Syntheses of (6S)-cephalosporins from 6-aminopenicillanic acid

TETRAHEDRON

Pergamon

Tetrahedron 56 (2000) 6053±6074

Syntheses of (6S)-Cephalosporins from 6-Aminopenicillanic Acid

Tomasz Fekner,^a,²Jack E. Baldwin,^aRobert M. Adlington,^aTimothy W. Jones,^bC. Keith Prout^b

and Christopher J. Scho®eld^a,

*

^aThe Dyson Perrins Laboratory and the Oxford Centre for Molecular Sciences, University of Oxford, South Parks Road,

Oxford OX1 3QY, UK

^bThe Chemical Crystallography Laboratory, 9 Parks Road, University of Oxford, Oxford OX1 3QY, UK

Received 20 April 2000; accepted 1 June 2000

AbstractÐTwo practical routes to (6S,7S)-cephalosporins from 6-aminopenicillanic acid (6-APA) are described. In the ®rst, 6-APA was

converted to (2S,4S,5S,6S)-penicillin sulfoxide 49, which underwent Morin ring expansion to a protected (6S,7S)-cephem 50. In the second,

ester 15 was converted to (2S,4S,5S,6R)-penicillin sulfoxide 58, which was then transformed into (6S,7R)-cephem 59. Different methods for

Despite the continued threat of resistance, b-lactams

remain the most important antibacterials in current clinical

use. In addition to their exploitation as antibacterials and

b-lactamase inhibitors, b-lactams are increasingly being

used as inhibitors of other medicinally important targets,

as exempli®ed by the pioneering Merck±Sharp & Dohme

work on the inhibition of elastase.¹

Penicillins and cephalosporins are biosynthesised with the

(2S,5R,6R)- and (6R,7R)-stereochemistry, respectively,²

Woodward et al. were the ®rst to report the total synthesis of

a cephalosporin.⁶More recently, Oberhauser and Meduna

which appear to be requisite for antibacterial activity

have reported the synthesis of (^)-7-aminocephalosporanic

mediated via inhibition of penicillin binding proteins.³It

is of interest that clavulanic acid 1, a potent b-lactamase

acid and (^)-7-epi-aminocephalosporanic acid.⁷At the

inhibitor, possesses the same structural featureÐthe (R)-

con®guration at the carbon ring juncture. However, in the

case of clavamycins, as exempli®ed by 2-hydroxy-methyl-

clavam 2, the ring juncture is (S)-con®gured.⁴Compounds

of this family, although inactive as antibacterials, exhibit

antifungal activity. Moreover, Pfaendler et al.⁵have

recently reported the synthesis and activities of the 3-(t-

butyl)-oxypenems 3 and ent-3. Interestingly, both enantio-

mers 3 and ent-3 were apparently active as antibacterials,

although it is unclear whether or not epimerisation of 3 to its

(5R)-epimer 4 occurs under the assay conditions.

onset of our work, it seemed desirable to develop a general

methodology for the synthesis of (6S)-cephems, with a view

to investigate biological and chemical activities of such

con®gured compounds (e.g. 5 and 6).

Keywords: cephalosporins; penicillins; rearrangements; epimerisation.

* Corresponding author. Tel.: 144-1865-275625; fax: 144-1865 275674;

e-mail: christopher.scho®eld@chem.ox.ac.uk

²

Present address: Department of Chemistry, University of Shef®eld,

Brook Hill, Shef®eld S3 7HF, UK.

PII: S0040-4020(00)00486-5

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T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

Scheme 1.

Scheme 2. Reagents and conditions: (a) PhtCO₂Et, Na₂CO₃, H₂O, rt, 2 h; 49%; (b) BnBr, Et₃N, DMF, rt, 6 h; 71%; (c) DBU (cat.), CH₂Cl₂, rt, 90 min; 98% or

NaH (1 equiv.), THF, rt, 17 h; 85%; (d) Cl₂(1 equiv.), CH₂Cl₂, CCl₄, rt, 30 min; (e) SnCl₂(1.06 equiv.), THF, rt, 2 h; (f) O₃, Me₂CO, 08C then chromato-

graphic separation; 25% over three steps (64% if based on recovered 12); (g) pTSA (cat.), DMF, 1008C, 90 min; 50%; (h) N₂H₄´H₂O, DMF, 2788C!rt,

30 min; 47%; (i) RCO₂H, DCC, THF, rt, 2 h; 85% (RPhCH₂) and 91% (RPhOCH₂); (j) AlCl₃, PhOMe, CH₂Cl₂, MeNO₂, 08C!rt, 6±8 h; 86% (RPhCH₂)

and 94% (RPhOCH₂).

In this paper we report syntheses of (6S,7R)- and (6S,7S)-

cephalosporins for analysis as enzyme inhibitors/anti-

bacterials/antifungals and intermediates in the preparation

from readily available and inexpensive 6-aminopenicillanic

acid 9 (6-APA).

³8

of ent-Cefadroxile 7. A part of this work has been

Scheme 2 summarises our ®rst successful synthesis. 6-APA

9 was protected as described by Vanderhaeghe and

Busson.¹⁴Thus, the sodium salt of 9 was treated with

Nefkens' reagent, N-carboethoxyphthalimide,¹⁵to give

acid 10¹⁶which was subsequently esteri®ed with benzyl

bromide in the presence of triethylamine to afford ester

11.^§The base-promoted epimerisation of the C-6 position

published in preliminary format.^9,10De Angelis et al. have

recently reported syntheses of phthalimido-protected

ent-cephems using 7-aminodeacetoxycephalosporanic acid

as the starting material.¹¹

Results and Discussion

§

Although penam 11 has been prepared by others, its existence in two

polymorphic forms has not been noted previously. Thus, the previously

reported low-melting form (Form I, mp 136±1388C) is transformed into a

higher-melting form (Form II, mp 153±1548C) either upon prolonged heat-

ing (ca. 20 min) at 1108C or during melting point determination when the

temperature increase is slow (ca. 18C min²¹, starting from 1008C). Form I,

C₂₃H₂₀N₂O₅S, was shown not to be a hydrate or solvate by elemental

In the ®rst successful approach to the (6S,7S)-cephem

nucleus 5 (Scheme 1) we envisioned its formation via the

well-established Morin rearrangement^12,13of a suitable

penicillin sulfoxide 8, which in turn would be synthesised

1

analysis. The H NMR (500 MHz) analysis con®rmed that no decomposi-

Cefadroxile exists in a number of different crystalline forms⁸and crys-

tallisation studies of its enantiomer 7 were also undertaken. The results of

the studies will be reported elsewhere.

tion occurred during the solid state transformation. The two forms are

distinguished in solid state by FT IR and X-ray powder diffraction analyses

(see Experimental).

³

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6055

Scheme 3. Reagents and conditions: (a) Cl₂(1 equiv.), CH₂Cl₂, CCl₄; (b) SnCl₂(1 equiv.), THF, rt.

of penam 11 was accomplished readily in excellent

yield using either a catalytic amount of 1,8-diaza-

bicyclo[5.4.0]undec-7-ene (DBU) or stoichiometric amount

of NaH to give the (6S)-epimer 12. As previously reported,¹⁷

irrespective of the base used, the cis-penicillin 11 could not

ture precedent suggested that the cis-closure mode in the

case of intermediates 24 and 25, derived from penicillin

12, may be even less probable than that of intermediates

13 and 14 corresponding to the favourably con®gured

penam 11.

1

be detected in the crude reaction mixture by H NMR

(200 MHz) analysis.

To our delight, subjecting penicillin 12 to the Kukolja proto-

col furnished a mixture of two diastereoisomers, the requi-

site cis-penicillin 26 and the parent trans-penicillin 12 in a

ratio of ca. 1:2. Earlier studies had indicated that the trans-

selectivity of the ring closure step could be in¯uenced by the

presence of moisture or when the process was performed in

boiling dioxane using tin(II) chloride dihydrate.¹⁹However,

use of either of these conditions, whilst diminishing signi®-

cantly the overall yield of penams 12 and 26, did not result

in bias of the product to the desired cis-isomer. Substitution

of tin(II) chloride with other divalent tin halides (SnBr₂,

SnF₂) was also not advantageous. Interestingly (Scheme

3), even when bulkier benzhydryl ester 31 was subjected

to the Kukolja protocol, the cis-penicillin 34 was obtained

along with the parent trans-penam 31 in a ratio of ca. 1:2.5.

In this case, however, the overall yield of the penams was

somewhat lower than in the case of its benzyl analogue,

which may re¯ect the acid-sensitive nature of diphenyl-

methyl esters. Surprisingly and contrary to the afore-

mentioned report,¹⁴in our hands trans-penam 27 afforded

a mixture of two penicillins 27 and cis-30 in a ratio of ca.

1.5:1 in excellent overall yield. Our results indicate that the

cis-closure is enhanced slightly for the less sterically

demanding esters within the series of (6S)-phthalimido-

penicillanates.

In planning the synthesis of cephem 5, we were cognisant

that a pivotal step would involve epimerisation of the C-5

position of penam 12. To our knowledge, only one method,

that was developed by Kukolja, allows epimerisation of the

C-5 position of penicillins bearing an imido substituent at

C-6.^18,19The reaction with 1 equiv. of chlorine or sulfuryl

chloride as a source of electrophilic halogen, results in

cleavage of the C₅±S bond of the penicillin thiazolidine

ring.¹⁸Subsequent tin(II) chloride-mediated re-cyclisation

(1 equiv. of anhydrous SnCl₂, THF, rt, 2 h) gives the desired

fused bicyclic penam system.¹⁹Unfortunately, it has also

been reported that the ring closure step is highly trans-

selective. For example (Scheme 3, entry 1), when ester 11

was subjected to the Kukolja protocol, cis- and trans-

penicillins 11 and 15 were obtained in a ca. 1:20 ratio,

respectively.¹⁴Similarly, benzhydryl ester 20 gave a

mixture of two diastereoisomers, 20 and 23, in a ca. 1:10

ratio, respectively¹⁹(Scheme 3, entry 3). The most

discouraging results reported involved subjecting methyl

esters 16 and 27 to the Kukolja protocol. It was reported

that the reactions resulted in clean formation of the trans-

penam 19 from ester 16¹⁹(Scheme 3, entry 2), and recovery

of the starting material in the case of the trans-penam 27,

without any trace of the appropriate `cis-closure' product.¹⁴

In the case of (6R)-phthalimidopenicillanates this high

stereoselectivity can be attributed to the bulk of the

phthalimido substituent that makes the cis-diastereoisomers

kinetically and thermodynamically signi®cantly less

favoured cyclisation products than their trans-analogues.

Moreover, it has been established, on the basis of base-

catalysed equilibration experiments, that a sterically

demanding ester substituent at C-2 prefers to occupy the

exo- rather than endo-face of penicillins.¹⁴Thus, the litera-

To investigate factors affecting the stereochemical outcome

of the Kukolja protocol, a series of penicillanates devoid of

the phthalimido group at the C-6 position were prepared and

subjected to the standard ring opening-cyclisation procedure

(Scheme 3, entries 7±9). Thus, when benzyl ester 35 was

subjected to the Kukolja protocol, its (5S)-epimer 38 and the

starting material 35 were obtained in a ca. 1:3 ratio, respec-

tively. Similarly, the methyl ester 39 gave its (5S)-epimer

42, along with the recovered starting material 39, in a ratio

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T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

However, the use of ozone as a selective oxidant circum-

vented the dif®culty. Spry has demonstrated that ozone is a

reagent of choice for the conversion of penicillins and

cepham derivatives into sulfoxides; the sulfoxides are

prepared in near quantitative yield, no overoxidation to

sulfones occurs, and workup procedures are simple.^20,21

Moreover, the selective oxidation of bicyclic b-lactams

with ozone had been clearly demonstrated by exclusive

oxidation of cepham 47 in the presence of penam 48.²¹

Thus (Scheme 4), when a 1:2 mixture of esters 26 and 12 in

cold acetone was carefully oxidised with ozo_kne, selective

formation of the desired sulfoxide 49 occurred. Only traces

of the sulfoxides derived from penicillin 12 could be

Figure 1.

Scheme 4. Reagents and conditions: (a) O₃, Me₂CO, 08C.

1

detected by H NMR (200 MHz) analysis. This operation

of ca. 1:4. For the benzhydryl ester 43 the selectivity of

the re-cyclisation step was markedly higher, and the (5S)-

penam 46 was obtained, together with the starting material

43, in a ratio of ca. 1:8, respectively. Note that for

6-unsubstituted penicillanates (e.g. 35, 39, and 43) cyclisa-

tion of the corresponding intermediate sulfenyl chlorides

takes place from the a-face less readily than for the inter-

mediates derived from (6S)-phthalimidopenicillanates (e.g.

12, 27, and 31). Thus, a factor(s) other than the presence and

con®guration of a 6-substituent must be involved in deter-

mining the stereochemical outcome of the ring closure reac-

tion. However, since removal of the phthalimido group from

the C-6 position of the penam molecule also changes elec-

tronic properties of the cyclisation step intermediates, it is

dif®cult to single out a decisive factor.

not only differentiated polarities of the two diastereo-

isomers, making their separation easy, but also afforded

the requisite sulfoxide 49 for subsequent penam-cephem

rearrangement. Separation of sulfoxide 49 from sul®de 12

was, even on a multi-gram scale, easily accomplished by

¯ash chromatography.^¶

The scope of this oxidation was investigated by a series of

competitive experiments involving four diastereoisomeric

k

The oxidation reaction was stereoselective giving a single isolated

epimeric sulfoxide of penam 26, whose con®guration, initially assigned

as (4S) on the ground of the well-documented steric control during sulfox-

idation of naturally con®gured 6-phthalimidopenicillanates, was unambigu-

ously con®rmed by single crystal X-ray analysis. Baldwin, J. E.; Adlington,

R. M.; Scho®eld, C. J.; Fekner, T. Unpublished work.

Structure of penam 26, including the absolute con®guration,

was con®rmed by single-crystal X-ray crystallographic

analysis (Fig. 1).

¶

Selective chlorinolysis of penam 12 from its mixture with the requisite

penam 26 was initially attempted. If successful, it would have enabled, by

repeating the Kukolja protocol, to improve the cis/trans ratio of the

products. Unfortunately, penam 26 undergoes the ring opening signi®cantly

faster than the epimer 12. Presumably, due to the easily accessible exo-face

of penam 26, the sulfur atom, with its well-exposed pro-(S) lone electron

pair, is preferentially attacked by electrophiles. This experiment suggested

that selective sulfoxidation of penam 26 from its mixture with 12 might be

feasible.

Unfortunately, separation of diastereoisomers 12 and 26

(Scheme 2) by ¯ash chromatography on a multi-gram

scale proved to be inef®cient and time-consuming. Further-

more, this obstacle precluded the recycling of penicillin 12.

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6057

Scheme 5. Estimated relative reactivity of benzyl 6-phthalimidopenicillanates towards sulfoxidation with ozone in acetone.

benzyl 6-phthalimidopenicillanates. Scheme 5 summarises

our results. Diastereoisomer 26 proved to be the most

reactive of the compounds tested. The high reactivity of

penam 26 may be attributed to the relative accessibility of

the pro-(S) lone electron pair of the sulphur.

ment^12,13and 6-APA 9 would be again a suitable starting

material.

The pathway, reagents, and conditions of the second

approach are summarised in Schemes 7, 9 and 10. Ester

15 was obtained from its epimer 11 as previously described

(Scheme 3). Oxidation with m-chloro-perbenzoic acid

(mCPBA) afforded sulfoxide 58 (Scheme 7), which was

identical to material obtained by epimerisation of the C-6

position of sulfoxide 49 with a catalytic amount of DBU.

The assignment of the (4S)-con®guration was con®rmed by

single-crystal X-ray crystallographic analysis of sulfoxide

58 (Fig. 4). It is the only one example in the series of benzyl

6-phthalimidopenicillanates studied (11, 12, 15, and 49),

where peracid (mCPBA) prefers to approach the molecule

from the face occupied by bulky phthalimido substituent.^pp

Cephem 50 was obtained in moderate yield via the Morin

rearrangement^12,13of sulfoxide 49 in hot DMF in the

presence of a catalytic amount of p-toluenesulfonic acid

(pTSA) (Scheme 2). The Ing-Manske^22,23dephthaloylation

using hydrazine hydrate furnished free amine 51 which was

subsequently acylated with appropriate arylacetic acids

using 1,3-dicyclohexylcarbodiimide (DCC) as a dehydrat-

ing agent to afford amides 52 and 53, in both cases in

excellent yield.²⁴Finally, debenzylation with AlCl₃as

reported by Tsuji et al.,²⁵produced free acids 54 and 55 in

excellent yields.

Sulfoxide 58 underwent the acid-catalysed Morin rearrange-

ment to give cephem 59. Interestingly, this reaction was

signi®cantly slower than that of sulfoxide 49 (8 h and

90 min, respectively, under the standard reaction

The structures of cephem 50 (Fig. 2) and the corresponding

amine 51 (Fig. 3) were con®rmed by single-crystal X-ray

crystallographic analyses.

²²

conditions ). Cooper has studied the penicillin sulfoxide±

Another successful approach to (6S,7S)-cephems (Scheme

6) relied on the observation that the target compound 5

might be easily obtained from its (7R)-epimer 56 by any

of the methods devised to convert (6R,7S)-cephems, avail-

able from various total syntheses, to the naturally con®gured

ones. (6S,7R)-Cephem 56 could be synthesised from the

appropriate penicillin sulfoxide 57 via the Morin rearrange-

sulfenic acid equilibrium with naturally con®gured penam

sulfoxides. He observed that, on heating in D₂O, the

6-phthalimido substituted penam sulfoxides incorporated

deuterium into one of the geminal methyl groups signi®-

cantly faster than their phenoxyacetamido (Penicillin V)

analogues.²⁶Amongst other possible explanations he postu-

lated that the phthalimido substituent introduces signi®cant

steric strain into the molecule (its interaction with the

b-methyl group seems to be the most important). This strain

increases ground-state energy of the molecule, which results

in a lower activation energy for the appropriate (pseudo)-

pericyclic process leading to the sulfenic acid. Since the

aforementioned sulfoxide±sulfenic acid equilibrium

consists the very ®rst stage of the Morin rearrangement, it

seems reasonable to explain the difference in reactivity of

cis- and trans-substituted 6-phthalimidopenicillanate-4-

oxides under the Morin rearrangement conditions using a

similar argument, i.e. there is a lower activation energy for

reaction of the cis-penam sulfoxides (e.g. 49) than for their

pp

Strictly speaking, the oxidant does not approach the molecule from the

face occupied by the phthalimido group, but it is probably a side-on type

approach in which the equatorial lone electron pair of sulfur reacts (it was

established by n.O.e. studies that the thiazolidine ring of sulfoxide 58

adopts in chloroform solution the `open' conformation, see: Experimental

section).

²²

An appropriate sulfoxide (200 mg, 0.44 mmol) and anhydrous pTSA

(20 mg, 0.12 mmol) in DMF (10 ml) were heated in a pre-equilibrated oil

bath at 100^38C until the sulfoxide had reacted (TLC analysis). Under

these conditions cis-penam sulfoxide 64 and trans-penam sulfoxide 65

were consumed within 30 and 220 min, respectively.

Figure 2.

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T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

As exempli®ed for a single deuterium incorporation into

sulfoxide 58 (Scheme 8), its thermal rearrangement gives

sulfenic acid 61, which exchanges the acid proton with D₂O

to form the deuterated analogue 62.^26,27After reversible ring

closure, the deuterium is placed selectively in one of the

geminal methyl groups (in this case b-CH₃) to give deuter-

ated penam sulfoxide 63.²⁶The act of the ring opening can

be then repeated resulting in incorporation of further

³³

deuterium atoms.

The results demonstrate that, as anticipated, the cis-penam

sulfoxide 64 incorporates deuterium much faster than its

trans-analogues 65 and 58 (Table 1). This outcome can be

rationalised by assuming a very facile formation of the inter-

mediate sulfenic acid from sulfoxide 64 for the reasons of

steric strain discussed earlier. The results imply that, under

the reaction conditions, formation of a sulfenic acid, and not

its further transformations, may be the bottleneck in the

Morin rearrangement of the trans-substituted 6-phthalimido-

penicillanate-4-oxides tested (i.e. 58 and 65). Interestingly,

Figure 3.

Scheme 6.

trans analogues (e.g. 58). It is also possible that geometric

constraints are responsible for the different observed rates of

reaction.²⁷

sulfoxide 60, devoid of the phthalimido group at C-6, incor-

porates deuterium slightly faster than sulfoxide 58. n.O.e.

Studies implied that the thiazolidine ring of sulfoxides 58

and 60 adopts, at least in chloroform solution, the open

conformation (see Experimental). Remarkably, sulfoxide

49 did not incorporate deuterium into either of the geminal

methyl groups but, instead, the reaction delivered the corre-

sponding sulfenic acid. This prompted us to investigate

formation of unusually stable sulfenic acids from various

(2S,5S,6S)-penicillanate-4-oxides in more detail. The results

of the studies have been published elsewhere.²⁸

To further investigate, deuterium incorporation studies for

various 6-phthalimidopenicillanate-4-oxides were con-

ducted. Since the bulkiness of the phthalimido group

seemed to be the dominant factor governing the ease of

sulfenic acid formation, it was decided to include into

these studies sulfoxide 60, which is devoid of substituents

at the C-6 position.

As in the previous approach, dephthaloylation of cephem 59

using hydrazine hydrate^22,23afforded amine 66 (Scheme 7).

DCC-mediated coupling²⁴with phenylacetic acid gave

³³

Deuterium incorporation was accomplished by heating the appropriate

penam sulfoxide (0.13 mmol) in re¯uxing benzene (15 ml) for 150 min in

the presence of a large excess of D₂O (300 ml, 15 mmol, 115 equiv.). Since

penam sulfoxides give under mass spectrometry conditions strong peaks of

dehydration products formed presumably via a sulfenic acid intermediate, it

was necessary to preclude distortion of the results via label loss in the mass

spectrometric analyses. Thus, prior to the mass spectrometry analysis, the

deuterated sulfoxides were reduced to the corresponding penams (KI, AcCl,

DMF, 08C). The deuterium distribution in 6-phthalimidopenicillanates was

calculated from the mass spectra using the well pronounced molecular ions

(MNH₄¹, m/z 454±457) and peaks arising from a simple ®ssion (with

hydrogen transfer) of the b-lactam ring (MH¹2PhtCHCO, m/z 250±

253). For the deuterated derivative of the 6-unsubstituted penam 60 the

molecular peak was of no analytical value and, consequently, only the

®ssion peak was used.

25

amide 67 in good yield. Debenzylation with AlCl₃

afforded contaminated acid 69 that was puri®ed as its benz-

hydryl ester 68. Final rapid deprotection with AlCl₃under

milder conditions gave pure acid 69. As shown in Schemes

9 and 10, amine 66 was converted to (6S,7S)-cephem

derivatives by two different methods. The ®rst utilised,

developed by Hiraoka and Kobayasi,²⁹involves preparation

and subsequent reduction of sulfenimines. Thus (Scheme 9),

amine 66 upon treatment with p-nitrobenzenesulfenyl

chloride in the presence of K₂CO₃afforded sulfenamide

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6059

Scheme 7. Reagents and conditions: (a) mCPBA, CHCl₃, 08C, 90 min; 85%; (b) pTSA, DMF, 1008C, 17 h; 33%; (c) N₂H₄´H₂O, DMF,2158C, 30 min; 39%;

(d) PhOCH₂CO₂H, DCC, THF, rt, 2 h; 89%; (e) AlCl₃, PhOMe, CH₂Cl₂, MeNO₂, rt, 8 h, then Ph₂CN₂, CH₂Cl₂, rt, 5 min; 52%; (f) AlCl₃, PhOMe, CH₂Cl₂,

MeNO₂, 08C, 30 min; 96%.

70 in good yield. Oxidation with active manganese dioxide

furnished sulfenimine 71, which was reduced with NaBH₄

to produce sulfenamide 72 as the major product, along with

a small amount (,5%) of the parent sulfenamide 71. Direct

acylation of cephem 72 with phenoxyacetyl chloride

afforded amide 53, prepared in our ®rst approach. It was

also possible to cleave reductively (KI/AcOH/MeOH) the

side chain of sulfenamide 72 with formation of free amine

51.

acetyl chloride to give amide 53 or reductively cleaved to

afford amine 51.

The second methodology utilised, devised by Firestone et

al.,³³was based on kinetically controlled protonation of

anions derived from the appropriate Schiff base (Scheme

10). Thus, condensation of amine 66 with p-nitrobenzalde-

hyde in the presence of MgSO₄furnished imine 75 in good

yield. Treatment with PhLi followed by DMF generated the

free anion, which was quenched with acetic acid giving a

mixture of two imines 77 and 76 in the ratio of ca. 2.5:1.

Hydrolysis of the mixture with pTSA in wet EtOAc,³⁴

followed by spontaneous crystallisation, gave pure salt 77,

not contaminated with its 7-epimer. It was also possible to

acylate the mixture of the Schiff bases³⁵and obtain, after

chromatographic separation, the requisite amide 53.

Gordon's modi®cation of the Hiraoka and Kobayashi's

methodology allows preparation of sulfenimines from

amines in one step.^30,31In this case the appropriate sulfenyl

chloride acts as oxidant converting the initially formed

sulfenamide to thiooxime. When amine 66 was treated

with three equivalents of freshly prepared p-toluenesulfenyl

chloride³²in the presence of propylene oxide and pulverised

Ê

4 A molecular sieves, sulfenimine 73 was obtained in good

yield. Subsequent reduction with NaBH₄afforded cis-

sulfenamide 74 which was directly acylated with phenoxy-

Conclusions

Two approaches for the synthesis of the enantiomers of

naturally con®gured cephalosporins have been developed.

Mechanistic observations have been made involving stereo-

selectivity in the Kukolja reaction and use of ozone as a

highly selective oxidant of diastereoisomeric penicillins.

The Morin penam sulfoxide-cephem rearrangement has

also been shown to be a practical method for preparation

of various cephalosporins with unnatural con®gurations.

Experimental

General experimental techniques

Melting points (mp) were recorded using a Gallenkamp or a

BuÈchi 510 capillary melting point apparatus. Values are

given to the nearest 18C, followed by the crystallisation

solvent(s) in parentheses. Optical rotations {[a]^t_D} were

taken using a Perkin±Elmer 241 polarimeter at 589 nm

(Na D-line) and the de®ned temperature `t' with a

Figure 4.

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T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

Scheme 8.

pathlength of 10.0 cm. Values are given in 10²¹deg cm²g

with concentrations given in 10²²g cm²³. Combustion

microanalyses were performed in-house by Mrs V.

Lamburn. Fourier Transform Infrared (FT IR) spectra

were recorded on a Perkin±Elmer 1750 Fourier Transform

Spectrometer as either KBr discs or CHCl₃solutions.

referenced to the residual solvent peak. Coupling constants

(J) are recorded in Hertz and quoted to the nearest 0.5 Hz.

The following abbreviations are used: `s' singlet, `d'

doublet, `dd' double doublet, `t' triplet, `q' quartet, `m'

multiplet, `AB' AB system, and `br' broad. Carbon Nuclear

Magnetic Resonance (¹³C NMR) spectra were recorded at

50.31 and at 125.77 MHz on a Varian Gemini 200 and

BruÈker AMX500 spectrometers, respectively. Chemical

shifts (d_C) are given in ppm and referenced to the residual

solvent peak, unless otherwise stated. Distortionless

Enhancement by Polarisation Transfer (DEPT) editing

was used for spectra recorded at 50.31 MHz, and in this

context the following abbreviations were used: `s'CH₀,

`d'CH₁, `t'CH₂, and `q'CH₃. Low Resolution Mass

Absorbtions (n_max) are reported in wavenumbers (cm²¹

)

and only main features of each spectrum are given. Abbre-

viations used are as follows: `s' strong, `m' medium, `w'

weak, `sh' shoulder, and `br' broad. Proton Nuclear

Magnetic Resonance (¹H NMR) spectra were recorded at

200 and 500 MHz on a Varian Gemini 200 and BruÈker

AMX500 spectrometers, respectively. Chemical shifts

(d_H) are given in ppm relative to tetramethylsilane and

Table 1.

Sulfoxide^a

Deuterium incorporation site^b

Average number of

deuterium atoms

incorporated

Deuterium distribution (%)^c

D₀

D₁

15

D₂

39

D₃

39

a-CH₃

b-CH₃

2.10^c(1.9)^d

0.88 (0.8)

0.24

7

38

83

72

40

11.5

25

18

4.5

3

4

1

0

0.31 (0.3)

^aThe geometry of the sulfoxide bond was established by single-crystal X-ray crystallographic analyses, chemical correlation, and/or ¹³C NMR studies.⁹For

every sulfoxide tested, the con®guration at sulfur remained unchanged after the deuterium incorporation.

^bEstablished by n.O.e. studies.

^cDetermined by mass spectrometry.

^dDetermined by ¹H NMR (500 MHz) analysis.

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6061

Scheme 9. Reagents and conditions: (a) p-O₂NC₆H₄SCl, K₂CO₃, CH₂Cl₂, 08C, 1 h; 83% or p-O₂NC₆H₄SCl, Et₃N, THF, 08C, 3 h; 63%; (b) active MnO₂, PhH,

Ê

rt, 1 h; 48% (70 to 71); (c) p-MeC₆H₄SCl (3 equiv.), propylene oxide, 4 A molecular sieves, CH₂Cl₂, 08C!rt, 3 h; 75% (66 to 73); (d) NaBH₄, THF, DMSO,

08C, 10 min; 53% (71 to 72) and 40 min, 50% (73 to 74); (e) KI, Na₂S₂O₃, CH₂Cl₂, MeOH, AcOH, 08C, 2 h; 99% (72 to 51) and ,100% (74 to 51); (f)

PhOCH₂COCl, CH₂Cl₂, 08C, 120 min; 85% (72 to 53) and 73% (74 to 53).

Spectrometry (LRMS) was performed on a V.G. Micromass

ZAB 1F (FAB/CI/DCI), a V.G. Masslab 20-250 (CI/DCI/

EI), or a V.G. BIO-Q (electrospray) spectrometer. Modes of

ionisation are described as Direct Chemical Ionisation

(DCI), Probe Chemical Ionisation (CI), Probe or In Beam

Chemical Impact (EI), or Fast Atom Bombardment (FAB).

Only molecular ions (M¹) and major peaks, as the mass-to-

charge ratio (m/z), are reported with intensities given as

percentages of the base peak. High Resolution Mass Spec-

trometry (HRMS) was performed by the staff of EPSRC

Mass Spectrometry Service Centre, Chemistry Department,

University of Wales, Swansea. The accurate mass measure-

ments are valid to ^10 ppm. Flash chromatography was

carried out using Merck Kiesegel 60 F₂₅₄(230±400 mesh)

or Janssen (35±70 mm) silica gel according to the method

described by Still et al.³⁶Only distilled solvents were used

as eluents. Thin layer chromatography (TLC) was

performed on Merck DC-Alufolien or glass plates pre-

coated with silica gel 60 F₂₅₄which were visualised either

by quenching of ultraviolet ¯uorescence (l_max254 nm), by

staining with iodine vapour, or by charring with 5% w/v

phosphomolybdic acid in 95% EtOH, 10% w/v ammonium

molybdate in 1 M H₂SO₄, 5% w/v ninhydrin in absolute

EtOH, or 10% KMnO₄in 1 M H₂SO₄. Eluents are given

in parentheses. Observed retention factors (R_f) are quoted

to the nearest 0.05 unless DR_ffor the compounds separated

was less than 0.1. All reaction solvents were distilled before

Ê

use and stored over activated 4 A molecular sieves, unless

otherwise indicated. Anhydrous dichloromethane, benzene,

triethylamine, and nitromethane were obtained by re¯uxing

over calcium hydride followed by distillation under an inert

atmosphere of argon. Anhydrous carbon tetrachloride was

obtained by distillation from phosphorus pentoxide.

Anhydrous tetrahydrofuran was obtained by distillation,

immediately before use, from sodium/benzophenone ketyl

under an inert atmosphere of nitrogen. Anhydrous N,N-

dimethylformamide was obtained by distillation from

calcium hydride under reduced pressure. Anhydrous 1,4-

dioxane was obtained by distillation from sodium.

Petroleum ether refers to the fractions of light petroleum

boiling between either 30±408C or 40±608C. Low boiling

solvents were evaporated under reduced pressure on a BuÈchi

RE111 Rotavapor at 308C, unless otherwise stated. High

boiling solvents were evaporated under reduced pressure

on a BuÈchi RE111 Rotavapor ®tted with a dry ice condenser

at p#2 mmHg. All reactions were performed under

anhydrous conditions and an inert atmosphere of argon in

the ¯ame-dried glassware with dry, freshly distilled

Scheme 10. Reagents and conditions: (a) p-O₂NC₆H₄CHO, MgSO₄, CH₂Cl₂, rt, 10 h; 83%; (b) PhLi, THF, DMF, then AcOH, and H₂O,2788C; (c) pTSA,

H₂O, EtOAc, rt, 30 min, 45% over two steps; (d) PhOCH₂COCl, CH₂Cl₂, rt, 20 h; 51% over two steps.

6062

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6063

solvents, unless otherwise noted. Yields refer to apparently

chromatographically and spectroscopically (¹H NMR)

homogenous materials, unless otherwise indicated.

Reagents were used as obtained from commercial sources

or puri®ed according to published procedures.³⁷The X-ray

single crystal analyses were performed by the staff of

Chemical Crystallography, University of Oxford. The

X-ray powder diffraction analyses were performed by Dr

Martin Vickers, Department of Crystallography, Birkbeck

College, London. Diazomethane was generated according to

the method described in Aldrich Technical Bulletin No.

AL-113.

crystallised from Et₂O to afford ester 10 (23.5 g, 71%). The

two polymorphic forms of penam 11 were also distin-

guished by X-ray powder diffraction analysis [Fig. 5,

Form I (left) and Form II (right)].

White crystalline solid; mp 136±1388C (Form I) and 153±

1548C (Form II) (both from Me₂CO) {lit.¹⁴mp 138±1408C

(from Me₂CO±Et₂O)}; (Found: C, 63.38; H, 4.49; N, 6.42.

Calcd for C₂₃H₂₀N₂O₅S: C, 63.28; H, 4.63; N, 6.42%); R_f

0.60 (petrol 40/60: EtOAc, 6:4); [a]²_D⁵1269 (c 1.1 in

CHCl₃) {lit.¹⁴[a]_D²⁵1253 (c 1.0 in CHCl₃)}; FT IR

(CHCl₃) n_max/cm²¹1799s and 1789s (b-lactam, phthali-

mide), 1729s (phthalimide, ester), and 1387S; FT IR (KBr

disc, Form I) n_max/cm²¹1777s (split in three; b-lactam,

phthalimide), 1741m (phthalimide), 1725s (ester), 1468w,

1394s, 1371m, 1313s, 1218w, 1198s, 1179m, 1155m,

1096m, 1086m, 959m, 937w, 925m, 893w, 764w, 747m,

(1)-(2S,5R,6R)-3,3-Dimethyl-7-oxo-6-phthalimido-4-thia-

1-azabicyclo[3.2.0]heptane-2-carboxylic acid (10). To a

vigorously stirred solution of 6-aminopenicillanic acid 9

(6-APA, 49.3 g, 228 mmol) and Na₂CO₃(24.2 g,

228 mmol) in water (350 ml) was added ®nely ground

N-carboethoxyphthalimide (50.0 g, 228 mmol). The

mixture was stirred at room temperature for 2 h and then

washed with CH₂Cl₂(3£100 ml). The aqueous layer was

mixed with a fresh portion of CH₂Cl₂(300 ml) and acidi®ed

during vigorous stirring with 1 M HCl (456 ml, 456 mmol).

Phases were separated and the extraction was completed

with two additional portions of CH₂Cl₂(2£100 ml). The

combined organic extracts were washed with water

(2£250 ml) and satd. brine (100 ml). The organic layer

was dried over MgSO₄, decolourised with activated carbon

(15 g), and evaporated in vacuo to afford the title compound

10 (38.8 g, 49%) as an off-white solid which was used in the

next step without further puri®cation. An analytical sample,

as a white crystalline solid, was obtained by triple crystal-

lisation from acetone: mp 168±1708C (from acetone) {lit.¹⁶

mp 167±1708C (dec.) (from acetone)}; (Found: C, 55.31; H,

3.95; N, 7.95. Calcd for C₁₆H₁₄N₂O₅S: C, 55.48; H, 4.08; N,

8.09%); [a]_D²⁵1276 (c 0.50 in CHCl₃) {lit.¹⁶[a]_D²⁸1278

(c 1.0 in n-butyl acetate)}; FT IR (KBr disc) n_max/cm²¹

3480s (carboxylic acid), 1790s and 1779s (b-lactam,

phthalimide), and 1723s (phthalimide, carboxylic acid);

¹H NMR (200 MHz, CDCl₃) d_H1.62 and 1.85 (2£3H,

2£s, 2£CH₃), 2.96 (1H, br s, CO₂H), 4.71 (1H, s, 2-H),

5.60 and 5.70 (2£1H, 2£d, J4 Hz, 5-H and 6-H), and

7.76±7.92 (4H_arom, m, Pht); ¹³C NMR (126 MHz, CDCl₃)

d_C27.97 and 30.38 (2£CH₃), 58.33, 66.64, and 70.88 (2-C,

5-C, and 6-C), 65.65 (3-C), 123.9 (Pht 3, 6-CH's), 131.5

(Pht ipso C), 134.6 (Pht 4, 5-CH's), 166.5, 168.8, and 171.3

(3£CvO); and LRMS [DCI (NH₃)] m/z 347 (MH¹, 20%),

187 (PhtCHCO¹, 20), 160 (MH¹2PhtCHCO, 100), 142

(M¹2PhtCHCO±H₂O, 55), and 100 (Me₂CvCH±

CO₂H¹, 20).

729w, 713m, and 703m; FT IR (KBr disc, Form II) n_max

/

cm²¹1803s (phthalimide), 1776m (b-lactam), 1746s

(phthalimide), 1723s (ester), 1467w (split in two), 1386s

sh, 1303m, 1241w, 1202s, 1186m, 1160m, 1131w, 1109m,

1

1079m, 959w, 934w, 893w, 750w, 726m, and 699w; H

NMR (200 MHz, CDCl₃) d_H1.44 and 1.80 (2£3H, 2£s,

2£CH₃), 4.70 (1H, s, 2-H), 5.22 (2H, s, CH₂Ph), 5.60 and

5.67 (2£1H, 2£d, J4 Hz, 5-H and 6-H), 7.39 (5H_arom, s,

Ph), and 7.74±7.90 (4H_arom, m, Pht); ¹H NMR n.O.e.

(500 MHz, CDCl₃) d_H1.44 a-CH₃!b-CH₃(4.5%), !2-H

(3.0%), !5-H (6.0%); 1.80 b-CH₃!a-CH₃(4.5%), !2-H

(16%); 4.70 2-H!b-CH₃(3.0%); 5.60 5-H!a-CH₃(1.5%),

!6-H (11%); and 5.67 6-H!5-H (8.0%); ¹³C NMR

(50.3 MHz, CDCl₃) d_C27.78 and 30.95 (q, 2£CH₃),

58.46, 66.94, and 70.87 (d, 2-C, 5-C, and 6-C), 66.07 (s,

3-C), 67.47 (t, CH₂Ph), 124.0 (d, Pht 3, 6-CH's), 128.9,

128.9, and 129.2 (d, Ph CH's), 131.6 (s, Pht ipso C),

134.8 (d, Pht 4, 5-CH's), 1345.0 (s, Ph ipso C), 166.9,

168.1, and 168.6 (s, 3£CvO); and LRMS [DCI (NH₃)]

m/z 454 (MNH¹₄, 5%), 437 (MH¹, 50), 250

(MH¹2PhtCHCO, 100), 187 (PhtCHCO¹, 10), and 91

(C₇H₇¹, 35).

Benzyl (1)-(2S,5R,6S)-3,3-dimethyl-7-oxo-6-phthalimido-

4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (12). The

title compound was synthesised according to the either one

of the two following methods.

The ®rst methodÐusing DBU. To a solution of ester 11

(35.1 g, 80.5 mmol) in CH₂Cl₂(300 ml) was added 1,8-

diazabicyclo[5.4.0]undec-7-ene (0.8 ml, 5.4 mmol) and the

mixture was stirred at room temperature for 90 min. The

solution was washed with 1 M NH₄Cl (2£150 ml), water

(3£200 ml), and satd. brine (100 ml). The organic phase

was dried over MgSO₄and evaporated in vacuo to afford

a white foam (34.8 g). Puri®cation by ¯ash chromatography

(silica gel, benzene/EtOAc, 9:1) gave ester 12 (34.3 g, 98%)

identical [¹H NMR (200 MHz), TLC, and FT IR] with the

product of the second method.

Benzyl (1)-(2S,5R,6R)-3,3-dimethyl-7-oxo-6-phthalimido-

4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (11). To

a stirred solution of acid 10 (26.1 g, 75.4 mmol) in DMF

(135 ml) was added triethylamine (10.5 ml, 75.4 mmol)

followed by benzyl bromide (11.5 ml, 96.7 mmol). The

mixture was stirred at room temperature for 6 h and then

poured into vigorously stirred ice water (700 ml). The

resulting suspension was extracted with CHCl₃

(3£250 ml) and the combined organic layers were washed

with satd. NaHCO₃(3£150 ml), water (3£150 ml), and satd.

brine (150 ml). The organic phase was dried over MgSO₄

and evaporated in vacuo to give a light yellow oil which was

The second methodÐusing sodium hydride. Sodium

hydride (,60% w/w suspension in mineral oil, 95 mg,

,2.4 mmol) was pre-washed with THF (2£5 ml) and

added, as a suspension in THF (5 ml), to a solution of

ester 11 (1.04 g, 2.38 mmol) in THF (40 ml). The mixture

was stirred at room temperature for 17 h and then the

6064

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

solvent evaporated in vacuo. The residual oil was dissolved

in EtOAc (50 ml) and quenched with water (5 ml). The

organic phase was washed with water (3£20 ml) and satd.

brine (10 ml), dried over MgSO₄, and evaporated in vacuo

to afford a yellow foam (980 mg). Puri®cation as described

in the ®rst method gave the title compound 12 (884 mg,

85%): white crystalline solid; mp 115±1168C (from

EtOAc/petrol 40/60); (Found: C, 63.16; H, 4.31; N, 6.30.

Calcd for C₂₃H₂₀N₂O₅S: C, 63.28; H, 4.63; N, 6.42%); R_f

0.50 (C₆H₆/EtOAc, 9:1); [a]²_D⁵1195 (c 1.8 in CHCl₃); FT

IR (CHCl₃) n_max/cm²¹1778s br (b-lactam, phthalimide),

1728s (phthalimide, ester), and 1390s; ¹H NMR

(200 MHz, CDCl₃) d_H1.43 and 1.64 (2£3H, 2£s,

2£CH₃), 4.67 (1H, s, 2-H), 5.23 (2H, s, CH₂Ph), 5.40 and

5.58 (2£1H, 2£d, J2 Hz, 5-H and 6-H), 7.36±7.39

based on recovered ester 12). Penam 26: white crystalline

solid, mp 127±1288C (from petrol 40/60±EtOAc); (Found:

C, 63.49; H, 4.39; N, 6.38. Calcd for C₂₃H₂₀N₂O₅S: C,

63.28; H, 4.63; N, 6.42%); R_f0.30 (C₆H₆/EtOAc, 10:1);

[a]²_D⁵2282 (c 1.1 in CHCl₃); FT IR (CHCl₃) n_max/cm²¹

1796s, 1780m (b-lactam, phthalimide), 1730s (phthalimide,

ester), and 1389s; ¹H NMR (200 MHz, CDCl₃) d_H1.69 and

1.70 (2£3H, 2£s, 2£CH₃), 4.03 (1H, s, 2-H), 5.27 and 5.62

(2£1H, 2£d, J4 Hz, 5-H and 6-H), 5.30 and 5.36 (2£1H,

ABq, J12 Hz, CH₂Ph), 7.34±7.49 (5H_arom, s, Ph), and

1

7.74±7.92 (4H_arom, m, Pht); H NMR n.O.e. (500 MHz,

CDCl₃, frequency cycling) d_H1.69 b-CH₃!2-H (17%),

!5-H (3.0%); 1.70 a-CH₃!2-H (3.0%); 4.03 2-H!a-

CH₃and b-CH₃(5.5%), !5-H (5.5%); 5.27 5-H!a-CH₃

and b-CH₃(7.5%), !2-H (6.0%), !6-H (15%); and 5.62

6-H!a-CH₃and b-CH₃(2.0%), !5-H (13%); ¹³C NMR

(50.3 MHz, CDCl₃) d_C27.25 and 30.03 (q, 2£CH₃), 59.01,

63.20, and 72.95 (d, 2-C, 5-C, and 6-C), 64.94 (s, 3-C),

67.77 (t, CH₂Ph), 124.0 (d, Pht 3, 6-CH's), 128.8 and

129.0 (d, Ph CH's), 131.7 (s, Pht ipso C), 134.7 (d, Pht 4,

5-CH's), 135.1 (s, Ph ipso C), 165.1, 165.4, and 166.9 (s,

3£CvO); and LRMS [DCI (NH₃)] m/z 454 (MNH₄¹, 15%),

437 (MH¹, 50), 250 (MH¹2PhtCHCO, 100), 187

(PhtCHCO¹, 20), and 91 (C₇H₇¹, 95).

1

(5H_arom, m, Ph), and 7.76±7.93 (4H_arom, m, Pht); H NMR

n.O.e. (500 MHz, CDCl₃) d_H1.43 a-CH₃!b-CH₃(7.5%),

!2-H (9.0%), !5-H (4.5%); 1.64 b-CH₃!a-CH₃(6.5%),

!2-H (20%), !6-H (12%), !5-H (1.5%); 4.67 2-H!a-

CH₃(1.5%), !b-CH₃(4.0%), !6-H (1.0%), !5-H (1.5%);

5.40 6-H!b-CH₃(2.0%), !5-H (3.5%); and 5.58 5-H!2-

H (1.0%), !6-H (3.0%); ¹³C NMR (50.3 MHz, CDCl₃) d_C

25.19 and 34.47 (q, 2£CH₃), 64.35 and 69.09 (d, 2-C, 5-C,

and 6-C; two signals overlapped), 67.15 (s, 3-C), 67.31 (t,

CH₂Ph), 124.1 (d, Pht 3, 6-CH's), 128.5, 128.7, and 128.9

(d, Ph CH's), 131.1 (s, Pht ipso C), 134.9 (d, Pht 4, 5-CH's),

135.1 (s, Ph ipso C), 166.7, 167.3, and 167.6 (s, 3£CvO);

and LRMS [DCI (NH₃)] m/z 454 (MNH₄¹, 15%), 437

(MH¹, 25), 250 (MH¹2PhtCHCO, 100), 187 (PhtCHCO¹,

5), and 91 (C₇H₇¹, 40).

According to the general procedure, the following syntheses

were also carried out.

Benzyl (2)-(2S,5S,6R)-3,3-dimethyl-7-oxo-6-phthalimido-

4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

(15).

Chlorinolysis of ester 11 (2.40 g, 5.50 mmol) gave a mixture

of two b-lactams, 13 and 14, in a ratio of ca. 4:1 as a light

yellow foam (2.81 g). Major product: benzyl (2S)-2-

[(3R,4S)-4-chloro-3-phthalimido)-2-oxazetidin-1-yl]-2-(1-

Benzyl (2)-(2S,5S,6S)-3,3-dimethyl-7-oxo-6-phthalimido-

4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (26). The

general procedure for the Kukolja protocol. A solution of

ester 12 (1.55 g, 3.56 mmol) in CH₂Cl₂(40 ml) and CCl₄

(20 ml) was treated with the equimolar amount of chlorine

(3.56 mmol, solution in CCl₄) and stirred at room tempera-

ture for 30 min. The solvents were evaporated in vacuo to

give a mixture of two compounds, 24 and 25, in a ratio of ca.

4:1 as a yellow foam. Major product: benzyl (2S)-2-

[(3S,4R)-4-chloro-3-phthalimido)-2-oxazetidin-1-yl]-2-(1-

1

chlorothio-1-methylethyl)-acetate 13; H NMR (200 MHz,

CDCl₃) d_H1.72 and 1.74 (2£3H, 2£s, 2£CH₃), 4.65 (1H, s,

2-H), 5.27 and 5.37 (2£1H, ABq, J12 Hz, CH₂Ph), 5.55

and 6.04 (2£1H, 2£d, J1.5 Hz, 3-H and 4-H), 7.36±7.46

(5H_arom, m, Ph), and 7.79±7.95 (4H_arom, m, Pht). Minor

product: benzyl (2S)-2-[(3R,4R)-4-chloro-3-phthalimido)-

2-oxazetidin-1-yl]-2-(1-chlorothio-1-methylethyl)-acetate

1

chlorothio-1-methylethyl)-acetate 24; H NMR (200 MHz,

14; H NMR (200 MHz, CDCl₃) d_H1.61 and 1.74 (2£3H,

CDCl₃) d_H1.76 (6H, s, 2£CH₃), 4.41 (1H, s, 2-H), 5.24 and

5.32 (2£1H, ABq, J12 Hz, CH₂Ph), 5.49 and 6.12 (2£1H,

2£d, J1.5 Hz, 3-H and 4-H), 7.42 (5H_arom, s, Ph), and

7.79±7.94 (4H_arom, m, Pht). Minor product: benzyl (2S)-2-

[(3S,4S)-4-chloro-3-phthalimido)-2-oxazetidin-1-yl]-2-(1-

2£s, 2£CH₃), 4.79 (1H, s, 2-H), 5.26 and 5.38 (2£1H, ABq,

J12 Hz, CH₂Ph), 5.62 and 6.23 (2£1H, 2£d, J4 Hz, 3-H

and 4-H), 7.36±7.46 (5H_arom, m, Ph), and 7.79±7.95 (4H_arom

,

m, Pht). Cyclisation in the presence of anhydrous SnCl₂

(1.10 g, 5.81 mmol) gave an off-white foam (2.42 g)

containing two compounds, 15 and 11, in a ratio of ca.

16:1. Puri®cation by ¯ash chromatography (silica gel, petrol

40/60±EtOAc, 6:4) afforded penam 15 (2.22 g, 92.5%):

white foam; HRMS Calcd for C₂₃H₂₁O₅N₂S (MH¹)

437.1188, found 437.1171; R_f0.50 (petrol 40/60±EtOAc,

6:4); [a]²_D⁵2123 (c 1.0 in CHCl₃) {lit.¹⁴[a]²_D⁵2104 (c

1.0 in CHCl₃)}; FT IR (CHCl₃) n_max/cm²¹1790s and 1780m

(b-lactam, phthalimide), 1728s (phthalimide, ester), and

1391s; ¹H NMR (200 MHz, CDCl₃) d_H1.39 and 1.66

(2£3H, 2£s, 2£CH₃), 3.92 (1H, s, 2-H), 5.23 and 5.30

(2£1H, ABq, J12 Hz, CH₂Ph), 5.44 and 5.56 (2£1H,

2£d, J2 Hz, 5-H and 6-H), 7.36±7.41 (5H_arom, m, Ph),

1

chlorothio-1-methylethyl)-acetate 25; H NMR (200 MHz,

CDCl₃) d_H1.70 and 1.75 (2£3H, 2£s, 2£CH₃), 4.49 (1H, s,

2-H), 5.21 and 5.34 (2£1H, ABq, J12 Hz, CH₂Ph), 5.53

and 5.94 (2£1H, 2£d, J4 Hz, 3-H and 4-H), 7.42 (5H_arom

,

s, Ph), and 7.79±7.94 (4H_arom, m, Pht).

The foam was dissolved in THF (50 ml) and treated with

anhydrous SnCl₂(715 mg, 3.77 mmol). The mixture was

stirred at room temperature for 2 h and then the solvent

was evaporated in vacuo. The residual oil was dissolved

in EtOAc (50 ml) and washed with water (3£50 ml) and

satd. brine (50 ml). The organic phase was dried over

MgSO₄and evaporated in vacuo to give a white foam

(1.47 g). Flash chromatography (silica gel, benzene/

EtOAc, 10:1) afforded the starting material 12 (837 mg,

54%) and the title compound 26 (470 mg, 30 or 66% if

and 7.75±7.94 (4H_arom

,

m, Pht); ¹H NMR n.O.e.

(500 MHz, CDCl₃) d_H1.39 a-CH₃!b-CH₃(4.5%), !2-H

(6.0%), !6-H (4.5%); 1.66 b-CH₃!a-CH₃(8.0%), !2-H

(18%), !5-H (17%); 3.92 2-H!b-CH₃(4.5%), !5-H

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6065

(2.0%); 5.44 5-H!b-CH₃(3.5%), !2-H (2.0%), !6-H

(3.5%); and 5.56 6-H!5-H (1.5%); ¹³C NMR (50.3 MHz,

CDCl₃) d_C24.52 and 31.24 (q, 2£CH₃), 59.70, 66.40, and

70.15 (d, 2-C, 5-C, and 6-C), 66.14 (s, 3-C), 67.88 (t,

CH₂Ph), 124.0 (d, Pht 3, 6-CH's), 128.9 and 129.1 (d, Ph

CH's), 131.7 (s, Pht ipso C), 134.9 (d, Pht 4, 5-CH's), 134.9

(s, Ph ipso C), 166.0, 166.8, and 166.9 (s, 3£CvO); and

LRMS [DCI (NH₃)] m/z 454 (MNH¹₄, 5%), 437 (MH¹, 5),

250 (MH¹2PhtCHCO, 100), 187 (PhtCHCO¹, 5), and 91

(C₇H₇¹, 40).

light yellow foam (470 mg). Major product: diphenylmethyl

(2S)-2-[(3R,4S)-4-chloro-3-phthalimido)-2-oxazetidin-1-

yl]-2-(1-chlorothio-1-methylethyl)-acetate 32; ¹H NMR

(200 MHz, CDCl₃) d_H1.66 and 1.71 (2£3H, 2£s,

2£CH₃), 4.45 (1H, s, 2-H), 5.42 and 6.08 (2£1H, 2£d,

J1.5 Hz, 3-H and 4-H), 6.99 (1H, s, CHPh₂), 7.31±7.51

(10H_arom, m, 2£Ph), and 7.77±7.95 (4H_arom, m, Pht). Minor

product: diphenylmethyl (2S)-2-[(3R,4R)-4-chloro-3-phthali-

mido)-2-oxazetidin-1-yl]-2-(1-chlorothio-1-methylethyl)-

1

acetate 33; H NMR (200 MHz, CDCl₃) d_H1.65 and 1.77

(2£3H, 2£s, 2£CH₃), 4.51 (1H, s, 2-H), 5.47 and 5.79

(2£1H, 2£d, J4 Hz, 3-H and 4-H), 6.99 (1H, s, CHPh₂),

7.31±7.51 (10H_arom, m, 2£Ph), and 7.77±7.95 (4H_arom, m,

Pht). Cyclisation in the presence of anhydrous SnCl₂

(158 mg, 0.84 mmol) gave a pale yellow foam (357 mg).

Puri®cation by ¯ash chromatography (silica gel, petrol 40/

60/EtOAc, 7:3) afforded the starting material 31 (158 mg,

39%) and the title compound 34 (60 mg, 14.5 or 24% if

based on recovered 31). Penam 34: white crystalline solid;

mp 175±1768C (from EtOAc/petrol 40/60); (Found: C,

68.15; H, 4.70; N, 5.50. Calcd for C₂₉H₂₄N₂O₅S: C, 67.95;

H, 4.72; N, 5.47%); R_f0.35 (petrol 40/60/EtOAc, 7:3);

Methyl (2)-(2S,5S,6S)-3,3-dimethyl-7-oxo-6-phthalimido-

4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

(30).

Chlorinolysis of ester 27^§§(501 mg, 1.39 mmol) gave a

mixture of two monocyclic b-lactams, 28 and 29, in a

ratio of ca. 5:1 as a light yellow foam (585 mg) Major

product: methyl (2S)-2-[(3R,4S)-4-chloro-3-phthalimido)-

2-oxazetidin-1-yl]-2-(1-chlorothio-1-methylethyl)-acetate

1

28; H NMR (200 MHz, CDCl₃) d_H1.68 and 1.72 (2£3H,

2£s, 2£CH₃), 3.83 (3H, s, CO₂CH₃), 4.34 (1H, s, 2-H), 5.52

and 6.12 (2£1H, 2£d, J1.5 Hz, 3-H and 4-H), and 7.75±

7.91 (4H_arom, m, Pht). Minor product: methyl (2S)-2-

[(3R,4R)-4-chloro-3-phthalimido)-2-oxazetidin-1-yl]-2-(1-

[a]²_D⁵2216 (c 0.65 in acetone); FT IR (KBr disc) n_max

/

1

chlorothio-1-methylethyl)-acetate 29; H NMR (200 MHz,

cm²¹1805m (phthalimide), 1779s (b-lactam), 1754s

(phthalimide), 1727s (ester), 1399s, and 1175s; H NMR

1

CDCl₃) d_H1.68 and 1.72 (2£3H, 2£s, 2£CH₃), 3.83 (3H, s,

CO₂CH₃), 4.49 (1H, s, 2-H), 5.65 and 6.01 (2£1H, 2£d,

J4 Hz, 3-H and 4-H), and 7.75±7.91 (4H_arom, m, Pht).

Cyclisation in the presence of anhydrous SnCl₂(279 mg,

1.47 mmol) gave a pale yellow foam (495 mg) containing

two compounds, 27 and 30, in a ratio of ca. 1.5:1. Separation

and puri®cation by ¯ash chromatography (silica gel,

CH₂Cl₂/EtOAc, 35:1) gave penam 27 (275 mg, 55%) and

the title compound 30 (163 mg, 33% or 72% if base on

recovered ester 27). Penam 30: white crystalline solid; mp

164±1668C (from EtOAc/petrol 30/40); (Found: C, 56.88;

H, 4.28; N, 7.65. Calcd for C₁₇H₁₆N₂O₅S: C, 56.66; H, 4.47;

N, 7.77%); R_f0.40 (CH₂Cl₂/EtOAc, 35:1); [a]²_D⁵2334 (c

1.2 in CHCl₃); FT IR (KBr disc) n_max/cm²¹1809m, 1797s

(phthalimide), 1780s (b-lactam), 1752s (phthalimide),

(200 MHz, CDCl₃) d_H1.63 and 1.73 (2£3H, 2£s,

2£CH₃), 4.10 (1H, s, 2-H), 5.27 and 5.66 (2£1H, 2£d,

J4 Hz, 5-H and 6-H), 7.07 (1H, s, CHPh₂), 7.28±7.54

(10H_arom, m, 2£Ph), and 7.71±7.92 (4H_arom, m, Pht); ¹³C

NMR (126 MHz, CDCl₃) d_C27.41 and 29.96 (2£CH₃),

59.06, 63.07, 65.13, 73.37, and 79.36 (2-C, 3-C, 5-C, 6-C,

and CHPh₂), 123.8 (Pht 3, 6-CH's), 126.9, 127.7, 128.0,

128.3, 128.5, and 128.7 (Ph's CH's), 131.5 (Pht ipso C),

134.5 (Pht 4, 5-CH's), 139.3 (Ph ipso C), 164.2, 165.0,

and 166.6 (3£CvO); LRMS [DCI (NH₃)] m/z 530

(MNH₄¹, ,1%), 512 (M¹, ,1), 326 (MH¹2PhtCHCO,

,1), and 167 (Ph₂CH¹, 100); and LRMS (FAB, 1) m/z

535 (MNa¹, 20) and 167 (Ph₂CH¹, 100).

1

1731s (ester), 1388s, 1252m, 1222m, 901m, and 715s; H

Diphenylmethyl (2S,5S)-3,3-dimethyl-7-oxo-4-thia-1-aza-

bicyclo[3.2._k0_k]heptane-2-carboxylate (46). Chlorinolysis

NMR (200 MHz, CDCl₃) d_H1.71 and 1.73 (2£3H, 2£s,

2£CH₃), 3.91 (3H, s, CO₂CH₃), 4.01 (1H, s, 2-H), 5.29

and 5.63 (2£1H, 2£d, J4 Hz, 5-H and 6-H), and 7.73±

7.92 (4H_arom, m, Pht); ¹³C NMR (126 MHz, CDCl₃) d_C

27.23 and 30.25 (2£CH₃), 52.55 (CO₂CH₃), 59.02, 63.46,

64.93, and 72.96 (2-C, 3-C, 5-C, and 6-C), 123.8 (Pht 3, 6-

CH's), 131.6 (Pht ipso C), 134.4 (Pht 4, 5-CH's), 165.0,

165.5 and 166.5 (3£CvO); and LRMS [DCI (NH₃)] m/z

378 (MNH₄¹, 15%), 361 (MH¹, 30), 204 (10), 187

(PhtCHCO¹, 10), 174 (MH¹2PhtCHCO, 100), and 132

(10).

38,39

of ester 43

(455 mg, 1.24 mmol) gave two com-

pounds, diphenylmethyl (2S)-2-[(4S and 4R)-4-chloro-2-

oxazetidin-1-yl]-2-(1-chlorothio-1-methylethyl)-acetates,

44 and 45, in a ratio of ca. 2.5:1 as a thick yellow oil

1

(517 mg). Major product 44: H NMR (200 MHz, CDCl₃)

d_H1.55 and 1.59 (2£3H, 2£s, 2£CH₃), 3.18 (1H, dd,

J15.5 Hz, J1.5 Hz, 3-H trans to 4-H), 3.57 (1H, dd,

J15.5 Hz, J4 Hz, 3-H cis to 4-H), 4.36 (1H, s, 2-H),

5.80 (1H, dd, J4 Hz, J1.5 Hz, 4-H), 6.94 (1H, s,

CHPh₂), and 7.28±7.52 (10H_arom, m, 2£Ph). Minor product

1

45: H NMR (200 MHz, CDCl₃) d_H1.58 and 1.61 (2£3H,

Diphenylmethyl

(2)-(2S,5S,6S)-3,3-dimethyl-7-oxo-6-

2£s, 2£CH₃), 3.18 (1H, dd, J15.5 Hz, J1.5 Hz, 3-H

phthalimido-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxy-

late (34). Chlorinolysis of ester 31^§§(405 mg, 0.79 mmol)

gave two compounds, 32 and 33, in a ratio of ca. 9:1, as a

kk

Penam 35 was obtained from (6S)-bromopenicillanic acid^38,39by esteri-

®cation with BnBr (Et₃N, DMF, rt, 15 h, 67%) followed by dehalogenation

with n-Bu₃SnH (PhH, re¯ux, 15 h, 97%) or from 6,6-dibromopenicillanic

acid⁴⁰by benzylation with BnBr (Et₃N, DMF, 10 h, 63%) followed by

reductive dehalogenation with n-Bu₃SnH (PhH, re¯ux, 24 h, 81%). Simi-

larly, penam 43 was prepared from (6S)-bromopenicillanic acid by ester-

i®cation with Ph₂CN₂(CH₂Cl₂, 5 min, 86%) followed by reduction with n-

Bu₃SnH (AIBN, PhH, rt, 15 h, 59%). Penam 39 was prepared from (6S)-

bromopenicillanic acid by esteri®cation with CH₂N₂(Et₂O, 5 min, 83%)

followed by catalytic hydrogenation (H₂, Pd/CaCO₃, 1 atm, 3 h, 62%).

§§

Penam 27 was obtained from acid 10 by esteri®cation with CH₂N₂

(CH₂Cl₂, rt, 5 min, 93%) followed by treatment of the resulting ester 16

with a catalytic amount of DBU (CH₂Cl₂, rt, 90 min, 98%). Penam 31 was

prepared in a one-pot process from acid 10 by esteri®cation with Ph₂CN₂

(CH₂Cl₂, 5 min, rt) followed by a catalytic amount of DBU (CH₂Cl₂, rt,

90 min, 69% overall).

6066

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

trans to 4-H), 3.52 (1H, dd, J15.5 Hz, J4 Hz, 3-H cis to

4-H), 4.49 (1H, s, 2-H), 5.55 (1H, dd, J4 Hz, J1.5 Hz,

4-H), 6.94 (1H, s, CHPh₂), and 7.28±7.52 (10H_arom, m,

2£Ph). Cyclisation in the presence of anhydrous SnCl₂

(249 mg, 1.31 mmol) gave a thick yellow oil containing

two compounds; the starting material 43 and its 5-epimer

46 in a ratio of ca. 8:1. Separation and puri®cation by ¯ash

chromatography (silica gel, petrol 40/60/EtOAc, 6:1)

afforded the starting material 43 (174 mg, 38%) and

penam 46 (18 mg, 4 or 6.5% if based on recovered substrate

43). Penam 46: white solid; HRMS Calcd for C₂₁H₂₅O₃N₂S

(MNH₄¹) 385.1603, found 385.1586; R_f0.25 (petrol 40/60/

EtOAc, 6:1); ¹H NMR (200 MHz, CDCl₃) d_H1.29 and 1.62

(2£3H, 2£s, 2£CH₃), 3.18 (1H, dd, J16 Hz, J2 Hz, 6-a-

H), 3.43 (1H, dd, J16 Hz, J4 Hz, 6-b-H), 3.85 (1H, s,

2-H), 5.08 (1H, dd, J4 Hz, J2 Hz, 5-H), 6.99 (1H, s,

CHPh₂), and 7.27±7.40 (10H_arom, m, 2£Ph); ¹H NMR

n.O.e. (500 MHz, CDCl₃) d_H1.29 a-CH₃!b-CH₃(14%),

!6-a-H (7.5%), !2-H (13%); 1.62 b-CH₃!a-CH₃

(7.0%), !2-H (22%), !5-H (11%); 3.18 6-a-H!6-b-H

(26%); 3.43 6-b-H!6-a-H (25%), !5-H (5.5%); 3.85

2-H!b-CH₃(10%), !5-H (3.0%); and 5.08 5-H!a!b-

CH₃(4.0%), !6-b-H (5.5%), !2-H (2.0%); ¹³C NMR

(126 MHz, CDCl₃) d_C25.52, 30.30, 45.21, 58.15, 65.38,

71.50, 78.88, 127.0, 127.9, 128.0, 128.3, 128.4, 128.5,

139.2, 139.3, 165.6, and 169.9; and LRMS [CI (NH₃)] m/z

385 (MNH₄¹, ,1%), 167 (Ph₂CH¹, 100), and 114

(MH¹2CH₂CO±CO₂CHPh₂, 5).

(7.0%), !2-H (19%), !5-H (13%); 3.20 6-a-H!6-b-H

(26%); 3.42 6-b-H!6-a-H (27%), !5-H (6.0%); 3.79

2-H!b-CH₃(7.5%), !5-H (3.5%); and 5.09 5!b-CH₃

(2.5%), !6-b-H (5.0%), !2-H (2.5%); ¹³C NMR

(50.3 MHz, CDCl₃) d_C25.27 and 30.42 (q, 2£CH₃), 44.85

(t, 6-CH₂), 58.35 and 71.72 (d, 2-C and 5-C), 65.38 (s, 3-C),

67.60 (t, CH₂Ph), 128.8 and 129.0 (d, Ph CH's), 135.2 (s, Ph

ipso C), 166.7 and 170.4 (s, 2£CvO); and LRMS [CI

(NH₃)] m/z 309 (MNH₄¹, 5%), 292 (MH¹, 100), 250

(MH¹2CH₂CO, 35), and 114 (MH¹2CH₂CO±CO₂CH₂Ph,

20), and 91 (C₇H₇¹, 45).

Methyl

(2)-(2S,5S)-3,3-dimethyl-7-oxo-4-thia-1-aza-

bicyclo[3.2.0]heptane-2-carboxylate (42). Chlorinolysis

of ester 39^kk(147 mg, 0.68 mmol) gave a brown oil

(174 mg) containing two compounds, methyl (2S)-2-[(4S

and 4R)-4-chloro-2-oxazetidin-1-yl]-2-(1-chlorothio-1-

methylethyl)-acetates, 40 and 41, in a ratio of ca. 2:1.

1

Major product 40: H NMR (200 MHz, CDCl₃) d_H1.54

and 1.66 (2£3H, 2£s, 2£CH₃), 3.23 (1H, dd, J17 Hz,

J1.5 Hz, 3-H trans to 4-H), 3.61 (1H, dd, J17 Hz,

J4 Hz, 3-H cis to 4-H), 3.79 (3H, s, CO₂CH₃), 4.22 (1H,

s, 2-H), and 5.88 (1H, dd, J4 Hz, J1.5 Hz, 4-H). Minor

1

product 41: H NMR (200 MHz, CDCl₃) d_H1.60 and 1.61

(2£3H, 2£s, 2£CH₃), 3.22 (1H, dd, J17 Hz, J1.5 Hz,

3-H trans to 4-H), 3.64 (1H, dd, J17 Hz, J4 Hz, 3-H

cis to 4-H), 3.78 (3H, s, CO₂CH₃), 4.46 (1H, s, 2-H), and

5.74 (1H, dd, J4 Hz, J1.5 Hz, 4-H). FT IR (CHCl₃) n_max

/

cm²¹1784s (b-lactam) and 1745s (ester). Cyclisation with

anhydrous SnCl₂(137 mg, 0.73 mmol) gave a light yellow

oil (135 mg) containing the starting material 39 and its

5-epimer 42 in a ratio of ca. 5:1. Separation and puri®cation

by ¯ash chromatography (silica gel, petrol 40/60/EtOAc,

7:3) gave the starting material 39 (104 mg, 71%) and

penam 42 (31 mg, 21 or 72% if based on recovered substrate

39). Penam 42: light yellow solid; HRMS Calcd for

C₉H₁₄NO₃S (MH¹) 216.0711, found 216.0694; R_f0.36

(petrol 40/60/EtOAc, 7:3); [a]²_D⁵2174 (c 0.45 in

CHCl₃); FT IR (CHCl₃) n_max/cm²¹1779s (b-lactam) and

Benzyl (2)-(2S,5S)-3,3-dimethyl-7-oxo-4-thia-1-azabicy-

clo[3.2.0]heptane-2-carboxylate (38). Chlorinolysis of

40

ester 35^kk

(440 mg, 1.51 mmol) gave two compounds,

benzyl (2S)-2-[(4S and 4R)-4-chloro-2-oxazetidin-1-yl]-2-

(1-chlorothio-1-methylethyl)-acetates, 36 and 37, in a ratio

of ca. 2:1, as a yellow oil (507 mg). Major product 36: H

1

NMR (200 MHz, CDCl₃) d_H1.56 and 1.65 (2£3H, 2£s,

2£CH₃), 3.21 (1H, dd, J15.5 Hz, J1 Hz, 3-H trans to

4-H), 3.61 (1H, dd, J15.5 Hz, J4 Hz, 3-H cis to 4-H),

4.29 (1H, s, 2-H), 5.20 and 5.29 (2£1H, ABq, J12 Hz,

CH₂Ph), 5.86 (1H, dd, J4 Hz, J1 Hz, 4-H), and 7.39

1

1748m (ester); H NMR (200 MHz, CDCl₃) d_H1.51 and

1

(5H_arom, s, Ph). Minor product 37: H NMR (200 MHz,

1.64 (2£3H, 2£s, 2£CH₃), 3.20 (1H, dd, J16 Hz,

J2.5 Hz, 6-a-H), 3.42 (1H, ddd, J16 Hz, J4 Hz,

J1.5 Hz, 6-b-H), 3.76 (1H, d, J1.5 Hz, 2-H), 3.82 (3H,

s, CO₂CH₃), and 5.08 (1H, dd, J4 Hz, J2.5 Hz, 5-H); ¹H

NMR n.O.e. (500 MHz, CDCl₃) d_H1.51 a-CH₃!b-CH₃

(5.0%), !6-a-H (4.0%), !2-H (4.0%); 1.64 b-CH₃!a-

CH₃(9.0%), !2-H (12%), !5-H (7.0%); 3.20 6-a-H!6-

b-H (18%); 3.42 6-b-H!6-a-H (21%), !5-H (6.5%); 3.76

2-H!b-CH₃(5.0%), !5-H (3.0%); and 5.08 5-H!b-CH₃

(4.0%), !6-b-H (5.0%); ¹³C NMR (126 MHz, CDCl₃) d_C

25.45, 30.45, 44.97, 52.35, 58.33, 65.13, 71.31, 166.9, and

170.1; and LRMS [CI (NH₃)] m/z 233 (MNH₄¹, 10%), 216

(MH¹, 100), 174 (MH¹2CH₂CO, 35), and 114 (10).

CDCl₃) d_H1.62 (6H, s, 2£CH₃), 3.21 (1H, dd, J15.5 Hz,

J1.5 Hz, 3-H trans to 4-H), 3.59 (1H, dd, J15.5 Hz,

J4 Hz, 3-H cis to 4-H), 4.48 (1H, s, 2-H), 5.19 and 5.27

(2£1H, ABq, J12 Hz, CH₂Ph), 5.70 (1H, dd, J4 Hz,

J1.5 Hz, 4-H), and 7.39 (5H_arom, s, Ph). FT IR (CHCl₃)

n

_max/cm²¹1784s (b-lactam) and 1742s (ester). Cyclisation

with anhydrous SnCl₂(304 mg, 1.60 mmol) afforded a

mixture of the starting material 35 and its 5-epimer 38, in

a ratio of ca. 3:1. Separation and puri®cation by ¯ash

chromatography (silica gel, CH₂Cl₂/EtOAc, 30:1) gave the

starting material 35 (216 mg, 49%) and penam 38 (87 mg,

20 or 39% if based on recovered substrate 35). Penam 38:

colourless oil; HRMS Calcd for C₁₅H₁₈NO₃S (MH¹)

292.1024, found 292.1007; R_f0.70 (CH₂Cl₂/EtOAc, 30:1);

[a]²_D⁵2191 (c 1.0 in CHCl₃); FT IR (CHCl₃) n_max/cm²¹

Benzyl (2)-(2S,4S,5S,6S)-3,3-dimethyl-7-oxo-6-phthali-

mido-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

4-oxide (49). Following the method for the preparation of

ester 26, penicillin 12 (1.01 g, 2.31 mmol) was converted to

a mixture of esters 12 and 26 in a ratio of ca. 1:2, respec-

tively. The mixture was dissolved in acetone (50 ml),

cooled in an ice bath, and treated with a stream of ozone

until ester 26 had reacted (¹H NMR, 200 MHz). The solvent

was evaporated in vacuo to give a white foam (999 mg).

1

1779s (b-lactam) and 1745m (ester); H NMR (200 MHz,

CDCl₃) d_H1.44 and 1.63 (2£3H, 2£s, 2£CH₃), 3.20 (1H,

dd, J15.5 Hz, J2 Hz, 6-a-H), 3.42 (1H, dd, J15.5 Hz,

J4 Hz, 6-b-H), 3.79 (1H, s, 2-H), 5.09 (1H, dd, J4 Hz,

J2 Hz, 5-H), 5.24 (2H, s, CH₂Ph), and 7.35±7.43 (5H_arom

,

1

m, Ph); H NMR n.O.e. (500 MHz, CDCl₃) d_H1.44 a-

CH₃!b-CH₃(3.0%), !2-H (5.0%); 1.63 b-CH₃!a-CH₃

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6067

Puri®cation by ¯ash chromatography (silica gel, CH₂Cl₂/

EtOAc, 4:1) afforded the starting material 12 (610 mg,

60%) and sulfoxide 49 (265 mg, 25 or 64% if based on

recovered penam 12). Sulfoxide 49: white crystalline

solid; mp 125±1268C (from EtOAc); (Found: C, 61.29; H,

4.70; N, 6.14. Calcd for C₂₃H₂₀N₂O₆S: C, 61.04; H, 4.46; N,

6.19%); R_f0.35 (CH₂Cl₂/EtOAc, 8:2); [a]²_D⁵274.9 (c 1.1

in CHCl₃); FT IR (CHCl₃) n_max/cm²¹1809s (b-lactam),

1780m (phthalimide), 1732s (phthalimide, ester), 1309s,

5.24 and 5.33 (2£1H, ABq, J12 Hz, CH₂Ph), 7.36±7.42

(5H_arom, m, Ph), and 7.76±7.92 (4H_arom, m, Pht); ¹³C NMR^¶¶

(50.3 MHz, CDCl₃) d_C20.25 (q, CH₃), 31.64 (t, SCH₂),

59.37 (d, 6-C and 7-C, overlapped), 67.27 (t, CH₂Ph),

124.1 (d, Pht 3, 6-CH's), 128.5 and 128.8 (d, Ph CH's),

131.7 (s, Pht ipso C), 134.9 (d, Pht 4, 5-CH's), 135.6 (s,

Ph ipso C), 161.4, 162.2, and 167.2 (s, 3£CvO); and LRMS

[DCI (NH₃)] m/z 452 (MNH₄¹, 10%), 435 (MH¹, 60), 248

(MH¹2PhtCHCO, 85), 187 (PhtCHCO¹, 10), and 91

(C₇H₇¹, 100).

1

and 1054m br (sulfoxide); H NMR (200 MHz, CDCl₃) d_H

1.54 and 1.61 (2£3H, 2£s, 2£CH₃), 4.30 (1H, s, 2-H), 4.56

and 5.93 (2£1H, 2£d, J4 Hz, 5-H and 6-H), 5.30 and 5.39

(2£1H, ABq, J12 Hz, CH₂Ph), 7.36±7.49 (5H_arom, m, Ph),

and 7.76±7.94 (4H_arom, m, Pht); ¹H NMR n.O.e. (500 MHz,

CDCl₃) d_H1.54 b-CH₃!2-H (16%), !5-H (6.5%); 1.61 a-

CH₃!2-H (2.5%); 4.30 2-H!b-CH₃(4.0%), !5-H (4.5%);

4.56 5-H!b-CH₃(1.5%), !2-H (5.0%), !6-H (16%); and

5.93 6-H!5-H (14%); ¹³C NMR (50.3 MHz, CDCl₃) d_C

19.77 and 20.51 (q, 2£CH₃), 54.96, 63.34, and 84.32 (d,

2-C, 5-C, and 6-C), 68.10 (t, CH₂Ph), 73.85 (s, 3-C),

124.2 (d, Pht 3, 6-CH's), 128.9 and 129.2 (d, Ph CH's),

131.6 (s, Pht ipso C), 134.8 (s, Ph ipso C), 135.1 (d, Pht

4, 5-CH's), 163.5, 164.9, and 166.7 (s, 3£CvO); and

LRMS [DCI (NH₃)] m/z 452 (M¹, 30%), 435

(MH¹2H₂O, 50), 248 (MH¹2PhtCHCO2H₂O, 100), 187

(PhtCHCO¹, 40), and 91 (C₇H¹₇, 100).

Benzyl (2)-(6S,7S)-7-amino-3-methyl-8-oxo-5-thia-1-aza-

bicyclo[4.2.0]oct-2-ene-2-carboxylate (51). The title

compound was prepared according to the following

methods.

The ®rst method. To a cooled to 2788C solution of cepha-

losporin 50 (1.77 g, 4.08 mmol) in DMF (50 ml) was added

1 M N₂H₄´H₂O in DMF (5.9 ml, 5.9 mmol). The cold bath

was removed and the reaction mixture stirred for 30 min.

The phthalhydrazide complex was decomposed by addition

of 1 M HCl (9.5 ml, 9.5 mmol) and the solvents were evapo-

rated in vacuo. The residual oil was dissolved, with vigorous

stirring, in water (80 ml) and the insoluble phthalhydrazide

removed by ®ltration through a thin pad of Celite^w. The

aqueous ®ltrate was layered with EtOAc (100 ml) and basi-

®ed with satd. NaHCO₃to pH 8. Phases were separated and

the extraction completed with two additional portions of

EtOAc (2£50 ml). The combined organic extracts were

washed with water (3£50 ml) and satd. brine (50 ml),

dried over MgSO₄, and evaporated in vacuo to give a

thick yellow oil (687 mg). Puri®cation by ¯ash chromato-

graphy (silica gel, CH₂Cl₂/EtOAc, 65:35) gave the title

compound 51 (587 mg, 47%) as a colourless gum which

solidi®ed upon standing. An analytical sample, as a white

crystalline solid, was obtained by double crystallisation

from EtOAc: mp 129±1308C (from EtOAc); (Found: C,

59.37; H, 5.03; N, 9.08. Calcd for C₁₅H₁₆N₂O₃S: C, 59.18;

H, 5.31; N, 9.21%); R_f0.35 (CH₂Cl₂/EtOAc, 65:35);

[a]²_D⁵267.9 (c 1.0 in CHCl₃); FT IR (CHCl₃) v_max/cm²¹

1776s (b-lactam) 1723s (ester), 1393s, and 1357m; ¹H

NMR (200 MHz, CDCl₃) d_H1.76 (2H, br s, NH₂), 2.10

(3H, s, CH₃), 3.19 and 3.51 (2£1H, ABq, J18 Hz,

SCH₂), 4.70 and 4.91 (2£1H, 2£d, J4.5 Hz, 6-H and

7-H), 5.27 (2H, s, CH₂Ph), and 7.34±7.40 (5H_arom, m, Ph);

¹³C NMR (50.3 MHz, CDCl₃) d_C19.98 (q, CH₃), 29.67 (t,

SCH₂), 58.56 and 63.52 (d, 6-C and 7-C), 67.45 (t, CH₂Ph),

128.6, 128.7, and 128.8 (d, Ph CH's), 135.5 (s, Ph ipso C),

162.7 and 169.2 (s, 2£CvO); and LRMS [DCI (NH₃)] m/z

305 (MH¹, 10%), 277 (100), 248 (MH¹2NH₂CHCO, 20),

108 (C₇H₇OH¹, 15), and 91 (C₇H₇¹, 45).

Competitive sulfoxidation of benzyl 6-phthalimido-

penicillanates with ozoneÐgeneral procedure

A solution of `Penam 1' (200 mg, 0.46 mmol) and `Penam

2' (200 mg, 0.46 mmol) in acetone (50 ml) was cooled in an

ice bath and treated, during vigorous stirring, with a stream

of ozone (O₃/O₂mixture, ca. 0.14 mmol O₃/min). The reac-

tion progress was monitored by ¹H NMR (200 MHz) and the

reaction was stopped when ca. 50% of the more reactive

penam was sulfoxidised. The solvent was evaporated in

1

vacuo to give a white foam which was analysed by H

NMR (200 MHz). The results presented in Scheme 5

correspond to the ®nal ratio of the appropriate sulfoxides,

determined from H NMR (200 MHz) spectra.

1

Benzyl (1)-(6S,7S)-3-methyl-8-oxo-7-phthalimido-5-thia-

1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (50). A solu-

tion of sulfoxide 49 (500 mg, 1.11 mmol) and anhydrous

p-toluenesulfonic acid (pTSA, 25 mg, 0.15 mmol) in DMF

(20 ml) was stirred at 1008C until sulfoxide 49 had reacted

(ca. 90 min). The reaction mixture was cooled in an ice bath

and the solvent evaporated in vacuo. The residual yellow oil

was dissolved in EtOAc (50 ml) and washed with satd.

NaHCO₃(50 ml), water (3£50 ml), and satd. brine

(50 ml). The organic layer was dried over MgSO₄and

evaporated in vacuo to give a yellow foam (467 mg). Puri-

®cation by ¯ash chromatography (silica gel, CH₂Cl₂/EtOAc,

15:1) afforded cephalosporin 50 (238 mg, 50%): white crys-

talline solid; mp 147±1498C (from EtOAc); (Found: C,

63.88; H, 3.84; N, 6.42. Calcd for C₂₃H₁₈N₂O₅S: C, 63.58;

H, 4.18; N, 6.42%); R_f0.60 (CH₂Cl₂/EtOAc, 15:1);

[a]²_D⁵111.1 (c 1.1 in CHCl₃); FT IR (CHCl₃) n_max/cm²¹

1785s br (b-lactam, phthalimide) 1726s (ester, phthali-

The second method. A cooled in an ice bath solution of

sulfenamide 72 (100 mg, 0.22 mmol) in CH₂Cl₂(2 ml)

was treated, during vigorous stirring, with a solution of KI

(420 mg, 2.53 mmol) in methanol (5 ml) and glacial AcOH

(0.8 ml, 14 mmol) followed by 1 M Na₂S₂O₃(0.55 ml,

0.55 mmol). The mixture was stirred at 08C until the starting

material 72 disappeared (by TLC analysis, 2 h). After this

time, the reaction mixture was diluted with EtOAc (20 ml)

1

mide), and 1392s; H NMR (200 MHz, CDCl₃) d_H2.33

(3H, s, CH₃), 3.01 and 3.63 (2£1H, ABq, J18 Hz,

¶¶

Signals corresponding to vinylic quaternary carbon atoms of cephems

were frequently not visible in ¹³C NMR.

SCH₂), 5.11 and 5.74 (2£1H, 2£d, J4 Hz, 6-H and 7-H),

6068

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

and washed successively with water (5£10 ml), satd.

NaHCO₃(10 ml), and satd. brine (10 ml). The organic

layer was dried over MgSO₄and evaporated in vacuo to

afford a yellow solid (85 mg) which was puri®ed by ¯ash

chromatography (silica gel, CH₂Cl₂/EtOAc, 65:35) to give

amine 51 (66 mg, 99%), identical [¹H NMR (200 MHz),

TLC, and FT IR] with the product obtained by the ®rst

method.

The ®rst method. Following the method for the preparation

of amide 52, amine 51 (128 mg, 0.42 mmol) was reacted

with phenoxyacetic acid (83 mg, 0.58 mmol) in the

presence of DCC (94 mg, 0.47 mmol). Puri®cation by

¯ash chromatography (silica gel, CH₂Cl₂/EtOAc, 9:1)

gave the title compound 53 (167 mg, 91%): white crystal-

line solid; mp 146±1488C (dec.) (from EtOAc/petrol 40/60);

(Found: C, 62.87; H, 5.38; N, 6.42. Calcd for C₂₃H₂₂N₂O₅S:

C, 62.99; H, 5.07; N, 6.39%); R_f0.80 (CH₂Cl₂/EtOAc, 9:1);

[a]²_D⁵258.6 (c 0.3 in acetone); FT IR (CHCl₃) n_max/cm²¹

3412s br (amide), 1785s (b-lactam), 1723m (ester), 1696s

The third method. A cooled in an ice bath solution of sul-

fenamide 74 (92 mg, 0.22 mmol) in CH₂Cl₂(2 ml) was

treated, during vigorous stirring, with a solution of KI

(420 mg, 2.53 mmol) in MeOH (5 ml) followed by glacial

AcOH (0.8 ml) and 1 M Na₂S₂O₃(0.55 ml, 0.55 mmol). The

mixture was stirred at stirred at 08C until the starting

material 74 had reacted (by TLC analysis, 2 h). The reaction

mixture was diluted with EtOAc (20 ml) and washed with

water (5£20 ml), satd. NaHCO₃(20 ml), and satd. brine

(10 ml). The organic layer was dried over MgSO₄and

evaporated in vacuo to give an off-white solid (76 mg)

which was puri®ed by ¯ash chromatography (silica gel,

CH₂Cl₂/EtOAc, 65:35) to afford amine 51 (65 mg,

,100%), identical [¹H NMR (200 MHz), TLC, and FT

IR] with the product obtained by the ®rst method.

1

(amide), 1521s (amide), and 1424s; H NMR (500 MHz,

CD₃CN) d_H2.07 (3H, s, CH₃), 3.32 and 3.55 (2£1H,

ABq, J18 Hz, SCH₂), 4.59 (2H, s, PhOCH₂), 5.06 (1H,

d, J5 Hz, 6-H), 5.23 and 5.27 (2£1H, ABq, J12.5 Hz,

CH₂Ph), 5.75 (1H, dd, J9 Hz, J5 Hz, 7-H), 6.98±7.04

and 7.32±7.45 (10H_arom, m, 2£Ph), and 7.57 (1H, d,

J9 Hz, NH); ¹³C NMR (126 MHz, CD₃CN) d_C19.41,

29.91, 57.41, 59.07, 67.18, 115.1, 122.2, 122.7, 128.7,

128.8, 128.9, 130.05, 132.6, 136.1, 158.0, 162.8, 164.6,

and 169.3; and LRMS [DCI (NH₃)] m/z 439 (MH¹, 3%),

248 (MH¹2PhOCH₂CONH±CHCO, 100), 192 (PhOCH_2-

CONHCHCOH¹, 3), and 91 (C₇H₇¹, 10).

The second method. A solution of sulfenamide 72 (53 mg,

0.12 mmol) in CH₂Cl₂(10 ml) was cooled in an ice bath,

treated with phenoxyacetyl chloride (48 ml, 0.35 mmol),

and the mixture was stirred at 08C until the starting material

72 had reacted (by TLC analysis, 90 min). The solvent was

evaporated in vacuo and the oily residue puri®ed by ¯ash

chromatography (silica gel, CH₂Cl₂/EtOAc, 9:1) to afford

cephem 53 (43 mg, 85%), identical [¹H NMR (200 MHz),

TLC, and FT IR] with the product obtained by the ®rst

method.

Benzyl (2)-(6S,7S)-3-methyl-8-oxo-7-phenylacetamido-

5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (52).

To an ice bath cooled solution of amine 51 (129 mg,

0.42 mmol) and phenylacetic acid (187 mg, 0.64 mmol) in

THF (5 ml) was added during vigorous stirring a cold

solution of N,N⁰-dicyclohexylcarbodiimide (187 mg,

0.64 mmol) in THF (5 ml). The bath was removed and the

mixture stirred at room temperature for 2 h. The solvent was

evaporated in vacuo and the residual oil dissolved in EtOAc

(20 ml). The N,N⁰-dicyclohexylurea formed was removed

by ®ltration and the ®ltrate washed with satd. NaHCO₃

(20 ml), water (3£20 ml), and satd. brine (20 ml). The

organic layer was dried over MgSO₄and evaporated in

vacuo to give a white foam (165 mg). Puri®cation by ¯ash

chromatography (silica gel, CH₂Cl₂/EtOAc, 9:1) gave

amide 52 (150 mg, 85%): white crystalline solid; mp

146±1488C (dec.) (from EtOAc/petrol 40/60); (Found: C,

65.41; H, 4.87; N, 6.63. Calcd for C₂₃H₂₂N₂O₄S: C, 65.38;

H, 5.26; N, 6.63%); R_f0.65 (CH₂Cl₂/EtOAc, 9:1);

[a]²_D⁵2118 (c 0.3 in acetone); FT IR (CHCl₃) v_max/cm²¹

1784s (b-lactam), 1723m (ester), 1686m br (amide), and

1517s (amide); ¹H NMR (200 MHz, CD₃CN) d_H2.15

(3H, s, CH₃), 3.28 and 3.55 (2£1H, ABq, J18 Hz,

SCH₂), 3.54 and 3.58 (2£1H, ABq, J14.5 Hz, PhCH₂CO),

4.99 (1H, d, J4.5 Hz, 6-H), 5.22 and 5.26 (2£1H, ABq,

J12 Hz, CH₂Ph), 5.67 (1H, dd, J8.5 Hz, J4.5 Hz, 7-H),

7.20 (1H, d, J8.5 Hz, NH), and 7.28±7.43 (10H_arom, m,

2£Ph); ¹³C NMR (126 MHz, CD₃CN) d_C19.42, 29.90,

42.49, 57.59, 59.65, 67.46, 127.3, 128.7, 128.8, 128.9,

129.6, 132.3, 135.9, 136.1, 162.8, 165.2, and 171.8; and

LRMS [DCI (NH₃)] m/z 423 (MH¹, 2%), 248

(MH¹2PhCH₂CONHCHCO, 100), 176 (PhCH₂CONHCH-

COH¹, 15), and 91 (C₇H₇¹, 20).

The third method. A cooled in an ice bath solution of sul-

fenamide 74 (126 mg, 0.29 mmol) in CH₂Cl₂(10 ml) was

treated with phenoxyacetyl chloride (122 ml, 0.88 mmol)

and the mixture was stirred at 08C until the starting material

74 had reacted (by TLC analysis, 2 h). The solvent was

evaporated in vacuo and the residue puri®ed by ¯ash chro-

matography (silica gel, CH₂Cl₂/EtOAc, 9:1) to give amide

53 (94 mg, 73%), identical [¹H NMR (200 MHz), TLC, and

FT IR] with the product obtained by the ®rst method.

The fourth method. As described for the preparation of

cephem 77, Schiff base 75 (250 mg, 0.57 mmol) in THF

(10 ml) was treated with PhLi (1.8 M solution in cyclo-

hexane/ether, 318 ml, 0.57 mmol) in the presence of DMF

(8 ml). The standard AcOH/H₂O workup procedure as

described above gave an off-white solid (253 mg) which

was dissolved in CH₂Cl₂(15 ml) and treated with phenoxy-

acetyl chloride (87 ml, 0.63 mmol). The mixture was stirred

at room temperature for 20 h and the solvent evaporated in

vacuo to give a light brown semi-solid (365 mg) which was

puri®ed by ¯ash chromatography (silica gel, CH₂Cl₂/

EtOAc, 9:1) to give amide 53 (128 mg, 51%) along with

its 7-epimer 67 (50 mg, 20%), identical [¹H NMR

(200 MHz), TLC, and FT IR] with the products obtained

by other methods.

Benzyl (2)-(6S,7S)-3-methyl-8-oxo-7-phenoxyacetamido-

5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (53).

The title compound was prepared according to the following

methods.

(2)-(6S,7S)-3-Methyl-8-oxo-7-phenylacetamido-5-thia-1-

azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (54). To an

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6069

ice bath cooled solution of ester 52 (150 mg, 0.36 mmol)

and anisole (232 ml, 2.13 mmol) in CH₂Cl₂(10 ml) was

added a cold solution of AlCl₃(143 mg, 1.07 mmol) in

MeNO₂(10 ml). The bath was removed and stirring con-

tinued at room temperature for 6 h. The reaction mixture

was diluted with EtOAc (30 ml) and washed with 1 M

HCl (3£30 ml) and satd. brine (30 ml). The organic layer

was extracted with 5% NaHCO₃(3£35 ml). The combined

aqueous extracts were washed with Et₂O (30 ml), acidi®ed

to pH 1 with 1 M HCl, and re-extracted with EtOAc

(3£50 ml). The combined organic layers were washed

with satd. brine (30 ml), dried over MgSO₄, and evaporated

in vacuo to afford acid 54 (101 mg, 86%): white crystalline

solid; mp 193±1958C (dec.) (from EtOAc/petrol 40/60);

(Found: C, 57.70; H, 5.15; N, 8.44. Calcd for

C₁₆H₁₆N₂O₄S: C, 57.81; H, 4.86; N, 8.44%); [a]²_D⁵2127

(c 0.3 in acetone); FT IR (KBr disc) n_max/cm²¹3200s br

(carboxylic acid), 1765s (b-lactam), 1704s (carboxylic

acid), 1658s (amide), 1551s (amide), 1367m, 1342m,

(100 ml). The organic layer was dried over MgSO₄and

evaporated in vacuo to give a white foam (18.6 g). Puri®ca-

tion by ¯ash chromatography (silica gel, benzene/EtOAc,

7:3) afforded sulfoxide 58 (17.6 g, 85%): white crystalline

solid; mp 143±1448C (from EtOAc/petrol 40/60); (Found:

C, 60.83; H, 4.85; N, 6.02. Calcd for C₂₃H₂₀N₂O₆S: C,

61.04; H, 4.46; N, 6.19%); R_f0.30 (C₆H₆/EtOAc, 7:3);

[a]²_D⁵291.7 (c 1.0 in CHCl₃); FT IR (CHCl₃) n_max/cm²¹

1803s br (b-lactam, phthalimide), 1729s (phthalimide,

1

ester), 1392s, and 1056m (sulfoxide); H NMR (200 MHz,

CDCl₃) d_H1.30 and 1.53 (2£3H, 2£s, 2£CH₃), 4.20 (1H, s,

2-H), 4.87 and 5.77 (2£1H, 2£d, J2.5 Hz, 5-H and 6-H),

5.22 and 5.30 (2£1H, ABq, J12 Hz, CH₂Ph), 7.39 (5H_arom

,

1

s, Ph), and 7.73±7.91 (4H_arom, m, Pht); H NMR n.O.e.

(500 MHz, CDCl₃) d_H1.30 a-CH₃!b-CH₃(5.0%), !2-H

(5.5%), !6-H (3.5%); 1.53 b-CH₃!a-CH₃(3.5%), !2-H

(15%), !5-H (16%); 4.20 2-H!b-CH₃(4.0%), !5-H

(2.0%); 4.87 5-H!b-CH₃(4.0%), !2-H (1.5%), !6-H

(4.5%); and 5.77 6-H!5-H (3.5%); ¹³C NMR (50.3 MHz,

CDCl₃) d_C18.87 and 19.56 (q, 2£CH₃), 55.49, 66.52, and

79.23 (d, 2-C, 5-C, and 6-C), 68.59 (t, CH₂Ph), 71.16 (s,

3-C), 124.2 (d, Pht 3, 6-CH's), 129.0 and 129.2 (d, Ph

CH's), 131.6 (s, Pht ipso C), 134.2 (s, Ph ipso C), 135.1

(d, Pht 4, 5-CH's), 165.2, 166.7, and 167.3 (s, 3£CvO); and

LRMS [DCI (NH₃)] m/z 453 (MH¹, 10%), 435

(MH¹2H₂O, 80), 299 (25), 247 (10), 204 (15), 108

(C₇H₇OH¹, 30), and 91 (C₇H¹₇, 100).

1

1261m, and 1236m; H NMR (500 MHz, CD₃CN) d_H2.08

(3H, s, CH₃), 3.28 and 3.54 (2£1H, ABq, J18 Hz, SCH₂),

3.55 and 3.58 (2£1H, ABq, J14.5 Hz, PhCH₂), 4.99 (1H,

d, J4.5 Hz, 6-H), 5.67 (1H, dd, J8 Hz, J4.5 Hz, 7-H),

7.20 (1H, d, J8 Hz, NH), and 7.26±7.36 (5H_arom, m, Ph);

¹³C NMR (126 MHz, CD₃CN) d_C19.87, 30.35, 42.96,

57.97, 60.05, 123.8, 127.7, 129.4, 130.1, 133.0, 136.4,

163.7, 165.8, and 172.1; and LRMS (electrospray, 2) m/z

331 (M2H¹, 100%), 287 (M2H¹2CO₂, 80), 265 (15), and

253 (85).

Benzyl (2)-(6S,7R)-3-methyl-8-oxo-7-phthalimido-5-thia-

1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (59). A stirred

solution of sulfoxide 58 (14.3 g, 31.6 mmol) and anhydrous

p-toluenesulfonic acid (pTSA, 4.30 g, 24.9 mmol) in DMF

(150 ml) was heated at 100^38C for 17 h. The reaction

mixture was cooled to room temperature, diluted with

EtOAc (200 ml) and washed with water (4£200 ml), satd.

NaHCO₃(3£100 ml), and satd. brine (100 ml). The organic

layer was dried over MgSO₄and evaporated in vacuo to

yield a brown foam (10.7 g). Flash chromatography (silica

gel, CH₂Cl₂/EtOAc, 20:1) followed by crystallisation from

EtOAc/petrol 40/60 gave cephalosporin 59 (4.52 g, 33%):

white crystalline solid; mp 171±1738C (from EtOAc/petrol

40/60); (Found: C, 63.84; H, 4.26; N, 6.47. Calcd for

C₂₃H₁₈N₂O₅S: C, 63.58; H, 4.18; N, 6.42%); R_f0.60

(CH₂Cl₂/EtOAc, 20:1); [a]²_D⁵217.8 (c 1.0 in CHCl₃); FT

IR (CHCl₃) n_max/cm²¹1786s br (b-lactam, phthalimide)

1728s (ester, phthalimide), and 1393m; ¹H NMR

(200 MHz, CDCl₃) d_H2.14 (3H, s, CH₃), 3.24 and 3.48

(2£1H, ABq, J18 Hz, SCH₂), 5.08 and 5.34 (2£1H,

2£d, J2.5 Hz, 6-H and 7-H), 5.33 and 5.40 (2£1H, ABq,

J12.5 Hz, CH₂Ph), 7.32±7.54 (5H_arom, m, Ph), and 7.77±

7.94 (4H_arom, m, Pht); ¹³C NMR (126 MHz, CDCl₃) d_C

19.45 (CH₃), 31.48 (SCH₂), 55.84 and 61.27 (6-C and

7-C), 67.49 (CH₂Ph), 123.9 (Pht 3, 6-CH's), 128.1, 128.3,

and 128.4 (Ph CH's), 131.6 (Pht ipso C), 134.6 (Pht 4,

(2)-(6S,7S)-3-Methyl-8-oxo-7-phenoxyacetamido-5-thia-

1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (55).

Following the method for the preparation of acid 54, ester

53 (167 mg, 0.38 mmol) was reacted with AlCl₃(152 mg,

1.44 mmol) in the presence of anisole (248 ml, 2.29 mmol).

The analogous workup procedure gave the title compound

55 (125 mg, 94%): white crystalline solid; mp 177±1798C

(dec.) (from EtOAc/petrol 40/60); (Found: C, 55.43; H,

4.21; N, 7.76. Calcd for C₁₆H₁₆N₂O₅S: C, 55.15; H, 4.64;

N, 8.04%); [a]²_D⁵278.0 (c 0.4 in acetone); FT IR (KBr

disc) n_max/cm²¹3200s br (carboxylic acid), 1759s (b-

lactam), 1734s (carboxylic acid), 1651s (amide), 1527s

1

(amide), 1228s, and 1196m; H NMR (500 MHz, CD₃CN)

d_H2.09 (3H, s, CH₃), 3.31 and 3.54 (2£1H, ABq, J18 Hz,

SCH₂), 4.59 (2H, s, PhOCH₂), 5.06 (1H, d, J4.5 Hz, 6-H),

5.73 (1H, dd, J8.5 Hz, J4.5 Hz, 7-H), 6.99±7.04 and

7.32±7.36 (5H_arom, m, Ph), and 7.59 (1H, d, J8.5 Hz,

NH),¹³C NMR (126 MHz, CD₃CN) d_C19.88, 30.39,

57.85, 59.48, 67.68, 115.6, 122.7, 123.3, 130.5, 133.3,

158.4, 165.2, and 169.7; and LRMS (electrospray, 2) m/z

347 (M2H¹, 100%), 303 (M2H¹±CO₂, 60), 269 (45), and

250 (15).

Benzyl (2)-(2S,4S,5S,6R)-3,3-dimethyl-7-oxo-6-phthali-

mido-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4-

oxide (58). A vigorously stirred solution of penam 15

(20.0 g, 45.9 mmol, ,95% purity) in CHCl₃(250 ml) was

cooled in an ice bath and treated dropwise, over 30 min,

with a solution of m-chloroperbenzoic acid (mCPBA,

,50% w/w, 14.4 g, ca. 45.9 mmol) in CHCl₃(80 ml),

which had been pre-dried (over MgSO₄). The mixture was

stirred at 08C for an additional hour and washed with water

(2£250 ml), satd. NaHCO₃(2£250 ml), and satd. brine

5-CH's), 135.3 (Ph ipso C), 159.1, 161.9, and 166.4

(3£CvO); and LRMS [DCI (NH₃)] m/z 452 (MNH₄

1

,

85%), 434 (M¹, 100), 248 (MH¹2PhtCHCO, 80), 108

(C₇H₇OH¹, 45), and 91 (C₇H₇¹, 50).

Benzyl (1)-(2S,4S,5R)-3,3-dimethyl-7-oxo-4-thia-1-aza-

bicyclo[3.2.0]heptane-2-carboxylate 4-oxide (60). A stir-

red solution of penam 35^kk(107 mg, 0.37 mmol) in CHCl₃

(15 ml) was cooled in an ice bath and treated, dropwise over

6070

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

45 min, with a solution of mCPBA (pre-dried with MgSO₄)

(,50% w/w, 127 mg, ,0.37 mmol) in CHCl₃(5 ml). The

stirring was continued at 08C until the starting material 35

had reacted (by TLC analysis, 40 min) and the reaction

mixture was washed with 5% Na₂CO₃(5 ml), water

(3£10 ml), and satd. brine (10 ml). The organic layer was

dried over MgSO₄and evaporated in vacuo to afford a white

foam (105 mg) which, on the basis of ¹H NMR (200 MHz)

analysis, consisted of two compounds, sulfoxide 60 and its

(4R)-epimer 82, in a ratio of ca. 4:1. Puri®cation by ¯ash

chromatography (silica gel, EtOAc/petrol 40/60, 7:3) gave

the two products; sulfoxide 60 (77 mg, 68%) and its (4R)-

epimer 82 (18 mg, 16%). The major product 60: white

crystalline solid; mp 117±1198C (from Me₂CO/petrol

40/60); (Found: C, 58.78; H, 5.32; N, 4.32. Calcd for

C₁₅H₁₇NO₄S: C, 58.62; H, 5.57; N, 4.56%); R_f0.33

(EtOAc/petrol 40/60, 7:3); [a]²_D⁵1243 (c 0.3 in CHCl₃);

FT IR (KBr disc) n_max/cm²¹1771s (b-lactam), 1725s

(ester), 1274s, 1210s, and 1051s (sulfoxide); ¹H NMR

(200 MHz, CDCl₃) d_H1.11 and 1.67 (2£3H, 2£s,

2£CH₃), 3.35 (2H, d, J3.5 Hz, 6-CH₂), 4.56 (1H, s,

2-H), 4.95 (1H, t, J3.5 Hz, 5-H), 5.16 and 5.30 (2£1H,

ABq, J12 Hz, CH₂Ph), and 7.40 (5H_arom, s, Ph); ¹H NMR

n.O.e. (500 MHz, CDCl₃) d_H1.11 a-CH₃!b-CH₃(5.0%),

!2-H (2.0%), !5-H (12%); 1.67 b-CH₃!a-CH₃(1.0%),

!2-H (16%); 3.35 6-CH₂!2-H (2.0%), !5-H (7.0%); 4.56

2-H!a-CH₃(2.0%), !b-CH₃(5.0%), !6-CH₂(1.0%), and

4.95 5-H!a-CH₃(6.5%), !b-CH₃(2.0%), !6-CH₂

(6.0%); ¹³C NMR (126 MHz, CDCl₃) d_C18.41, 20.13,

36.00, 65.54, 67.83, 70.89, 73.87, 128.7, 128.8, 128.8,

134.7, 168.2, and 170.6; and LRMS [CI (NH₃)] m/z 325

(MNH₄¹, 15%), 308 (MH¹, 100), 290 (MH¹2H₂O, 20),

108 (C₇H₇OH¹, 25), and 91 (C₇H₇¹, 75). The minor product

82: white solid; R_f0.22 (EtOAc/petrol 40/60, 7:3);

[a]²_D⁵1189 (c 1.0 in CHCl₃); FT IR (CHCl₃) n_max/cm²¹

19.57, 31.40, 59.21, 67.62, 68.83, 123.8, 128.2, 128.4,

128.5, 128.7, 135.3, 162.3, and 164.8; and LRMS [DCI

(NH₃)] m/z 322 (MNH₄¹, 10%), 305 (MH¹, 50), 277

(100), 248 (MH¹2NH₂CHCO, 40), 108 (C₇H₇OH¹, 30),

and 91 (C₇H₇¹, 35).

Benzyl (2)-(6S,7R)-3-methyl-8-oxo-7-phenoxyacetamido-

5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (67).

According to the general coupling procedure described for

the preparation of amide 52, amine 66 (406 mg, 1.34 mmol)

and phenoxyacetic acid (305 mg, 2.00 mmol) were reacted

in the presence of DCC (362 mg, 1.74 mmol). The standard

workup procedure, followed by ¯ash chromatography

(silica gel, CH₂Cl₂/EtOAc, 9:1), afforded amide 67

(519 mg, 89%): white crystalline solid; mp 182±1848C

(dec.) (from EtOAc/petrol 40/60); (Found: C, 63.12; H,

4.92; N, 6.29. Calcd for C₂₃H₂₂N₂O₅S: C, 62.99; H, 5.07;

N, 6.39%); R_f0.80 (CH₂Cl₂/EtOAc, 9:1); [a]²_D⁵240.5 (c

0.45 in acetone); FT IR (CHCl₃) n_max/cm²¹3416m br

(amide), 1780s (b-lactam), 1724m (ester), 1698m (amide),

1

1521s (amide), 1441m, and 1424s; H NMR (500 MHz,

CD₃CN) d_H2.01 (3H, s, CH₃), 3.14 and 3.41 (2£1H,

ABq, J18 Hz, SCH₂), 4.48 (2H, s, PhOCH₂), 4.67 (1H,

d, J2 Hz, 6-H), 4.98 (1H, dd, J8 Hz, J2 Hz, 7-H),

5.16 and 5.29 (2£1H, ABq, J12 Hz, CH₂Ph), 6.87±7.40

(10H_arom, m, 2£Ph), and 7.56 (1H, d, J8 Hz, NH); ¹³C

NMR (126 MHz, CD₃CN) d_C19.33, 31.07, 56.88, 63.13,

66.85, 67.32, 114.5, 122.0, 123.5, 128.2, 128.3, 129.1,

129.6, 135.0, 156.8, 160.7, 161.9, and 168.4; and LRMS

[DCI (NH₃)] m/z 456 (MNH₄¹, 10%), 439 (MH¹, 5), 248

(MH¹2PhOCH₂CONHCHCO, 100), 192 (PhOCH_2-

CONHCHCOH¹, 20), and 91 (C₇H₇¹, 20).

Diphenylmethyl (2)-(6S,7R)-3-methyl-8-oxo-7-phenoxy-

acetamido-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxy-

late (68). Following the method for the preparation of acid

54, a solution of ester 67 (445 mg, 1.02 mmol) and anisole

(662 ml, 6.10 mmol) in CH₂Cl₂(10 ml) was treated with a

solution of AlCl₃(405 mg, 3.05 mmol) in MeNO₂(10 ml)

and the reaction mixture was stirred at room temperature for

8 h. The standard workup procedure gave crude acid 69

(289 mg) contaminated, as judged from ¹H NMR

(500 MHz) analysis, with its double bond isomer, (6S,7R)-

3-methyl-8-oxo-7-phenoxyacetamido-5-thia-1-azabicyclo-

[4.2.0]oct-3-ene-2-carboxylic acid; ¹H NMR (500 MHz,

CD₃CN) d_H1.89 (3H, s, CH₃), 4.74 (1H, s, 4-H), 4.99

(1H, dd, J8.5 Hz, J1.5 Hz, 7-H), 4.55 (2H, s,

PhOCH₂), 4.98 (1H, d, J1.5 Hz, 6-H), 6.08 (1H, t,

J1.5 Hz, 2-H), 6.99±7.05 and 7.33±7.37 (5H_arom, m, Ph),

and 7.90 (1H, d, J8.5 Hz, NH).

1

1790s (b-lactam), 1753s (ester), and 1061s (sulfoxide); H

NMR (200 MHz, CDCl₃) d_H1.27 and 1.56 (2£3H, 2£s,

2£CH₃), 3.36 (1H, dd, J16.5 Hz, J2 Hz, 6-b-H), 3.61

(1H, dd, J16.5 Hz, J4.5 Hz, 6-a-H), 4.42 (1H, s, 2-H),

4.61 (1H, dd, J4.5 Hz, J2 Hz, 5-H), 5.18 and 5.28

(2£1H, ABq, J12 Hz, CH₂Ph), and 7.39 (5H_arom, s, Ph);

¹³C NMR (126 MHz, CDCl₃) d_C15.48, 24.29, 40.71, 64.03,

67.98, 70.77, 72.56, 128.8, 128.8, 128.9, 134.5, 167.1, and

169.0; and LRMS (AFCI) m/z 308 (MH¹, 100%), 290

(MH¹2H₂O, 15), 280 (15), and 206 (20).

Benzyl (2)-(6S,7R)-7-amino-3-methyl-8-oxo-5-thia-1-aza-

bicyclo[4.2.0]oct-2-ene-2-carboxylate (66). Following the

®rst method for the preparation of amine 51, cephalosporin

59 (1.08 g, 2.49 mmol) in DMF (20 ml) was reacted with a

1 M solution of hydrazine hydrate in DMF (5.0 ml,

5.0 mmol) at 2158C for 30 min. Puri®cation by ¯ash chro-

matography (silica gel, EtOAc/CH₂Cl₂, 6:5) gave amine 66

(296 mg, 39%) as a yellow oil which solidi®ed upon stand-

ing: R_f0.35 (EtOAc/CH₂Cl₂, 5:4); HRMS Calcd for

C₁₅H₁₇N₂O₃S (MH¹) 305.0977, found 305.0960;

[a]²_D⁵295.2 (c 1.4 in CHCl₃); FT IR (CHCl₃) n_max/cm²¹

The crude product was dissolved in CH₂Cl₂(10 ml) and

treated with diphenyldiazomethane over 5 min until light

pink colour of the solution was persistent. Excess diphenyl-

diazomethane was decomposed by stirring with silica gel

(3 g). After ®ltration (ether), the solvent was evaporated in

vacuo to afford an off-white foam (410 mg). Puri®cation by

¯ash chromatography (silica gel, EtOAc/CH₂Cl₂, 10:1) gave

ester 68 (273 mg, 52%): white solid; R_f0.45 (CH₂Cl₂/

EtOAc, 10:1); [a]²_D⁵226.2 (c 0.50 in CHCl₃); FT IR

(CHCl₃) n_max/cm²¹1780s (b-lactam), 1725m (ester),

1695s (amide), 1521m (amide), and 1496S; ¹H NMR

(500 MHz, CDCl₃) d_H2.08 (3H, s, CH₃), 3.20 and 3.40

1

1773s (b-lactam) 1726s (ester), 1392m, and 1362m; H

NMR (200 MHz, CDCl₃) d_H1.68 (2H, br s, NH₂), 2.06

(3H, s, CH₃), 3.15 and 3.47 (2£1H, ABq, J18 Hz,

SCH₂), 4.13 and 4.45 (2£1H, 2£d, J2 Hz, 6-H and 7-H),

5.25 and 5.35 (2£1H, ABq, J12 Hz, CH₂Ph), and 7.33±

7.42 (5H_arom, m, Ph); ¹³C NMR (126 MHz, CDCl₃) d_C

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6071

(2£1H, ABq, J17.5 Hz, SCH₂), 4.57 (2H, s, PhOCH₂),

4.73 (1H, d, J2 Hz, 6-H), 5.03 (1H, dd, J8 Hz,

J2 Hz, 7-H), and 6.92±7.50 (17H, m, 3£Ph1

NH1CHPh₂); ¹³C NMR (126 MHz, CDCl₃) d_C19.75,

31.47, 57.74, 63.73, 67.11, 79.15, 114.7, 122.4, 127.1,

127.6, 128.0, 128.1, 128.5, 128.5, 129.9, 131.9, 139.6,

156.9, 160.9, 161.4, and 168.5; and LRMS [DCI (NH₃)]

m/z 532 (MNH₄¹, 5%), 192 (PhOCH₂CONHCHCOH¹,

30), and 167 (Ph₂CH¹, 65).

CH₃), 31.25 (t, SCH₂), 56.76 and 75.84 (d, 6-C and 7-C),

67.63 (t, CH₂Ph), 122.2 and 124.3 (d, O₂NC₆H₄CH's),

123.7 and 129.6 (s, 2-C and 3-C), 128.7 (d, Ph CH's),

135.3 (s, Ph ipso C), 145.8 and 151.6 (s, 2£Ar ipso C),

161.8 and 162.3 (s, 2£CvO); and LRMS [DCI (NH₃)] m/

z 475 (MNH₄¹, 10%), 458 (MH¹, 7), 305 (30), 277 (40),

248 (MH¹2O₂NC₆H₄SNHCHCO, 100), 108 (C₇H₇OH¹,

20), and 91 (C₇H₇¹, 20).

The second method. An ice bath cooled solution of amine 66

(373 mg, 1.23 mmol) and triethylamine (205 ml, 1.47

mmol) in THF (10 ml) was treated with a solution of

p-nitrobenzenesulfenyl chloride (294 mg, 1.47 mmol) in

THF (10 ml) and the mixture was stirred at 08C and for

3 h at room temperature. The reaction mixture was diluted

with EtOAc (50 ml) and washed with satd. NaHCO₃

(10 ml), water (3£10 ml), and satd. brine (10 ml). The

organic layer was dried over MgSO₄and evaporated in

vacuo to give a yellow foam (430 mg) which was puri®ed

by ¯ash chromatography (silica gel, CH₂Cl₂/EtOAc, 50:1)

to afford sulfenamide 70 (356 mg, 63%), identical [¹H NMR

(200 MHz), TLC, and FT IR] with the product obtained by

the ®rst method.

(2)-(6S,7R)-3-Methyl-8-oxo-7-phenoxyacetamido-5-thia-

1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (69). To

an ice bath cooled solution of ester 68 (126 mg,

0.25 mmol) and anisole (160 ml, 1.47 mmol) in CH₂Cl₂

(5 ml) was added a cold solution of AlCl₃(99 mg,

0.735 mmol) in MeNO₂(5 ml). The reaction mixture was

stirred at 08C until the starting material 68 disappeared (by

TLC analysis, 30 min). The standard workup, as described

for the preparation of acid 54, gave the title compound 69

(82 mg, 96%): white crystalline solid; mp 183±1858C (dec.)

(from EtOAc/petrol 40/60); (Found: C, 55.31; H, 4.42; N,

8.06. Calcd for C₁₆H₁₆N₂O₅S: C, 55.15; H, 4.64; N, 8.04%);

[a]²_D⁵298.8 (c 0.25 in acetone); FT IR (KBr disc) n_max

/

cm²¹3333s (amide), 3261s br (carboxylic acid), 1738s and

1734s (b-lactam and carboxylic acid), 1687s (amide), 1543s

Benzyl (2)-(6S)-3-methyl-7-[[(4-nitrophenyl)thio]imino]-

8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

(71). To a solution of sulfenamide 70 (165 mg, 0.36 mmol)

in benzene (10 ml) was added active manganese dioxide

(Merck, 6.0 g) and the mixture was vigorously stirred at

room temperature until the starting material 70 had reacted

(by TLC analysis, 1 h). The reaction mixture was ®ltered

through a thin pad of Celite^wand the ®ltrate was evaporated

in vacuo to give a brown foam (158 mg). Puri®cation by

¯ash chromatography (silica gel, CH₂Cl₂/EtOAc, 50:1)

afforded thiooxime 71 (79 mg, 48%): bright yellow crystal-

line solid; mp 148±1498C (from EtOAc/petrol 40/60);

(Found: C, 55.60; H, 3.50; N, 9.33. Calcd for

C₂₁H₁₇N₃O₅S₂: C, 55.37; H, 3.77; N, 9.23%); R_f0.60

(CH₂Cl₂/EtOAc, 50:1); [a]²_D⁵2132 (c 0.75 in CHCl₃);

FT IR (CHCl₃) n_max/cm²¹1780s (b-lactam) and 1726m

1

(amide), 1497m, and 1242s; H NMR (500 MHz, CD₃CN)

d_H2.10 (3H, s, CH₃), 2.26 (1H, br s, CO₂H), 3.26 and 3.55

(2£1H, ABq, J18 Hz, SCH₂), 4.55 (2H, s, PhOCH₂), 4.81

(1H, d, J2 Hz, 6-H), 4.85 (1H, dd, J8 Hz, J2 Hz, 7-H),

7.00±7.04 and 7.33±7.37 (5H_arom, m, Ph), and 7.91 (1H, d,

J8 Hz, NH); ¹³C NMR (126 MHz, CD₃CN) d_C19.44,

31.51, 57.36, 64.28, 67.71, 115.6, 122.7, 124.3, 130.3,

130.6, 158.4, 162.6, 163.6, and 169.8; and LRMS [DCI

(NH₃)] m/z 366 (MNH₄¹, ,1%), 349 (MH¹, ,1), 305

(MH¹2CO₂, 5), 210 (35), 192 (PhOCH₂CONHCHCOH¹,

35), 158 (MH¹2CO₂±PhOCH₂CONHCHCO, 40), and 94

(15).

Benzyl (2)-(6S,7R)-3-methyl-7-(4-nitrobenzenesulfena-

mido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car-

boxylate (70). The title compound was obtained according

to the following methods.

1

(ester); H NMR (500 MHz, CDCl₃) d_H2.22 (3H, s, CH₃),

3.27 (1H, d, J18 Hz, SCH), 3.50 (1H, br s, SCH), 5.27 and

5.38 (3H, m, 6-H1CH₂Ph), 7.35±7.46 (5H_arom, m, Ph), 7.69

(2H_arom, br d, J8.5 Hz, C₆H₄NO₂), and 8.27 (2H_arom, ddd,

J8.5 Hz, J2.5 Hz, J2 Hz, C₆H₄NO₂); and LRMS [DCI

(NH₃)] m/z 473 (MNH₄¹, 15%), 456 (MH¹, 15), 305 (30),

277 (40), 248 (MH¹2O₂NC₆H₄SNHCHCO, 100), 108

(C₇H₇OH¹, 20), and 91 (C₇H₇¹, 20).

The ®rst method. To an ice bath cooled solution of amine 66

(427 mg, 1.40 mmol) in CH₂Cl₂(15 ml) was added potas-

sium carbonate (427 mg, 3.09 mmol) followed by a solution

of p-nitrobenzenesulfenyl chloride (564 mg, 2.83 mmol) in

CH₂Cl₂(5 ml). The reaction mixture was stirred at 08C for

1 h and washed with water (3£30 ml) and satd. brine

(20 ml). The organic layer was dried over MgSO₄and

evaporated in vacuo to afford a yellow oil (730 mg) which

was puri®ed by ¯ash chromatography (silica gel, CH₂Cl₂/

Benzyl (2)-(6S,7S)-3-methyl-7-(4-nitrobenzenesulfena-

mido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car-

boxylate (72). To an ice bath cooled solution of thiooxime

71 (92 mg, 0.20 mmol) in THF (4 ml) and DMSO (1 ml)

was added during vigorous stirring a solution of sodium

borohydride (34 mg, 0.85 mmol) in THF (2.5 ml) and

DMSO (2.5 ml). After 10 min at 08C the reaction mixture

was quenched with glacial AcOH (1 ml), diluted with

EtOAc (50 ml), and washed with water (3£20 ml), satd.

NaHCO₃(40 ml), and satd. brine (20 ml). The organic

layer was dried over MgSO₄and evaporated in vacuo to

give a brown oil (90 mg) which was puri®ed by ¯ash chro-

matography (silica gel, CH₂Cl₂/EtOAc, 50:1) to afford

sulfenamide 72 (49 mg, 53%): bright yellow foam; HRMS

EtOAc, 50:1) to give sulfenamide 70 (536 mg, 83%): bright

yellow foam; HRMS Calcd for C₂₁H₂₃N₄O₅S₂(MNH₄

1

)

475.1144, found 475.1110; R_f0.35 (CH₂Cl₂/EtOAc, 50:1);

[a]²_D⁵231.7 (c 0.65 in CHCl₃); FT IR (CHCl₃) n_max/cm²¹

1

1776s (b-lactam) and 1726m (ester); H NMR (200 MHz,

CDCl₃) d_H2.04 (3H, s, CH₃), 3.15 and 3.44 (2£1H, ABq,

J18 Hz, SCH₂), 3.97 (1H, d, J6.5 Hz, NH), 4.43 (1H, dd,

J6.5 Hz, J2 Hz, 7-H), 4.59 (1H, d, J2 Hz, 6-H), 5.21

and 5.29 (2£1H, ABq, J12 Hz, CH₂Ph), 7.29±7.43

(5H_arom, m, Ph), 7.40 and 8.14 (2£2H_arom, 2£d, J9 Hz,

C₆H₄NO₂); ¹³C NMR (50.3 MHz, CDCl₃) d_C19.44 (q,

6072

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

Calcd for C₂₁H₂₃N₄O₅S₂(MNH¹₄) 475.1144, found

475.1110; R_f0.50 (CH₂Cl₂/EtOAc, 50:1); [a]²_D⁵2140 (c

0.65 in CHCl₃); FT IR (CHCl₃) n_max/cm²¹1781s (b-

lactam), 1724s (ester), 1598m, 1581m, 1517S, and 1341s;

¹H NMR (200 MHz, CDCl₃) d_H2.12 (3H, s, CH₃), 3.24 and

3.51 (2£1H, ABq, J18 Hz, SCH₂), 3.89 (1H, d, J9 Hz,

NH), 4.77 (1H, dd, J9 Hz, J4.5 Hz, 7-H), 4.94 (1H, d,

J4.5 Hz, 6-H), 5.19 and 5.29 (2£1H, ABq, J12 Hz,

CH₂Ph), 7.30±7.46 (5H_arom, m, Ph), 7.45 and 8.14

(2£2H_arom, 2£d, J9 Hz, C₆H₄NO₂); ¹³C NMR (50.3

MHz, CDCl₃) d_C20.06 (q, CH₃), 30.08 (t, SCH₂), 58.49

and 72.98 (d, 6-C and 7-C), 67.63 (t, CH₂Ph), 121.9 and

124.3 (d, O₂NC₆H₄'s CH's), 122.6 and 132.4 (s, 2-C and 3-

C), 128.7 and 128.9 (d, Ph CH's), 135.4 (s, Ph ipso C), 145.8

and 151.9 (s, 2£Ar ipso C), 162.4 and 165.1 (s, 2£CvO);

and LRMS [DCI (NH₃)] m/z 475 (MNH₄¹, 2%), 458 (MH¹,

1), 303 (25), 277 (60), 248 (MH¹2O₂NC₆H₄SNH±CHCO,

30), 126 (100), 108 (C₇H₇OH¹, 20), and 91 (C₇H₇¹, 50).

427.1150; R_f0.50 (CH₂Cl₂/EtOAc, 50:1); [a]²_D⁵2151 (c

1.3 in acetone); FT IR (CHCl₃)n_max/cm²¹1779s (b-lactam),

1723s (ester), 1493m, 1384m, 1360s, 1303m, 1152m, and

1105m; ¹H NMR (200 MHz, CDCl₃) d_H2.12 (3H, s, CH₃),

2.34 (3H, s, ArCH₃), 3.20 and 3.48 (2£1H, ABq, J18 Hz,

SCH₂), 3.59 (1H, d, J8.5 Hz, NH), 4.80 (1H, dd,

J8.5 Hz, J4.5 Hz, 7-H), 4.87 (1H, d, J4.5 Hz, 6-H),

5.24 and 5.32 (2£1H, ABq, J12.5 Hz, CH₂Ph), and

7.15±7.39 (9H_arom

,

m, aromatic CH`s); ¹³C NMR

(50.3 MHz, CDCl₃) d_C20.04 and 21.01 (q, 2£CH₃), 30.14

(t, SCH₂), 58.68 and 73.16 (d, 6-C and 7-C), 67.54 (t,

CH₂Ph), 112.7 and 132.1 (s, 2-C and 3-C), 125.5, 128.6,

128.9, and 130.0 (d, aromatic CH's), 135.5, 136.7, and

137.3 (s, 3£Ar ipso C), 162.6 and 165.7 (s, 2£CvO); and

LRMS [DCI (NH₃)] m/z 444 (MNH₄¹, 4%), 427 (MH¹, 20),

399 (100), 303 (30), 277 (50), 248 (MH¹2H₃CC₆H₄SNH±

CHCO, 65), 204 (20), 108 (C₇H₇OH¹, 10), and 91 (C₇H₇

100).

,

1

Benzyl (2)-(6S)-3-methyl-7-[[(4-methylphenyl)thio]imino]-

8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

(73). To a vigorously stirred and cooled in an ice bath solu-

tion of amine 66 (471 mg, 1.55 mmol) in CH₂Cl₂(30 ml)

was added propylene oxide (4 ml) followed by pulverised

Benzyl (2)-(6S,7R)-3-methyl-7-(4-nitrobenzylideneamino)-

8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

(75). To a solution of amine 66 (266 mg, 0.88 mmol) in

CH₂Cl₂(20 ml) was added anhydrous MgSO₄(2.5 g)

followed by p-nitrobenzaldehyde (132 mg, 0.88 mmol)

and the mixture was stirred at room temperature for 10 h.

Filtration, followed by evaporation of the solvent in vacuo,

gave an off-white solid (340 mg) which was puri®ed by

¯ash chromatography (silica gel, CH₂Cl₂/EtOAc, 25:1) to

give imine 75 (317 mg, 83%): white crystalline solid; mp

150±1518C (from EtOAc/petrol 40/60); (Found: C, 60.05;

H, 4.09; N, 9.49. Calcd for C₂₂H₁₉N₃O₅S: C, 60.39; H, 4.36;

N, 9.61%); R_f0.60 (CH₂Cl₂: EtOAc, 25:1); [a]²_D⁵2228 (c

0.15 in acetone); FT IR (CHCl₃) n_max/cm²¹1769s (b-

lactam), 1719s (ester), 1519s, and 1346S; ¹H NMR

(200 MHz, CDCl₃) d_H2.13 (3H, s, CH₃), 3.24 (1H, d,

J18 Hz, SCH), 3.56 (1H, dd, J18 Hz, J1 Hz, SCH),

4.84 and 4.92 (2£1H, 2£d, J1.5 Hz, 6-H and 7-H), 5.26

and 5.38 (2£1H, ABq, J12 Hz, CH₂Ph), 7.33±7.49

(5H_arom, m, Ph), 7.93 and 8.29 (2£2H_arom, 2£dd, J9 Hz,

Ê

molecular 4 A sieves (3.3 g) and the resulting mixture was

treated with a solution of p-toluenesulfenyl chloride

(786 mg, 4.96 mmol) in CH₂Cl₂(5 ml). The reaction

mixture was allowed to warm to room temperature over

3 h and then ®ltered through a thin pad of Celite^w. The

®ltrate was evaporated in vacuo to give a brown oil

(570 mg) which was puri®ed by ¯ash chromatography

(silica gel, CH₂Cl₂) to afford thiooxime 73 (490 mg,

75%): white crystalline solid; mp 140±1428C (from

EtOAc/petrol 40/60); (Found: C, 62.18; H, 4.49; N, 6.49.

Calcd for C₂₂H₂₀N₂O₃S₂: C, 62.24; H, 4.75; N, 6.60%); R_f

0.50 (CH₂Cl₂); [a]²_D⁵2134 (c 1.3 in CHCl₃); FT IR (KBr

disc) n_max/cm²¹1778s (b-lactam), 1717s (ester), and 1358s;

¹H NMR (500 MHz, CDCl₃) d_H2.19 (3H, br s, CH₃), 2.38

(3H, s, ArCH₃), 3.23 (1H, d, J18 Hz, SCH), 3.46 (1H, br d,

J18 Hz, SCH), 5.28 and 5.30 (2£1H, ABq, J12.5 Hz,

CH₂Ph), 5.34 (1H, br s, 6-H), and 7.34±7.48 (9H_arom, m,

aromatic CH`s); ¹³C NMR (126 MHz, CDCl₃) d_C19.99,

21.17, 31.14, 60.92, 67.77, 123.8, 127.2, 128.5, 128.6,

128.8, 129.9, 135.1, 138.4, and 161.6; and LRMS [DCI

(NH₃)] m/z 442 (MNH₄¹, 5%), 425 (MH¹, 25), 320 (30),

303 (30), 248 (MH¹2H₃CC₆H₄SNvCCO, 30), 124 (45),

108 (C₇H₇OH¹, 50), and 91 (C₇H₇¹, 100).

J2 Hz, C₆H₄NO₂), and 8.57 (1H, d, J1 Hz, HCvN); ¹³

C

NMR (126 MHz, CDCl₃) d_C19.71, 31.57, 57.10, 67.59,

80.88, 123.7, 123.8, 128.4, 128.5, 128.6, 129.3, 129.7,

135.3, 140.6, 160.7, 162.0, and 162.2; and LRMS [DCI

(NH₃)] m/z 438 (MH¹, 10%), 248 (MH¹2

O₂NC₆H₄CHNCHCO, 100), 112 (50), and 91 (C₇H₇¹, 60).

Preparation of p-toluenesulfonic salt of benzyl (2)-

(6S,7S)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo-

[4.2.0]oct-2-ene-2-carboxylate (77). To a cooled (2788C)

solution of Schiff base 75 (132 mg, 0.30 mmol) in THF

(5 ml) was added, with vigorous stirring, phenyl lithium

(1.8 M solution in cyclohexane/ether, 168 ml, 0.30 mmol)

followed by DMF (4 ml) to give a deep blue solution.

After 2 min at 2788C the mixture was quenched with a

solution of glacial AcOH (19 ml, 0.33 mmol) and water

(27 ml, 1.5 mmol) in THF (1 ml). The resulting yellow solu-

tion was diluted with EtOAc (50 ml) and washed succes-

sively with 1 M NaH₂PO₄(2£20 ml), water (3£30 ml), 1 M

Na₂HPO₄(2£20 ml), and satd. brine (20 ml). The organic

layer was dried over MgSO₄and evaporated in vacuo to

afford an off-white solid (135 mg). Puri®cation by ¯ash

chromatography (silica gel, CH₂Cl₂/EtOAc, 25:1) gave a

white solid (123 mg, 93%) which, on the basis of ¹H

Benzyl (2)-(6S,7S)-3-methyl-8-oxo-5-thia-7-(4-toluene-

sulfenamido)-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

(74). To an ice bath cooled solution of thiooxime 73

(312 mg, 0.74 mmol) in THF (30 ml) and DMSO (5 ml)

was added, dropwise over 10 min, a solution of sodium

borohydride (122 mg, 3.22 mmol) in THF (5 ml) and

DMSO (5 ml). The resulting solution, deep violet in colour,

was stirred at 08C for 40 min and quenched with glacial

AcOH (1.3 ml). The reaction mixture was washed with

satd. NaHCO₃(50 ml), water (3£30 ml), and satd. brine

(30 ml). The organic layer was dried over MgSO₄and

evaporated in vacuo to afford a yellow foam (315 mg). Puri-

®cation by ¯ash chromatography (silica gel, CH₂Cl₂/EtOAc,

50:1) gave sulfenamide 74 (157 mg, 50%): light yellow oil;

HRMS Calcd for C₂₂H₂₃N₂O₃S₂(MH¹) 427.1184, found

T. Fekner et al. / Tetrahedron 56 (2000) 6053±6074

6073

3. Waxman, D. J.; Strominger, J. L. b-Lactam Antibiotics:

Biochemical Modes of Action; In Chemistry and Biology of b-

Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic:

London, 1982; Vol. 3, pp 209±295.

NMR (200 MHz, ) analysis, consisted of two epimeric

imines, 76 and 75, in a ratio of ca. 2.5:1. The solid was

dissolved in EtOAc (2.5 ml) containing water (82 ml,

4.5 mmol) and treated with p-toluenesulfonic acid mono-

hydrate (86 mg, 0.45 mmol). The mixture was stirred at

room temperature for 30 min and a white solid which crys-

tallised from the reaction mixture was ®ltered and washed

on the ®lter with EtOAc (3£1 ml) and Et₂O (2£1 ml).

Drying in vacuo afforded salt 77 (65 mg, 49% or 45%

from imine 75): white crystalline solid; mp 173±1748C

(dec.) (from EtOAc); FT IR (KBr disc) n_max/cm²¹1784s

(b-lactam) 1722s (ester), 1640m, 1597m, 1546S, 1499m,

4. Baggaley, K. H.; Brown, A. G.; Scho®eld, C. J. Nat. Prod. Rep.

1997, 14, 309±333.

5. Pfaendler, H. R.; Neumann, T.; Bartsch, R. Synthesis 1992,

1179±1184.

6. Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.;

Oppolzer, W.; Ramage, R.; Ranganathan, S.; VorbruÈggen, H.

J. Am. Chem. Soc. 1966, 88, 852±853.

7. Oberhauser, T.; Meduna, V. Tetrahedron 1996, 52, 7691±7702.

8. (a) US Patent 3,489,751, 1970. (b) US Patent 3,489,752, 1970.

(c) US Patent 3,985,741, 1976. (d) US Patent 4,504,657, 1985.

9. Fekner, T. Syntheses of Unnaturally Con®gured Penicillins and

Cephalosporins, University of Oxford, 1996.

1

1454m, 1387S, 1371s, 1295s, 1251s, 1224s, and 1185s; H

NMR (500 MHz, CDCl₃) d_H2.16 (3H, s, CH₃), 2.35 (3H, s,

Ar CH₃), 3.47 and 3.54 (2£1H, ABq, J17.5 Hz, SCH₂),

5.00 and 5.19 (2£1H, 2£d, J4.5 Hz, 6-H and 7-H), 5.27

and 5.30 (2£1H, ABq, J12 Hz, CH₂Ph), 7.32 and 7.65

10. Fekner, T.; Baldwin, J. E.; Adlington, R. M.; Scho®eld, C. J.

Chem. Commun. 1996, 1989±1990.

(2£2H_arom

,

2£d, J8 Hz, C₆H₄CH₃), and 7.39±7.46

11. De Angelis, F.; Mozzetti, C.; Di Tullio, A.; Nicoletti, R. Chem.

Commun. 1999, 253±254.

(5H_arom, m, Ph); and LRMS (electrospray, 1) m/z 305

(MH¹, 40%) and 277 (MH¹2CO, 100).

12. Morin, R. B.; Jackson, B. G.; Mueller, R. A.; Lavagnino, E. R.;

Scanlon, W. B.; Andrews, S. L. J. Am. Chem. Soc. 1963, 85, 1896±

1897.

Coordinates for crystal strcutures will be deposited with the

Cambridge Crystallographic Database. Selected data are:

13. Morin, R. B.; Jackson, B. G.; Mueller, R. A.; Lavagnino, E. R.;

Scanlon, W. B.; Andrews, S. L. J. Am. Chem. Soc. 1969, 91, 1401±

1407.

Penam 26. C₂₃H₂₀N₂O₅S, M_r436.4814. Orthorhombic,

Ê

Ê ³

a5.907(5), b16.138(2), c21.958(3) A, V2093.4 A

(by least-squares re®nement for 25 re¯ections, l

14. Busson, R.; Vanderhaeghe, H. J. Org. Chem. 1976, 41, 2561±

2565.

Ê

1.5412 A), space group P2₁P2₁P2₁, Z4 Hz, D_x

1.3850 Mg m²³. Colourless needles.

15. Nefkens, G. H. L.; Tesser, G. I.; Nivard, R. J. F. Recl. Trav.

Chim. Pays-Bas. 1960, 79, 688±698.

Cephem 50. C₂₃H₁₈N₂O₅S, M_r434.4656. Orthorhombic,

16. Sheehan, J. C.; Henery-Logan, K. R. J. Am. Chem. Soc. 1962,

84, 2983±2990.

Ê

Ê ³

a5.491(1), b13.441(3), c27.756(5) A, V2048.5 A

Ê

(25 re¯ections, l1.5412 A), space group P2₁P2₁P2₁,

17. (a) Wolfe, S.; Lee, W. H. J. Chem. Soc., Chem. Commun.

1968, 242±245. (b) Cooper, R. D. G.; Demarco, P. V.; Spry,

D. O. J. Am. Chem. Soc. 1969, 91, 1528±1529. (c) Jackson, J. R.;

Stoodley, R. J. J. Chem. Soc., Chem. Commun. 1971, 647±648.

(d) Jackson, J. R.; Stoodley, R. J. J. Chem. Soc., Perkin Trans. 1

1972, 895±899.

Z4 Hz, D_x1.4087 Mg m²³

.

Amine 51. C₁₅H₁₆N₂O₃S, M_r304.363. Orthorhombic,

Ê

Ê ³

a12.184(2), b12.145(1), c9.924(2) A, V1468.4 A

Ê

(25 re¯ections, l1.5412 A), space group P2₁P2₁P2₁,

Z4 Hz, D_x1.37.68 Mg m²³. Colourless cubes.

18. Kukolja, S. J. Am. Chem. Soc. 1971, 93, 6267±6269.

19. Kukolja, S. J. Am. Chem. Soc. 1971, 93, 6269±6270.

20. Spry, D. O. J. Am. Chem. Soc. 1970, 92, 5006±5008.

21. Spry, D. O. J. Org. Chem. 1972, 37, 793±795.

22. Ing, H. R.; Manske, R. H. F. J. Chem. Soc. 1926, 2348±2351.

Sulfoxide 58. (C₂₃H₂₀N₂O₆S)₂, M_r904.96. Monoclinic,

Ê

a13.280(3), b14.947(3), c11.086(1) A, b95.17(1)8,

Ê ³

V2191.6 A (25 re¯ections, l1.5412 A), space group

P2₁, Z2 Hz, D_x1.37 Mg m²³. Colourless prisms.

Â

23. Heymes, R.; Amiard, G.; Nomine, G. Bull. Soc. Chim. Fr.

1974, 3-4, 563±566.

24. Naito, T.; Hoshi, H.; Aburaki, S.; Abe, Y.; Okumura, J.;

Tomatsu, K.; Kawaguchi, H. J. Antibiot. 1987, 40, 991±1006.

25. Tsuji, T.; Kataoka, T.; Yoshioka, M.; Sendo, Y.; Nishitani, Y.;

Hirai, S.; Maeda, T.; Nagata, W. Tetrahedron Lett. 1979, 30,

2793±2796.

Acknowledgements

We thank ICI for a scholarship (to T. F.) and F. Hoffmann-

La Roche for a gift of 6-APA. We thank Dr R. T. Aplin for

mass spectroscopic analyses, Dr M. Vickers for powder

diffraction studies, Mrs E. McGuinness and Dr T. Claridge

for their assistance with high-®eld NMR experiments.

26. Cooper, R. D. G. J. Am. Chem. Soc. 1970, 92, 5010±5011.

27. Cooper, R. D. G.; Spry, D. O. Rearrangements of

Cephalosporins and Penicillins; In Cephalosporins and Penicillins.

Chemistry and Biology; Flynn, E. H., Ed.; Academic: New York,

1972, pp 183±254.

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Syntheses of (6S)-cephalosporins from 6-aminopenicillanic acid

DOI: 10.1016/S0040-4020(00)00486-5

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