Application of lanthanide catalysis in the penicillin to cephalosporin conversion

Article abstract of DOI:10.1016/S0040-4020(02)00982-1

seco-Penicillin sulfinyl carboxylates and chlorides were cyclized to produce the corresponding 3-methylenecepham systems, intermediates for cephalosporin antibiotic manufacture, either under thermal or ytterbium(III) triflate catalyzed conditions.

Full text of DOI:10.1016/S0040-4020(02)00982-1

Tetrahedron 58 (2002) 8313–8319
Application of lanthanide catalysis in the penicillin to
cephalosporin conversion
a
b
a
Anthony G. M. Barrett,a D. Christopher Braddock, Robin D. G. Cooper and Julian P. Henschke
,
*
aDepartment of Chemistry, Imperial College of Science, Technology and Medicine, South Kensington, London SW7 2AY, UK
bCooper Consulting Inc, 6740 Dover Road, Indianapolis, IN 46220, USA
Received 23 May 2002; accepted 6 June 2002
Abstract—seco-Penicillin sulfinyl carboxylates and chlorides were cyclized to produce the corresponding 3-methylenecepham systems,
intermediates for cephalosporin antibiotic manufacture, either under thermal or ytterbium(III) triflate catalyzed conditions. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Both penicillins and cephalosporins have found widespread
use in the treatment of bacterial infections.15 The primary
drawbacks associated with several important cephalosporin
antibiotics relate to the difficulty and expense of their
synthetic production from penicillin precursors. For
example, the manufacture of cefaclor 4 and related
cephalosporin antibiotics, involves the cyclization of the
seco-penicillin sulfinyl chloride 2 into the corresponding
3-methylenecepham b-sulfoxide 3 using stoichiometric
quantities of tin(IV) chloride (Scheme 1). Clearly this
transformation is neither optimal from the viewpoint of
atom economy nor from the potential for environmental
risk. In this paper we wish to report our studies of
ytterbium(III) triflate catalysis for the cyclization of sulfinyl
chloride 2 and related transformations. We additionally
report the synthesis and characterization of seco-penicillin
sulfinyl carboxylates.
Lanthanide(III) triflates and related species have enjoyed
recent attention as catalysts for a wide range of reactions in
organic synthesis.1,2 The interest stems from their apparent
ability to function as strong Lewis acids even in Lewis basic
solvents such as tetrahydrofuran and water, and by their
relatively high turnover numbers compared to traditional
Lewis acids.3 For instance, ytterbium(III) triflate was found
to catalyze the Mukaiyama aldol reaction of silyl ketene
acetals with aqueous formaldehyde solution.4 In the latter
category, these compounds have been found to be effective
catalysts (10 mol%) for Friedel–Crafts acylation reactions5,6
where typically ‘classical’ Lewis acid catalysts must be used
in at least stoichiometric quantities.7 Notably, in many cases
the lanthanide(III) triflate may be recovered from a reaction
mixture by extraction into an aqueous phase and recycled by
evaporation.
We have recently reported several novel catalytic appli-
cations of lanthanide(III) triflates including atom economic
electrophilic nitration of arenes in the absence of sulfuric
acid,8 oxidation of benzylic alcohols with nitric acid,9 the
preparation of resorcinarenes,10 and alcohol acetylation
using acetic acid.11 For the resorcinarene10 and nitration
chemistry9,12,13 it has been demonstrated that the lantha-
nide(III) triflates operate via Lewis assisted enhancement of
Brønsted acidity.14 Thus, lanthanide(III) triflates may
function not only as mild Lewis acids but also as a
convenient and recyclable source of the strong Brønsted
acid triflic acid.
2. Results and discussion
2.1. Synthesis of seco-penicillin sulfinyl carboxylates
Given the highly oxophilic, rather than halophilic, nature of
lanthanide triflates we proposed to prepare novel analogues
of sulfinyl chloride 2 that contained an oxygen based
leaving group. By analogy to Friedel–Crafts acylation of
olefins and arenes with carboxylic anhydrides we chose to
investigate the hitherto unknown seco-penicillin sulfinyl
carboxylates as functional equivalents of the currently used
sulfinyl chloride. Sulfinyl carboxylates have received little
attention in the literature, probably as a result of their
instability. In fact, Oae et al.16 has shown that simple
sulfinyl carboxylates prepared from methanesulfinyl
chloride and silver acetate or benzoate could only be
studied in solution, and decomposed through disproportion-
ation upon evaporation of the solvent. We hoped to utilize
Keywords: ytterbium(III) triflate; cephalosporin; antibiotics; sulfinyl
carboxylate.
*
Corresponding author. Tel.: þ44-207-594-5767; fax: þ44-207-594-5805;
e-mail: m.sahrle@ic.ac.uk
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00982-1

8314
A. G. M. Barrett et al. / Tetrahedron 58 (2002) 8313–8319
Scheme 1. Reagents and conditions: (i) PhMe, D, N-chlorophthalimide; (ii) PhMe, SnCl4; V¼PhOCH2CONH.
this instability in the development of a mild protocol for
the conversion of seco-penicillin sulfinyl carboxylates into
3-methylenecephams.
experiment to observe that reaction of sulfinyl chloride 6,21,22
with silver acetate (1.1 equivalents) at 2208C in deutero-
chloroform provided a new, albeit impure, component, that
consisted of two diastereoisomers with the characteristic
cis-azetidinone23 resonances in the 1H NMR spectrum.
These were assigned as the two sulfur centered diastereo
isomers (assigned a and b) of 7 on the basis of their spectral
data (Table 1) and chemical reactivity (vide infra). On a
preparative scale, the same transformation was achieved by
the use of silver acetate (1 equivalent) in carbon
tetrachloride at reflux to give sulfinyl acetate as a 1:1
mixture of diastereoisomers epimeric at sulfur (85%).
We began our investigation with the phthalimido penicillin
a-sulfoxide 517,18 since its derivatives are more robust19
than the corresponding penicillin V systems. Chlorination
of sulfoxide 5 using N-chlorosuccinimide in carbon
tetrachloride (Scheme 2) gave the seco-penicillin sulfinyl
chloride 6 (87% of the mixture) along with an inseparable
mixture of chloroazetidinone 1020 (13% as a mixture of
epimers). We were initially encouraged in a 1H NMR
Scheme 2. Reagents and conditions: (i) NCS, CCl4; (ii) AgOAc or AgOBz, CCl4, D; (iii) 10 mol% [Yb(OH2)9](OTf)3, MeNO2, 20 8C; (iv) Et3N, CH2Cl2,
208C; (v) MeOH, 208C. Phth¼phthalimido.
Table 1. 1H NMR signals from sulfinyl carboxylates 7, 8, 13, 14 and 15
R1
R2
R3
dH3
dH2
dH4a,b
dH(C3-Me)
0
0
dH2
Compound
7a
7b
8a
8b
13a
13b
14a
14b
15a
15b
Phth
Phth
Phth
Phth
V
V
V
V
V
SO2Ac
SO2Ac
SO2Bz
SO2Bz
SO2Ac
SO2Ac
SO2Pv
SO2Pv
SO2Adm
SO2Adm
Me
Me
Me
Me
PNB
PNB
PNB
PNB
PNB
PNB
5.83 (d)
5.76 (d)
5.94 (d)
5.88 (d)
6.11 (dd)
5.73 (dd)
6.22 (dd)
5.74 (dd)
6.23 (dd)
5.76 (dd)
5.42 (d)
5.39 (d)
5.85 (d)
5.59 (d)
5.22 (d)
5.13 (d)
5.24 (d)
5.08 (d)
5.23 (d)
5.07 (d)
4.98 (s)a
5.07 (s)a
4.63 (s)
5.11 (s)
4.97 (s)
4.92 (s)b
4.98 (s)
5.08 (s),a 5.12a (s)
5.24 (d),a 5.18a (s)
4.91 (m), 5.17 (s)
5.29 (d), 5.15 (s)
5.24 (q), 5.08 (s)
5.18 (q), –c
2.00a (s)
2.03a (s)
2.02 (s)
2.05 (s)
1.96 (bs)
1.89 (bs)
1.97 (s)
1.88 (s)
–
5.26 (m), 5.09 (s)
c
c
–
4.99 (s)
–
5.26 (m), 5.10 (s)
c
c
c
V
–
–
–
CDCl3, 270 MHz; Phth¼Phthalimido; V¼PhOCH2CONH; Pv¼COtBu; Adm¼1-adamantylcarbonyl.
a
Interchangeable between 7a and 7b.
Tentative assignment.
Obscured by other resonances.
b
c

A. G. M. Barrett et al. / Tetrahedron 58 (2002) 8313–8319
8315
Sulfinyl acetate 7 underwent cyclization to furnish the
desired phthalimido 3-methylenecepham sulphoxide 9 in
the presence of hydrated or anhydrous ytterbium(III) triflate
in tetrahydrofuran, dichloromethane, 2,4-pentanedione,
acetonitrile, methyl acetate, nitromethane or nitroethane.
The best conditions for formation of sulfoxide 9 from
acetate 7 were the use of ytterbium(III) triflate nonahydrate
(10 mol%) in nitromethane at room temperature giving a
73% NMR yield of cepham 9. Similarly, seco-penicillin
sulfinyl benzoate 8, derived from sulfinyl chloride 6 using
silver benzoate, also underwent ytterbium(III) triflate
catalyzed cyclization in nitromethane providing the
3-methylenecepham 9 in 50% yield as judged by NMR
spectroscopy.
2.2. Penicillin V system
Scheme 3. Reagents and conditions: (i) NCS, PhMe, D; (ii) RCO2M (Na, K,
Cs, or Ag), PhMe, THF or PhMe, Et2O, 208C.
Having successfully realized our methodology in the model
system, we began investigating its application in the
exact penicillin V system used in cefaclor 4 manufacture
(Scheme 3). The requisite sulfinyl chloride 2,21,22 which was
used immediately as a crude solution in toluene, was
prepared from penicillin V sulfoxide 1.25 Efforts to prepare
the penicillin V derived sulfinyl acetate 13 from 2 utilized
silver, sodium, potassium or cesium acetate. In contrast to
the finding in the model system, sulfinyl acetate 13 was
more successfully prepared using sodium acetate than with
silver acetate resulting in the formation of acetate 13 in
93% purity containing the known26 cis-chloroazetidinone
19 (2%) and an unidentified azetidinone impurity (ca. 4%).
However, the product was highly sensitive and the reaction
failed with trace amounts of moisture present, nor could 13
Pleasingly, sulfinyl acetate 7 was found to be much more
stable than other sulfinyl carboxylates reported16 and did not
decompose during aqueous work-up. However, we were
unable to isolate the sulfinyl acetate 7 by normal phase
chromatography as it rapidly decomposed and the presence
of impurities precluded its microanalysis. Although the
sulfinyl acetate 7 was found to be considerably more water
tolerant than sulfinyl chloride 6, it reacted in an identical
manner to the chloride 6 when allowed to react with
triethylamine or methanol, providing the known 3-cephem
1124 and methyl sulfinate 12, respectively, thereby behaving
in a manner fully consistent with the proposed assignment
of structure as the sulfinyl acetate 7.
Table 2. One pot conversion of seco-penicillin sulfinyl carboxylates 13 and 14 and chloride 2 into 3-methylenecepham 3
Entry
X
Time (h)
Solvent
CH2Cl2
PhMe-THF
None
None
PhMe
PhMe-Et2O
None
MeNO2
MeNO2
PhMe
Temperature (8C)
% Yielda (3a, 3b)
Catalyst (10 mol%)
Additive
1
2
3
4
5
6
7
8
OAc
OAc
OAc
OAc
OAc
OPv
OPv
OPv
OPv
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
4
4.5
1
0.5
120
168
47
23
92
96
504
17
40
117
21
22.5
22
Reflux
Reflux
70
125
20
20
75
20
20
20
20
70
20
20
20
20
20
–, – (1:1)b
–, – (1:2.7)b
16, 7 (1:0.1)
21, 6 (1:0.2)
–, – (0:1)b
14, 27
31, 10
33, 10
20b
–
0
0
49, 4
None
None
None
None
None
None
None
Yb(OTf)3
None
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
None
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
–
–
–
–
–
–
–
–
9
–
10
11
12
13
14
15
16
17
NaOPvc
PhMe
PhMe
–
–
MeNO2
MeNO2
MeNO2
MeCN
MeNO2
NaOPvc
Trace
NaOPvc
46, –d
30, –d
48e
–
–
–
Pv¼COtBu; V¼PhOCH2CONH.
a
Isolated yields, based on penicillin V sulfoxide 1. Numbers in parentheses are 1H NMR determined ratio of 3:16.
Products not isolated. Yield/ratio determined by H NMR only.
1 Equivalent of fused material.
Not isolated.
Product precipitated as 87:13 mixture of 3a and succinimide.
b
c
d
e
1

8316
A. G. M. Barrett et al. / Tetrahedron 58 (2002) 8313–8319
be isolated by chromatography. As before, the sulfinyl
acetate 13 was formed as sulfur epimers with one
diastereoisomer predominating (1.0:0.2).
the product was detected (entry 14). To our surprise sulfinyl
chloride 2 itself underwent direct cyclization in nitro-
methane in the presence of ytterbium(III) triflate (10 mol%)
to furnish 3-methylenecepham b-sulfoxide 3a in 46% yield
in the absence of sodium pivaloate (entry 15). This was
unexpected because sulfinyl chloride 2 did not undergo
cyclization in the presence of ytterbium(III) triflate
(10 mol%) at room temperature (entry 11) or at 708C
(entry 12) in toluene. This result meant that we could
directly cyclize the sulfinyl chloride 2 to the 3-methylene-
cepham sulfoxide 3a without the need for sulfinyl
carboxylates making the process now competitive with
Kukolja’s tin(IV) tetrachloride methodology, with the
significant advantage that only catalytic quantities of the
Lewis acid are required. As a comparison, it is worth noting
that in Kukolja’s21,28 conversion of penicillin V sulfoxide 1
(12 mmol scale) to 3-methylenecepham b-sulfoxide 3a
using the industrial protocol, a 36% overall yield was
obtained. Previously we have shown that acidic solvents
such as nitromethane, acetic acid and acetonitrile combine
with metal triflates to produce strong Brønsted acid(s) which
can promote catalysis. It might be speculated that the
primary form of catalysis in this reaction is Brønsted acid,10
rather than Lewis acid. Consistent with this acetonitrile
(entry 16) was also a suitable solvent for cyclization
from sulfinyl chloride 2 but toluene, tetrahydrofuran,
N,N-dimethylacetamide and dichloromethane were not.
Attempts to induce the cyclization with reduced quantities
of nitromethane in the reaction medium using toluene as a
co-solvent were unsuccessful.
Sulfinyl acetate 13 underwent spontaneous cyclization to
produce the desired 3-methylenecepham b-sulfoxide 3a
either by heating the neat crude acetate 13 in vacuo or in a
range of solvents (Table 2, entries 1–5). The epimeric
sulfoxide 3b was also generated along with varying
quantities of 3-cephem 1627 (and numerous side products).
Despite some promise the instability and difficulty in
preparation of the sulfinyl acetate 13 and the low yield of
cepham 3 was only modest (30% based on 1) and therefore
we sought to elaborate more stable analogues.
The sterically hindered sulfinyl pivaloate 14 and sulfinyl
1-adamantanecarboxylate 15 were also prepared by the
action of sodium pivolate and sodium 1-adamantanecarb-
oxylate on the sulfinyl chloride 2 respectively (Scheme 3).
The pivaloate 14 proved to be easier to handle, more stable
to heat, water and mild acid than the corresponding acetate
13. The sulfinyl 1-adamantanecarboxylate 15 was obtained
in comparable yield and, since its cyclization did not
proceed in superior yield to the pivaloate 14, was not
investigated further.
1
In the preparation of sulfinyl pivaloate 14 the H NMR
spectrum indicated that it was formed in ca. 75% yield
(internal standard) from the sulfinyl chloride 2 as a mixture
of diastereoisomers (ca. 2–4:1.0) epimeric at sulfur. Pivalic
anhydride was also found to be present in the crude mixture,
probably formed by nucleophilic attack at the pivaloate
carbonyl of sulfinyl pivaloate 14 by sodium pivaloate.
In support of this we note that a 24% yield of sulfinic acid 18
was isolated from the reaction precipitate following
acidification and extraction. It is expected that this mode
of reactivity also occurred in the formation of the sulfinyl
acetate 13, partially accounting for the low yields of the
desired sulfoxides 3 in the subsequent cyclization step.
Finally, we briefly examined the possibility of removing
chromatographic purification from the process. When the
crude product mixture (after cyclization according to entry
17) was allowed to precipitate from ethyl acetate pure
3-methylenecepham b-sulfoxide 3a (48%) free from all
other impurities, except succinimide, (87:13, respectively)
was obtained. A further 20% (1H NMR spectroscopy) of
3-methylenecepham sulfoxide 3a remained in the filtrate.
Pivaloate 14 also underwent cyclization to the 3-methyl-
enecepham sulfoxides 3a and 3b either in solution or by
heating in vacuo (Table 2, entries 6, 7) in improved yield
(41% isolated yield) compared to the acetate 13, albeit with
extended reaction times. Moreover, under the influence of
catalytic quantities of ytterbium(III) triflate (10 mol%) in
nitromethane solution the reaction could be conducted at
room temperature in 24 h to give comparable conversion
(entry 8). In an effort to improve the procedure, we believed
that the in situ decomposition leading to pivalic anhydride
could be minimized by a one-pot preparation and cycli-
zation protocol. Sulfinyl chloride 2 did not undergo
cyclization in toluene in the presence of ytterbium(III)
triflate (10 mol%) with added sodium pivaloate (entry 10).
When, however, the reaction was conducted with sodium
pivaloate (1 equivalent) in nitromethane a 49% isolated
yield of 3-methylenecepham b-sulfoxide 3a and a 4% yield
of the a-sulfoxide 3b was obtained (entry 13). Interestingly
the ratio of the b- to a-sulfoxides was much higher than
seen in previous cyclization reactions. A small amount of
pivalic anhydride (1H NMR spectroscopy) in the product
mixture suggested the intermediacy of the pivaloate 14. In
the absence of the lanthanide catalyst, only trace amounts of
In conclusion, we have shown that hitherto unreported
azetidinone sulfinyl carboxylates undergo cyclization into
3-methylenecepham sulfoxides under a range of catalyzed
or non-catalyzed conditions. Moreover, we discovered that
sulfinyl chloride 2 itself could be directly converted into the
desired product in nitromethane or acetonitrile in the
presence of ytterbium(III) triflate catalyst (10 mol%). We
believe that the lack of cyclization of sulfinyl chloride 2 in
solvents (toluene, tetrahydrofuran, dichloromethane and
DMAC) other than those previously10 identified (nitro-
methane and acetonitrile) reinforces our findings that
lanthanide(III) and other metal triflate salts react with
weakly acidic solvents to produce strong Brønsted acids
which can be responsible for the primary mode of catalysis.
3. Experimental
3.1. General
All reactions were conducted under a dry inert atmosphere
(argon or nitrogen). All glassware was dried in an oven
(ca. 1508C), or flame dried, and cooled under a dry inert

A. G. M. Barrett et al. / Tetrahedron 58 (2002) 8313–8319
8317
atmosphere before use. Solvents and reagents were purified
and dried as described by Perrin and Armarego.29 Carbon
Me), 3.79 (s, 8a-CO2Me), 3.87 (s, 8b-CO2Me), 4.63 (s,
8a-H2), 4.91 (m, 8a-H4), 5.11 (s, 8b-H2), 5.15 (s, 8b-H4),
5.17 (s, 8a-H4), 5.29 (d, J¼1.5 Hz, 8b-H4), 5.59 (d, J¼
5.5 Hz, 8b-H20), 5.85 (d, J¼5.2 Hz, 8a-H20), 5.88 (d, J¼
5.5 Hz, 8b-H30), 5. 94 (d, J¼5.2 Hz, 8a-H30), 7.31–7.71 (m,
Ph), 7.76 (m, Phth), 7.89 (m, Phth), 8.03–8.12 (m, Ph); 13C
NMR (CDCl3) d 20.9, 21.0, 52.5, 52.8, 55.8, 56.4, 58.5,
60.4, 75.8, 80.7, 116.9, 118.9, 123.7, 124.0, 127.2, 128.3,
128.5, 128.6, 130.0, 130.1, 130.5, 130.9, 131.5, 133.5,
134.6, 138.7, 163.6, 164.0, 164.1, 168.8, 177.2. ESIMS
(MeCN, trace AcOH) m/z 535 [20%, (MþK)þ], 519 [100,
(MþNa)þ], 514 [60, (MþNH4)þ]; ESIMS (MeCN, CsI) m/z
629 [100%, (MþCs)þ].
˚
tetrachloride was distilled from P2O5 and stored over 4 A
molecular sieves under a dry inert atmosphere. Silica Gel 60
(Merck) was used for column chromatography (eluants are
given in parentheses). Anhydrous sodium acetate is
hygroscopic and was fused in situ under vacuum (ca.
0.1 mmHg). Sodium pivaloate was purchased from Aldrich
as a hydrate (level of hydration not specified) and was fused
in situ under vacuum (ca. 0.1 mmHg). ESI mass spectra
were recorded in the positive ion mode. Anhydrous
Yb(OTf)3 was prepared by drying the nonahydrate (Aldrich)
in vacuo at 1908C for 24 h, cooled (Ar) and used
immediately without exposure to the atmosphere. For
determination of the yields in the conversion of 7 the
internal standard method was used. A reference mixture of 9
and the internal standard 1,3,5-tri-tert-butylbenzene was
prepared for calibration. The integral was measured for the
trimethyl signal (d 1.34 in CDCl3) of the internal standard
and was compared to those of both azetidinone signals
(d 5.95 and 4.90) summed together for the (R)-9.
3.1.3. (4R,6R,7R)-Methyl 7-phthalimido-3-methylene-
cepham-4-carboxylate 1-oxide (9a and 9b).21 General
procedure for Yb(OTf)3 catalyzed cyclization of sulphinyl
acetate 7. Solutions of 7 (15 mg, ca. 35 mmol) in anhydrous
THF, CH2Cl2, MeCN, Ac2CH2, MeOAc, MeNO2 or EtNO2
(500 mL) were stirred at room temperature in the presence
of anhydrous Yb(OTf)3 (2 mg, 3.5 mmol; for runs in THF,
CH2Cl2, MeCN, MeOAc, MeNO2) or [Yb(OH2)9](OTf)3
(2.7 mg, 3.5 mmol; for runs in Ac2CH2, MeNO2 or EtNO2).
The mixtures were diluted with CHCl3 (1 mL) and washed
with brine (0.5 mL), dried (MgSO4), filtered and evapo-
3.1.1. (2R)-Methyl 2-[(2R,3R)-2-acetoxysulfinyl-4-oxo-3-
phthalimido-1-azetidinyl]-3-methyl-3-butenoate
(7).
AgOAc (110 mg, 0.66 mmol) was added to 6 (0.66 mmol)
in CCl4 (14 mL) prepared as described by Kukolja.21,22 The
mixture was stirred under reflux for 40 min, and the mixture
was diluted with CHCl3 (20 mL) and filtered. The solid
residue was washed with CHCl3 (10 mL) and was filtered.
The combined CHCl3 extracts were washed with H2O
(5 mL) and brine (10 mL), dried (MgSO4), and evaporated
to give a white foam (295 mg). 1H NMR spectroscopy
indicated that the product mixture contained sulfinyl acetate
7 (purity 85%) as a 1:1 mixture of diastereoisomers: IR (thin
film, KBr) 1792, 1778, 1725, 1387 cm21; 1H NMR (CDCl3,
300 MHz) d 1.91 (s, 3H, OAc), 2.00 (s, 3H, C3-Me), 2.03 (s,
3H, C3-Me), 2.12 (s, 3H, OAc), 3.83 (s, 3H, CO2Me), 3.85
(s, 3H, CO2Me), 4.98 (s, 1H), 5.07 (s, 1H), 5.08 (s, 1H), 5.12
(s, 1H), 5.18 (s, 1H), 5.24 (d, J¼1.3 Hz, 1H), 5.390(d, J¼
5.3 Hz, 1H, 7b-H20), 5.42 (s, J¼5.0 Hz, 1H, 7a-H2 ), 5.76
(d, J¼5.0 Hz, 1H, 7b-H30), 5.83 (d, J¼5.3 Hz, 1H, 7a-H30),
7.78 (m, Phth), 7.88 (m, Phth); 13C NMR (CDCl3) d 20.3,
20.8, 21.0, 21.1, 52.6, 52.7, 55.8, 56.5, 58.9, 60.5, 75.3,
79.2, 116.9, 118.7, 123.9, 131.0, 131.5, 134.6, 135.0, 137.3,
138.9, 163.6, 163.8, 166.3, 166.5, 167.5, 167.8, 168.5,
168.6; CIMS m/z 394 [93%, (MþNH4258)þ], 377 [34,
(MþH258)þ], 376 [94, (M258)þ], 359 (48), 346 (51), 329
(35), 130 (100), 124 (47), 112 (91); ESIMS (MeCN) m/z 473
[40%, (MþK)þ], 457 [100, (MþNa)þ], 435 [60, (MþH)þ];
ESIMS (MeCN, CsI) 567 [100%, (MþCs)þ].
1
rated. H NMR spectroscopy was used to determine the
efficacy of the reaction using the internal standard method.
Yb(OTf)3 catalyzed cyclization of sulphinyl acetate 7 in
MeNO2. [Yb(OH2)9](OTf)3 (2.7 mg, 3.5 mmol, 10 mol%)
was added to 7 (15 mg, ca. 35 mmol) in MeNO2 (500 mL).
The mixture was stirred at room temperature for 5 h, and
was diluted with CHCl3 (1.5 mL) and washed with brine
(0.2 mL). The aqueous washings were extracted with CHCl3
(0.5 mL) and the combined CHCl3 extracts were dried
(MgSO4), filtered and evaporated to provide 9 (12 mg). Tri-
tert-butylbenzene (8.6 mg, 0.035 mmol) was added to the
product and the mixture was dissolved in CDCl3 (500 mL)
1
and analysed by H NMR spectroscopy: this indicated the
mixture contained cepham 9 (73%).
3.1.4. (2R)-4-Nitrobenzyl 2-[(2R,3R)-2-acetoxysulfinyl-4-
oxo-3-phenoxyacetamido-1-azetidinyl]-3-methyl-3-
butenoate (13). A mixture of fused NaOAc (16 mg,
0.19 mmol) and THF (3 mL) was sonicated for 0.5 h to
which a PhMe (70 mL) solution of 2 (0.20 mmol), prepared
as described by Kukolja,21,22 was added. The mixture was
stirred for 18 h, filtered through a 0.45 mm PTFE syringe
1
filter and evaporated under a stream of inert gas. H NMR
spectroscopy indicated the residue contained sulfinyl acetate
13 as two diastereoisomers, epimeric at sulfur, in a 1.0:0.2
ratio. The sulfinyl acetate 13 was too unstable to obtain a
13C NMR spectrum: 1H NMR (CDCl3, 270 MHz) d 1.89 (bs,
13b-C3-Me), 1.96 (bs, 13a-C3-Me), 2.01 (s, 13a-OCOMe),
2.13 (s, 13b-OCOMe), 4.40 (s), 4.47 (d, J¼15.0 Hz,
13a-PhOCH2), 4.53 (s), 4.59 (d, J¼15.0 Hz, 13a-PhOCH2),
4.64 (s), 4.72 (s), 4.92 (s, 13b-H2), 4.97 (s, 13a-H2), 5.08 (s,
13a-H4b), 5.13 (d, J¼5.1 Hz, 13b-H200), 5.18 (q, J¼1.5 Hz,
13b-H4a), 5.22 (d, J¼4.6 Hz, 13a-H2 ), 5.24 (q, J¼1.5 Hz,
13a-H4a), 5.29 (d, J¼9.0 Hz, 13a-CO2CH2), 5.34 (d, J¼
9.2 Hz, 13a-CO2CH2), 5.73 (dd, J¼4.9, 8.3 Hz, 13b-H30),
6.11 (dd, J¼4.9, 10.6 Hz, 13a-H30), 6.86–7.08 (m, Ph),
7.13–7.36 (m, Ph), 7.47–7.60 (m, ArNO2), 8.09 (d,
3.1.2. (2R)-Methyl 2-[(2R,3R)-2-benzoyloxysulfinyl-4-
oxo-3-phthalimido-1-azetidinyl]-3-methyl-3-butenoate
(8). AgOBz (16 mg, 0.07 mmol) was added to
6
(0.07 mmol) in CCl4 (1.4 mL) prepared as described by
Kukolja.21,22 The mixture was stirred under reflux for
40 min, and the mixture was diluted with CHCl3 (4 mL),
dried (MgSO4), filtered and evaporated to furnish crude 8
(35 mg, 0.07 mmol, 100%) as a colorless oil. 1H NMR
spectroscopy revealed sulfinyl benzoate 8 was obtained as a
mixture of two diastereoisomers (1.0:1.5 ratio): IR (thin
film, KBr) 1788, 1781, 1725, 1388 cm21 1H NMR
;
(270 MHz, CDCl3) d 2.02 (s, 8a-C3-Me), 2.05 (s, 8b-C3-

8318
A. G. M. Barrett et al. / Tetrahedron 58 (2002) 8313–8319
J¼10.40 Hz, NH), 8.19–8.28 (m, ArNO2); ESIMS (MeCN,
NaCl) m/z 582.5; ESIMS (MeCN, KCl) m/z 598.4; ESIMS
(MeCN, CsCl) m/z 692.4.
Uncatalyzed cyclization of sulfinyl pivaloate 14. A crude
solution of 14 (2 mmol) in PhMe (70 mL) and Et2O (20 mL)
was stirred at room temperature for 7 days. The solvent
mixture was evaporated and the product chromatographed
(SiO2, EtOAc:CH2Cl2 1:4) to provide 3a (140 mg, 14%) and
3b (265 mg, 27%). These compounds showed the following
3.1.5. (2R)-4-Nitrobenzyl 2-[(2R,3R)-2-(tert-butylcarbo-
nyloxy)sulfinyl-4-oxo-3-phenoxyacetamido-1-azetidi-
nyl]-3-methyl-3-butenoate (14). A PhMe (70 mL) solution
of 2 (1.99 mmol), prepared as described by Kukolja,21,22
1
data: 3a: Rf 0.15 (EtOAc:CHCl3 1:4); H NMR (CDCl3,
270 MHz) d 3.56 (1H, d, J¼13.9 Hz, H2), 3.75 (1H, d, J¼
14.1 Hz, H2), 4.54 (2H, s, PhOCH2), 4.90 (1H, d, J¼4.6 Hz,
H6), 5.27 (2H, s, CO2CH2), 5.31 (1H, s, H4), 5.48 (1H, d,
J¼1.6 Hz, C3¼CH2), 5.78 (1H, s, C3¼CH2), 6.03 (1H, dd,
J¼4.6, 10.6 Hz, H7), 6.90–7.05 (3H, m, Ph), 7.25–7.33
(2H, m, Ph), 7.45–7.53 (2H, m, ArNO2), 8.13 (1H, d, J¼
10.4 Hz, NH), 8.21–8.28 (2H, m, ArNO2); 3b: Rf 0.06
t
was added to a sonicated mixture of fused BuCO2Na
t
(283 mg of BuCO2Na.xH2O; x not specified, 2 mmol) in
Et2O (20 mL) and the mixture was stirred for 22 h. The
precipitate was allowed to settle, the liquid layer was filtered
through a 0.45 mm PTFE syringe filter and was evaporated
using short path distillation at room temperature, without
exposure of the product to the atmosphere, giving crude
1
(EtOAc:CHCl3 1:4); H NMR (CDCl3, 270 MHz) d 3.60
1
sulfinyl pivaloate 14 as a yellow foam: H NMR (CDCl3,
(1H, d, J¼12.7 Hz, H2), 4.04 (1H, d, J¼12.7 Hz, H2), 4.57
(2H, s, PhOCH2), 4.81 (1H, d, J¼4.4 Hz, H6), 5.15 (1H, s,
H4), 5.31 (2H, s, CO2CH2), 5.46 (1H, dd, J¼4.4, 7.9 Hz,
H7), 5.50 (2H, s, C3¼CH2), 6.90–7.10 (3H, m, Ph), 7.30–
7.36 (2H, m, Ph), 7.39 (1H, d, J¼8.1 Hz, NH), 7.52 (2H, m,
ArNO2), 8.26 (2H, m, ArNO2). Both sets of data
corresponded with those reported in the literature.21,30
270 MHz) d 1.11 (s, 9H, 14a-CMe3), 1.21 (s, 14b-CMe3),
1.88 (bs, 14b-C3-Me), 1.97 (bs, 14a-C3-Me), 4.40 (d, J¼
14.8 Hz, 14a-PhOCH2), 4.57 (d, J¼15.0 Hz, 14a-PhOCH2),
4.88 (s), 4.98 (s, 14a-H2), 5.08 (d, J¼4.9 Hz0, 14b-H20), 5.09
(s, 14a-H4b), 5.24 (d, J¼4.9 Hz, 14a-H2 ), 5.25 (d, J¼
12.9 Hz, 14a-CO2CH2), 5.26 (q, J¼1.5 Hz, 14a-H4a), 5.34
(d, J¼12.9 Hz, 14a-CO2CH2), 5.74 (obscured dd, 14b-H30),
6.22 (dd, J¼4.6, 10.6 Hz, 14a-H30), 6.86–7.02 (m, Ph),
Thermal cyclization of sulfinyl pivaloate 14. Neat 14
(2 mmol) prepared above was heated at 758C under 0.1
mmHg for 47 h. After being cooled to room temperature, the
product was chromatographed (SiO2, EtOAc:CH2Cl2 1:4) to
provide cepham 3a (311 mg, 31%) and cepham 3b (101 mg,
10%).
7.15–7.36 (m, Ph), 7.52 (m, ArNO2), 8.23 (m, ArNO2); 13
C
NMR (CDCl3, 67.5 Hz) d 21.7, 26.34, 26.5, 39.3, 58.0, 58.2,
66.0, 66.9, 73.6, 114.7, 119.0, 122.1, 123.8, 128.7, 129.6,
138.3, 141.3, 147.8, 156.7, 166.5, 167.9, 168.3, 175.7.
ESIMS (MeCN, KCl) 640.0 [29% (MþK)þ], 320.4 (34),
304.4 (44), 124.3 (53), 108.3 (100). The precipitate formed
during the reaction was treated with a mixture of CHCl3
(20 mL) and 1 M HCl (8 mL) and was vigorously stirred for
10 min. The CHCl3 was separated, washed with H2O and
brine, dried (MgSO4), evaporated and filtered to give
sulfinic acid 1826 (246 mg, 24%) as yellow foam with a 1H
NMR spectrum identical with authentic material.
Yb(OTf)3 catalyzed cyclization of sulfinyl pivaloate 14. A
filtered solution of 14 (0.60 mmol) in dry MeOH free
MeNO2 (15 mL) was added to anhydrous Yb(OTf)3 (37 mg,
0.06 mmol) and the mixture was stirred at room temperature
for 23 h. The mixture was diluted with CHCl3 (5 mL) and
washed with H2O (3£2 mL), brine (3 mL), dried (MgSO4),
filtered and evaporated to give a yellow foam (259 mg).
Chromatography (SiO2, EtOAc:CHCl3 1:4; EtOAc:CHCl3
4:6) gave cepham 3a (99 mg, 33%) and cepham 3b (31 mg,
10%).
3.1.6. (2R)-4-Nitrobenzyl 2-[(2R,3R)-2-(1-adamantyl-
carbonyloxy)sulfinyl-4-oxo-3-phenoxyacetamido-1-aze-
tidinyl]-3-methyl-3-butenoate (15). NaH (23 mg of 60%
dispersion, 0.60 mmol) was added to 1-adamantane carb-
oxylic acid (108 mg, 0.60 mmol) in dry THF (6 mL) at 08C.
After stirring for 10 min, the mixture was allowed to warm
up to room temperature and was stirred for 1 h. Chloride 221,
22 (0.60 mmol) in PhMe (21 mL) was added and the mixture
was stirred for 25 h. The precipitate was allowed to settle
and the product mixture was filtered through a 0.45 mm
PTFE syringe filter and evaporated under a stream of dry
Yb(OTf)3 catalyzed cyclization of sulfinyl chloride 2 in
presence of NaOPv. A filtered PhMe (21 mL) solution of 2
(0.60 mmol), prepared as described by Kukolja,21,22 was
t
stirred in the presence of fused BuCO2Na (85 mg of
tBuCO2Na.xH2O; x not specified, 0.6 mmol) and anhydrous
Yb(OTf)3 (37 mg, 0.06 mmol) for 40 h at room temperature.
The product was diluted with CHCl3 (5 mL) and washed
with H2O (3£2 mL), brine (3 mL), dried (MgSO4), filtered
and evaporated. Chromatography (SiO2, EtOAc:CHCl3 1:4)
gave cepham 3a (146 mg, 49%) and cepham 3b (11 mg,
4%).
1
nitrogen: H NMR (CDCl3, 270 MHz) d 1.72 (bm), 1.93
(bm), 2.03 (bm), 4.43 (d, J¼14.8 Hz, 15a-PhOCH2), 4.60
(d, J¼14.8 Hz, 15a-PhOCH2), 4.89 (s), 4.99 (s, 15a-H2),
5.07 (d, J¼4.9 Hz, 15b-H20), 5.10 (s, 15a-H4b), 5.23 (d, J¼
4.6 Hz, 15a-H20), 5.26 (q, J¼1.6 Hz, 15a-H4a), 5.28
(obscured d, 15a-CO2CH2), 5.35 (d, J¼12.9 Hz, 15a-
CO2CH2), 5.76 (dd, J¼5.0, 8.7 Hz, 15b-H30), 6.23 (dd,
J¼4.7, 10.7 Hz, 15a-H30), 6.86–7.05 (m, Ph), 7.14–7.35
(m, Ph), 7.52 (m, ArNO2), 8.24 (m, ArNO2); 13C NMR
(CDCl3, 67.5 Hz) d 21.4, 27.1, 35.6, 41.1, 58.0, 65.9, 66.8,
73.5, 114.6, 118.8, 122.0, 123.6, 128.6, 129.4, 138.1, 141.3,
147.6, 156.7, 166.4, 167.9, 168.1, ca. 182.
Yb(OTf)3 catalyzed cyclization of sulfinyl chloride 2. Crude
2 (1.99 mmol), prepared as described by Kukolja,21,22 was
dissolved in dry MeOH free MeNO2 (50 mL), filtered
through a 0.45 mm PTFE syringe filter onto anhydrous
Yb(OTf)3 (124 mg, 0.06 mmol). The mixture was stirred at
room temperature for 22 h, diluted with EtOAc (100 mL)
and washed with H2O (50 mL), a mixture of saturated
aqueous NaHCO3 and brine (1:1, 20 mL), brine (20 mL),
dried (MgSO4), filtered and evaporated to give a tan colored
foam. The foam was dissolved in EtOAc (2 mL) and solids
3.1.7. (4R,6R,7R)-4-Nitrobenzyl 3-methylene-7-phenoxy-
acetamidocepham-4-carboxylate-1-oxide (3a21 and 3b30).

A. G. M. Barrett et al. / Tetrahedron 58 (2002) 8313–8319
8319
R. M.; Ramprasad, D. J. Chem. Soc., Perkin Trans. 1 1999,
867–871.
allowed to precipitate. After removal of the filtrate, the
precipitate was washed twice with EtOAc (1 mL) and dried
under vacuum. The H NMR spectrum of the crystalline
solid was consistent with the product consisting of
succinimide (13% of mixture) and 3-methylenecepham
sulfoxide 3a (87% of mixture: equivalent to 0.96 mmol,
48% yield).
1
13. Waller, F. J.; Ramprasad, D.; Barrett, A. G. M.; Braddock,
D. C. In Catalysis of Organic Reactions; Herkes, F. E., Ed.;
Marcel Dekker: New York, 1998; pp 289–305.
14. Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc.
1994, 116, 11179–11180.
15. For examples see: Kleemann, A.; Engel, J.; Kutscher, B.;
Reichert, D. Pharmaceutical Substances; 3rd ed.; Thieme:
Stuttgart, 1999.
Acknowledgements
16. Morishita, T.; Furukawa, N.; Oae, S. Tetrahedron 1981, 37,
3115–3120.
We thank GlaxoSmithKline for the most generous endow-
ment (to A. G. M. B), the Wolfson Foundatation for
establishing the Wolfson Center for Organic Chemistry in
Medical Sciences, and the EPSRC.
17. Sheehan, J. C.; Henery-Logan, K. R. J. Am. Chem. Soc. 1962,
84, 2984–2990.
18. Animati, F.; Botta, M.; Angelis, F. D.; Dorigo, A.; Grgurina,
I.; Nicoletti, R. J. Chem. Soc., Perkin Trans. 1 1983,
2281–2286.
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