separated, and
the aqueous layer was washed with EtOAc (3 × 50 mL). The
remaining aqueous slurry was dissolved in 1 M HCl (10 mL)
and extracted with EtOAc (3 × 50 mL). The combined organic
extracts were washed with brine (2 × 20 mL), dried (MgSO4),
and concentrated to give, after flash chromatography on silica
gel (2:1 hexanes-EtOAc), 28 (235 mg, 61%), a 5:1 mixture of
what are assumed to be double-bond stereoisomers (1H NMR
analysis), as a yellow foam: 1H NMR (major isomer) (CDCl3,
500 MHz) δ 8.23 (d, J ) 8.8 Hz, 2H), 7.46 (d, J ) 8.6 Hz, 2H),
7.31 (t, J ) 8.0 Hz, 2H), 7.12 (d, J ) 7.1 Hz, 1H), 7.03 (t, J )
7.3 Hz, 1H), 6.91 (d, J ) 7.4 Hz, 2H), 5.39 (s, 1H), 5.26-5.39
(m, 1H), 5.25 (s, 2H), 4.52 (s, 2H), 4.07-4.15 (m, 1H), 3.18 (dt,
J ) 14.9, 3.4 Hz, 1H), 2.24 (d, J ) 1.0 Hz, 3H) 2.02 (m, 1H),
1.86 (dt, J ) 13.2, 4.1 Hz, 1H), 1.29-1.22 (m, 1H); (minor
isomer) δ 8.22 (d, J ) 8.3 Hz, 2H), 7.68 (d, J ) 8.6 Hz, 2H),
7.16 (d, J ) 6.9 Hz, 1H), 5.79 (s, 1H), 2.73 (dt, J ) 14.8, 3.3
Hz, 1H), 2.17 (s, 3H); 13C NMR (major isomer) (CDCl3, 125
MHz) δ 168.6, 167.4, 165.5, 156.8, 147.9, 141.9, 130.5, 129.8,
128.3, 124.2, 124.0, 122.4, 114.6, 67.0, 66.0, 58.1, 52.9, 52.4,
24.8, 24.1, 23.1; (minor isomer) δ 167.6, 165.1, 142.2, 129.5,
124.5, 65.8, 58.3, 53.4, 52.7, 25.1, 24.5, 22.3; IR (CH2Cl2) 3683,
3415, 1767, 1694 cm-1; MS (FAB) m/e 514.1372 (514.1371 calcd
for C25H25N3O7Cl, MH), Anal. Calcd for C25H24ClN3O7: N3O7-
CC, 58.43; H, 4.74; N, 8.18; Found: C, 58.24; H, 4.87; N, 7.96.
p -Nit r ob en zyl (7R,8R)-7â-(P h en oxya cet a m id o)-3-h y-
d r oxy-1-ca r ba -1-d eth ia -3-cep h em -4-ca r boxyla te (29). A
solution of 28 (105 mg, 0.204 mmol) and 1:1 CH2Cl2-MeOH
(10 mL) was saturated with ozone at -78 °C. After the
observation of a deep blue color, excess ozone was flushed from
D
577
546
+84.6°, [R]24
+141.9°, [R]24
+161.4° (c 1.1, CHCl3); 1H
435
405
NMR (CDCl3, 500 MHz) δ 7.33 (d, J ) 7.6 Hz, 1H), 7.32 (t, J
) 7.7 Hz, 2H), 7.03 (t, J ) 7.3 Hz, 1H), 6.92 (d, J ) 8.0 Hz,
2H), 6.42 (br s, 1H), 5.34 (dd, J ) 8.1, 5.2 Hz, 1H), 4.54 (s,
2H), 4.00 (app quintet, J ) 4.7 Hz, 1H), 2.17-2.20 (m, 2H),
1.75 (t, J ) 2.4 Hz, 3H), 1.61-1.67 (m, 1H), 1.48-1.53 (m, 1H);
13C NMR (CD3CN, 125 MHz) δ 169.7, 167.7, 158.5, 130.6,
122.6, 115.6, 78.7, 77.0, 67.8, 58.9, 54.2, 54.1, 30.6, 16.0; IR
(CH2Cl2) 3685, 3413, 1776, 1694 cm-1; MS (FAB) m/e 287.1398
(287.1396 calcd for C16H19N2O3, MH).
p-Nitr oben zyl 2-Hyd r oxy-2-[(3R,4R)-3-(p h en oxya ceta -
m id o)-4-(3-p en tyn yl)-2-oxoa zetid in -1-yl]a ceta te (26). Fol-
lowing the general procedure of Woodward,31 a mixture of 24
(400 mg, 1.40 mmol), p-nitrobenzyl glyoxylate hydrate (25, 650
mg, 2.86 mmol), dry DMF (5 mL), dry toluene (10 mL), and 4
Å molecular sieves (2 g, activated for 8 h at 150 °C and 0.1
mm) was stirred at rt for 8 h. The reaction mixture was then
filtered through a pad of Celite, the residue was washed with
EtOAc (3 × 100 mL), and the combined eluents were concen-
trated (50 °C, 1 mm) to give 1.40 g of a mixture of the crude
hemiaminal 26 and 25; this yellow oil was used without further
purification. A pure sample of 26, a 2:1 mixture of diastere-
omers (1H NMR analysis), was obtained as a light yellow oil
by flash chromatography (1:1 EtOAc-hexanes): 1H NMR
(CDCl3, 500 MHz) (major isomer) δ 8.19 (d, J ) 8.5 Hz, 2H),
(31) Earnest, I.; Gosteli, J .; Greengrass, C. W.; Holick, W.; J ackman,
D. E.; Pfaendler, H. R.; Woodward, R. B. J . Am. Chem. Soc. 1978, 100,
8214.

9216 J . Org. Chem., Vol. 62, No. 26, 1997
Metais et al.
the solution with nitrogen and Me2S (150 µL, 2.0 mmol) was
added. The reaction was warmed to rt and concentrated to
give a yellow oil, which was dissolved in EtOAc (50 mL) and
washed with water (3 × 5 mL) and brine (1 × 5 mL), and dried
(MgSO4). Concentration, followed by rapid chromatography
of the residue on silica gel (1:1 EtOAc-hexanes, then 10:1
CHCl3-MeOH), afforded the known enol 29 (81 mg, 77%) as
) 18.9, 3.4 Hz, 1H), 2.37 (ddd, J ) 18.6, 12.4, 5.7 Hz, 1H),
2.08-2.11 (m, 1H), 1.52-1.58 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ 170.2, 168.8, 164.5, 162.2, 162.1, 158.6, 148.6, 147.8,
141.8, 137.0, 129.9, 129.5, 128.8, 127.9, 126.9, 123.7, 122.5,
121.3, 114.5, 67.1, 66.8, 58.6, 52.9, 51.9, 32.9, 29.6, 28.0, 22.0;
IR (CH2Cl2) 3683, 3415, 1776, 1738, 1716 cm-1; MS (FAB) m/e
778.1531 (778.1540 calcd for C34H30N6O14S, M), 778, 713, 588,
391, 335. Anal. Calcd for C34H32N6O15S (32a ‚H2O): C, 51.25;
H, 4.04; N, 10.55; S, 4.02. Found: C, 51.44; H, 3.98; N, 10.39;
S, 3.95.
an unstable yellow oily solid: [R]24 +34.3°, [R]24
+37.0°,
D
577
[R]24546 +42.7° (c 0.5, THF); 1H NMR (CDCl3, 500 MHz) δ 11.04
(s, 1H), 8.21 (d, J ) 8.0 Hz, 2H), 7.66 (d, J ) 8.4 Hz, 2H),
7.49-7.54 (m, 1H), 7.32 (t, J ) 7.6 Hz, 2H), 7.04 (t, J ) 7.2
Hz, 1H), 6.91 (d, J ) 8.0 Hz, 2H), 5.51 (d, J ) 13.5 Hz, 1H),
5.35-5.37 (m, 1H), 5.26 (d, J ) 13.5 Hz, 1H), 4.55 (s, 2H),
3.87-3.89 (m, 1H), 2.46-2.55 (m, 2H), 1.95-2.01 (m, 1H),
1.82-1.83 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 168.9, 166.7,
166.1, 165.2, 156.8, 147.7, 142.3, 129.8, 128.2, 123.7, 122.4,
114.6, 103.2, 67.0, 65.5, 57.1, 52.2, 25.6, 21.3; IR (CH2Cl2) 3685,
3414, 1770, 1732 cm-1; MS (FAB) m/e 468.1400 (468.1406 calcd
for C23H22N3O8, MH).
Diastereomer 32b was prepared in an identical fashion from
30 and (S)-31. Reverse-phase HPLC analysis (Alltima C18
,
10 µM, 2:1 MeOH-H2O) indicated the presence of a single
diastereomer: mp 120-125 °C; [R]24 -58.1°, [R]24 -60.1°,
D
577
[R]24546 -73.8°, [R]24435 -218.1°, [R]24405 -300.7° (c 0.5, CHCl3);
1H NMR (CDCl3, 500 MHz) δ 9.13 (s, 1H), 9.02 (s, 2H), 8.59
(d, J ) 7.7 Hz, 1H), 8.18 (d, J ) 8.3 Hz, 2H), 7.54 (d, J ) 8.3
Hz, 2H), 7.32 (t, J ) 7.7 Hz, 2H), 7.09 (d, J ) 6.4 Hz, 1H),
7.04 (t, J ) 7.1 Hz, 1H), 6.90 (d, J ) 7.9 Hz, 2H), 5.42 (d, J )
13.1 Hz, 1H), 5.34 (d, J ) 13.1 Hz, 1H), 5.23 (t, J ) 5.6 Hz,
1H), 5.06 (t, J ) 3.6 Hz, 1H), 4.48 (s, 2H), 3.83 (m, 1H), 3.84
(s, 3H), 3.45 (dd, J ) 14.3, 4.0 Hz, 1H), 3.31 (dd, J ) 14.3, 3.8
Hz, 1H), 2.74 (dd, J ) 18.9, 2.9 Hz, 1H), 2.39-2.44 (m, 1H),
1.51-1.67 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 169.7, 168.9,
163.9, 162.9, 162.8, 156.8, 148.7, 147.1, 141.6, 136.6, 129.8,
129.2, 129.0, 127.6, 126.1, 123.7, 122.4, 121.3, 114.6, 67.9, 66.9,
58.8, 53.1, 33.0, 29.7, 27.9, 25.6, 22.3; IR (CH2Cl2) 3685, 3600,
3413, 1777, 1749, 1716, 1694, 1678 cm-1; MS (FAB) m/e 801
(MNa).
p-Nitr oben zyl (7R,8R)-7â-(P h en oxya ceta m id o)-3-[[(tr i-
flu or om eth yl)su lfon yl]oxy]-1-ca r ba -1-d eth ia -3-cep h em -
4-ca r boxyla te (30). A CH2Cl2 solution of trifluoromethane-
sulfonic anhydride (freshly distilled from P2O5, 230 µL, 23
µmol, 0.10 M solution in CH2Cl2) was rapidly added to a
solution of 29 (10 mg, 21 µmol) and triethylamine (250 µL, 25
µmol, 0.1 M solution in CH2Cl2) and CH2Cl2 (5 mL) at -40 °C.
After 15 min, the reaction mixture was poured into a saturated
aqueous solution of NaHCO3 (10 mL). The resulting mixture
was extracted with CH2Cl2 (3 × 20 mL), and the extracts were
combined, washed with brine (1 × 5 mL), dried (MgSO4), and
concentrated to give 12 mg (95%) of the known triflate 30 as
a yellow oil.
Ack n ow led gm en t. This research was supported by
a grant from the National Heart, Lung, and Blood
Institute (HL-25854) and postdoctoral fellowships to
E.M. (Rotary Club) and M.I.R. (Fonds National Suisse
de la Recherche Scientifique). NMR and mass spectra
were determined using instruments acquired with the
assistance of NSF and NIH shared instrumentation
grants. We particularly thank Drs. Larry C. Blaszczak
and Matthew J . Fisher of the Lilly Research Laborato-
ries for samples of (3R,4R)-3-(phenoxyacetamido)-4-
acetoxyazetidin-2-one (18) and Drs. Lowell Hatfield and
J ohn Gardner of the Lilly Research Laboratories for
advice.
p-Nitr oben zyl 3-[[(2R)-2-[(3,5-d in itr oben zoyl)a m in o]-
2-(m eth oxyca r bon yl)eth yl]th io]-(7R,8S)-7â-(p h en oxya c-
eta m id o)-1-ca r ba -1-d eth ia -3-cep h em -4-ca r boxyla te (32a ).
A solution of 30 (18 mg, 30 µmol), i-Pr2NEt (300 µL of a 0.10
M solution in MeCN), and dry MeCN (5 mL) was cooled to 0
°C in an ice bath. A solution of (R)-31 (9.8 mg, 30 µmol) and
dry MeCN (1 mL) was added rapidly, and after 10 min, water
(5 mL) was added to the pink reaction mixture. The resulting
mixture was then extracted with EtOAc (3 × 20 mL). The
organic extracts were collected, washed with brine (1 × 5 mL),
dried (MgSO4), and concentrated to give 40 mg of a tan oil.
Purification of this oil by flash chromatography on silica gel
(1:1 hexanes-EtOAc) gave 32a (23 mg, 98%) as a yellowish
oil, which rapidly forms a solid hydrate on standing. Reverse-
phase HPLC analysis of 32a (Alltima C18, 10 µM, 2:1 MeOH-
H2O) indicated the presence of a single diastereomer: mp 238
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for 10bcd , 12bcd , 13bcd ,
14bcd , 15bc, 19, 21, 25, and 31 and 1H NMR spectra (500
MHz in CDCl3) of 10a bcd , 12a bcd , 13a bcd , 14a cd , 15bc,
16a , 17, 24, 26, 32a , and 32b (33 pages). This material is
containing in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
°C (dec); [R]24 +6.9°, [R]24
+7.1°, [R]24
+5.26° (c 0.8,
D
577
546
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 9.29 (d J ) 2.0 Hz, 2H),
9.21 (d, J ) 1.6 Hz, 1H), 8.97 (d, J ) 8.8 Hz, 1H), 8.22 (d, J )
8.4 Hz, 2H), 7.60 (d, J ) 8.7 Hz, 2H), 7.34 (t, J ) 8.0 Hz, 2H),
7.06 (t, J ) 7.4 Hz, 1H), 7.02 (d, J ) 6.8 Hz, 1H), 6.90 (d, J )
8.4 Hz, 2H), 5.58 (d, J ) 13.1 Hz, 1H), 5.48 (d, J ) 13.5 H,
1H), 5.39 (t, J ) 6 Hz, 1H), 5.33-5.36 (m, 1H), 4.57 (s, 2H),
3.95 (dd, J ) 11.6, 4.0 Hz, 1H), 3.82 (dd, J ) 14.5, 1.5 Hz,
1H), 3.61 (s, 3H), 3.00 (dd, J ) 14.7, 5.6 Hz, 1H), 2.92 (dd, J
J O971433W