Synthesis and decarboxylation of Δ2-cephem-4,4-dicarboxylic acids

1238

Synthesis and decarboxylation of ∆²-cephem-4,4-

dicarboxylic acids

Saul Wolfe, Stephen Ro, Chan-Kyung Kim, and Zheng Shi

Abstract: Penicillin V was converted in 14 steps into ∆²-cephems having hydrogen at C-3, hydrogen or methyl at C-2,

and two methoxycarbonyl, two benzyloxycarbonyl, or one methoxycarbonyl and one benzyloxycarbonyl substituent at

C-4. Deprotection of these ∆²-cephem-4,4-dicarboxylic acid esters by alkaline hydrolysis (in the case of methyl esters)

or hydrogenolysis (in the case of benzyl esters) led in all cases to rapid decarboxylation of the ∆²-cephem-4,4-

dicarboxylic acid or ∆²-cephem-4,4-dicarboxylic acid monoester. With hydrogen at C-2, hydrolysis of the dimethyl ester

with 1 equiv of base produced a ∆²-cephem. With 2 equiv of base, and with all compounds having methyl at C-2, hy-

drolysis or hydrogenolysis afforded 4α-substituted-∆²-cephems.

In contrast, simpler benzyl or methyl acetamidomalonates could be deprotected without difficulty to afford stable

malonic acids. Reasons for the differences in ease of decarboxylation were examined using semiempirical (AM1) and

ab initio (3-21G) molecular orbital calculations. The decarboxylation barriers of unionized cephem or acetamido

malonic acids were found to be high (35–40 kcal mol^–1). Although the monoanion of acetamidomalonic acid retained a

high barrier, the epimeric monoanions of a ∆²-cephem malonic acid decarboxylated with barriers of only 2 kcal mol^–1.

Key words: mercaptoazetidinone, bromomalonate esters, MO calculations, sulfoxides, hydrogenolysis.

Résumé : On a transformé la pénicilline V en quatorze étapes en ∆²-céphèms portant un hydrogène en C-3, un hydro-

gène ou un méthyle en C-2 et deux méthoxycarbonyles, deux benzoyloxycarbonyles ou un méthoxycarbonyle et un

benzoyloxycarbonyle comme substituants en C-4. Le déprotection de ces esters de ∆²-céphem-4,4-dicarboxylique par

hydrolyse alcaline (dans le cas des esters méthyliques) ou par hydrogénolyse (dans les cas des esters benzyliques)

conduit dans tous les cas à une décarboxylation rapide de l’acide ∆²-céphem-4,4-dicarboxylique ou de son monoester.

L’hydrolyse de l’ester diméthylique du produit portant un hydrogène en C-2 à l’aide d’un équivalent de base conduit à

un ∆²-céphem. Avec deux équivalents de base ainsi qu’avec tous les composés portant un groupe méthyle en C-2,

l’hydrolyse ou l’hydrogénolyse conduit à des ∆²-céphems portant un substituant en position 4α.

Par ailleurs, il est possible de déprotéger sans difficulté les acétamidomalonates de benzyle ou de méthyle plus simples

pour obtenir des acides maloniques stables. Faisant appel à des calculs d’orbitales moléculaires semi-empiriques (AM1)

et ab initio, on a étudié les différences dans la facilité de ces décarboxylations. On a trouvé que les barrières à la dé-

carboxylation des acides céphems dicarboxyliques et des acétamidomaloniques non ionisés sont relativement élevées

(35-40 kcal/mol). Même si la barrière est encore élevée pour le monoanion de l’acide acétamidomalonique, les monoa-

nions épimères d’un acide ∆²-céphem malonique se décarboxylent avec une barrière qui n’est que d’environ 2 kcal

mol^–1.

Mots clés : mercaptoazétidinone, esters de l’acide bromomalonique, calculs OM, sulxoydes, hydrogénolyse.

[Traduit par la Rédaction] Wolfe et al. 1258

Introduction

The antibacterial activity of the ∆²-cephem-4α-carboxylic

acid 1 is 100 times less than that of the ∆³-cephem 2 (1).

Since cephalosporins undergo ∆³W ∆²equilibration in solu-

tion to give mixtures in which the 4α-carboxy-∆²-isomers

(3a) usually predominate (2), there is a resultant loss of ac-

tivity, and the origin of this loss of activity has received con-

siderable attention (3).

(4). Most workers accept that this chemical reaction pro-

ceeds by deprotonation of the serine OH, coupled to

nucleophilic addition of the resulting anion to the β-lactam

carbonyl group (5). In terms of this mechanism, the decrease

in antibacterial activity that accompanies the isomerization

to 3a would be a consequence of the decreased susceptibility

of the β-lactam carbonyl group of a ∆²-cephem towards

nucleophilic attack. Indeed 1 is most readily obtained by al-

kaline hydrolysis of the methyl ester of 2 (6).

The cephalosporin receptor is a serine peptidase whose

active site hydroxyl group is acylated by the β-lactam ring

Received January 29, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on August 22, 2001.

S. Wolfe,¹S. Ro, C.-K. Kim,²and Z. Shi. Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.

¹Corresponding author (telephone: (604) 291-5972; fax: (604) 291-5973; e-mail: swolfe@sfu.ca).

²On leave from Department of Chemistry, Inha University, Inchon, 402–751, Korea.

Can. J. Chem. 79: 1238–1258 (2001)

DOI: 10.1139/cjc-79-8-1238

Wolfe et al.

1239

However, in the case of an exocellular peptidase from

Streptomyces R61, which has been studied in some detail

(7), including a crystal structure (8), the catalytic efficiencies

towards 6-aminopenicillanic acid, cephaloglycine and peni-

cillin G are 0.2, 22, and 13 000, respectively, but the corre-

sponding second-order rate constants for alkaline hydrolysis

of the β-lactam rings of these compounds are 0.15, 0.90, and

0.50 M^–1s^–1(7). The absence of any correlation between the

trends in the enzymatic and nonenzymatic rate constants is

not consistent with the claim that the acyl-enzyme is formed

by nucleophilic addition to the β-lactam carbonyl group.

In a different approach to the problem, following an ex-

amination of the crystal structures of active and inactive β-

lactam compounds, Cohen (9) proposed that 3a are inactive

as a consequence of a misfit with the receptor, and suggested

that their 4β-carboxy epimers (3b) would exhibit a better fit,

with restored activity. However, the activity of a ∆²-cephem-

4β-carboxylic acid proved to be less than that of its 4α-

epimer (10).

more rapidly than ∆³-cephems with the hydroxyl group of

the peptidase receptor, but are less effectively complexed; in

addition, in agreement with Cohen, it was suggested that

epimerization to 3b would lead to improved complexation

with the receptor, at the expense of an inherent decrease in

reactivity with the serine hydroxyl group.

These findings led to the idea that the presence of the 4β-

carboxyl group in a ∆²-cephem-4,4-dicarboxylic acid such as

4 might allow effective complexation to the peptidase, and

the concurrent presence of the 4α-carboxyl group might en-

hance the rate of the acylation step, the two effects together

leading to enhanced antibacterial activity in a ∆²-cephem.

The work reported here was undertaken to test this idea. Al-

though it was known that the malonate 5 had yielded only

the decarboxylated product 6 following alkaline hydrolysis

and acidification (12), that reaction mixture was maintained

at pH 2 for 1 h prior to the isolation of the product. It was

hoped that decarboxylation could be avoided in the present

work by the elimination of an extended acidic treatment fol-

lowing the deprotection of a ∆²-cephem-4,4-dicarboxylic

acid diester.

Independently, structure-activity studies and calculations

by Wolfe and Hoz (11) led to the proposal that 3a react

In Scheme 1, dimethyl bromomalonate, prepared by irra-

diating a solution of bromine and dimethyl malonate, was

reacted with the thiazoline azetidinone 12 (14) in the pres-

ence of benzyl trimethylammonium hydroxide (Triton B)

to give 13 in 50% yield. Coupling with allyl bromide in the

presence of Triton B or sodium hydride produced 14 which,

upon ozonolysis and treatment with dimethyl sulfide af-

forded an aldehyde (15) in quantitative yield. Exposure of

this aldehyde to 3% perchloric acid in a 1:1 solution of di-

chloromethane–acetone (15), led to hydrolysis to the

mercaptoazetidinone 16, followed by cyclization to the

hydroxycepham 17 in 94% yield from 14.

Syntheses of substrates

Malonyl-substituted thiazoline-azetidinones of type 7 have

often been reported in the literature (13), usually as interme-

diates in syntheses requiring the attachment of an acetate

chain to the β-lactam nitrogen. By virtue of its acidic α-pro-

ton, 7 also serves as a potential branch point for the con-

struction of a new ring. The conversion of penicillin V into

the ∆²-cephem 19 is summarized in Scheme 1. Scheme 2

summarizes a different sequence leading to the 2-methyl-∆²-

cephems 24.

1240

Can. J. Chem. Vol. 79, 2001

Scheme 1. Reagents and conditions: (a) CH₃I, DMF; (b) AcOH, H₂O₂, CH₂Cl₂; (c) P(OMe)₃, MgSO₄, toluene; (d) Et₃N; (e) KMnO₄,

MgSO₄, EtOH; (f) Triton B, BrCH(CO₂CH₃), DMF, –50 to 20°C; (g) Triton B or NaH, allyl bromide; (h) O₃, CH₂Cl₂-CH₃OH, –78°C,

then Me₂S; (i) HClO₄, CH₂Cl₂–acetone; (j) Ac₂O, H₂SO₄, AcOH; (k) pTsOH, toluene, ∆.

The configuration at C-2 and the conformation of the six-

membered ring of 17 (see 17a) were evident from the ¹H NMR

spectrum, which showed J_H2H3and J_H2H3′= 2.3 and 3.9 Hz,

respectively. The axial orientation of the hydroxyl group is

evidence of an S-C-O Edward–Lemieux effect (16).

The dehydration of 17 was unexpectedly difficult and was

best achieved in 52% yield by acetylation to 18, followed by

heating with p-toluenesulfonic acid in refluxing toluene.

In Scheme 2, the dimethyl malonate 14 and its dibenzyl

ester and mixed methyl benzyl ester analogs, prepared by

the reaction of 12 with the appropriate bromomalonate fol-

lowed by allylation, were treated with iodine in a mixture of

methylene chloride and water to give the 2β-substituted

iodomethylcephams 20 (13). In each case, the configuration

at C-2 and the conformation shown in 20a could be assigned

on the basis of a positive NOE between H₂and H₆, and from

H₂H₃coupling constants of 1.9 and 12.2 Hz.

At this point, the synthetic plan called for

dehydrohalogenation of 20 to 23, and isomerization to 24.

However, exposure of 20 to sodium hydride or 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) or Triton B produced

complex mixtures. To circumvent the possibility that this

was the result of participation by sulfur in the elimination of

iodide, the iodomethylcephams were first oxidized to the

sulfoxides 21 using sodium periodate in aqueous methanol.

Dehydrohalogenation with DBU now proceeded smoothly

to give the exomethylene sulfoxides 22, which afforded the

exomethylene cephams 23 following reduction with phos-

phorus tribromide. Isomerization to 24 was achieved using

trifluoroacetic acid.

In the case of the epimeric methyl benzyl esters (R₁= Me,

R₂= CH₂Ph), which were formed in a 1:1 ratio in the cou-

pling with 12, separation was achieved at the stage of the

exomethylene sulfoxide 22. Since 2D-NOESY experiments

were inconclusive in allowing configurations to be assigned

to the epimers of 22–24, the technique of aromatic solvent-

induced shifts (ASIS) (17) was applied to 24. Changing the

solvent from deuterated chloroform to benzene leads to an

upfield chemical shift of atoms or groups on the convex (α)

face of the molecule, because the V-shaped bicyclic ring sys-

tem blocks access of the solvent to the concave (β) face.

As seen in Table 1, except for H₃, the change from chloro-

form to benzene leads to an upfield shift of the protons. The

data suggest that epimer A has the benzyl ester on the α face

and that epimer B has the methyl ester on the α face.

To corroborate these conclusions, ASIS measurements

were performed on a compound of known stereochemistry,

the methyl ester of penicillin V. In deuterated chloroform,

Wolfe et al.

1241

Scheme 2. Reagents and conditions: (a) Triton B, DMF, –50 to 20°C; (b) Triton B or NaH, allyl bromide; (c) I₂, CH₂Cl₂–H₂O;

(d) NaIO₄, MeOH–H₂O; (e) DBU, CH₂Cl₂; (f) PBr₃, DMF, 0°C; (g) TFA, CH₂Cl₂, 0°C.

Table 1. Chemical shifts (δ) of epimer A and epimer B of 24.

Epimer A

CDCl₃

Epimer B

CDCl₃

∆ (CDCl₃–C₆D₆, ppm)

Proton

C₆D₆

Epimer A

Epimer B

H₃

H₆

H₇

5.85

5.31

5.77

4.56

3.77

5.24

6.02

5.18

5.61

3.99

3.52

4.99

5.86

5.33

5.80

4.56

3.74

5.27

6.05

5.13

5.58

4.03

3.23

5.27

–0.17

0.13

0.17

0.57

0.26

0.25

–0.18

0.20

0.22

0.53

0.50

–0.03

PhOCH₂

4-CO2CH₃

4-CO₂CH₂PH

1242

Can. J. Chem. Vol. 79, 2001

the ester methyl group, which occupies the convex face of

the molecule, is found at 3.76 ppm. In deuterated benzene

the chemical shift is 3.20 ppm, a difference of 0.56 ppm.

The corresponding difference in epimer B is 0.50 ppm.

∆³-cephems. Cephems of type 27, having hydrogen at C-3,

are known to be active, and one of these, ceftizoxime, is a

widely used antibiotic (18).

Following these initial experiments, subsequent hydroly-

ses were performed with a minimum of manipulation: reac-

tion mixtures were acidified, and the products quickly

extracted into an appropriate organic solvent and esterified

with diazomethane. Using this protocol, the reaction of 19

with 2 equiv of potassium hydroxide produced a 7:1 mixture

of decarboxylated ∆²- and ∆³-cephem esters (28 and 29, re-

spectively). However, 1 equiv of potassium hydroxide re-

versed the 28:29 ratio to 1:4 (see Fig. 1).

These results suggest that a carboxylate anion 30, formed

in the first hydrolysis step, undergoes rapid decarboxylation

concerted with a shift of the double bond, as depicted in 30

→ 31. Subsequently, C-2 deprotonation of 31, leading, via

32, to the more stable ∆²-isomer 28, competes with the hy-

drolysis of the second ester.

Deprotection of the ∆²-cephem-4,4-

dicarboxylic acid esters

Alkaline hydrolysis of 19

In an initial set of experiments, 19 was treated at –8°C

with 2 equiv of potassium hydroxide in aqueous pyridine,

and the solvent was then removed under reduced pressure

below 30°C. This afforded a product that exhibited signifi-

cant antibacterial activity against a penicillin-sensitive strain

of Staphylococcus aureus. However, the product was not the

1

malonate salt 25. As seen in 26 and 27, the HMR spectrum

(in D₂O) was that of a mixture of decarboxylated ∆²- and

Wolfe et al.

1243

1

Fig. 1. (a) The 5.5–6.6 ppm region in the H NMR spectrum of

1; (b) spectrum of a mixture of 28 and 29; (c) after exposure of

19 to 1 equiv of KOH in aqueous pyridine.

Hydrogenolysis of 24 (R₁= R₂= CH₂Ph)

Experiments were performed using 10% palladium on car-

bon, in aqueous ethanol containing 2 equiv of sodium bicar-

bonate (Method A), and in aqueous acetic acid (pH 4 to 5)

(Method B). Products were isolated by filtration through

Celite, followed by evaporation or lyophilization and conver-

sion to the methyl ester. This led, in ethanol, to the ∆²-ester

34 as the sole product (>90%). In acetic acid, the products

were 34 and the cepham 37, whose stereochemistry was elu-

cidated from the H₂H₃coupling constants, a positive NOE

between H₂and H₆and the absence of an NOE between H₄

and H₆.

Alkaline hydrolysis of 24 (R₁= R₂= Me)

The foregoing analysis suggested that the introduction of

an electron-releasing C-2-methyl group, as in 24, might af-

fect the results of alkaline hydrolysis in two ways: prefera-

bly, the concerted decarboxylation pathway that is presumed

to cause the lability of the ∆²-cephem-4,4-dicarboxylic acid

would become disfavoured; alternatively, if this is not the

case and the initial product is again a ∆³-ester (33), this ester

should resist isomerization of the double bond, because C-2

deprotonation leading to the more stable ∆²-ester 34 would

be disfavoured.

In the event, the hydrolysis of the dimethyl ester (24, R₁=

R₂= Me) with either 1 or 2 equiv of potassium hydroxide in

aqueous pyridine, followed by the usual work-up, afforded

the same product in each case, the ∆²-cephem 34.

The simplest explanation of these results is that the

carboxylate anion 35 decarboxylates rapidly to 36. Although

the concerted decarboxylation pathway leading initially to

the ∆³-isomer is disfavoured, the presence of the C-2-methyl

group leads to direct decarboxylation to the ∆²-isomer as the

predominant pathway. An alternative explanation is that, de-

spite our expectations regarding the kinetic acidity of 33, un-

der alkaline conditions the introduction of the C-2-methyl

group somehow enhances the ∆³→ ∆²rearrangement. This

point was addressed using the dibenzyl ester 24 (R₁= R₂=

CH₂Ph).

Thus, in contrast to the C-2-unsubstituted diester 19,

which, following the exposure of one carboxyl group,

decarboxylates with rearrangement of the double bond, in

the case of the C-2-methylated esters there is rapid

decarboxylation without rearrangement of the double bond.

Hydrogenolysis of the epimeric methyl benzyl esters 24

(R₁, R₂= Me, CH₂Ph)

As summarized in Scheme 3, hydrogenolysis using

Method B resulted in decarboxylation with the formation of

34 in both cases. Carbanion 36 is implicated as an interme-

diate in these reactions since the decarboxylation of 38 pro-

ceeds with inversion of configuration at C-4. The pK₁of

malonic acid is 2.85 at 298 K (19), so that in aqueous acetic

acid the ∆²-cephem-4,4-dicarboxylic acid 38 would be fully

ionized.

Preparation and deprotection of

acetamidomalonate esters

There are numerous examples of stable β-lactam-

containing malonic acids (20). The Meldrum acid derivative

39 hydrolyzes under basic conditions to give the malonic

acid 40, whose decarboxylation to 41 requires refluxing

ethyl acetate in the presence of formic acid. The malonic

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Can. J. Chem. Vol. 79, 2001

Scheme 3. Reagents and conditions: (a) H₂, Pd/C, HOAc–H₂O; (b) CH₂N₂, CH₂Cl₂–EtOH, 0°C.

acid 42 can be isolated and converted to the penam 43.

Based on these precedents, the rapid decarboxylation ob-

served in all cases following deprotection of 19 and 24 was

unexpected. In an effort to understand this result, the

dibenzyl acetamidomalonates 44 and 45 were synthesized

(see Experimental) and subjected to hydrogenolysis fol-

lowed by esterification with diazomethane. The products,

isolated in 81% and 82% yields, respectively, were the

dimethyl malonates 46 and 47. Subsequent experiments es-

tablished that the malonic acid precursors of 46 and 47

could be maintained at room temperature for at least 24 h

without noticeable decomposition.

Wolfe et al.

1245

Fig. 2. Neutral decarboxylation of 48 (AM1 calculations). Min 1–min 5 are the five lowest energy structures of the diacid; TSα and

TSβ are the transition structures for α- and β-decarboxylation. Energies are in kcal mol^–1, relative to min 1 and TSβ.

come vanishingly small. It is noteworthy that the monoanion

of phenylmalonic acid decarboxylates 3 to 4 times faster

Theoretical considerations

The reasons for the differences in ease of decarboxylation

were examined using semiempirical and ab initio molecular

orbital calculations. With AM1 (21), calculations on 4,4-

dicarboxy-∆²-cephem (48) yielded 5 minima corresponding

to torsion within the carboxyl groups. The most stable struc-

ture (min 1) and the least stable structure (min 5) differ in

energy by 2.3 kcal mol^–1(Fig. 2). The two most stable struc-

tures (min 1 and min 2) have the Z-conformation (22). The

next two (min 3 and min 4) have one carboxyl group in the

Z-conformation and other in the E-conformation. The least

stable structure (min 5) has both carboxyl groups in the E-

conformation.

than the undissociated acid (24).

The calculations are consistent with experiment: the

undissociated cephem and acetamidomalonic acids have

comparable (high) decarboxylation barriers, which disappear

in the case of the cephem monoanions. Since these anions

would be fully formed at pH > 3 in water solvent, it does not

appear possible to test the prediction that 4,4-dicarboxy-∆²-

cephems will have significant antibacterial activity.

Experimental

The transition structures TSα and TSβ, calculated for the

decarboxylation of the α- and β-carboxyl groups of 48 are

included in Fig. 2. The β-decarboxylation barrier, corre-

sponding to decarboxylation from the concave face of the

molecule, is lower by 2.4 kcal mol^–1.

The transition structures are late, as proton transfer is al-

most complete. The barrier, calculated from min 1 is

40.1 kcal mol^–1. In Bach’s high level ab initio calculations

(23), malonic acid was found to have a decarboxylation bar-

rier of 33.2 kcal mol^–1. The experimental barrier is 30.8 kcal

mol^–1(23). Since the calculated neutral barriers are high, the

facile decarboxylations observed experimentally cannot be

attributed to the decarboxylation of a 4,4-dicarboxy-∆²-

cephem or its monoester.

On the other hand, the α- and β-decarboxylation barriers

of the monoanions 49 (Fig. 3) are vanishingly small (2.04

and 2.08 kcal mol^–1, respectively).

Figures 4 and 5 show the results of ab initio (3-21G) cal-

culations of the decarboxylation barriers of acetamido-

malonic acid (35.2 kcal mol^–1) and its monoanion (26.3 kcal

mol^–1). The barrier decreases in the anion, but does not be-

General

All reactions were performed under dry nitrogen using

oven-dried (140°C, 24 h) glassware. The glassware was al-

lowed to cool in a desiccator under vacuum and assembled

cold, capped with rubber septa, and evacuated with dry ni-

trogen gas. Solvents were distilled prior to use and dried, as

necessary, by literature procedures (25). Diazomethane was

prepared by treatment of a cold solution of N-methyl-N-

nitrosotoluene-4-sulfonamide (DIAZALD) in 95% ethanol

1

with 1.0 mL portions of 12.5 M sodium hydroxide. Both H

and ¹³C nuclear magnetic resonance (NMR) spectra were re-

corded on a Bruker Model AMX 400 Spectrometer operat-

ing at 400.1 MHz and 100.6 MHz, respectively. Chemical

shifts (δ) are reported in parts per million (ppm) relative to

tetramethylsilane (TMS) in an appropriate deuterated sol-

vent. Infrared (IR) spectra were obtained on a Bomen–

Hartmann–Braun spectrometer (1% KBr or 1% solution).

High-resolution mass spectra refer to either direct inlet elec-

tron impact (EI) measurements or chemical ionization (CI)

measurements, using isobutane, and were provided by Dr. G.

Eigendorf at the University of British Columbia. Low-

1246

Can. J. Chem. Vol. 79, 2001

Fig. 3. Decarboxylation of the monoanions of 48 (AM1 calculations). Energies are in kcal mol^–1; bond lengths are in Å. Net atomic

charges are shown in parentheses.

Fig. 4. Decarboxylation of acetamidomalonic acid (3-21G calcu-

Fig. 5. Decarboxylation of the monoanion of acetamidomalonic

acid (3-21G calculations). Bond lengths are in Å; bond angles

are in deg.

lations). Energies are in kcal mol^–1; bond lengths are in Å.

Analytical thin-layer chromatography was carried out on

precoated Merck Silica gel 60 F-254 plates with aluminium

backing. Spots were observed under short-wavelength ultra-

violet light, or were visualized with iodine vapour,

ninhydrin, or ceric sulfate. Flash column chromatography

was carried out on Merck Silica gel 60 (230–400 Mesh), ac-

cording to the method of Still et al. (26), unless stated other-

wise, using only distilled solvents under dry nitrogen gas.

Elemental analyses were performed by M.K. Yang on a

resolution mass spectra refer to direct inlet EI measurements

or CI measurements, using isobutane, or fast-atom bombard-

ment (FAB), employing xenon gas, on a Kratos MS50 Spec-

trometer operated at 70 eV by G. Owens at Simon Fraser

University. Melting points (mp) were determined on a

Fisher–Johns apparatus, and are uncorrected. Optical rota-

tions were obtained using a Rudolph automatic polarimeter.

Wolfe et al.

1247

Carlo Erba model 1106 elemental analyzer at Simon Fraser

University.

mixture was refluxed overnight, with stirring, and then

cooled and filtered through Celite. The filtrate was concen-

trated under reduced pressure, using a Javex trap, to afford a

yellow oil having a crude weight of 68 g (140%). Purifica-

tion by column chromatography, using ethyl acetate – hex-

anes (1:1), afforded 10 as a white solid (43.9 g, 87%), mp

56–58°C. [α]²_D⁰–165.6° (c 0.157, CHCl₃). Mass spectrum

(CI, m/z): 347 (M+1). IR (KBr) (cm^–1): 1765, 1738. ¹H

NMR (CDCl₃): 7.28 (2H, t, Ar), 7.00 (1H, t, Ar), 6.93 (2H,

d, Ar), 6.01 (1H, dt, 1.2, 4.1 Hz, H-3), 5.93 (1H, d, 4.2 Hz,

H-4), 5.10 (1H, q, 1.4 Hz, allylic H), 4.97 (1H, dd, 1.4,

14.6 Hz, CHH), 4.92 (1H, br s, =CHH), 4.91 (1H, dd, 1.4,

14.6 Hz, CHH), 4.84 (1H, br s, =CHH), 3.76 (3H, s, ester

CH₃), 1.75 (3H, br s, CH₃). ¹³C NMR (CDCl₃): 173.23

(thiazoline N=C), 169.30 (ester C=O), 165.02 (β-lactam

C=O), 157.73, 129.64, 121.97, 114.84 (aromatic), 134.67

(CH₂=CH), 117.46 (CH₂=CCH₃), 92.25 (C-3), 67.78

(PhOCH₂), 67.21 (C-4), 58.86 (CHCO₂CH₃), 52.52

(CO₂CH₃), 21.52 (CH₂=CCH₃). Anal. calcd. for

C₁₇H₁₈N₂O₄S: C 58.94, H 5.24, N, 8.09; found: C 59.27, H

5.26, N 7.78.

Penicillin V methyl ester (8)

Methyl iodide (14.0 mL, 31.9 g, 225 mmol) was added

dropwise, with stirring, to a suspension of penicillin V

(77.0 g, 198 mmol) in dimethylformamide (400 mL).

Stirring was continued at room temperature for 17 h. The

solvent was then removed under reduced pressure, and the

residual oil was diluted with dichloromethane (300 mL),

washed successively with water (4 × 150 mL), and saturated

sodium chloride (300 mL), dried over magnesium sulfate

and evaporated to give the product as an orange oil (72.3 g,

94%), which crystallized upon trituration with ether; mp 60

to 61°C. [α]²_D⁰+124.1° (c 0.137, CHCl₃). Mass spectrum (CI,

m/z): 365 (M+1). IR (KBr) (cm^–1): 3366, 1786, 1744, 1701.

¹H NMR (CDCl₃): 7.35 (4H, t, Ar + NH), 7.05 (1H, t, Ar),

6.94 (1H, d, Ar), 5.75 (1H, dd, 4.3, 9.3 Hz, H-6), 5.59 (1H,

d, 4.3 Hz, H-5), 4.57 (1H, d, 15.1 Hz, CHH), 4.55 (1H, d,

15.1 Hz, CHH), 4.47 (1H, s, H-3), 3.78 (3H, s, ester CH₃),

1.60 (3H, s, CH₃), 1.49 (3H, s, CH₃). ¹³C NMR (CDCl₃):

172.96 (acetamido C=O), 168.04 (β-lactam C=O), 167.87

(ester C=O), 157.11, 129.86, 122.47, 114.20 (aromatic),

70.57 (C-3), 67.85 (C-5), 67.38 (PhOCH₂), 64.79 (C-2),

58.23 (C-6), 52.35 (CO₂CH₃), 31.91 (CH₃), 26.91 (CH₃).

Anal. calcd. for C₁₇H₂₀N₂O₅S: C 56.03, H 5.53, N 7.69;

found: C 55.75, H 5.55, N 7.59.

Isomerization of 10

Triethylamine (8.5 mL, 61 mmol) was added dropwise,

with stirring, to a solution of 10 (48.3 g, 140 mmol) in di-

chloromethane (270 mL). The solution was stirred for 3 h,

and the solvent was then evaporated under reduced pressure.

The residue crystallized from warm methanol to give 30.1 g

(62%) of 11, mp 64–66°C. [α]²_D⁰+24.4° (c 0.205, CHCl₃).

Mass spectrum (CI, m/z): 347 (M+1). IR (KBr) (cm^–1):

Penicillin V methyl ester sulfoxide (9)

Hydrogen peroxide (34.0 mL of 50%, 17.0 g, 500 mmol)

was added, with stirring during 1 h, to a solution of penicil-

lin V methyl ester (72.3 g, 198 mmol) in dichloromethane

(800 mL) and glacial acetic acid (92 mL). Stirring was con-

tinued for 17 h, and the yellow solution was then washed

1

1759, 1723, 1643, 1597. H NMR (CDCl₃): 7.26 (2H, m,

Ar), 6.99 (1H, t, Ar), 6.94 (2H, d, Ar), 6.06 (1H, dt, 1.2,

4.0 Hz, H-3), 5.87 (1H, d, 4.0 Hz, H-4), 4.99 (1H, dd, 1.2,

14.3 Hz, CHH), 4.93 (1H, dd, 1.2, 14.3 Hz, CHH), 3.75 (3H,

s, ester CH₃), 2.22 (3H, s, =CCH₃), 1.76 (3H, s, =CCH₃).

¹³C NMR (CDCl₃): 172.09 (thiazoline N=C), 163.76 (β-

lactam C=O), 163.37 (ester C=O), 157.74, 129.67, 122.03,

114.86 (aromatic), 155.79 (NC=C(CH₃)₂), 118.72

(NC=C(CH₃)₂), 92.70 (C-3), 69.51 (C-4), 67.74 (PhOCH₂),

51.90 (CO₂CH₃), 23.77, 21.88 (C=C(CH₃)₂). Anal. calcd. for

C₁₇H₁₈N₂O₄S: C 58.94, H 5.24, N 8.09; found: C 59.25, H

5.20, N 8.10.

successively with saturated sodium bicarbonate (2

×

200 mL), water (2 × 200 mL), and saturated sodium chloride

(400 mL), dried over magnesium sulfate and evaporated.

The resulting yellow foam crystallized upon treatment with

hot methanol (150 mL). The product was collected and

washed with cold methanol (40 mL) to give 76.4 g (78%) of

the methyl ester of penicillin V sulfoxide; mp 118–120°C

(lit. (27) mp 121.5 to 122.5°C). [α]²_D⁰+202.7° (c 0.148,

CHCl₃). Mass spectrum (CI, m/z): 381 (M+1). IR (KBr)

1

(cm^–1): 3380, 1802, 1757, 1694, 1065. H NMR (CDCl₃):

Thiazoline azetidinone (12)

8.26 (1H, d, 10.4 Hz, NH), 7.29 (2H, m, Ar), 7.01 (1H, t,

Ar), 6.94 (2H, d, Ar), 6.09 (1H, dd, 4.6, 10.5 Hz, H-6), 5.04

(1H, d, 4.6 Hz, H-5), 4.68 (1H, s, H-3), 4.53 (2H, s,

PhOCH₂), 3.82 (3H, s, ester CH₃), 1.73 (3H, s, 2-CH₃), 1.22

(3H, s, shows nOe with H-5 at 5.04 ppm, 2-CH₃). ¹³C NMR

(CDCl₃): 173.08 (acetamido C=O), 168.30 (β-lactam, ester

C=O), 157.20, 129.72, 122.26, 115.02 (aromatic), 76.57

(C5), 75.32 (C2), 67.29 (PhOCH₂), 66.55 (C-3), 55.67 (C-6),

52.91 (ester CH₃), 19.44 (CH₃), 18.73 (CH₃). Anal. calcd.

for C₁₇H₂₀N₂O₆S: C 53.67, H 5.30, N 7.36; found: C 53.30,

H 5.30, N 7.36.

A solution of potassium permanganate (12.2 g, 77 mmol)

and magnesium sulfate (8.41 g, 70 mmol) in water (480 mL)

was added during 80 min to a solution of 11 (30.1 g,

87 mmol) in 95% ethanol (600 mL). Additional potassium

permanganate (5 × 3.6 g, 114 mmol) was subsequently

added every 10 min. The solvent was then removed under

reduced pressure, and the brown residue was shaken with

ethyl acetate (720 mL) and water (360 mL), and filtered. The

organic layer was separated and the aqueous phase was ex-

tracted with ethyl acetate (3 × 100 mL). The combined or-

ganic extracts were washed with saturated sodium chloride

(1000 mL), dried over magnesium sulfate, and evaporated.

The residue was treated with hot ethyl acetate to give 12 as

yellowish-white crystals (15.9 g, 78%), mp 157 to 158°C

(lit. (27) mp 157 to 158°C). [α]²_D⁰+121.4° (c 0.14, CHCl₃).

Mass spectrum (CI, m/z): 235 (M+1). IR (KBr) (cm^–1):

Rearrangement of penicillin V sulfoxide

Trimethylphosphite (70.0 mL, 73.6 g, 593 mmol) was

added to a mixture of penicillin V methyl ester sulfoxide

(53.0 g, 139 mmol) and anhydrous magnesium sulfate

(33.0 g, 274 mmol) in benzene (1100 mL). The reaction

1

3216, 1757, 1719. H NMR (CDCl₃): 7.29 (2H, m, Ar), 7.02

1248

Can. J. Chem. Vol. 79, 2001

(1H, t, Ar), 6.98 (2H, d, Ar), 6.34 (1H, br s, NH), 6.08 (1H,

dd, 0.9, 3.9 Hz, H-3), 5.33 (1H, d, 3.9 Hz, H-4), 5.02 (1H,

dd, 0.9, 14.3 Hz, CHH), 4.93 (1H, dd, 0.9, 14.3 Hz, CHH).

¹³C NMR (CDCl₃): 172.12 (thiazoline N=C), 164.36 (β-

lactam C=O), 157.79, 129.69, 122.08, 114.92 (aromatic),

94.83 (C-3), 68.00 (PhOCH₂), 62.86 (C-4). Anal. calcd. for

C₁₁H₁₀N₂O₂S: C 56.39, H 4.30, N 11.96; found: C 56.01, H

4.31, N 11.57.

s, benzyl CH₂), 4.92 (1H, s, CH). ¹³C NMR (CDCl₃): 164.28

(ester C=O), 134.58–128.29 (aromatic), 68.72 (PhCH₂O),

42.20 (COCHBrCO). Anal. calcd. for C₁₇H₁₅O₄Br: C 56.22,

H 4.16; found: C 55.84, H 4.09.

Benzyl methyl bromomalonate

Dimethyl malonate (10 mL, 11.56 g, 87.5 mmol), in

methanol (70 mL), was treated with a solution of potassium

hydroxide (4.89 g, 87.2 mmol) in methanol (70 mL). The so-

lution was stirred for 24 h, then refrigerated overnight. The

white crystals were filtered, rinsed with cold methanol, and

dried to give 9.72 g (65%) of potassium methyl malonate,

mp 160–162°C (dec). Mass spectrum (CI, m/z): 103 (M+1-

Dimethyl bromomalonate (28)

Bromine (1.8 mL, 5.58 g, 35 mmol) was added dropwise

with stirring, during 60 min, to a solution of dimethyl

malonate (3.46 mL, 4.0 g, 35 mmol) in carbon tetrachloride

(15 mL), with irradiation by a 150 W bulb mounted beneath

the reaction vessel. When the evolution of gas had ceased,

water (50 mL) was added and the phases were separated.

The aqueous layer was extracted with chloroform (2 ×

40 mL) and the combined organic extracts were washed suc-

cessively with saturated sodium bicarbonate (2 × 75 mL)

and saturated sodium chloride (100 mL), dried over magne-

sium sulfate, and evaporated. The residue was distilled, and

the fraction boiling at 105–108°C and 11 torr (1 torr =

133.322 Pa) was collected as a colourless oil (5.02 g, 62%).

¹H NMR (CDCl₃): 4.85 (1H, s, CH), 3.83 (6H, s, CH₃).

1

(K+CH₃)). IR (KBr) (cm^–1): 1738, 1728. H NMR (D₂O):

3.56 (3H, s, CH₃), 3.15 (2H, s, CH₂). ¹³C NMR (D₂O):

176.78 (carboxyl C=O), 174.80 (ester C=O), 55.36

(CO₂CH₃). Anal. calcd. for C₄H₅O₄K: C 30.76, H 3.23;

found: C 30.69, H 3.19.

Benzyl bromide (3.8 mL, 5.46 g, 31.9 mmol) was added

to a suspension of potassium methyl malonate (5.63 g,

32.7 mmol) in dimethylformamide (80 mL). The mixture

was stirred for 22 h, diluted with ethyl acetate (150 mL),

washed with water (3 × 150 mL), dried over magnesium sul-

fate, and evaporated to give benzyl methyl malonate as a

colourless oil (6.47 g, 97%). IR (neat) (cm^–1): 1755, 1732.

1

Mass spectrum (CI, m/z): 209 (M+1). H NMR (CDCl₃):

Dibenzyl malonate

7.36 (5H, m, Ar), 5.19 (2H, s, PhCH₂), 3.74 (3H, s, CH₃),

3.44 (2H, s, malonyl CH₂). ¹³C NMR (CDCl₃): 166.83 (ester

C=O), 166.31 (ester C=O), 135.42, 128.60, 128.42, 128.25

(aromatic), 67.18 (CO₂CH₂Ph), 52.41 (CO₂CH₃), 41.30

(malonyl CH₂). Anal. calcd. for C₁₁H₁₂O₄: C 46.01, H 3.86;

found: C 46.03, H 3.88.

Concentrated sulfuric acid (0.2 mL of 96%, 0.2 g,

1.96 mmol) was slowly added to a suspension of malonic

acid (20.1 g, 193 mmol) and benzyl alcohol (47.0 mL,

49.1 g, 454 mmol) in toluene (70 mL). Employing a Dean–

Stark trap, the mixture was heated to reflux for 2 h, and ap-

proximately 7 mL of water were removed. The solution was

cooled, diluted with ethyl acetate (100 mL), and washed suc-

cessively with saturated sodium bicarbonate (2 × 100 mL),

water (2 × 100 mL) and saturated sodium chloride

(100 mL), dried over magnesium sulfate, and evaporated.

The residue was distilled, and the fraction boiling at 188°C

and 0.2 torr (1 torr = 133.322 Pa) was collected as a colour-

less oil (50.0 g, 91%). Mass spectrum (EI, m/z): 285 (M). IR

(neat) (cm^–1): 1745. ¹H NMR (CDCl₃): 7.35–7.32 (10H, m,

Ar), 5.18 (4H, s, benzyl CH₂), 3.48 (2H, s, malonyl

CH₂).¹³C NMR (CDCl₃): 166.18 (ester C=O), 135.34,

128.59, 128.41, 128.27 (aromatic), 67.26 (PhCH₂O), 41.61

(COCH₂CO).

With irradiation by a 150 W Westinghouse reflector spot-

light mounted underneath the reaction vessel, bromine

(2.7 mL, 8.38 g, 52.4 mmol) was added dropwise during

60 min, with stirring, to a solution of benzyl methyl

malonate (11.0 g, 52.8 mmol) in carbon tetrachloride

(40 mL). Once the evolution of gas had ceased, water

(40 mL) was added and the phases were separated. The

aqueous layer was extracted with chloroform (2 × 40 mL)

and the combined organic extracts were washed with satu-

rated sodium bicarbonate (2 × 120 mL) and saturated so-

dium chloride (120 mL), dried over magnesium sulfate, and

evaporated. The residue was purified by column chromatog-

raphy using ethyl acetate – hexanes (30:70) to give the prod-

uct as a colourless oil (10.3 g, 68%). Mass spectrum (CI,

m/z): 287, 289 (M+1). IR (neat) (cm^–1): 1767, 1746. ¹H

NMR (CDCl₃): 7.36 (5H, m, Ar), 5.25 (2H, s, PhCH₂), 4.89

(1H, s, malonyl CH), 3.80 (3H, s, CH₃). ¹³C NMR (CDCl₃):

164.97 (ester C=O), 164.38 (ester C=O), 134.68, 128.89,

128.74, 128.33 (aromatic), (CO₂CH₂Ph), 53.92 (CO₂CH₃),

42.02 (malonyl CH).

Dibenzyl bromomalonate (20a, 29)

With irradiation by a 250 W bulb mounted beside the re-

action vessel, bromine (6.5 mL, 20.2 g, 126 mmol) was

added dropwise during 2 h, with stirring, to a solution of

dibenzyl malonate (19.6 g, 69.0 mmol) in carbon tetrachlo-

ride (51 mL). Water (50 mL) was then added and the layers

were separated. The aqueous layer was extracted with di-

chloromethane (2 × 40 mL) and the combined organic ex-

tracts were washed successively with saturated sodium

bicarbonate (2 × 75 mL) and saturated sodium chloride

(100 mL), dried over magnesium sulfate, and evaporated.

The oily residue (22.0 g) was purified by column chroma-

tography using ethyl acetate – hexanes (1:8) to yield 6.91 g

(28%) of the product as a colourless oil, which solidified in

the freezer as white crystals, mp 26 to 27°C. IR (neat) (cm^–1):

Coupling of 12 with dimethyl bromomalonate

A solution of 12 (4.45 g, 19 mmol) in dimethylformamide

(40 mL) was cooled to –55°C and Triton B (15.0 mL of a

40% methanolic solution, 6.36 g, 38 mmol) was added

dropwise. Stirring was continued for 30 min, and a solution

of dimethylbromomalonate (4.85 g, 23 mmol) in

dimethylformamide (20 mL) was then added dropwise.

Stirring was continued overnight, and the mixture was

1

1744. H NMR (CDCl₃): 7.36–7.30 (10H, m, Ar), 5.22 (4H,

Wolfe et al.

1249

warmed to room temperature. Ethyl acetate (450 mL), satu-

rated sodium chloride (110 mL), and 1.0 M hydrochloric

acid (50 mL) were added, and the organic phase was sepa-

rated, washed with water (2 × 120 mL) and saturated sodium

chloride (150 mL), dried over magnesium sulfate, and evap-

orated under reduced pressure. The residue was purified by

column chromatography using ethyl acetate – hexanes (2:3)

to give 13 (3.33 g, 50%). [α]²_D⁰–88.2° (c 0.17, CHCl₃). IR

(neat) (cm^–1): 1782, 1755, 1748, 1682. Mass spectrum (EI,

m/z): 364 (M). ¹H NMR (CDCl₃): 7.29 (2H, t, Ar), 7.00 (1H,

t, Ar), 6.92 (2H, d, Ar), 6.09 (1H, dt, 1.2, 4.2 Hz, H-3), 6.00

(1H, d, 4.2 Hz, H-4), 5.12 (1H, s, CH), 4.98 (1H, dd, 1.2,

14.3 Hz, PhOCHH), 4.89 (1H, dd, 1.2, 14.3 Hz, PhOCHH),

3.82 (3H, s, CH₃), 3.72 (3H, s, CH₃). ¹³C NMR (CDCl₃):

172.99 (thiazoline N=C), 165.12 (β-lactam C=O), 164.29

(ester C=O), 157.78, 129.64, 122.02, 114.86 (aromatic),

93.17 (C-3), 68.10 (C-4), 67.90 (PhOCH₂), 60.29 (malonyl

CH), 55.96 (CO₂CH₃), 53.40 (CO₂CH₃). Anal. calcd. for

C₁₆H₁₆N₂O₆S: C 52.74, H 4.43, N 7.69; found: C 52.39, H

4.36, N 7.85.

tional 22 h. Ethyl acetate (200 mL) was added and the solu-

tion was washed successively with 0.1 M hydrochloric acid

(200 mL), water (3 × 200 mL), and saturated sodium chlo-

ride (200 mL), dried over magnesium sulfate, and evapo-

rated. Purification by column chromatography using ethyl

acetate – hexanes (1:1) gave the product as a light yellow,

viscous oil (5.45 g, 75%). Mass spectrum (CI, m/z): 365

((M+1)-PhCH₂). IR (neat) (cm^–1): 1784, 1761, 1748. ¹H

NMR (CDCl₃): isomer A: 7.32 (8H, m, Ar), 6.91 (2H, m,

Ar), 6.08 (1H, dt, 1.2, 4.1 Hz, H-3), 5.98 (1H, d, 4.1 Hz,

H-4), 5.25 (1H, d, 12.3 Hz, PhCHH), 5.22 (1H, d, 12.3 Hz,

PhCHH), 5.15 (1H, s, malonyl CH), 4.97 (1H, dd, 1.2,

14.3 Hz, PhOCHH), 4.86 (1H, dd, 1.2, 14.3 Hz, PhOCHH),

3.69 (3H, s, CH₃); isomer B: 7.32 (8H, m, Ar), 7.01 (2H, m,

Ar), 6.09 (1H, dt, 1.2, 4.1 Hz, H-3), 5.99 (1H, d, 4.1 Hz, H-4),

5.18 (2H, s, PhCH₂), 5.17 (1H, s, malonyl CH), 4.91 (1H,

dd, 0.8, 14.3 Hz, PhOCHH), 4.68 (1H, 1.3, 14.3 Hz,

PhOCHH), 3.80 (3H, s, CH₃). ¹³C NMR (CDCl₃): 173.02,

172.93 (thiazoline N=C, both isomers), 165.08, 164.55,

164.40, 164.32, 164.25, 163.79 (β-lactam C=O, ester C=O,

both isomers), 157.74, 134.45–114.84 (aromatic, both iso-

mers), 93.15, 93.10 (C-3, both isomers), 68.52, 68.47

(CO₂CH₂Ph, both isomers), 68.09, 68.03 (C-4, both isomers),

67.85, 67.80 (PhOCH₂, both isomers), 56.23, 56.13 (malonyl

CH, both isomers). Anal. calcd. for C₂₂H₂₀N₂O₆S·0.5H₂O: C

58.79, H 4.71, N 6.23; found: C 58.95, H 4.55, N 6.41.

Coupling of 12 with dibenzyl bromomalonate

Triton B (15.4 mL of a 40% methanolic solution, 6.52 g,

39 mmol) was slowly added at –55°C to a solution of the

azetidinone (4.4 g, 19 mmol) in dimethylformamide

(40 mL). The red solution was stirred for 30 min at –55°C

and then treated dropwise with

a solution of the

bromomalonate (7.1 g, 20 mmol) in dimethylformamide

(20 mL). When the addition was complete the reaction mix-

ture was warmed to 0°C and stirring was continued for

2.5 h. Ethyl acetate (450 mL), saturated sodium chloride

(110 mL), and 1.0 M hydrochloric acid (50 mL) were added

and the organic phase was separated, washed with water (2 ×

120 mL) and saturated sodium chloride (150 mL), dried over

magnesium sulfate, and evaporated under reduced pressure.

The residue crystallized from hot ethyl acetate – hexanes

(1:2) to yield 4.8g (49%) of the product as yellow crystals,

mp 90–92°C. [α]²_D⁰–71.8° (c 0.209, CHCl₃). Mass spectrum

(FAB, m/z): 516 (M). IR (KBr) (cm^–1): 1768, 1744. ¹H NMR

(acetone-d₆): 7.36 –7.29 (12H, m, Ar), 6.97 (3H, m, Ar),

6.14 (1H, dt, 1.2, 4.1 Hz, H-3), 6.03 (1H, d, 4.1 Hz, H-4),

5.32 (1H, s, CH), 5.24 (2H, s, benzyl CH₂), 5.19 (2H, s,

benzyl CH₂), 4.96 (1H, dd, 1.2, 14.4 Hz, CHH), 4.76 (1H,

dd, 1.2, 14.4 Hz, CHH). ¹³C NMR (CDCl₃): 172.90

(thiazoline N=C), 164.50 (β-lactam C=O), 164.40 (ester

C=O), 163.73 (ester C=O), 157.79, 134.43–114.86 (aro-

matic), 93.12 (C-3), 68.55 (CO₂CH₂Ph), 68.11 (C-4), 67.86

(PhOCH₂), 56.49 (NCH(CO₂CH₂Ph)₂). Anal. calcd. for

C₂₈H₂₄N₂O₆S: C 65.10, H 4.68, N 5.42; found: C 64.81, H

4.62, N 5.48.

Allylation of 13

The dimethyl ester (3.32 g, 9.53 mmol) was dissolved in

dimethylformamide (33 mL), the solution was cooled to

0°C, and a 40% methanolic solution of Triton B (5.6 mL,

2.06 g, 12.3 mmol) was added dropwise during 20 min.

Allyl bromide (2.5 mL, 3.5 g, 29 mmol) was then added in

one portion. The reaction mixture was stirred at 0°C for 2 h

and diluted with ethyl acetate (100 mL). The organic layer

was washed successively with water (3 × 100 mL) and satu-

rated sodium chloride (100 mL), dried over sodium sulfate,

and evaporated to give an orange oil. Chromatography on

silica gel using ethyl acetate – hexanes (3:7) gave 14 as a

viscous pale yellow oil (3.47 g, 94%). [α]²_D⁰–21.1° (c 0.285,

CHCl₃). Mass spectrum (EI, m/z): 404 (M). IR (neat) (cm^–1):

1

3401, 1778, 1755, 1748, 1678. H NMR (CDCl₃): 7.30 (2H,

t, Ar), 7.00 (1H, t, Ar), 6.94 (2h, d, Ar), 6.01 (1H, d, 4.2 Hz,

H-4), 5.92 (1H, dt, 1.2, 4.2 Hz, H-3), 5.71 (1H, ddt, 7.2,

10.1, 17.4 Hz, CH=CH₂), 5.19–5.10 (2H, m, CH=CH₂), 4.99

(1H, dd, 1.2, 14.3 Hz, PhOCHH), 4.89 (1H, dd, 1.2,

14.3 Hz, PhOCHH), 3.80 (3H, s, CH₃), 3.76 (3H, s, CH₃),

3.10 (1H, ddt, 1.1, 7.2, 14.4 Hz, CHHCH=CH₂), 3.04 (1H,

ddt, 1.1, 7.2, 14.4 Hz, CHHCH=CH₂). ¹³C NMR (CDCl₃):

172.87 (thiazoline N=C), 166.67 (β-lactam C=O), 166.21

(ester C=O), 164.15 (ester C=O), 157.84, 129.63, 121.97,

114.87 (aromatic), 131.17 (CH=CH₂), 120.29 (CH=CH₂),

90.84 (C-3), 70.04 (C-4), 68.80 (malonyl CH), 67.95

(PhOCH₂), 53.46 (CO₂CH₃), 53.37 (CO₂CH₃), 38.18

(CH₂CH=CH₂). Anal. calcd. for C₁₉H₂₀N₂O₆S: C 56.43, H

4.98, N 6.93; found: C 56.39, H 4.92, N 6.91.

Coupling of 12 with the mixed bromomalonate

To a solution of the thiazoline azetidinone (4.01 g,

17.1 mmol), cooled to –55°C in dimethylformamide

(40 mL), were added dropwise with stirring Triton B

(13.5 mL of a 40% methanolic solution, 5.70 g, 34.1 mmol),

followed by a solution of the bromomalonate (5.4 g,

16.9 mmol) in dimethylformamide (15 mL). When the addi-

tion was complete, the reaction mixture was warmed to

−40°C and stirring was continued for 1 h. The cooling bath

was then removed and stirring was continued for an addi-

Allylation of the dibenzyl ester

Sodium hydride (0.658 g of a 60% suspension in mineral

oil, 16.5 mmol) was added in portions at 0°C to a solution of

the dibenzyl ester (4.05 g, 7.84 mmol) in

1250

Can. J. Chem. Vol. 79, 2001

dimethylformamide (60 mL). The mixture was stirred for

20 min at 0°C, warmed to room temperature, recooled to 0°

and treated, during 15 min, with allyl bromide (1.6 mL,

2.2 g, 18 mmol). The ice bath was removed after an addi-

tional 20 min, and the bright red reaction mixture was stirred

for 16 h. Water (500 mL) was added and the mixture was

extracted with dichloromethane (4 × 50 mL). The combined

organic extracts were washed with water (3 × 100 mL) and

saturated sodium chloride (200 mL), dried over magnesium

sulfate, and evaporated to yield a yellow oil (2.4 g). Purifi-

cation by column chromatography using ethyl acetate – hex-

anes (1:1) gave the product as a bright yellow viscous oil

(1.5 g, 34%). [α]²_D⁰–26.9° (c 0.557, CHCl₃). Mass spectrum

both isomers), 67.86, 67.80 (PhOCH₂, both isomers), 53.41,

53.31 (CO₂CH₃, both isomers), 38.23, 38.02 (CH₂CH=CH₂).

Anal. calcd. for C₂₅H₂₄N₂O₆S: C 62.49, H 5.03, N 5.83;.

Found: C 62.28, H 5.17, N 5.78.

Conversion of 14 into the hydroxycepham 17

A solution of 14 (8.14 g, 20.1 mmol) in dichloromethane

(100mL) and methanol (50 mL) was cooled to –78°C, and

treated with ozone at a rate of 1.5 L min^–1until a blue col-

our persisted. Excess ozone was purged using nitrogen gas,

and the reaction was quenched with dimethyl sulfide

(12.3 mL, 10.4 g, 167.5 mmol). The cooling bath was then

removed and the solution was allowed to warm to room tem-

perature. Evaporation of the solvent afforded a yellow syrup

(9.0 g). This was dissolved in a mixture of dichloromethane

(150 mL) and acetone (150 mL), and treated with 3%

perchloric acid (25 mL, 0.75 g, 7.47 mmol). The mixture

was stirred for 90 min and then diluted with ethyl acetate

(300 mL), washed with saturated sodium chloride (6 ×

100 mL), dried over magnesium sulfate, and evaporated

to give a yellow oil. Purification by column chromatography

using ethyl acetate – hexanes (1:1) yielded 17 (8.0 g, 94%).

[α]²_D⁰+217.7° (c 0.40, CHCl₃). Mass spectrum (CI, m/z): 407

((M+1)-H₂O). IR (KBr) (cm^–1): 3480, 3341, 1778, 1753,

1

(CI, m/z): 557 (M+1). IR (CH₂Cl₂) (cm^–1): 1777, 1750. H

NMR (CDCl₃): 7.34–7.26 (12H, m, Ar), 7.00 (1H, t, Ar),

6.90 (2H, d, Ar), 5.92 (1H, d, 4.2 Hz, H-4), 5.84 (1H, dt,

1.2, 4.2 Hz, H-3), 5.66 (1H, ddt, 7.0, 8.5, 10.0 Hz, =CH),

5.16 (2H, s, benzyl CH₂), 5.11 (2H, s, benzyl CH₂), 5.07–

5.04 (2H, m, =CH₂), 4.82 (1H, dd, 1.2, 14.2 Hz, PhOCHH),

4.52 (1H, dd, 1.2, 14.2 Hz, PhOCHH), 3.10 (1H, ddt, 1.0,

7.0, 14.0 Hz, allyl CHH), 3.07 (1H, ddt, 1.0, 7.0, 14.0 Hz,

allyl CHH). ¹³C NMR (CDCl₃): 172.83 (thiazoline N=C),

165.90 (β-lactam C=O), 165.53 (ester C=O), 164.17 (ester

C=O), 134.60 (CH=CH₂), 157.82, 134.48–114.88 (aro-

matic), 120.46 (CH=CH₂), 90.76 (C-3), 70.14 (C-4), 68.83

(NCCH=CH₂), 68.43 (PhCH₂O), 67.83 (PhOCH₂), 38.16

(CH₂CH=CH₂). Anal. calcd. for C₃₁H₂₈N₂O₆S: C 66.89, H

5.07, N 5.03; found: C 67.20, H 5.37, N 5.19.

1

1680. H NMR (CDCl₃): 7.38 (1H, d, 9.3 Hz, NH), 7.31

(2H, t, Ar), 7.01 (1H, t, Ar), 6.92 (2H, d, Ar), 5.77 (1H, dd,

4.6, 9.3 Hz, H-7), 5.55 (1H, d, 4.6 Hz, H-6), 5.35 (1H, 2.3,

3.9, H2), 4.52 (2H, s, PhOCH₂), 3.85 (3H, s, CH₃), 3.81

(3H, s, CH₃), 2.78 (1H, dd, 3.9, 14.4 Hz, H-3), 2.53 (1H, dd,

2.3, 14.4 Hz, H-3). ¹³C NMR (CDCl₃): 168.91 (acetamido

C=O), 167.83 (β-lactam C=O), 165.04 (ester C=O), 163.76

(ester C=O), 156.94, 129.76, 122.36, 114.84 (aromatic),

70.71 (C-2), 67.11 (PhOCH₂), 61.70 (C-7), 59.01 (C-6),

54.63 (C-4), 53.94 (CO₂CH₃), 53.47 (CO₂CH₃), 35.62 (C-3).

Anal. calcd. for C₁₈H₂₀N₂O₈S: C 50.94, H 4.75, N 6.60;

found: C 50.58, H 4.89, N 6.16.

Allylation of the mixed ester

The azetidinone (4.35 g, 10.2 mmol) was dissolved in

dimethylformamide (35 mL), the solution was cooled to

0°C, and 40% methanolic Triton B (6.0 mL, 2.21 g,

13.2 mmol) was added dropwise over 20 min, with stirring.

Then allyl bromide (2.6 mL, 3.63 g, 30.0 mmol) was added

and stirring was continued for 2 h at 0°C. Ethyl acetate

(150 mL) was added and the solution was washed with water

(3 × 150 mL) and saturated sodium chloride (150 mL), dried

over sodium sulfate, and evaporated to give an orange oil.

Chromatography on silica gel using ethyl acetate – hexanes

(1:1) gave the product as a yellow oil (3.94 g, 83%). IR

Dehydration of 17

A solution of 17 (200 mg, 0.47 mmol) in acetic anhydride

(1.4 mL, 1.5 g, 14.8 mmol) was treated, with stirring, with a

1% w/v solution of sulfuric acid in acetic acid (0.3 mL,

3 mg, 0.03 mmol). After 2.5 h, sodium acetate hexahydrate

(750 mg, 3.9 mmol) was added and stirring was continued

overnight. Ethyl acetate (50 mL) was added and the organic

layer was washed successively with water (2 × 50 mL) and

saturated sodium bicarbonate (50 mL), dried over magne-

sium sulfate, and evaporated to give a pale yellow oil. A so-

lution of this oil in toluene (150 mL) was treated with p-

toluenesulfonic acid monohydrate (70 mg, 0.37 mmol), and

the mixture, protected from moisture by a calcium chloride

drying tube, was refluxed overnight. The solvent was then

evaporated under reduced pressure. The residue was purified

by column chromatography using ethyl acetate – hexanes

(3:2) to give the 4,4-dimethoxycarbonyl-∆²-cephem 19 as a

yellow foam (489 mg, 52%). [α]²_D⁰+400.0° (c 0.26, CHCl₃).

Mass spectrum (CI, m/z): 407 (M+1). IR (KBr) (cm^–1):

1

(neat) (cm^–1): 1778, 1755, 1746. H NMR (CDCl₃): isomer

A: 7.29 (8H, t, Ar), 6.91 (2H, t, Ar), 5.98 (1H, d, 4.1 Hz, H-

4), 5.90 (1H, dt, 1.1, 4.2 Hz, H-3), 5.70 (1H, ddt, 6.5, 10.0,

17.0 Hz, CH₂CH=CH₂), 5.21 (2H, s, PhCH₂), 5.15–5.06

(2H, m, CH₂CH=CH₂), 4.93 (1H, dd, 1.1, 14.3 Hz,

PhOCHH), 4.79 (1H, dd, 1.2, 14.3 Hz, PhOCHH), 3.73 (3H,

s, CH₃), 3.14–3.01 (2H, m, CH₂CH=CH₂). Isomer B: 7.33

(8H, t, Ar), 7.00 (2H, t, Ar), 5.95 (1H, d, 4.2 Hz, H-4), 5.86

(1H, dt, 1.1, 4.2 Hz, H-3), 5.68 (1H, ddt, 6.5, 10.0, 17.0 Hz,

CH₂CH=CH₂), 5.17 (2H, s, PhCH₂), 5.15–5.06 (2H, m,

CH₂CH=CH₂), 4.86 (1H, dd, 1.0, 14.3 Hz, PhOCHH), 4.61

(1H, dd, 1.3, 14.2 Hz, PhOCHH), 3.69 (3H, s, CH₃), 3.14–

3.01 (2H, CH₂CH=CH₂). ¹³C NMR (CDCl₃): 172.93, 172.87

(thiazoline N=C, both isomers), 166.50, 166.124, 165.99,

165.58, 164.23, 164.12 (β-lactam C=O, ester C=O, both iso-

mers), 157.78, 131.04–128.34, 127.60–121.94, 114.84 (aro-

matic, both isomers), 134.67, 134.53 (CH=CH₂, both

isomers), 120.45, 120.41 (CH=CH₂, both isomers), 90.77

(C-3, both isomers), 70.11, 70.03 (CO₂CH₂Ph, both iso-

mers), 68.86, 68.71 (malonyl C, both isomers), 68.39 (C-4,

1

3310, 1786, 1748, 1690. H NMR (CDCl₃): 7.39 (1H, d,

9.0 Hz, NH), 7.33 (2H, t, Ar), 7.04 (1H, t, Ar), 6.94 (2H, d,

Ar), 6.47 (1H, d, 10.4 Hz, H-2), 6.07 (1H, d, 10.4 Hz, H-3),

5.81 (1H, dd, 4.2, 9.0 Hz, H-7), 5.31 (1H, d, 4.2 Hz, H-6),

4.56 (2H, s, PhOCH₂), 3.87 (3H, s, CH₃), 3.84 (3H, s, CH₃).

Wolfe et al.

1251

¹³C NMR (CDCl₃): 168.58 (acetamido C=O), 166.07 (β-

lactam C=O), 164.28 (ester C=O), 163.23 (ester C=O),

157.10, 129.82, 122.48, 114.96 (aromatic), 122.20 (C-2),

115.18 (C-3), 67.37 (PhOCH₂), 63.67 (C-4), 59.67 (C-7),

55.08 (C-6), 54.00 (CO₂CH₃), 53.66 (CO₂CH₃). Anal. calcd.

for C₁₈H₁₈N₂O₇S: C 53.20, H 4.46, N 6.89; found: C 53.38,

H 4.66, N 6.55.

(CHCH₂I), 37.31 (C-2), 5.95 (C-3). Anal. calcd. for

C₃₁H₂₉N₂IO₂S: C 53.15, H 4.17, N 4.00; found: C 53.15, H

4.02, N 3.89.

Conversion of the allylated methyl benzyl ester to 20

(R₁= Me, R₂= CH₂Ph)

Iodine (1.64 g, 6.46 mmol) was added in two portions

over 30 min to a solution of the mixed ester (both

diastereomers) (2.75 g, 5.90 mmol) in a biphasic mixture of

dichloromethane (83 mL) and water (41 mL). The purple so-

lution was stirred at room temperature for 5 h, the reaction

was quenched with 1% sodium sulfite (50 mL), and the or-

ganic layer was then washed successively with water (2 ×

80 mL) and saturated sodium chloride (80 mL), dried over

magnesium sulfate, and evaporated. Purification by column

chromatography using ethyl acetate – hexanes (1:1) afforded

the product as a white foam (3.34 g, 94%). Mass spectrum

(CI, m/z): 363 ((M+1)-(I+CO₂CH₂Ph)).IR (KBr) (cm^–1):

Conversion of the allylated dimethyl ester to 20 (R₁=

R₂= Me)

A solution of the dimethyl ester (3.38 g, 8.70 mmol) in a

mixture of dichloromethane (123 mL) and water (61 mL)

was treated in two portions during 30 min with iodine

(2.45 g, 9.65 mmol). The purple reaction mixture was stirred

at room temperature for 5.5 h, and the reaction was then

quenched with 1% sodium sulfite (50 mL). The organic

layer was washed successively with water (2 × 150 mL) and

saturated sodium chloride (150 mL), dried over magnesium

sulfate, and evaporated to give a yellow foam. Purification

by column chromatography using ethyl acetate – hexanes

(1:1) afforded a white foam (3.24 g, 68%). [α]²_D⁰+177.8° (c

0.135, CHCl₃). Mass spectrum (CI, m/z): 423 ((M+1)-I). IR

1

3310, 1778, 1748, 1688. H NMR (CDCl₃): isomer A: 7.41–

7.29 (8H, m, Ar + NH), 7.03 (1H, t, Ar), 6.93 (2H, d, Ar),

5.80 (1H, dd, 4.6, 9.6 Hz, H-7), 5.38 (1H, d, 4.6 Hz, H-6),

5.25 (2H, s, PhCH₂), 4.53 (2H, s, PhOCH₂), 3.78 (3H, s,

CH₃), 3.19 (1H, dd, 5.3, 10.3 CHHI), 3.09 (1H, dd, 8.0,

10.3 Hz, CHHI), 2.81 (1H, m, H-2), 2.70 (1H, dd, 1.9,

14.1 Hz, H-3), 2.00 (1H, dd, 12.2, 14.1 Hz, H-3). Isomer B:

7.41–7.30 (8H, m, Ar + NH), 7.04 (1H, t, Ar), 6.93 (2H, d,

Ar), 5.84 (1H, dd, 4.6, 9.6 Hz, H-7), 5.39 (1H, d, 4.6 Hz, H-6),

5.28 (1H, d, 12.1 Hz, PhCHH), 5.17 (1H, d, 12.1 Hz,

PhCHH), 4.54 (2H, s, PhOCH₂), 3.74 (3H, s, CH₃), 3.27

(1H, dd, 5.4, 10.3 Hz, CHHI), 3.18 (1H, dd, 7.8, 10.3 Hz,

CHHI), 2.96 (1H, m, H-2), 2.73 (1H, dd, 1.8, 14.0 Hz, H-3),

2.04 (1H, dd, 12.4, 14.0 Hz, H-3). ¹³C NMR (CDCl₃):

168.44 (acetamido C=O), 166.34 (β-lactam C=O), 164.40

(ester C=O), 164.29 (ester C=O), 157.09, 134.44, 129.81,

129.05, 128.83, 128.65, 122.45, 114.99 (aromatic), 68.60

(CO₂CH₂Ph), 67.33 (PhOCH₂), 65.96 (C-4), 58.88 (C-7),

58.23 (C-6), 53.74 (CO₂CH₃), 38.71 (CH₂I), 37.28 (C-2),

5.98 (C-3). Anal. calcd. for C₂₅H₂₅N₂IO₇S: C 48.09, H 4.04,

N 4.49; found: C 48.41, H 4.02, N 4.29.

1

(KBr) (cm^–1): 3318, 1780, 1748, 1690. H NMR (CDCl₃):

7.32 (3H, t, Ar + NH), 7.03 (1H, t, Ar), 6.93 (2H, d, Ar),

5.82 (1H, dd, 4.6, 9.5 Hz, H-7), 5.39 (1H, d, 4.6 Hz, H-6),

4.54 (2H, s, PhOCH₂), 3.86 (3H, s, CH₃), 3.85 (3H, s, CH₃),

3.28 (1H, dd, 5.4, 10.3 Hz, CHHI), 3.18 (1H, dd, 8.0,

10.3 Hz, CHHI), 2.95 (1H, m, H-2), 2.74 (1H, dd, 1.9,

14.1 Hz, H-3), 2.03 (1H, dd, 12.2, 14.1 Hz, H-3). Anal.

calcd. for C₁₉H₂₁IN₂O₇S: C 41.62, H 3.86, N 5.11; found: C

41.81, H 3.86, N 5.02.

Conversion of the allylated dibenzyl ester to 20 (R₁=

R₂= CH₂Ph)

Iodine (1.35 g, 5.3 mmol) was added in three portions

over 30 min to a biphasic solution of the dibenzyl ester

(2.8 g, 5.0 mmol) in dichloromethane (70 mL) and water

(35 mL). The mixture was stirred for 3 h, additional di-

chloromethane (98 mL) was added, and the organic layer

was then separated and washed successively with saturated

sodium bicarbonate (200 mL), 0.01 M sodium sulfite

(200 mL), water (200 mL), and saturated sodium chloride

(200 mL), dried over magnesium sulfate, and evaporated.

Chromatography using ethyl acetate – hexanes (1:1) gave

2.63 g (74%) of the iodomethylcepham as a yellow foam.

[α]²_D⁰+162.5° (c 0.39, CHCl₃). Mass spectrum (CI, m/z): 439

((M+1)-I-CO₂CH₂Ph). IR (KBr) (cm^–1): 3318, 1780, 1746,

Synthesis of 21 (R₁= R₂= Me)

A solution of the iodomethylcepham (3.24 g, 5.91 mmol)

in methanol (250 mL) was treated dropwise with stirring,

during 15 min, with a solution of sodium periodate (1.34 g,

6.27 mmol) in methanol (28 mL) and water (28 mL). When

the addition was complete, the mixture was heated to 35°C,

and stirring was continued for 2.0 h. A white precipitate was

removed by filtration, and washed with ethyl acetate

(200 mL). The combined filtrates were washed successively

with water (200 mL) and saturated sodium chloride

(200 mL), dried over magnesium sulfate, and evaporated

to give a brown foam. Column chromatography using ethyl

acetate – hexanes (2:3) gave the sulfoxide as a pale yellow

foam (1.19 g, 36%). Mass spectrum (CI, m/z): 437 ((M+1)-

1

1688. H NMR (CDCl₃): 7.34–7.23 (13H, m, Ar + NH),

7.03 (1H, t, Ar), 6.94 (2H, d, Ar), 5.82 (1H, dd, 4.6, 9.6 Hz,

H-7), 5.40 (1H, d, 4.6 Hz, H-6), 5.27 (1H, d, 12.0 Hz,

benzyl CHH), 5.20 (1H, d, 11.9 Hz, benzyl CHH), 5.17 (1H,

d, 12.0 Hz, benzyl CHH), 5.09 (1H, d, 11.9 Hz, benzyl

CHH), 4.53 (2H, s, PhOCH₂), 3.20 (1H, dd, 5.3, 10.2 Hz,

CHHI), 3.08 (1H, dd, 8.1, 10.2 Hz, CHHI), 2.84 (1H, m,

shows nOe with H-6 at 5.40 ppm, H-2), 2.71 (1H, dd, 1.9,

14.1 Hz, H-3), 2.03 (1H, dd, 12.3, 14.1 Hz, H-3). ¹³C NMR

(CDCl₃): 168.42 (acetamido C=O), 166.33 (β-lactam C=O),

164.36 (ester C=O), 163.86 (ester C=O), 157.09, 134.46,

134.32, 129.82, 128.97, 128.80, 128.62, 128.56, 122.45,

114.99 (aromatic), 69.05, 68.58 (CO₂CH₂Ph), 67.33

(PhOCH₂), 66.16 (C-4), 58.88 (C-7), 58.28 (C-6), 38.72

1

I). H NMR (CDCl₃): 8.05 (1H, d, 10.6 Hz, NH), 7.30 (2H,

t, Ar), 7.01 (1H, t, Ar), 6.93 (2H, d, Ar), 6.12 (1H, dd, 4.8,

10.6 Hz, H-7), 4.85 (1H, d, 4.7 Hz, H-6), 4.55 (2H, s,

PhOCH₂), 3.89 (3H, s, CH₃), 3.86 (3H, s, CH₃), 3.46 (1H,

dd, 7.2, 10.7 Hz, CHHI), 3.26 (1H, dd, 8.0, 10.7 Hz, CHHI),

2.86 (1H, dd, 12.7, 14.7 Hz, H-3), 2.68 (1H, m, H-2), 2.30

(1H, dd, 2.0, 14.7 Hz, H-3).

1252

Can. J. Chem. Vol. 79, 2001

(814 mg, 1.44 mmol) in dichloromethane (30 mL). The solu-

tion was stirred for 1.0 h, and then washed successively with

0.5 M hydrochloric acid (50 mL) and water (50 mL), dried

over sodium sulfate, and evaporated. Purification by column

chromatography using ethyl acetate – hexanes (3:2) gave the

exomethylene compound as a white foam (226 mg, 36%).

[α]²_D⁰+136.8° (c 0.095, CHCl₃). Mass spectrum (CI, m/z):

Synthesis of 21 (R₁= R₂= CH₂Ph)

A solution of sodium periodate (44.0 mg, 0.21 mmol) in

50% methanol (0.7 mL) was added dropwise at 55°C to a

solution of the iodomethylcepham (113.6 mg, 0.16 mmol) in

methanol (7 mL). When the addition was complete, more

50% methanol (2 mL) was added, and the solution was

stirred at 60°C for 2 h and then diluted with water (20 mL).

Extraction with dichloromethane (4 × 10 mL), drying over

magnesium sulfate and evaporation, followed by column

chromatography using ethyl acetate – hexanes (1:1) yielded

the β-sulfoxide (53.7 mg, 62%). Mass spectrum (CI, m/z):

455 ((M+1)-I-CO₂CH₂Ph). IR (KBr) (cm^–1): 3381, 1788,

1

437 (M+1). IR (KBr) (cm^–1): 3370, 1786, 1750, 1694. H

NMR (CDCl₃): 8.21 (1H, d, 10.8 Hz, NH), 7.30 (2H, t, Ar),

7.01 (1H, t, Ar), 6.93 (2H, d, Ar), 6.05 (1H, dd, 4.7,

10.8 Hz, H-7), 5.93 (1H, s, CH=CHH), 5.65 (1H, s,

CH=CHH), 4.80 (1H, d, 4.7 Hz, H-6), 4.55 (2H, s,

PhOCH₂), 3.90 (3H, s, CH₃), 3.88 (1H, d, 14.3 Hz, H-3),

3.82 (3H, s, CH₃), 2.75 (1H, d, 14.3 Hz, H-3). ¹³C NMR

(CDCl₃): 168.56 (acetamido C=O), 166.29 (β-lactam C=O),

164.00 (ester C=O), 163.58 (ester C=O), 157.23, 129.69,

122.19, 114.93 (aromatic), 144.42 (C-2), 122.64 (C=CH₂),

71.40 (C-6), 67.21 (PhOCH₂), 66.60 (C-4), 59.34 (C-7),

54.06 (CO₂CH₃), 53.63 (CO₂CH₃), 27.59 (C-3). Anal. calcd.

for C₁₉H₂₀N₂O₈S·H₂O: C 50.22, H 4.88, N 6.16; found: C

49.91, H 4.86, N 5.87.

1

1746, 1692, 1082. H NMR (CDCl₃): 8.07 (1H, d, 10.5 Hz,

NH), 7.34–7.23 (12H, m, Ar), 7.03 (1H, t, Ar), 6.92 (2H, d,

Ar), 6.11 (1H, dd, 4.8, 10.5 Hz, H-7), 5.29 (1H, d, 12.0 Hz,

benzyl CHH), 5.21 (1H, d, 11.8 Hz, benzyl CHH), 5.19 (1H,

d, 12.0 Hz, benzyl CHH), 5.11 (1H, d, 11.8 Hz, benzyl

CHH), 4.85 (1H, d, 4.8 Hz, H-6), 4.54 (2H, s, PhOCH₂),

3.38 (1H, dd, 7.6, 10.7 Hz, CHHI), 3.16 (1H, dd, 7.9,

10.7 Hz, CHHI), 2.84 (1H, dd, 12.7, 14.7 Hz, β-H-3), 2.52

(1H, m, H-2), 2.23 (1H, dd, 1.8, 14.7 Hz, α-H-3). ¹³C NMR

(CDCl₃): 168.65 (acetamido C=O), 166.30 (β-lactam C=O),

163.95 (ester C=O), 162.97 (ester C=O), 157.18, 134.38,

134.21, 129.91, 129.80, 129.72, 129.17, 128.90, 128.74,

128.66, 128.63, 128.58, 128.49, 128.36, 122.38, 122.28,

115.00, 114.92 (aromatic), 69.31 (CO₂CH₂Ph), 69.26 (C-6)

68.85 (CO₂CH₂Ph), 67.23 (PhOCH₂), 65.21 (C-4), 58.97

(C-7), 55.36 (C-2), 24.96 (CHCH₂I), 1.16 (C-3).

Dehydroiodination of 21 (R₁= R₂= CH₂Ph)

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.40 mL, 0.41 g,

2.7 mmol) was added dropwise to a solution of the sulfoxide

(0.44 g, 0.61 mmol) in dichloromethane (20 mL). The solu-

tion was stirred for 40 min and 0.5 M hydrochloric acid

(20 mL) was then added. The organic layer was separated

and washed successively with water (20 mL), saturated so-

dium bicarbonate (20 mL), and saturated sodium chloride

(20 mL), dried over magnesium sulfate, and evaporated.

Chromatography using ethyl acetate – hexanes (1:1) gave

0.19 g (52%) of the product as a white foam, mp 55–57°C.

[α]²_D⁰+166.7° (c 0.072, CHCl₃). Mass spectrum (CI, m/z):

454 ((M+1)-CO₂CH₂Ph). IR (KBr) (cm^–1): 3362, 1788,

Synthesis of 21 (R₁= Me, R₂= CH₂Ph)

A solution of the mixed iodomethylcephams (2.83 g,

4.71 mmol) in methanol (200 mL) was treated, during

15 min, with a solution of sodium periodate (1.32 g,

6.17 mmol) in 50% methanol (46 mL). The reaction mixture

was heated to 35°C and stirred for 2.5 h. A white precipitate

was then removed by filtration and washed with ethyl ace-

tate (200 mL). The filtrate was washed successively with

water (200 mL) and saturated sodium chloride (200 mL),

dried over magnesium sulfate, and evaporated to give a

brown foam. Column chromatography using ethyl acetate –

hexanes (1:1) yielded the mixed sulfoxides as a pale yellow

foam (1.52 g, 52%). Mass spectrum (CI, m/z): 378 ((M+1)-

(I+CO₂CH₂Ph)). IR (CHCl₃) (cm^–1): 3364, 1782, 1748,

1

1748, 1694, 1044. H NMR (CDCl₃): 8.23 (1H, d, 10.6 Hz,

NH), 7.35–7.23 (12H, m, Ar), 7.00 (1H, t, Ar), 6.92 (2H, d,

Ar), 6.03 (1H, dd, 4.7, 10.6 Hz, H-7), 5.71 (1H, s, =CHH),

5.31 (1H, d, 12.0 Hz, benzyl CHH), 5.24 (1H, s, benzyl

CHH), 5.21 (1H, s, benzyl CHH), 5.12 (1H, s, =CHH), 5.03

(1H, d, 12.0 Hz, benzyl CHH), 4.81 (1H, d, 4.7 Hz, H-6),

3.84 (1H, d, 14.2 Hz, H-3), 2.66 (1H, d, 14.2 Hz, H-3). ¹³C

NMR (CDCl₃): 168.54 (acetamido C=O), 165.54 (β-lactam

C=O), 164.18 (ester C=O), 163.00 (ester, C=O), 157.24,

134.43, 129.69, 129.12, 128.88, 128.80, 128.68, 128.65,

128.58, 122.18, 114.94 (aromatic), 143.87 (C-2), 122.77

(=CH₂), 71.33 (C-6), 69.24 (CO₂CH₂Ph), 68.52

(CO₂CH₂Ph), 67.21 (PhOCH₂), 66.52 (C-4), 59.28 (C-7),

27.49 (C-3). Anal. calcd. for C₃₁H₂₈N₂O₈S: C 62.91, H 4.98,

N 5.10; found: C 63.25, H 4.79, N 4.76.

1

1692. H NMR (CDCl₃): isomer A: 8.04 (1H, d, 10.6 Hz,

NH), 7.40–7.26 (7H, m, Ar), 7.00 (1H, t, Ar), 6.92 (2H, d,

Ar), 6.10 (1H, dd, 4.8, 10.6 Hz, H-7), 5.26 (2H, s, PhCH₂),

4.81 (1H, d, 4.8 Hz, H-6), 4.54 (2H, s, PhOCH₂), 3.81 (3H,

s, CH₃), 3.36 (1H, dd, 7.7, 10.7 Hz, CHHI), 3.11 (1H, dd,

7.8, 10.7 Hz, CHHI), 2.81 (1H, dd, 12.7, 14.8 Hz, H-3), 2.22

(1H, dd, 2.0, 14.8 Hz, H3), 2.48 (1H, m, H-2). Isomer B:

8.08 (1H, d, 10.6 Hz, NH), 7.40–7.26 (7H, m, Ar), 7.00 (1H,

t, Ar), 6.92 (2H, d, Ar), 6.13 (1H, dd, 4.8, 10.6 Hz, H-7),

5.30 (1H, d, 11.9 Hz, PhCHH), 5.23 (1H, d, 11.9 Hz,

PhCHH), 4.87 (1H, d, 4.8 Hz, H-6), 4.54 (2H, s, PhOCH₂),

3.76 (3H, s, CH₃), 3.46 (1H, dd, 7.4, 10.7 Hz, CHHI), 3.26

(1H, dd, 8.0, 10.7 Hz, CHHI), 2.87 (1H, dd, 12.7, 14.1 Hz,

H-3), 2.28 (1H, dd, 1.8, 14.7 Hz, H-3), 2.69 (1H, m, H-2).

Dehydroiodination of 21 (R₁= Me, R₂= CH₂Ph)

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.4 mL, 0.41 g,

2.67 mmol) was added to a solution of the mixed sulfoxides

(1.27 mg, 2.07 mmol) in dichloromethane (42 mL). The so-

lution was stirred for 1.5 h and then washed successively

with 0.5 M hydrochloric acid (50 mL) and water (50 mL),

dried over sodium sulfate, and evaporated. Purification by

column chromatography using ethyl acetate – hexanes (1:1)

afforded two compounds (514 mg, 49%): epimer B (R_f0.25,

Dehydroiodination of 21 (R₁= R₂= Me)

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.26 mL, 0.27 g,

1.74 mmol) was added to a solution of the sulfoxide

Wolfe et al.

1253

308 mg) and epimer A (R_f0.14, 207 mg). Epimer A: [α]_D²⁰

exomethylene sulfoxide (0.14 g, 0.24 mmol) in

dimethylformamide (5.4 mL). Stirring was continued for 1 h

and the mixture was then poured onto ice (60 g) and ex-

tracted with ethyl acetate (3 × 40 mL). The organic extract

was washed successively with water (4 × 40 mL) and satu-

rated sodium chloride (100 mL), dried over anhydrous so-

dium sulfate, and evaporated to give the product as a yellow

foam. Chromatography on Brockmann neutral alumina (40–

200 mm mesh) and elution with ethyl acetate – hexanes

(1:1) gave a white foam (0.13 g, 97%). [α]²_D⁰+206.1° (c

0.165, CHCl₃). IR (KBr) (cm^–1): 3414, 1783, 1747, 1690. ¹H

NMR (CDCl₃): 7.40 (1H, d, 9.5 Hz, NH), 7.34–7.24 (12H,

m, Ar), 7.03 (1H, t, Ar), 6.93 (2H, d, Ar), 5.74 (1H, dd, 4.4,

9.5 Hz, H-7), 5.41 (1H, d, 4.4 Hz, H-6), 5.37 (1H, s,

=CHH), 5.27 (1H, d, 12.0 Hz, benzyl CHH), 5.20 (1H,

7.6 Hz, benzyl CHH), 5.18 (1H, d, 7.6 Hz, benzyl CHH),

5.09 (1H, d, 12.0 Hz, benzyl CHH), 5.15 (1H, s, =CHH),

4.54 (2H, s, PhOCH₂), 3.01 (1H, d, 14.0 Hz, H-3), 2.97 (1H,

dt, 0.5, 14.0 Hz, H-3). ¹³C NMR (CDCl₃): 168.40

(acetamido C=O), 165.68 (β-lactam C=O), 164.74 (ester

C=O), 164.08 (ester C=O), 157.13, 134.52, 129.80, 128.82,

128.67, 128.60, 128.54, 122.44, 115.00 (aromatic), 132.25

(C-2), 121.46 (=CH₂), 68.93 (CO₂CH₂Ph), 68.31

(CO₂CH₂Ph), 67.40 (PhOCH₂), 66.68 (C-4), 58.91 (C-7),

+123.8° (c 0.84, CHCl₃). IR (KBr) (cm^–1): 3363, 1789,

1

1749, 1695. H NMR (CDCl₃): 8.21 (1H, d, 10.6 Hz, NH),

7.39–7.27 (7H, m, Ar), 7.00 (1H, t, Ar), 6.94 (2H, d, Ar),

6.02 (1H, dd, 4.7, 10.6 Hz, H-7), 5.70 (1H, s, C=CHH), 5.29

(1H, d, 11.7 Hz, PhCHH), 5.17 (1H, d, 11.7 Hz, PhCHH),

5.10 (1H, br s, C=CHH), 4.78 (1H, d, 4.7 Hz, H-6), 4.54

(2H, s, PhOCH₂), 3.85 (3H, s, CH₃), 3.83 (1H, br d,

14.2 Hz, H-3), 2.74 (1H, d, 14.2 Hz, H-3). ¹³C NMR

(CDCl₃): 168.57 (acetamido C=O), 166.20 (β-lactam C=O),

164.08 (ester C=O), 162.95 (C=O), 157.24, 134.48, 129.70,

129.02, 128.66, 128.57, 122.19, 114.94 (aromatic), 144.34

(C-2), 122.74 (C=CH₂), 71.40 (C6), 69.17 (CO₂CH₂Ph),

67.21 (PhOCH₂), 66.78 (C-4), 59.34 (C-7), 53.50 (CO₂CH₃),

27.57 (C-3). Anal. calcd. for C₂₅H₂₄N₂O₈S: C 58.59, H 4.72,

N 5.47; found: C 58.44, H 4.77, N 5.17. Epimer B: [α]_D²⁰

+122.7° (c 0.073, CHCl₃). IR (KBr) (cm^–1): 3364, 1786,

1

1750, 1694. H NMR (CDCl₃): 8.24 (1H, d, 10.6 Hz, NH),

7.37–7.26 (7H, m, Ar), 7.01 (1H, t, Ar), 6.94 (2H, d, Ar),

6.06 (1H, dd, 4.6, 10.6 Hz, H-7), 5.92 (1H, s, C=CHH), 5.64

(1H, br s, C=CHH), 5.40 (1H, d, 12.0 Hz, PhCHH), 5.22

(1H, d, 12.0 Hz, PhCHH), 4.83 (1H, d, 4.6 Hz, H-6), 4.55

(2H, s, PhOCH₂), 3.89 (1H, br d, 14.3 Hz, H-3), 3.71 (3H, s,

CH₃), 2.74 (1H, d, 14.3 Hz, H-3). ¹³C NMR (CDCl₃):

168.55 (acetamido C=O), 165.58 (β-lactam C=O), 164.09

(ester C=O), 163.55 (C=O), 157.21, 134.52, 129.68, 129.19,

129.00, 128.82, 122.17, 114.91 (aromatic), 143.86 (C-2),

122.69 (C=CH₂), 71.29 (C-6), 68.55 (CO₂CH₂Ph), 67.18

(PhOCH₂), 66.32 (C-4), 59.27 (C-7), 53.93 (CO₂CH₃), 27.41

(C-3). Anal. calcd. for C₂₅H₂₄N₂O₈S·0.5H₂O: C 57.57, H

4.86, N 5.37; found: C 57.62, H 4.76, N 5.27.

57.89

(C-6),

39.40

(C-3).

Anal.

calcd.

for

C₃₁H₂₈N₂O₇S·H₂O: C 63.04, H 5.12, N 4.74; found: C

62.89, H 4.96, N 4.99.

Reduction of 22 (R₁= Me, R₂= CH₂Ph) (epimer A)

A solution of the exomethylene sulfoxide (epimer A)

(135 mg, 0.26 mmol) in dimethylformamide (6 mL) was

cooled to 0°C and treated with phosphorus tribromide

(53 µL, 151 mg, 0.56 mmol). The solution was stirred for

20 min at 0°C and then poured onto ice (10 g) and extracted

with ethyl acetate (2 × 20 mL). The organic layer was

washed successively with water (3 × 40 mL) and saturated

sodium chloride (40 mL), dried over sodium sulfate, and

evaporated. Purification by chromatography using ethyl ace-

tate – hexanes (1:1) afforded a white foam (120 mg, 79%).

IR (KBr) (cm^–1): 3302, 1786, 1748, 1692. ¹H NMR

(CDCl₃): 7.41 (1H, d, 9.4 Hz, NH), 7.37–7.29 (7H, m, Ar),

7.03 (1H, t, Ar), 6.93 (2H, d, Ar), 5.74 (1H, dd, 4.4, 9.4 Hz,

H-7), 5.43 (1H, s, C=CHH), 5.40 (1H, d, 4.4 Hz, H-6), 5.36

(1H, d, 12.1 Hz, PhCHH), 5.34 (1H, s, C=CHH), 5.18 (1H,

d, 12.1 Hz, PhCHH), 4.54 (2H, s, PhOCH₂), 3.72 (3H, s,

CH₃), 3.02 (1H, d, 14.1 Hz, H-3), 2.99 (1H, d, 14.1 Hz, H-3).

¹³C NMR (CDCl₃): 168.45 (acetamido C=O), 166.31 (β-

lactam C=O), 164.10 (ester C=O), 164.00 (ester C=O),

157.16, 134.62, 129.80, 128.54, 128.63, 128.36, 122.42,

115.02 (aromatic), 132.63 (C-2), 121.00 (C=CH₂), 68.84

(CO₂CH₂Ph), 67.41 (PhOCH₂), 66.77 (C-4), 58.95 (C-7),

57.87 (C-6), 53.31 (C-3), 39.40 (C-3). Anal. calcd. for

C₂₅H₂₄N₂O₇S: C 60.47, H 4.87, N 5.64; found: C 60.50, H

4.84, N 5.50.

Reduction of 22 (R₁= R₂= Me)

A solution of the sulfoxide (175 mg, 0.40 mmol) in

dimethylformamide (10 mL) was cooled to 0°C, and treated

with phosphorus tribromide (75 µL, 114 mg, 0.42 mmol).

The reaction mixture was stirred for 30 min at 0°C, poured

onto ice (20 g), and extracted with ethyl acetate (2 ×

20 mL). The organic layer was washed successively with

water (2 × 40 mL) and saturated sodium chloride (40 mL),

dried over anhydrous sodium sulfate, and evaporated. Chro-

matography using ethyl acetate – hexanes (1:1) afforded the

exomethylene cepham as a white foam (171 mg, 95%). [α]_D²⁰

+305.9° (c 0.085, CHCl₃). IR (KBr) (cm^–1): 3370, 1782,

1

1751, 1688. H NMR (CDCl₃): 7.41 (1H, d, 9.3 Hz, NH),

7.33 (2H, t, Ar), 7.04 (1H, t, Ar), 6.94 (2H, d, Ar), 5.75 (1H,

dd, 4.4, 9.3 Hz, H-7), 5.48 (1H, d, 0.9 Hz, C=CHH), 5.41

(1H, d, 4.4 Hz, H-6), 5.41 (1H, d, 0.9 Hz, C=CHH), 4.55

(2H, s, PhOCH₂), 3.87 (3H, s, CH₃), 3.82 (3H, s, CH₃), 3.03

(1H, d, 14.0 Hz, H-3), 2.99 (1H, dt, 0.9, 14.0 Hz, H-3). ¹³C

NMR (CDCl₃): 168.49 (acetamido C=O), 166.39 (β-lactam

C=O), 164.74 (esters C=O), 157.12, 129.79, 122.37, 114.94

(aromatic), 132.58 (C2), 121.39 (C=CH₂), 67.31 (PhOCH₂),

66.54 (C-4), 58.92 (C-7), 57.91 (C-6), 53.86 (CO₂CH₃),

53.50 (CO₂CH₃), 39.46 (C-3). Anal. calcd. for

C₁₉H₂₀N₂O₇S·0.25H₂O: C 53.70, H 4.86, N 6.59; found: C

53.63, H 5.08, N 6.70.

Reduction of 22 (R₁= Me, R₂= CH₂Ph) (epimer B)

A solution of the exomethylene sulfoxide (epimer B)

(135 mg, 0.26 mmol) in dimethylformamide (6 mL) was

cooled to 0°C and treated with phosphorus tribromide

(53 µL, 151 mg, 0.56 mmol). The solution was stirred for

20 min at 0°C and then poured onto ice (10 g) and extracted

Reduction of 22 (R₁= R₂= CH₂Ph)

Phosphorus tribromide (0.046 mL, 0.13 g, 0.48 mmol)

was added, with stirring, at 0°C to a solution of the

1254

Can. J. Chem. Vol. 79, 2001

with ethyl acetate (2 × 20 mL). The organic layer was

washed successively with water (3 × 40 mL) and saturated

sodium chloride (40 mL), dried over anhydrous sodium sul-

fate, and evaporated. Purification by chromatography using

ethyl acetate – hexanes (1:1) afforded a white foam

(115 mg, 76%). Mass spectrum (CI, m/z): 362 ((M+1)-

134.56, 129.82, 128.65, 128.53, 128.10, 122.44, 114.96 (aro-

matic), 132.91 (C-2), 110.48 (C-3), 68.99 (CO₂CH₂Ph), 68.36

(CO₂CH₂Ph), 67.32 (PhOCH₂), 64.66 (C-4), 59.44 (C-7),

56.26 (C-6), 24.30 (CH₃). Anal. calcd. for C₃₁H₂₈N₂O₇S: C

64.71, H 5.01, N 5.35; found: C 65.02, H 4.93, N 4.89.

1

CO₂CH₂Ph). IR (KBr) (cm^–1): 3333, 1782, 1750, 1690. H

Isomerization of 23 (R₁= Me, R₂= CH₂Ph) (isomer A)

A solution of the exomethylenecepham (isomer A)

(77 mg, 0.13 mmol) in dichloromethane (5 mL) was cooled

to 0°C, treated with trifluoroacetic acid (1.7 mL, 2.52 g,

22.1 mmol), stirred for 45 min, and then evaporated to dry-

ness. Column chromatography using ethyl acetate – hexanes

(1:1) gave a white foam (63 mg, 88%). [α]²_D⁰+227.6° (c

0.145, CHCl₃). IR (KBr) (cm^–1): 3422, 1788, 1748, 1692,

NMR (CDCl₃): 7.39 (1H, d, 9.4 Hz, NH), 7.38–7.29 (7H, m,

Ar), 7.03 (1H, t, Ar), 6.93 (2H, d, Ar), 5.72 (1H, dd, 4.4,

9.4 Hz, H-7), 5.39 (1H, d, 4.4 Hz, H-6), 5.38 (1H, d, 0.8 Hz,

C=CHH), 5.23 (1H, d, 12.0 Hz, PhCHH), 5.22 (1H, d,

12.0 Hz, PhCHH), 5.17 (1H, d, 0.8 Hz, C=CHH), 4.53 (2H,

s, PhOCH₂), 3.79 (3H, s, CH₃), 2.99 (1H, d, 14.0 Hz, H-3),

2.95 (1H, dt, 0.8, 14.0 Hz, H-3). ¹³C NMR (CDCl₃): 168.43

(acetamido C=O), 165.73 (β-lactam C=O), 164.75 (ester

C=O), 164.65 (ester C=O), 157.15, 134.58, 129.80, 128.90,

128.70, 128.62, 122.41, 114.99 (aromatic), 132.23 (C-2),

121.71 (C=CH₂), 68.34 (CO₂CH₂Ph), 67.39 (PhOCH₂), 66.49

(C-4), 58.95 (C-7), 57.93 (C-6), 53.70 (CO₂CH₃), 39.36 (C-

3). Anal. calcd. for C₂₅H₂₄N₂O₇S: C 60.47, H 4.87, N 5.64;

found: C 60.47, H 4.87, N 5.39.

1

1686. H NMR (CDCl₃): 7.39–7.30 (8H, m, Ar + NH), 7.04

(1H, t, Ar), 6.94 (2H, d, Ar), 5.86 (1H, q, 1.3 Hz, H-3), 5.77

(1H, dd, 4.2, 9.1 Hz, H-7), 5.34 (1H, d, 16.4 Hz, PhCHH),

5.31 (1H, d, 4.2 Hz, H-6), 5.14 (1H, d, 16.4 Hz, PhCHH),

4.56 (2H, s, PhOCH₂), 3.74 (3H, s, CH₃), 1.99 (3H, d,

1.2 Hz, CH₃). ¹³C NMR (CDCl₃): 168.64 (acetamido C=O),

165.66 (β-lactam C=O), 164.57 (ester C=O), 163.64 (ester

C=O), 157.10, 134.68, 129.82, 128.68, 128.15, 122.45,

114.96 (aromatic), 68.33 (CO₂CH₂Ph), 67.31 (PhOCH₂),

64.51 (C-4), 59.48 (C-7), 56.15 (C-6), 53.75 (CO₂CH₃),

24.31 (CH₃). Anal. calcd. for C₂₅H₂₄N₂O₇S: C 60.47, H

4.87, N 5.64; found: C 60.21, H 4.73, N 5.78.

Isomerization of 23 (R₁= R₂= Me)

The exomethylenecepham (150 mg, 0.36 mmol) was dis-

solved in dichloromethane (5 mL), the solution was cooled

to 0°C, and trifluoroacetic acid (4.0 mL, 2.70 g, 51.9 mmol)

was added with stirring. Stirring was continued for 45 min at

0°C, and the solvent was then removed under reduced pres-

sure. Column chromatography using ethyl acetate – hexanes

(1:1) gave the 2-methyl-∆²-cephem as a white foam

(122 mg, 81%). [α]²_D⁰+187.5° (c 0.08, CHCl₃). IR (KBr)

Isomerization of 23 (R₁= Me, R₂= CH₂Ph) (isomer B)

The exomethylenecepham (isomer B) (46 mg, 0.08 mmol)

was dissolved in dichloromethane (5 mL), and the solution

was cooled to 0°C and treated with trifluoroacetic acid

(1.0 mL, 1.48 g, 13.0 mmol). The solution was stirred at 0°C

for 45 min, and then evaporated. Purification by column

chromatography using ethyl acetate – hexanes (1:1) gave a

white foam (42 mg, 91%). [α]²_D⁰+253.9° (c 0.086, CHCl₃).

IR (KBr) (cm^–1): 3412, 1788, 1748, 1692. ¹H NMR

(CDCl₃): 7.38–7.30 (8H, m, Ar + NH), 7.04 (1H, t, Ar), 6.93

(2H, d, Ar), 5.87 (1H, q, 1.3 Hz, H-3), 5.79 (1H, dd, 4.1,

9.0 Hz, H-7), 5.35 (1H, d, 12.1 Hz, PhCHH), 5.33 (1H, d,

4.1 Hz, H-6), 5.20 (1H, d, 12.1 Hz, PhCHH), 4.56 (2H, s,

PhOCH₂), 3.74 (3H, s, CH₃), 2.00 (3H, d, 1.2 Hz, CH₃). ¹³C

NMR (CDCl₃): 168.27 (acetamido C=O), 166.01 (β-lactam

C=O), 163.73 (ester C=O), 163.45 (ester C=O), 156.86,

134.44, 129.55, 128.28, 128.10, 122.18, 114.72 (aromatic),

132.55 (C-2), 110.35 (C-3), 68.60 (CO₂CH₂Ph), 67.09

(PhOCH₂), 64.33 (C-4), 59.19 (C-7), 55.99 (C-6), 53.13

(CO₂CH₃), 24.06 (CH₃). Anal. calcd. for C₂₅H₂₄N₂O₇S: C

60.47, H 4.87, N 5.64; found: C 59.92, H 4.96, N 5.69.

1

(cm^–1): 3306, 1786, 1748, 1688. H NMR (CDCl₃): 7.39

(1H, d, 9.0 Hz, NH), 7.32 (2H, t, Ar), 7.04 (1H, t, Ar), 6.94

(2H, d, Ar), 5.85 (1H, q, 1.4 Hz, H-3), 5.79 (1H, dd, 4.2,

9.0 Hz, H-7), 5.31 (1H, d, 4.2 Hz, H-6), 4.57 (2H, s,

PhOCH₂), 3.86 (3H, s, CH₃), 3.83 (3H, s, CH₃), 2.01 (3H, d,

1.4 Hz, CH₃). ¹³C NMR (CDCl₃): 168.70 (acetamido C=O),

166.39 (β-lactam C=O), 164.68 (ester C=O), 163.59 (ester

C=O), 157.13, 129.82, 122.45, 114.98 (aromatic), 132.58

(C-2), 110.65 (C-3), 67.34 (PhOCH₂), 64.40 (C4), 59.49 (C-

7), 56.13 (C-6), 53.90 (CO₂CH₃), 53.54 (CO₂CH₃), 24.34

(CH₃). Anal. calcd. for C₁₉H₂₀N₂O₇S: C 54.28, H 4.79, N

6.66; found: C 54.33, H 4.87, N 6.77.

Isomerization of 23 (R₁= R₂= CH₂Ph)

Trifluoroacetic acid (3 mL) was added dropwise, with stir-

ring at 0°C, to a solution of the exomethylene cepham

(0.13 g, 0.23 mmol) in dichloromethane (3 mL). The solu-

tion was stirred for 40 min and then evaporated to afford the

2-methyl-∆²-cephem (0.13 g, 100%) as a yellow foam. [α]²_D⁰

+227.8° (c 0.18, CHCl₃). Mass spectrum (CI, m/z): 439

((M+1)-(CO₂CH₂Ph)). IR (CHCl₃) (cm^–1): 3418, 1788,

Diazotization of dibenzyl malonate (30)

Anhydrous potassium carbonate (6.58 g, 47.6 mmol) was

added to

a solution of dibenzyl malonate (4.50 g,

1

1748, 1696. H NMR (CDCl₃): 7.35–7.22 (13H, m, Ar +

15.8 mmol) in acetone (45 mL). The mixture was stirred for

15 min, cooled to 0°C, and a solution of benzenediazonium

chloride, prepared by addition of a solution of sodium nitrite

(1.10 g, 16 mmol) in water (13.2 mL) to a solution of aniline

hydrochloride (2.07 g, 16.0 mmol) in 1.0 M hydrochloric

acid (16.2 mL), was added dropwise. The ice bath was re-

moved and stirring was continued at room temperature for

10 min. The reaction mixture was then poured onto crushed

NH), 7.04 (1H, t, Ar), 6.93 (2H, d, Ar), 5.87 (1H, 1.3 Hz, H-

3), 5.78 (1H, q, 4.2, 9.1 Hz, H-7), 5.33 (1H, d, 4.2 Hz, H-6),

5.24 (1H, d, 12.2 Hz, benzyl CHH), 5.21 (1H, d, 12.3 Hz,

benzyl CHH), 5.18 (1H, d, 12.2 Hz, benzyl CHH), 5.11 (1H,

d, 12.3 Hz, benzyl CHH), 1.99 (3H, d, 1.3 Hz, CH₃). ¹³C

NMR (CDCl₃): 168.50 (acetamido C=O), 165.63 (β-lactam

C=O), 163.99 (ester C=O), 163.75 (ester C=O), 157.10,

Wolfe et al.

1255

ice and extracted with ethyl acetate (3 × 100 mL), dried over

magnesium sulfate, and evaporated to afford a red oil which

slowly solidified in the freezer. Trituration with anhydrous

methanol produced yellow needles (5.21 g, 85%), mp 47–

49°C. Mass spectrum (CI, m/z): 389 (M+1). IR (KBr) (cm^–1):

1726, 1530. ¹H NMR (CDCl₃): 7.42–7.13 (15H, m, Ar),

5.34 (2H, s, benzyl CH₂), 5.33 (2H, s, benzyl CH₂), 3.48

(1H, s, NH). ¹³C NMR (CDCl₃): 163.17 (ester C=O), 163.04

(ester C=O), 141.80–115.73 (aromatic), 66.74 (CO₂CH₂Ph).

Anal. calcd. for C₂₃H₂₀N₂O₄: C 71.12, H 5.19, N 7.21;

found: C 71.17, H 4.97, N 7.10.

Hydrolysis of 19

A

A solution of 19 (79 mg, 0.19 mmol) in pyridine (12 mL)

was cooled to –8°C and 0.99 M potassium hydroxide

(0.4 mL, 22.2 mg, 0.40 mmol, 2.1 mol equiv) was added,

with stirring. Stirring was continued for 2.5 h, and the sol-

vent was then removed under reduced pressure. The residue

was dissolved in water (20 mL) and the solution was ex-

tracted with ethyl acetate (2 × 20 mL). The organic layer

was dried and evaporated to give unreacted diester (4 mg).

The aqueous layer was acidified to pH 4 with 0.1 N hydro-

chloric acid and extracted with ethyl acetate (2 × 10 mL).

The extract was dried over anhydrous sodium sulfate and

evaporated to give a 7:1 mixture (by ¹H NMR) of 4-carboxy-

∆²- and 4-carboxy-∆³-cephems.

Dibenzyl acetamidomalonate

Zinc dust (7.23 g, 110.6 mg-atoms) was added to a solu-

tion of the diazo compound (6.50 g, 16.7 mmol) in acetic

anhydride (29.0 mL, 31.4 g, 307.4 mmol) and glacial acetic

acid (116 mL). The mixture was stirred at room temperature

for 1 h, at 40°C for 20 min, and then filtered. The insoluble

material was rinsed with glacial acetic acid (10 mL) and the

combined filtrates were treated with water to the cloud point.

The product was allowed to crystallize, collected, and

recrystallized from absolute ethanol to give dibenzyl

acetamidomalonate (1.97 g, 35%) as white needles, mp 107–

109°C. Mass spectrum (CI, m/z): 342 (M+1). IR (KBr) (cm^–1):

1

∆²-Cephem: H NMR (acetone-d₆): 8.17 (1H, d, 8.7 Hz,

NH), 7.30 (2H,m, Ar), 7.00 (3H, m, Ar), 6.50 (1H, dd, 2.5,

10.4 Hz, H-2), 5.97 4.1 Hz, H-6), 4.94 (1H, d, 2.5, 4.4 Hz,

H-4), 4.64 (2H, s, PhOCH₂).

1

∆³-Cephem: H NMR (acetone-d₆): 8.00 (1H, d, 9.2 Hz,

NH), 7.28 (2H, m, Ar), 6.94 (3H, m, Ar), 6.58 (1H, dd, 2.6,

6.4 Hz, H-3), 5.94 (1H, dd, 4.9, 9.2 Hz, H-7), 5.15 (1H, d,

4.9 Hz, H-6), 4.70 (2H, s, PhOCH₂), 3.65(1H, dd, 2.6,

19.1 Hz, SCHH), 3.51 (1H, dd, 6.4, 19.1 Hz, SCHH).

A solution of the mixed 4-carboxy-∆²- and 4-carboxy-∆³-

cephems in dichloromethane (10 mL) was cooled to 0°C and

diazomethane was added, followed after 5 min by one drop

of acetic acid. The solvent was evaporated and the residue

was purified by preparative layer chromatography, using

ethyl acetate – hexanes (1:1), to give a 7:1 mixture of ∆²-

and ∆³-esters (8 mg).

1

3299, 1753, 1657. H NMR (CDCl₃): 7.32 (6H, m, Ar), 7.25

(4H, m, Ar), 6.54 (1H, s, 7.0 Hz, NH), 5.29 (1H, d, 7.0 Hz,

CH), 5.20, 5.16 (4H, ABq, 18.7 Hz, benzyl CH₂), 2.07 (3H,

s, CH₃). ¹³C NMR (CDCl₃): 169.66 (acetyl C=O), 166.17

(ester C=O), 134.72–128.19 (aromatic), 68.18 (CO₂CH₂Ph),

56.55 (CH₃CONHCH), 22.71 (CH₃CO). Anal. calcd. for

C₁₉H₁₉NO₅: C 66.85, H 5.61, N 4.10; found: C 66.65, H

5.59, N 4.25.

Dibenzyl allyl acetamidomalonate

∆²-Ester: Mass spectrum (CI, m/z): 349 (M+1). IR (KBr)

A solution of dibenzyl acetamidomalonate (38.1 mg,

0.112 mmol) in acetone (4.0 mL) was treated with anhy-

drous potassium carbonate (40.5 mg, 0.293 mmol) and so-

dium iodide (23.9 mg, 0.159 mmol). The mixture was stirred

for 10 min, and allyl bromide (0.02 mL, 28.0 g,

0.231 mmol) was added. The mixture was then refluxed,

with stirring, for 19 h, cooled, and ethyl acetate (10 mL) and

water (2 mL) were added. The organic layer was separated,

washed successively with 5% hydrochloric acid (10 mL),

water (10 mL) and saturated sodium chloride (10 mL), dried

over magnesium sulfate, and evaporated to give an oil which

slowly solidified. Crystallization using hot ethyl acetate –

hexanes afforded white needles (30.9 mg, 82%), mp 81 to

82°C. Mass spectrum (CI, m/z): 382 (M+1). IR (KBr) (cm^–1):

1

(cm^–1): 3408, 1784, 1751, 1697. H NMR (CDCl₃): 7.40

(1H, d, 9.2 Hz, NH), 7.32 (2H, t, Ar), 7.04 (1H, t, Ar), 6.93

(2H, d, Ar), 6.32 (1H, dd, 2.5, 10.4 Hz, H-2), 5.87 (1H, dd,

4.3, 10.4 Hz, H-3), 5.81 (1H, dd, 4.2, 9.2 Hz, H-7), 5.23

(1H, d, 4.2 Hz, H-6), 4.95 (1H, dd, 2.5, 4.3 Hz, H-4), 4.5

(2H, s, PhOCH₂). ¹³C NMR (CDCl₃): 168.50 (acetamido

C=O), 167.55 (β-lactam C=O), 164.37 (ester C=O), 156.97,

129.79, 122.40, 114.82 (aromatic), 119.65 (C-2), 113.35 (C-

3), 67.20 (PhOCH₂), 60.03 (C-7), 53.32 (C-6), 53.04

(CO₂CH₃),

49.33

(C-4).

Anal.

calcd.

for

C₁₆H₁₆N₂O₅S·0.25H₂O: C 54.46, H 4.71, N 7.84; found: C

54.21, H 4.90, N 7.44.

1

∆³-Ester: Mass spectrum (CI, m/z): 349 (M+1). H NMR

1

3231, 1744, 1642. H NMR (CDCl₃): 7.30 (6H, m, Ar), 7.24

(CDCl₃): 7.28 (1H, d, 9.4 Hz, NH), 7.31 (2H, t, Ar), 7.04

(1H, t, Ar), 6.93 (2H, d, Ar), 6.56 (1H, dd, 2.5, 6.3 Hz, H-3),

5.97 (1H, dd, 5.0, 9.4 Hz, H-7), 5.00 (1H, d, 5.0 Hz, H-6),

4.57 (2H, s, PhOCH₂), 3.60 (1H, dd, 2.5, 19.2 Hz, SCHH),

3.42 (1H, dd, 6.4, 19.2 Hz, SCHH).

(4H, m, Ar), 6.75 (1H, s, NH), 5.48 (1H, ddt, 7.4, 10.2,

16.9 Hz, =CH), 5.16, 5.10 (4H, ABq, 12.2 Hz, benzyl CH₂),

5.02 (1H, ddt, 1.0, 1.0, 10.2 Hz, =CHH), 4.97 (1H, ddt, 1.0,

1.0, 16.9 Hz, =CHH), 3.10 (2H, ddd, 1.0, 1.0, 7.4 Hz, allyl

CH₂), 2.01 (3H, s, CH₃). ¹³C NMR (CDCl₃): 169.00 (acetyl

C=O), 167.44 (ester C=O), 134.94, 128.57, 128.52, 128.30

(aromatic), 131.08 (CH₂CH=CH₂), 119.96 (CH₂CH=CH₂),

B

A solution of 19 (80 mg, 0.23 mmol) in pyridine (1 mL)

was cooled to –8°C, and 0.99 M potassium hydroxide

(0.2 mL, 0.20 mmol, 0.9 mol equiv) was added, with stir-

ring. Stirring was continued for 2.5 h, and the solvent was

then removed under reduced pressure. The residue was dis-

68.14

(CO₂CH₂Ph),

66.51

(CH₃CONHC),

37.05

(CH₂CH=CH₂), 22.92 (CH₃CONH). Anal. calcd. for

C₂₂H₂₃NO₅: C 69.28, H 6.08, N 3.67; found: C 69.23, H

6.08, N 4.40.

1256

Can. J. Chem. Vol. 79, 2001

solved in water (10 mL) and the solution was extracted with

ethyl acetate (2 × 25 mL). The organic layer was dried and

evaporated to give unreacted diester (3 mg). The aqueous

layer was acidified to pH 4 with 0.1 N hydrochloric acid and

extracted with ethyl acetate (2 × 10 mL). The extract was

dried over sodium sulfat and evaporated to give a 5.4:1 ∆³:∆²

mixture of 4-carboxycephems. A solution of this mixture in

dichloromethane (10 mL) was cooled to 0°C and treated

with diazomethane. After 5 min, one drop of acetic acid was

added, and the solvent was evaporated. The residue was pu-

rified by preparatory layer chromatography, using ethyl ace-

tate – hexanes (1:1), to give a 5.4:1 ∆²:∆³mixture of 4-

methoxycarbonylcephems (7 mg).

(CDCl₃): 168.52 (acetamido C=O), 168.37 (ester C=O),

164.74 (β-lactam C=O), 157.13, 129.82, 122.44, 114.96 (aro-

matic), 130.07 (C-2), 108.68 (C-3), 67.36 (PhOCH₂), 59.97

(C-7), 54.57 (C-6), 52.84 (ester CH₃), 50.07 (C-4), 24.28

(CH₃).

B

To a solution of the dibenzyl ester (26.5 mg, 0.046 mmol)

in 95% ethanol (6.0 mL) and water (3.0 mL) were added so-

dium bicarbonate (8.9 mg, 0.106 mmol) and 10% palladium

on carbon (82.3 mg). The apparatus was flushed thrice with

nitrogen and thrice with hydrogen, and then stirred rapidly

under hydrogen for 25 min. The mixture was filtered

through Celite and the Celite was rinsed with water (3 ×

5 mL). The filtrate was concentrated under reduced pressure

to remove ethanol, and then lyophilized to give a white solid

(16.9 mg). This material, in dimethylformamide (0.2 mL),

was treated with methyl iodide (5.5 µL, 12.5 mg,

0.088 mmol). The mixture was stirred for 2.5 h and then di-

luted with dichloromethane (5 mL), washed successively

with water (3 × 5 mL) and saturated sodium chloride

(5 mL), dried over magnesium sulfate, and evaporated

to give the methyl ester of 2-methyl-∆²-cephem V (3.5 mg,

91%).

C

A solution of 19 (24 mg, 0.06 mmol) in acetonitrile

(4 mL) and water (2 mL) was cooled to –5°C, and treated,

with stirring, with 0.99 M potassium hydroxide (1.2 mL,

6.7 mg, 0.12 mmol). Stirring was continued for 1.5 h, and

the solvent was then evaporated under reduced pressure. The

residue was dissolved in water (20 mL) and the solution was

extracted with ethyl acetate (2 × 20 mL). The organic layer

was dried and evaporated to give unreacted diester (4 mg).

The aqueous layer was acidified to pH 4 with 0.1 N sulfuric

acid and extracted with ethyl acetate (2 × 10 mL). The ex-

tract was dried over sodium sulfate and evaporated to give

the 4-carboxy-∆²-cephem. A solution of this compound in

dichloromethane (10 mL) was cooled to 0°C and treated

with diazomethane. After 5 min, one drop of acetic acid was

added and the solvent was then removed. The residue was

purified by preparatory layer chromatography using ethyl ac-

etate – hexanes (1:1) to give the ∆²-ester (5 mg, 29%).

C

To a solution of the dibenzyl ester (34.3 mg, 0.056 mmol)

in glacial acetic acid (7.5 mL) and water (3.6 mL) was

added 10% palladium on carbon (71.2 mg). The apparatus

was purged in the usual manner and the mixture was stirred

rapidly under hydrogen for 20 min and then centrifuged. The

pellet was suspended in ice-cold 68% acetic acid (5.0 mL)

and centrifuged again. The combined supernatants were

lyophilized, and the white residue, in a mixture of absolute

ethanol (2.0 mL) and dichloromethane (5.0 mL), was treated

with diazomethane. The solution was stirred for 2 h and the

solvent was then removed under reduced pressure. Chroma-

tography of the residue using ethyl acetate – hexanes

(1:1) gave two products, the 4-methoxycarbonyl-∆²-cephem

(R_f0.50, 4.3 mg, 21%) as a white solid, mp 125 to 126°C,

and the 4-methoxycarbonyl-∆²-cepham (R_f0.44, 1.5 mg,

2%) as a colourless film. [α]²_D⁰+160.0° (c 0.050, CHCl₃).

Mass spectrum (CI, m/z): 365 (M+1). HR-MS-CI calcd. for

C₁₇H₂₀N₂O₅S: 365.1171 (M+1); found: 365.1164. IR

Deprotection of 24

A

A solution of the dimethyl ester (19 mg, 0.045 mmol) in

pyridine (0.24 mL) was cooled to 0°C and treated with 1 M

potassium hydroxide (0.048 mL, 1.9 mg, 0.045 mmol, 1 mol

equiv). Stirring was continued for 2.5 h, and the solvent was

then removed under reduced pressure. The residue was dis-

solved in water (20 mL) and this solution was extracted with

ethyl acetate (2 × 20 mL). The organic layer was evaporated

and dried to give unreacted diester (7 mg). The aqueous

layer was acidified to pH 4 with 0.1 N hydrochloric acid and

extracted with ethyl acetate (2 × 10 mL). The extract was

dried over sodium sulfate and evaporated. The residue was

dissolved in dichloromethane (7 mL), cooled to 0°C, and

diazomethane was added. After 30 min, one drop of acetic

acid was added, and the solvent was removed. Column chro-

matography of the residue, using ethyl acetate – hexanes

(2:3), afforded the 4-methoxycarbonyl-∆²-ester. [α]_D²⁰

+424.2° (c 0.165, CHCl₃). Mass spectrum (CI, m/z): 363

(M+1). HR-MS-CI calcd. for C₁₇H₁₈N₂O₅S: 363.1015

(M+1); found: 363.1018 (M+1). IR (CHCl₃) (cm^–1): 3412,

1

(CHCl₃) (cm^–1): 3414, 1778, 1751, 1694. H NMR (CDCl₃):

7.31 (3H, m, Ar + NH), 7.05 (1H, t, Ar), 6.96 (2H, d, Ar),

5.76 (1H, dd, 4.5, 9.7 Hz, H-7), 5.27 (1H, d, 4.5 Hz, H-6),

4.80 (1H, dd, 2.0, 6.2 Hz, H-4), 4.55 (2H, s, PhOCH₂), 3.78

(3H, s, ester CH₃), 3.06 (1H, ddq, 2.0, 6.3, 6.8 Hz, CHCH₃),

2.25 (1H, ddd, 2.0, 2.0, 14.1 Hz, α-H-3), 1.69 (1H, ddd, 6.3,

12.0, 14.1 Hz, β-H-3), 1.25 (3H, d, 6.8 Hz, CH₃). ¹³C NMR

(CDCl₃): 169.75 (acetamido C=O), 168.36 (ester C=O),

165.39 (β-lactam C=O), 157.83, 129.78, 122.40, 115.03 (aro-

matic), 67.43 (PhOCH₂), 59.13 (C-7), 56.25 (C-6), 52.68

(ester CH₃), 50.26 (C-4), 34.86 (C-2), 31.81 (C-3), 21.34

(CH₃).

1

1778, 1751, 1694. H NMR (CDCl₃): 7.36–7.30 (3H, m, Ar

+ NH), 7.04 (1H, t, Ar), 6.94 (2H, d, Ar), 5.81 (1H, dd, 4.1,

9.2 Hz, H-7), 5.62 (1H, dq, 1.3, 2.7 Hz, =CH), 5.23 (1H, dd,

0.4, 4.1 Hz, H-6), 4.96 (1H, ddq, 0.4, 2.0, 2.7 Hz, shows

nOe with H-3 and CH₃at 5.62 and 1.96 ppm, respectively,

allyl CH), 1.96 (3H, dd, 1.3, 2.0 Hz, CH₃). ¹³C NMR

D

To a solution of isomer A (46 mg, 0.093 mmol) in glacial

acetic acid (10 mL) and water (4.7 mL) was added 10% pal-

ladium on carbon (103 mg). The apparatus was purged in the

Wolfe et al.

1257

usual manner and the mixture was stirred rapidly under hy-

drogen for 20 min and then centrifuged. The pellet was sus-

pended in ice-cold 67% acetic acid (5.0 mL) and centrifuged

again. The combined supernatants were lyophilized, and the

white residue, in a mixture of absolute ethanol (2.0 mL) and

dichloromethane (5.0 mL), was treated with diazomethane.

The solution was stirred for 2 h and the solvent was then re-

moved under reduced pressure. Chromatography using ethyl

acetate – hexanes (1:1) gave the 4-methoxycarbonyl-∆²-

cephem (23.3 mg).

and thrice with hydrogen and then stirred under hydrogen

for 1 h and centrifuged. The pellet was suspended in 61%

acetic acid (4.0 mL), centrifuged again, and the combined

supernatants were lyophilized to give the malonic acid. This

was dissolved in a mixture of dichloromethane (1.8 mL) and

95% ethanol (0.3 mL), the solution was cooled in an ice

bath, and excess diazomethane was introduced in a stream of

dry nitrogen. The solution was stirred for 2 h, evaporated,

and the residue, in ethyl acetate (2 mL), was flushed through

a short column of silica gel. Evaporation and crystallization

from ethyl acetate – hexanes afforded dimethyl n-propyl

acetamidomalonate as white needles (19.2 mg, 82%) mp 127

to 128°C. Mass spectrum (CI, m/z): 232 (M+1). IR (KBr)

E

To a solution of isomer B (46 mg, 0.093 mmol) in glacial

acetic acid (10 mL) and water (4.7 mL) was added 10% pal-

ladium on carbon (110 mg). The apparatus was purged in the

usual manner and the mixture was stirred rapidly under hy-

drogen for 20 min and then centrifuged. The pellet was sus-

pended in ice-cold 68% acetic acid (5.0 mL) and centrifuged

again. The combined supernatants were lyophilized, and the

residue, in a mixture of absolute ethanol (2.0 mL) and di-

chloromethane (5.0 mL), was treated with diazomethane.

The solution was stirred for 2 h and the solvent was then re-

moved under reduced pressure. Chromatography using ethyl

acetate – hexanes (1:1) afforded the ∆²-cephem (8.8 mg) and

the cepham (7.0 mg).

1

(cm^–1): 3273, 1748, 1642. H NMR (CDCl₃): 6.77 (1H, br s,

NH), 3.77 (6H, s, ester CH₃), 2.29 (2H, m, CH₂), 2.03 (3H,

s, acetamido CH₃), 1.12 (2H, m, CH₂), 0.90 (3H, t, 7.3 Hz,

CH₃). ¹³C NMR (CDCl₃): 168.89 (acetamido C=O), 168.75

(ester C=O), 66.62 (CH₃CONHC(CO₂CH₃)₂), 53.30

(CO₂CH₃), 34.52 (CH₃CONHCCH₂CH₂CH₃), 22.96

(CH₃CONH), 17.08 (CH₃CONHCCH₂CH₂CH₃), 13.74

(NHCCH₂CH₂CH₃). Anal. calcd. for C₁₀H₁₇NO₅: C 51.94, H

7.41, N 6.06; found: C 52.13, H 7.44, N 5.88.

Acknowledgements

This research was supported by the Natural Sciences and

Engineering Research Council of Canada (NSERC). The au-

thors thank Dr. Raymond Bowers, Dr. Blair Johnston, Avtar

Sundher, Jason Galpin, and Marie-Claire Wilson for prelimi-

nary synthetic studies related to this project.

Deprotection of model malonates

A

To a solution of dibenzyl acetamidomalonate (29.9 mg,

0.088 mmol) in glacial acetic acid (4.1 mL) and water

(2.6 mL) was added 10% palladium on carbon (119.8 mg).

The apparatus was flushed thrice with nitrogen, thrice with

hydrogen and the mixture was then stirred rapidly under hy-

drogen for 55 min and centrifuged. While the supernatant

was cooled in an ice bath, the pellet was suspended in ice-

cold 61% acetic acid (4 mL) and centrifuged again. The

combined supernatants were lyophilized to give

acetamidomalonic acid as a fluffy white solid. An ice-cold

solution of this material in a mixture of dichloromethane

(1.8 mL) and 95% ethanol (0.3 mL) was treated, in 10 min

intervals, with diazomethane, bubbled in from a DIAZALD

reaction mixture using a stream of dry nitrogen. The solvent

was removed under reduced pressure and the residue, in

ethyl acetate, was filtered through a short layer of silica gel.

Crystallization from hot methanol gave dimethyl

acetamidomalonate as white needles (13.5 mg, 81%), mp

126–128°C. Mass spectrum (EI, m/z): 189 (M). IR (KBr)

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B

To

a

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1258

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Article Doi

Synthesis and decarboxylation of Δ2-cephem-4,4-dicarboxylic acids

DOI: 10.1139/v01-100

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