Synthesis of thienamycin-like 2-iso-oxacephems with optional stereochemistry

Tetrahedron: Asymmetry 17 (2006) 3111–3127

Synthesis of thienamycin-like 2-iso-oxacephems

with optional stereochemistry

*

´

Zsuzsanna Santa, Jozsef Nagy and Jozsef Nyitrai

Institute for Organic Chemistry, Budapest University of Technology and Economics, PO Box 91, Budapest H-1521, Hungary

Received 5 October 2006; accepted 15 November 2006

Abstract—All four trans-stereoisomers of 7-(1-hydroxyethyl)-2-iso-oxacephem-4-carboxylic acids, which are the 2-iso-oxacephem ana-

logues of Thienamycin, have been synthesized. (aR,6R,7R)- and (aS,6S,7S)-7-(1-hydroxyethyl)-3-methyl-2-iso-oxacephem-4-carboxylic

acids have been prepared starting from ^L- and D-threonine, the conﬁguration at the a-position was inverted by using Mitsunobu reactions

providing the (aS,6R,7R)- and (aR,6S,7S)-diastereomers of the compounds above. A synthetic route to the cis-annelated analogues was

also worked out.

1. Introduction

1b. The syntheses were carried out enantioselectively in

the sequences marked with a and b. Only one of the enan-

tiomer sequences is depicted in the schemes. Letters a and b

mean compounds prepared from ^L- or D-threonine, respec-

tively. Starting from ^L- and D-threonine, which in turn led

to (aR,6R,7R)- and (aS,6S,7S)-3a and 3b.⁹The only

remaining problem to be solved was to remove the O-acetyl

group without destroying the b-lactam moiety. Treatment

of compounds 1a and 1b with methanolic sodium meth-

oxide at ambient temperature provided the 7-(1-hydroxy-

ethyl) derivatives 2a and 2b which, after hydrogenolysis,

yielded the desired products 3a and 3b. Under the circum-

stances of atmospheric hydrogenolysis, the tetrasubstituted

double bond in the 2-iso-oxacephem ring remains intact

(Scheme 1).

Due to the developed resistance of bacteria against b-lac-

tam antibiotics, the search for novel antibiotics remains a

challenging problem.¹Although a broad range of resis-

tance mechanisms exists,²the production of b-lactamase

enzymes is the most important mechanism through which

bacteria have become resistant to b-lactam antibiotics.^3,4

Thienamycin, the ﬁrst representative of carbapenem deriv-

atives,^5,6exhibits a broad antibacterial spectrum and is

stable against b-lactamases due to the hydroxyethyl side

chain. This fact, together with the known antibacterial

activity of some 2-iso-oxacephems,⁷led us to the combina-

tion of these structural elements. Although it turned out

that the type B b-lactamases (zinc-metalloenzymes) cata-

lyze the hydrolysis of carbapenem derivatives as well,⁸

our aim to synthesize enantiomerically pure thienamycin-

like 2-iso-oxacephems with three stereogenic centres

remains a synthetic chemical challenge.

As we have shown in our previous paper, ^D-allo-threonine

is an appropriate starting material for 7-(1-hydroxyethyl)-

2-iso-oxacephem-4-carboxylic acid with Thienamycin-like

conﬁguration.⁹Starting with this compound was not feasi-

ble due to its high cost. Starting with ^D-threonine meant

2. Results and discussion

OH

O

AcO

H

The aim of this research was to synthesize all eight stereo-

isomers of 7-(1-hydroxyethyl)-3-methyl-2-iso-oxacephem-

4-carboxylic acids. In a recent paper, we have already

reported the stereoselective synthesis of precursors 1a and

H

ii

i

O

N

O

COOH

COOCH₂Ph

2a

3a

1a

*

Corresponding author. Tel./fax: +36 1 463 2205; e-mail: nyitrai@

mail.bme.hu

Scheme 1. Reagents: (i) NaOMe/MeOH; (ii) H₂/Pd/C, MeOH.

doi:10.1016/j.tetasy.2006.11.034

3112

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

that the conﬁguration must be inverted at the a-hydroxy

carbon atom. Preliminary experiments were carried out

using Mitsunobu reactions on model compound 2a for

inversion on the a-carbon atom. Acids containing a heavy

atom (4-bromobenzoic acid: 4a; bromoacetic acid: 5a) were

used in order to obtain derivatives for X-ray investigations.

Unfortunately, these compounds could not be crystallized.

The corresponding inverted 7-(1-acetoxyethyl) derivatives

6a and 6b were formed in good yields. Because they are

crystalline at rt, unlike 1a and 1b, and the NMR spectra

and speciﬁc rotations are diﬀerent, the conﬁguration of

the a-carbon atom of 6a and 6b must diﬀer from that of

1a and 1b. The deacetylation and hydrogenolysis furnished

the corresponding 7-(1-hydroxyethyl)-2-iso-oxacephem-4-

carboxylic acids 8a and 8b. The latter exhibits the same

stereochemical pattern (aR,6S,7S) as thienamycin

(aR,5R,6S). The spatial arrangement on the bridgehead

carbon is the same in the two compounds; the non-equiva-

lent stereodescriptors (6S and 5R, respectively) are due to

the Cahn–Ingold–Prelog convention (Scheme 2).

hydroxy compound 11a.⁹Depending on reaction condi-

tions, two diﬀerent compounds were formed by

mesylation. Compound 11a, reacting with mesyl chloride

in pyridine, furnished a 1:1 mixture of 2-methyl-3-oxa-6-

azabicyclo[3.2.0]heptan-7-one 12a and the desired dimesyl-

ate 13a. The conﬁguration of carbon 2 in 12a might be

questionable. Our eﬀorts in preparing the bromo derivative

14a were successful (a by-product, dibromo derivative 15a

was also formed). Unfortunately, since the single crystal of

14a decomposed on X-ray irradiation, the X-ray crystallo-

graphic measurement did not provide direct evidence of the

conﬁguration of the carbon atoms at positions 1, 2 and 5.

The fact that in its ¹H NMR spectrum there was a coupling

between 2-H and 1-H but none between 4-H and 5-H

makes it likely that the ring closure did not eﬀect the con-

ﬁguration on C-2, similar to our previous experience⁹

(Scheme 3).

Dimesylate 13a was also formed from 11a with mesyl chlo-

ride in THF by adding triethylamine at 0 ꢁC. This com-

pound was deprotected on the nitrogen to 16a, which we

hoped would transform easily using our method^11,12to

the corresponding 2-iso-oxacephem 17a. Unfortunately,

this compound did not prove to be suitable for the trans-

formation, because during the ring closure step (boiling

in chloroform in the presence of NEt₃) elimination of the

mesylate occurred, resulting in 17a and the unsaturated

derivative 18a in poor yields (Scheme 4).

After our success in the synthesis of the four stereoisomers

3a and 3b and 8a and 8b of the trans-2-iso-oxacephem

skeleton, we turned our attention to the synthesis of the

cis-isomers. Over the course of the synthetic route leading

to these compounds, the cis-acetoxy ester 9a,¹⁰which was

derived from dimethyl malonate and ^L-threonine, could

be reduced via the hydroxy carboxylic acid 10a to the di-

RCOO

H

O

N

O

i

COOCH₂Ph

4 R = p-BrC₆H₄

5 R = BrCH₂

OH

O

OH

O

AcO

OH

H

iv

iii

ii

O

N

O

COOH

COOCH₂Ph

7a

8a

6a

2a

Scheme 2. Reagents and conditions: (i) RCOOH, DEAD or DIAD, PPh₃, THF; R p-BrC₆H₄or BrCH₂; (ii) AcOH, DEAD, PPh₃, THF, 0 ꢁC; (iii)

NaOMe/MeOH; (iv) H₂/Pd/C, MeOH.

O

2

1

4

5

iii

iv

13a +

OH

OAc

N

v

CH₂OH

PMP

COOH

PMP

COOMe

PMP

O

PMP

ii

i

12a

O

N

O

N

O

OMs

N

+

9a

10a

11a

CH₂OMs

PMP

N

PMP = p-methoxyphenyl

O

Br

OMe

14a

Br

15a

O

OMe

13a

Scheme 3. Reagents and conditions: (i) 1 M HCl, reﬂux; (ii) (a) ClCOOEt, NEt₃, THF, ꢀ20 ꢁC; (b) NaBH₄; (iii) MsCl, pyridine; (iv) MsCl, NEt₃, THF;

(v) Br₂, acetic acid.

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

3113

OMs

H

CH₂OMs

PMP

CH₂OMs

ii

i

O

+

O

N

NH

16a

O

COOCH₂Ph

18a

13a

17a

Scheme 4. Reagents and conditions: (i) CAN, acetonitrile/water, ꢀ10 ꢁC; (ii) (a) benzyl 2,3-dioxobutyrate, NEt₃, THF; (b) SOCl₂, pyridine, ꢀ20 ꢁC; (c)

Zn, acetic acid, 5 ꢁC; (d) NEt₃, CHCl₃, reﬂux.

1

Due to the side reaction leading to 18a, we tried to selec-

tively re-acetylate the hydroxy carboxylic acid 10a on the

side chain hydroxyl group. On treatment with acetyl chlo-

ride, a ring closure occurred instead of acetylation, furnish-

ing the corresponding lactone 19a. This compound could

be reduced with sodium borohydride to diol 11a in a very

good yield (Scheme 5).

from the two possible ones, was answered based on its H

NMR spectrum, in which the chemical shift of the a-car-

bon is always about 4 ppm if it bears a free hydroxyl group

and about 5.5 ppm, if it bears an acetoxy group. In the case

of detritylation carried out in 1 M HCl/dioxane, com-

pound 11a was regained. Atmospheric hydrogenolysis of

the tritylated/acetylated intermediate did not bring about

any reaction (Scheme 5).

It is very common in carbohydrate chemistry that primary

and secondary hydroxyl groups can be distinguished by a

tritylation/acetylation/detritylation sequence. In our case,

this method did not provide satisfactory results. When

the detritylation was carried out in acetic acid, the reaction

surprisingly provided the acetylated derivative on the pri-

mary hydroxyl group 20a (and not on the secondary) and

the diacetyl derivative 21a. The formation of 20a could

be explained by an intramolecular transacetylation as a

consequence of the spatial proximity of the hydroxyl

groups. Compounds 20a and 21a were also formed by di-

rect acetylation of 11a, the physical properties of which

were the same as those of the products of the previous reac-

tion sequence. The question, as to which regioisomer is 20a

These unsuccessful attempts prompted us to ﬁnd a new

orthogonal protecting group strategy for the synthesis of

the cis-annelated ring systems. The benzyl group was con-

sidered as a good candidate for that role, with it being a

protecting group removable by a non-hydrolytic route.

Starting with dibenzyl malonate and using the same route

described for the methyl esters^10,11via intermediates 22,

23a and 23b!25a and 25b aﬀorded the diastereomeric mix-

tures of acetoxy benzyl esters 26a and 26b and 27a and 27b,

respectively (the conﬁguration of these compounds was

determined based on the coupling constants between 2-H

and 3-H, which are diﬀerent and typical in the cis and trans

derivatives) (Scheme 6).

OH

O

OH

OAc

OH

O

COOH

PMP

CH₂OH

PMP

CH₂OAc

PMP

CH₂OAc

PMP

iii

i

ii

+

N

O

PMP

O

10a

20a

21a

19a

11a

Scheme 5. Reagents and conditions: (i) AcCl, pyridine, THF; (ii) NaBH₄, MeOH; (iii) (a) TrCl, pyridine, reﬂux; (b) AcCl, pyridine, THF; (c) acetic acid,

reﬂux.

OAc

iv

COOBn

v

iii

COOBn

i

ii

COOH

Br

HN

Br

COOBn

O

N

O

PMP

O

PMP

MeO

25a

24a

vi

23a

22

MeO

OAc

CH₂OH

COOBn

PMP

COOBn

PMP

viii

COOH

vii

N

+

N

O

PMP

N

O

PMP

28a

26a

27a

29a

Scheme 6. Reagents and conditions: (i) Br₂, CCl₄; (ii) p-anisidine, ether; (iii) (2R^*,3S^*)-3-acetoxy-2-bromobutyryl chloride, toluene, 80 ꢁC; (iv) DBU,

toluene; (v) 1 N NaOH, pyridine, 0 ꢁC; (vi) 2-picoline, 140 ꢁC; (vii) H₂/Pd/C, DMF; (viii) NaBH₄, tert-butyl alcohol.

3114

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

OAc

OH

OAc

O

O AcO

COOH

PMP

CH₂OH

PMP

CH₂OAc

PMP

CH₂OAc

PMP

i

O

+

N

O

PMP PMP

29a

30a

20a

32a

31b

Scheme 7. Reagents and conditions: (i) (a) ClCOOEt, NEt₃, THF, ꢀ20ꢁC; (b) NaBH₄.

Compounds 28a and 28b are the same intermediates, which

could be transformed to the known trans-iso-oxacephems

as described earlier.⁹The free carboxylic acids 29a and

29b can be obtained by hydrogenolysis without the loss

of the acetyl protecting group. The reduction to the corre-

sponding alcohol acetates 30a and 30b was carried out by

using the mixed anhydride method.¹³It is worth mention-

ing that the isolated intermediate of this reaction proved to

be an anhydride (31b isolated from the b series). The

isomeric alcohol acetates 20a and 20b (as a result of

transacetylation) also appeared in the reaction mixtures.

Compounds 30a and 30b and 20a and 20b could not be

separated, their mixture was used in the next reaction, their

ratio was determined from the NMR spectra, as compound

20a had been previously synthesized (see above). A by-

product, which is the result of reduction in the side chain,

was also isolated in trace amounts (32a isolated from the a

series) (Scheme 7).

The hydrogenolysis of 18a and 18b did not lead to the cor-

responding unsaturated carboxylic acids because they

decomposed during this procedure. Compounds 36a and

36b were debenzylated with catalytic hydrogenolysis to

38a and 38b (Scheme 8).

Compounds 36a and 36b could be transformed to the epi-

mers at the a-C atom by the Mitsunobu reaction similarly

to the trans-series.

3. Conclusion

A general synthetic route has been developed for all

stereoisomers of 7-(1-hydroxyethyl)-3-methyl-2-iso-oxace-

phem-4-carboxylic acids. In the case of cis-2-iso-oxace-

phem series, the acetoxy compounds 35 and 35b get out

of the synthetic pathway providing mainly 7-ethylidene

derivatives 18a and 18b and the yield, of the hydroxyethyl

esters 36a and 36b were not high enough to carry out the

Mitsunobu reaction to produce the corresponding diaste-

reomers (aS,6S,7R and aR,6R,7S).

The mesylation of the mixtures 30a and 30b and 20a and

20b provided only the desired compounds 33a and 33b.

The further transformations were carried out similarly as

described for the trans-series.⁹Unfortunately, the deacetyl-

ation of 35a and 35b with catalytic sodium methoxide fur-

nished again the mixture of the elimination products 18a

and 18b and the desired 36a and 36b. The isomeric unsat-

urated compound 37a could also be isolated and character-

ized. The conﬁguration of the double bond in 18 and 37

All of the bicyclic b-lactams were sent to two laboratories

for antibacterial screening. These compounds were tested

twice on Staphylococcus aureus ATCC 25923 up to

100 mg/L (in liquid medium), but none of them showed

any antibacterial activity. Ampicillin was used as a positive

1

was determined from their H NMR spectra based on the

´

magnetic anisotropy of the neighbouring b-lactam

carbonyl group. Our assignment is in accordance with the

literature data.¹⁴Various methods were tried for deacetyl-

ation of 35a and 35b, but the results were the same. These

observations can be explained by the fact that the H-7 is

more accessible for the alkoxide base in the cis-series than

that in the trans-series.

control (Laboratoire de Biochimie UMR CNRS 7573 Ecole

Nationale Superieure de Chimie de Paris). The same com-

pounds were tested on 26 species by using Neomycin as

control substance in Novartis/Vienna, but none of them

showed any activity. The beta-lactamase assays were car-

ried out at Nabriva Therapeutics/Vienna without any posi-

tive results.

OAc

OH

H

CH₂OMs

NH

CH₂OMs

PMP

CH₂OH

PMP

CH₂OAc

PMP

iii

i

ii

O

+

N

O

COOBn

35a

34a

33a

30a

20a

iv

OH

O

OH

O

H

v

O

+

N

O

COOBn

COOH

37a

18a

36a

38a

Scheme 8. Reagents and conditions: (i) MsCl, NEt₃, THF, 0 ꢁC; (ii) CAN, acetonitrile/water, ꢀ10 ꢁC; (iii) (a) benzyl 2,3-dioxobutyrate, NEt₃, THF;

(b) SOCl₂, pyridine, ꢀ20 ꢁC; (c) Zn, acetic acid, 5 ꢁC; (d) NEt₃, CHCl₃, reﬂux; (iv) NaOMe/MeOH, 0 ꢁC; (v) H₂/Pd/C, MeOH.

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

3115

4. Experimental

163.33 (COOBn), 166.04 (CON). HRMS m/z 317.1272

(C₁₇H₁₉O₅N calcd 317.1263).

4.1. General

4.3. Benzyl (6S,7S)-7-[(1S)-1-hydroxyethyl]-3-methyl-2-iso-

oxacephem-4-carboxylate 2b

Melting points were determined on a hot stage melting

point apparatus and are uncorrected. Optical rotations (c

1.0 g/100 cm³in CH₂Cl₂) unless stated otherwise, [a]_Dval-

ues are given in 10^ꢀ1deg cm²g^ꢀ1and were taken on a Per-

kin–Elmer 241 polarimeter calibrated by measuring the

Prepared analogously to 2a from 1b⁹(0.48 g; 1.34 mmol)

and gave 2b (0.40 g, 95%) as a yellow oil. It was pure

enough for further reactions, but was puriﬁed by prep.

1

optical rotations of both enantiomers of menthol. The H

TLC (CH₂Cl₂–EtOAc 6:9) for analytical investigations.

and ¹³C NMR spectra were obtained using a Bruker

DRX 500 spectrometer (¹H 500.33 MHz, ¹³C 125.75

MHz) or a Bruker 300 spectrometer (¹H 300.13, ¹³C

75.48 MHz), respectively, at 298 K in CDCl₃as a solvent,

unless stated otherwise. The digital resolution of both spec-

trometers is 0.3 Hz. Chemical shifts were given on the delta

scale as parts per million (ppm) with tetramethylsilane

(TMS) as the internal standard. The IR spectra were

recorded on a Zeiss Specord M80 spectrophotometer. High

resolution FABMS was measured on a MAT 312 instru-

ment equipped with a Maspec II32 data system using

V/E scan or on a Waters-Micromass LCT apparatus using

ESI+ method (8a,b). Elemental analyses (C, H, N, S) were

conducted using the Elemental Analyser VARIO EL III

(Elementar Analysensysteme Gmbh), their results were

found to be in good agreement ( 0.4%) with the calculated

values. Column and thin-layer chromatography were car-

ried out on Merck Kieselgel 60 (0.063–0.2 mm) and Merck

Kieselgel 60 F₂₅₄Alufolien, respectively. For preparative

22:5

½aꢁ_D¼ þ184:2. IR (ﬁlm): m 3448 (OH), 2976 (CH), 1752

(br, CON, COO), 1616 (Ar), 1392, 1208, 1128, 1080,

1024, 696 cm^ꢀ^{1 1}H NMR (500 MHz): d 1.37 (3H, d,

.

J = 6.2 Hz, b-Me), 2.23 (3H, s, 3-Me), 2.97 (1H, dd,

J_aH= 5.6 Hz, J_trans= 1.7 Hz, 7-H), 3.45 (1H, ddd,

J_1HA= 9.5 Hz, J_1HB= 3.7 Hz, J_trans= 1.7 Hz, 6-H), 3.69

(1H, m ꢂ t, 1-H_A), 4.25 (1H, m ꢂ qui, a-H), 4.65 (1H,

dd, J_gem= 10.7 Hz, J_6H= 3.7 Hz, 1-H_B), 5.27 (2H, s,

CH₂Ph), 7.30–7.46 (5H, m, ArH). ¹³C NMR (75 MHz): d

18.21 (b-Me), 21.31 (3-Me), 43.94 (6-C), 63.40 (7-C),

65.52 (a-C), 66.92 (CH₂Ph), 69.57 (1-C), 106.99 (4-C),

128.25, 128.32 and 128.65 (Ar-2⁰,3⁰,4⁰-C), 136.20 (Ar-1⁰-

C), 154.95 (3-C), 163.35 (COOBn), 166.09 (CON). HRMS:

317.1270 (C₁₇H₁₉O₅N calcd 317.1263).

4.4. (6R,7R)-7-[(1R)-1-Hydroxyethyl]-3-methyl-2-iso-

oxacephem-4-carboxylic acid 3a

Compound 2a (70 mg; 0.2 mmol) was hydrogenated under

normal pressure in the presence of 10% Pd/C catalyst

(10 mg) in methanol (20 mL) for an hour (TLC: CH₂Cl₂–

EtOAc 1:1, UV, Rf₂0.3, Rf₃0; CH₂Cl₂–MeOH 10:3,

UV, Rf₃0.4). The catalyst was ﬁltered oﬀ and washed with

methanol. The ﬁltrate was evaporated under reduced pres-

sure. The resulting colourless oil solidiﬁes on ether to give

TLC Merck PSC ready-for-use plates (Kieselgel 60 F₂₅₄

,

20 · 20 cm, 2 mm) were used. TLC spots were detected

by UV and/or phosphomolybdic acid (PMA). All solvents

were distilled and dried before use.

4.2. Benzyl (6R,7R)-7-[(1R)-1-hydroxyethyl]-3-methyl-2-iso-

oxacephem-4-carboxylate 2a

3a (35 mg, 78%) as a white solid. Mp 117–119 ꢁC.

20

½aꢁ_D¼ ꢀ220:8 (MeOH). IR (KBr): m 3416 (br, COOH),

NaOMe/MeOH solution (0.2 M, 0.8 mL; 0.16 mmol) was

added to a solution of benzyl (6R,7R)-7-[(1R)-1-acetoxy-

ethyl]-3-methyl-2-iso-oxacephem-4-carboxylate 1a⁹(0.5 g;

1.4 mmol) in methanol (30 mL) and stirred for 2 h at rt

(TLC: CH₂Cl₂–EtOAc 1:1, UV + PMA, Rf₁0.75, Rf₂

0.28). After completion the mixture was neutralized with

1 M HCl, and the methanol was evaporated under reduced

pressure. The residue was taken up in 10 mL EtOAc,

washed with water, brine and dried (MgSO₄). The solvent

was evaporated under reduced pressure to give 2a (0.42 g,

95%) as a yellow oil. It was pure enough for further reac-

1

1744 (CON), 1192, 1120, 720, 696, 540 cm^ꢀ1. H NMR

(500 MHz, MeOD-d₄): d 1.35 (3H, d, J = 6.5 Hz, b-Me),

2.19 (3H, s, 3-Me), 3.03 (1H, m, 7-H), 3.47 (1H, m, 6-H),

3.69 (1H, m ꢂ t, 1-H_A), 4.12 (1H, m ꢂ qui, a-H), 4.64

(1H, dd, J_gem= 10.6 Hz, J_6H= 3.6 Hz, 1-H_B). ¹³C NMR

(75 MHz, MeOD-d₄): d 17.90 (b-Me), 21.48 (3-Me), 45.51

(6-C), 64.11 (7-C), 65.85 (a-C), 70.30 (1-C), 110.66 (4-C),

152.70 (3-C), 168.72 (CON).^ꢀHRMS m/z 227.0787

(C₁₀H₁₃NO₅calcd 227.0794).

4.5. (6S,7S)-7-[(1S)-1-Hydroxyethyl]-3-methyl-2-iso-

oxacephem-4-carboxylic acid 3b

tions, but puriﬁed by prep. TLC (CH₂Cl₂–EtOAc 6:9) for

23:5

analytical investigations. ½aꢁ_D¼ ꢀ184:3. IR (ﬁlm): m

3448 (OH), 2976 (CH), 1752 (br, CON, COO), 1616 (Ar),

1392, 1208, 1132, 1084, 1024, 700 cm^ꢀ1

.

¹H NMR

Prepared analogously to 3a from 2b (120 mg; 0.38 mmol)

and gave 3b (70 mg, 81%) as a white hygroscopic solid.

(500 MHz): d 1.38 (3H, d, J = 6.2 Hz, b-Me), 2.25 (3H, s,

3-Me), 3.00 (1H, dd, J_aH= 5.7 Hz, J_trans= 1.7 Hz, 7-H),

19

Mp 117–119 ꢁC. ½aꢁ_D¼ þ220:4 (MeOH). IR (KBr): m

3432 (br, COOH), 1752 (br, CON, COO), 1624, 1208,

3.48

(1H,

ddd,

J_1HA= 9.5 Hz,

J_1HB= 3.6 Hz,

1

1120, 720, 696, 540 cm^ꢀ1. H NMR (500 MHz, MeOD-

J_trans= 1.7 Hz, 6-H), 3.69 (1H, m ꢂ t, 1-H_A), 3.75 (1H, s,

OH), 4.27 (1H, m ꢂ qui, a-H), 4.67 (1H, dd,

J_gem= 10.7 Hz, J_6H= 3.5 Hz, 1-H_B), 5.28 (2H, s, CH₂Ph),

7.30–7.46 (5H, m, ArH). ¹³C NMR (75 MHz): d 18.21 (b-

Me), 21.44 (3-Me), 44.04 (6-C), 63.37 (7-C), 65.68 (a-C),

66.94 (CH₂Ph), 69.55 (1-C), 107.03 (4-C), 128.26, 128.35

and 128.66 (Ar-2⁰,3⁰,4⁰-C), 136.23 (Ar-1⁰-C), 154.94 (3-C),

d₄): d 1.35 (3H, d, J = 6.5 Hz, b-Me), 2.19 (3H, s, 3-Me),

3.03 (1H, m, 7-H), 3.47 (1H, m, 6-H), 3.69 (1H, m ꢂ t,

^ꢀIn all of the hydroxy-2-iso-oxacephem-4-carboxylic acids, the carboxylic

acid CO signal in the ¹³C NMR spectra is missing due to its diﬀuse

shape.

3116

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

1-H_A), 4.12 (1H, m ꢂ qui, a-H), 4.64 (1H, dd,

J_gem= 10.6 Hz, J_6H= 3.6 Hz, 1-H_B). ¹³C NMR (75 MHz,

MeOD-d₄): d 17.97 (b-Me), 21.48 (3-Me), 45.52 (6-C),

64.13 (7-C), 65.81 (a-C), 70.37 (1-C), 110.28 (4-C), 153.25

(3-C), 168.88 (CON). HRMS m/z 227.0777 (C₁₀H₁₃NO₅

calcd 227.0794).

4.8. Benzyl (6R,7R)-7-[(1S)-1-acetoxyethyl]-3-methyl-2-iso-

oxacephem-4-carboxylate 6a

PPh₃(0.4 g; 1.5 mmol) and abs. acetic acid (0.4 mL;

6.3 mmol) were added to a solution of 2a (0.2 g;

0.63 mmol) in THF (20 mL). A solution of 40% DEAD/

toluene (0.5 mL; 1.25 mmol) in THF (5 mL) was added

to it dropwise at 0 ꢁC. The solution was stirred for an hour

(TLC: CH₂Cl₂–EtOAc 10:1, UV + PMA, Rf₂0.05, Rf₆

0.5). The product was isolated after evaporation of the sol-

vent by ﬂash chromatography (CH₂Cl₂!CH₂Cl₂–EtOAc

10:0.5). The white solid crystalline material was triturated

4.6. Benzyl (6R,7R)-7-{(1S)-1-[(4-bromobenzoyl)oxy]-

ethyl}-3-methyl-2-iso-oxacephem-4-carboxylate 4a

PPh₃(0.08 g; 0.35 mmol) and 4-bromobenzoic acid (0.06 g;

0.35 mmol) were added to a solution of 2a (0.1 g;

0.31 mmol) in THF (5 mL). A solution of DEAD

(0.05 mL; 0.35 mmol) in THF (1 mL) was added dropwise

to it at rt. The mixture was stirred for a day (TLC:

CH₂Cl₂–EtOAc 10:1, UV + PMA, Rf₂0.05, Rf₄0.45).

The solvent was removed under reduced pressure and the

with ether to give 6a (0.15 g, 68%) as white crystals. Mp

21

132 ꢁC. ½aꢁ_D¼ ꢀ190:0. IR (KBr): m 1780 (COO), 1744

(CON), 1704 (COO), 1624 (Ar), 1376, 1296, 1248, 1208,

1

1136, 768, 752 cm^ꢀ1. H NMR (500 MHz): d 1.40 (3H, d,

J = 6.5 Hz, b-Me), 1.95 (3H, s, MeCO), 2.25 (3H, s, 3-

Me), 2.98 (1H, dd, J_aH= 7.1 Hz, J_trans= 1.9 Hz, 7-H),

product was isolated by prep. TLC (CH₂Cl₂–EtOAc 10:1)

3.47

(1H,

ddd,

J_1HA= 9.4 Hz,

J_1HB= 3.7 Hz,

22

to give 4a (60 mg, 40%) as a yellow oil. ½aꢁ_D¼ ꢀ59:8. IR

J_trans= 1.9 Hz, 6-H), 3.67 (1H, m ꢂ t, 1-H_A), 4.64 (1H,

dd, J_gem= 10.6 Hz, J_6H= 3.7 Hz, 1-H_B), 5.25 (2H, AB,

J_gem= 12.5 Hz, CH₂Ph), 5.35 (1H, m ꢂ qui, a-H), 7.27–

7.40 (5H, m, ArH). ¹³C NMR (75 MHz): d 18.01 (b-Me),

18.85 (3-Me), 21.18 (MeCO), 45.01 (6-C), 61.80 (7-C),

66.93 (a-C), 67.88 (CH₂Ph), 69.48 (1-C), 106.85 (4-C),

128.23, 128.38 and 128.62 (Ar-2⁰,3⁰,4⁰-C), 136.11 (Ar-1⁰-

C), 154.87 (3-C), 163.15 (COOBn), 164.09 (CON), 170.30

(MeCOO). C₁₉H₂₁NO₆requires C 63.5; H 5.9; N 3.9;

found C 63.7; H 5.8; N 3.85.

(ﬁlm) m 2936 (CH), 1768 (CON), 1720 (COO), 1616 (Ar),

1592 (Ar), 1392, 1360, 1272, 1104, 760, 696 cm^ꢀ^{1 1}H

.

NMR (500 MHz): d 1.52 (3H, d, J = 6.3 Hz, b-Me), 2.26

(3H, s, 3-Me), 3.14 (1H, d, J_aH= 6.2 Hz, 7-H), 3.61 (1H,

d, J_1HA= 9.5 Hz, 6-H), 3.72 (1H, m ꢂ t, 1-H_A), 4.66 (1H,

dd, J_gem= 10.5 Hz, J_6H= 3.5 Hz, 1-H_B), 5.23 (2H, AB,

J_gem= 12.5 Hz, CH₂Ph), 5.56 (1H, qui, J = 6.3 Hz, a-H),

7.22–7.40 (5H, m, ArH), 7.45 (2H, d, J_ortho= 8.2 Hz, Ar-

3⁰,5⁰-H), 7.81 (2H, d, J_ortho= 8.2 Hz, Ar-2⁰, 6⁰-H). ¹³C

NMR (125 MHz): d 17.80 (b-Me), 18.60 (3-Me), 44.60 (6-

C), 61.52 (7-C), 66.62 (a-C), 68.32 (CH₂Ph), 69.06 (1-C),

106.36 (4-C), 127.52, 127.65, 127.75, 127.98, 128.29,

130.74, 131.34 and 135.36 (Ar–C), 154.33 (3-C), 162.52

(COOBn), 164.48 (CON), 176.43 (ArCOO).

4.9. Benzyl (6S,7S)-7-[(1R)-1-acetoxyethyl]-3-methyl-2-iso-

oxacephem-4-carboxylate 6b

Prepared analogously to 6a from 2b (0.4 g; 1.27 mmol) and

gave 6b (0.36 g, 80%) as white crystals. Mp 132 ꢁC.

21

4.7. Benzyl (6R,7R)-7-[(1S)-1-(bromoacetoxy)ethyl]-3-

methyl-2-iso-oxacephem-4-carboxylate 5a

½aꢁ_D¼ þ191:1. IR (KBr): m 1784 (COO), 1744 (CON),

1704 (COO), 1624 (Ar), 1376, 1296, 1248, 1208, 1136,

768, 752 cm^ꢀ^{1 1}H NMR (500 MHz): d 1.40 (3H, d,

.

PPh₃(0.09 g; 0.33 mmol) and bromoacetic acid (and 0.05 g;

0.33 mmol) were added to a solution of 2a (0.09 g;

J = 6.5 Hz, b-Me), 1.95 (3H, s, MeCO), 2.24 (3H, s, 3-

Me), 2.98 (1H, dd, J_aH= 7.1 Hz, J_trans= 1.9 Hz, 7-H),

0.3 mmol) in THF (5 mL).

A

solution of DIAD

3.47

(1H,

ddd,

J_1HA= 9.4 Hz,

J_1HB= 3.7 Hz,

(0.05 mL; 0.33 mmol) in THF (1 mL) was added dropwise

to it at rt. The mixture was stirred overnight (TLC:

CH₂Cl₂–EtOAc 10:1, UV + PMA, Rf₂0.05, Rf₅0.5). The

solvent was removed under reduced pressure and the prod-

uct was isolated by prep. TLC (CH₂Cl₂–EtOAc 15:1) to

J_trans= 1.9 Hz, 6-H), 3.67 (1H, m ꢂ t, 1-H_A), 4.64 (1H,

dd, J_gem= 10.6 Hz, J_6H= 3.7 Hz, 1-H_B), 5.25 (2H, AB,

J_gem= 12.5 Hz, CH₂Ph), 5.35 (1H, m ꢂ qui, a-H), 7.29–

7.45 (5H, m, ArH). ¹³C NMR (125 MHz): d 18.04 (b-

Me), 18.88 (3-Me), 21.20 (MeCO), 45.07 (6-C), 61.86 (7-

C), 66.96 (a-C), 67.95 (CH₂Ph), 69.50 (1-C), 106.91 (4-C),

128.26, 128.42 and 128.65 (Ar-2⁰,3⁰,4⁰-C), 136.16 (Ar-1⁰-

C), 154.86 (3-C), 163.17 (COOBn), 164.07 (CON), 170.31

(MeCOO). C₁₉H₂₁NO₆requires C 63.5; H 5.9; N 3.9;

found C 63.5; H 5.7; N 3.85.

give 5a (40 mg, 31%) as a yellow oil and 60 mg (66%) of

21

starting material was also recovered. ½aꢁ_D¼ ꢀ117:5. IR

(ﬁlm): m 2960 (CH), 1768 (CON), 1712 (COO), 1620 (Ar),

1

1392, 1356, 1276, 1132, 1088 cm^ꢀ1. H NMR (500 MHz):

d 1.45 (3H, d, J = 6.3 Hz, b-Me), 2.25 (3H, s, 3-Me), 3.01

(1H, dd, J_aH= 7.5 Hz, J_trans= 1.9 Hz, 7-H), 3.48 (1H,

ddd, J_1HA= 9.5 Hz, J_1HB= 3.7 Hz, J_trans= 1.9 Hz, 6-H),

3.68 (2H, s, CH₂Br), 3.68 (1H, m ꢂ t, 1-H_A), 4.66 (1H,

dd, J_gem= 10.7 Hz, J_1HB= 3.7 Hz, 1-H_B), 5.25 (2H, AB,

J_gem= 12.5 Hz, CH₂Ph), 5.42 (1H, m ꢂ qui, a-H), 7.27–

7.45 (5H, m, ArH). ¹³C NMR (75 MHz): d 18.04 (b-Me),

18.67 (3-Me), 25.74 (CH₂Br), 44.99 (6-C), 61.51 (7-C),

66.95 (a-C), 69.37 (CH₂Ph), 70.06 (1-C), 106.78 (4-C),

128.29, 128.44 and 128.63 (Ar-2⁰,3⁰,4⁰-C), 136.06 (Ar-1⁰-

C), 155.01 (3-C), 163.04 (COOBn), 163.46 (CON), 166.65

(BrCH₂COO).

4.10. Benzyl (6R,7R)-7-[(1S)-1-hydroxyethyl]-3-methyl-2-

iso-oxacephem-4-carboxylate 7a

NaOMe/MeOH (0.1 M, 0.4 mL; 0.04 mmol) was added to

a solution of 6a (0.1 g; 0.28 mmol) in methanol (10 mL)

and stirred for 2 h at rt (TLC: CH₂Cl₂–EtOAc 1:1,

UV + PMA, Rf₆0.75, Rf₇0.28). After completion the mix-

ture was neutralized with 1 M HCl and the methanol was

evaporated under reduced pressure. The residue was dis-

solved in 10 mL EtOAc, washed with water, with brine

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

3117

and dried over MgSO₄. The solvent was evaporated under

reduced pressure to give 7a (70 mg, 80%) as a yellow oil.

This was pure enough for further reactions, but puriﬁed

by prep. TLC (CH₂Cl₂–EtOAc 6:9) for analytical investiga-

tions, the resulting white solid was recrystallized from

250.0695 (C₁₀H₁₃NO₅Na⁺calcd 250.0691) and 266.0427

(C₁₀H₁₃NO₅K⁺calcd 266.0431).

4.13. (6S,7S)-7-[(1R)-1-Hydroxyethyl]-3-methyl-2-iso-

oxacephem-4-carboxylic acid 8b

ether/hexane to give needle-like white crystals. Mp 94–

23

95 ꢁC. ½aꢁ_D¼ ꢀ190:7. IR (KBr): m 3360 (OH), 2952 (CH),

Prepared analogously to 8a from 7b (70 mg; 0.2 mmol) and

1756 (CON), 1712 (COO), 1612 (Ar), 1392, 1216, 1136,

gave 8b (40 mg, 88%) as a white solid. Mp 139–140 ꢁC.

20

1088, 1064, 696 cm^ꢀ1. H NMR (500 MHz): d 1.34 (3H,

½aꢁ_D¼ þ231:8 (MeOH). IR (KBr): m 3440 (br, COOH),

1

d, J = 6.3 Hz, b-Me), 2.13 (1H, br s, OH), 2.23 (3H, s, 3-

Me), 2.86 (1H, dd, J_aH= 6.3 Hz, J_trans= 1.6 Hz, 7-H),

1736 (br, CON, COO), 1628, 1576, 1400, 1148, 792 cm^ꢀ1

.

¹H NMR (500 MHz, MeOD-d₄):

d 1.27 (3H, d,

3.54

(1H,

ddd,

J_1HA= 9.5 Hz,

J_1HB= 3.6 Hz,

J = 6.5 Hz, b-Me), 2.16 (3H, s, 3-Me), 2.84 (1H, m, 6-H),

3.48 (1H, m, 7-H), 3.67 (1H, m ꢂ t, 1-H_A), 4.21 (1H,

m ꢂ qui, a-H), 4.60 (1H, dd, J_gem= 10.7 Hz,

J_6H= 3.7 Hz, 1-H_B). ¹³C NMR (75 MHz, MeOD-d₄): d

17.76 (b-Me), 22.08 (3-Me), 46.28 (6-C), 64.82 (7-C),

66.15 (a-C), 70.20 (1-C), 111.85 (4-C), 151.05 (3-C),

168.60 (CON). HRMS m/z measured as Na/K adduct

250.0699 (C₁₀H₁₃NO₅Na⁺calcd 250.0691) and 266.0439

(C₁₀H₁₃NO₅K⁺calcd 266.0431).

J_trans= 1.7 Hz, 6-H), 3.68 (1H, m ꢂ t, 1-H_A), 4.30 (1H,

qui, J = 6.3 Hz, a-H), 4.67 (1H, dd, J_gem= 10.7 Hz,

J_6H= 3.6 Hz, 1-H_B), 5.27 (2H, s, ArCH₂), 7.30–7.46 (5H,

m, ArH). ¹³C NMR (125 MHz): d 18.28 (b-Me), 22.12 (3-

Me), 44.50 (6-C), 64.35 (7-C), 65.40 (a-C), 66.95 (CH₂–

Ph), 69.69 (1-C), 107.01 (4-C), 128.27, 128.37 and 128.66

(Ar-2⁰,3⁰,4⁰-C), 136.19 (Ar-1⁰-C), 154.98 (3-C), 163.42

(COOBn), 165.82 (CON). HRMS m/z 317.1275

(C₁₇H₁₉O₅N calcd 317.1263).

4.14. (3R,4S)-3-[(1R)-1-(Methanesulfonyloxy)ethyl]-4-

[(methanesulfonyloxy)methyl]-1-(4-methoxyphenyl)-azeti-

din-2-one 13a

4.11. Benzyl (6S,7S)-7-[(1R)-1-hydroxyethyl]-3-methyl-2-

iso-oxacephem-4-carboxylate 7b

Prepared analogously to 7a from 6b (0.1 g; 0.28 mmol) and

Mesyl chloride (0.5 mL; 6.5 mmol) was added to a solution

of (3R,4S)-3-[(1R)-1-hydroxyethyl]-4-(hydroxymethyl)-1-

(4-methoxyphenyl)azetidin-2-one 11a⁹(0.5 g; 2 mmol) in

THF (15 mL) at ꢀ5 ꢁC, and then NEt₃(0.7 mL; 5 mmol)

was added to it dropwise. After 1 h of stirring at the same

temperature (TLC: CH₂Cl₂–EtOAc 10:1, UV, Rf₁₁0.05,

Rf₁₃0.19), the white precipitate was dissolved by adding

water, the mixture was extracted with 3 · 30 mL EtOAC.

The organic phase was washed with brine, dried over

MgSO₄, and the solvent removed under reduced pressure.

The light yellow oil was triturated with ether and the pre-

gave 7b (80 mg, 91%) as needle-like white crystals. Mp

31

95 ꢁC. ½aꢁ_D¼ þ190:4. IR (KBr): m 3360 (OH), 2952 (CH),

1756 (CON), 1712 (COO), 1616 (Ar), 1392, 1216, 1136,

1

1088, 1064, 696 cm^ꢀ1. H NMR (300 MHz): d 1.34 (3H,

d, J = 6 Hz, b-Me), 2.23 (3H, s, 3-Me), 2.86 (1H, d,

J_aH= 6 Hz, 7-H), 3.53 (1H, m, 6-H), 3.68 (1H, m ꢂ t, 1-

H_A), 4.30 (1H, qui, J = 6 Hz, a-H), 4.67 (1H, dd,

J_gem= 10.6 Hz, J_6H= 3.5 Hz, 1-H_B), 5.27 (2H, s, CH₂Ph),

7.30–7.46 (5H, m, ArH). ¹³C NMR (75 MHz): d 18.09 (b-

Me), 21.96 (3-Me), 44.36 (6-C), 64.18 (7-C), 65.26 (a-C),

66.77 (CH₂Ph), 69.53 (1-C), 106.86 (4-C), 128.09, 128.20

and 128.49 (Ar-2⁰,3⁰,4⁰-C), 136.04 (Ar-1⁰-C), 154.79 (3-C),

163.24 (COOBn), 165.64 (CON). HRMS m/z 317.1253

(C₁₇H₁₉O₅N calcd 317.1263).

cipitating white crystals were ﬁltered to give 13a (0.69 g,

20

85%). Mp 129–130 ꢁC. ½aꢁ_D¼ ꢀ87:5. IR (KBr): m 1756

(CON), 1516 (Ar), 1352, 1336 (Ms), 1248, 1168 (Ms),

892, 840 cm^ꢀ^{1 1}H NMR (500 MHz): d 1.74 (3H, d,

.

J = 6.5 Hz, b-Me), 3.05 + 3.13 (2 · 3H, 2 · s, 2 · SMe),

3.64 (1H, dd, J_aH= 3.5 Hz, J_4H= 5.5 Hz, 3-H), 3.80 (3H,

s, OMe), 4.51 (1H, q, J = 5.5 Hz, 4-H), 4.72 (2H, dAB,

J_gem= 11 Hz, J_4H= 5.5 Hz, CH₂), 5.30 (1H, qd,

4.12. (6R,7R)-7-[(1S)-1-Hydroxyethyl]-3-methyl-2-iso-

oxacephem-4-carboxylic acid 8a

Compound 7a (70 mg; 0.2 mmol) was hydrogenated under

normal pressure in the presence of 10% Pd/C catalyst

(10 mg) in methanol (20 mL) for an hour (TLC: CH₂Cl₂–

EtOAc 1:1, UV, Rf₇0.3, Rf₈0, CH₂Cl₂–MeOH 10:3,

UV, Rf₈0.4). The catalyst was ﬁltered oﬀ and washed with

methanol. The solvent was evaporated under reduced pres-

sure. The resulting colourless oil solidiﬁed on ether to give

J_3H= 3.5 Hz, J_CH¼ 6:5 Hz, a-H), 6.90 (2H, d,

3

J_ortho= 9.0 Hz, Ar-3⁰,5⁰-H), 7.35 (2H, d, J_ortho= 9.0 Hz,

Ar-2⁰,6⁰-H). ¹³C NMR (125 MHz): d 20.56 (b-Me), 37.62

and 40.12 (2 · SMe), 53.33, 55.59 and 56.12 (3-C, 4-C,

OMe), 66.96 (CH₂), 74.25 (a-C), 114.66 (Ar-3⁰,5⁰-C),

119.07 (Ar-2⁰,6⁰-C), 130.04 (Ar-1⁰-C), 156.84 (Ar-4⁰-C),

162.03 (CON). C₁₅H₂₁NO₈S₂requires C 44.2; H 5.2; N

3.44; S 15.7; found C 44.3; H 5.1; N 3.3; S 15.8.

8a (40 mg, 88%) as a white solid. Mp 139–140 ꢁC.

20

½aꢁ_D¼ ꢀ232:3 (MeOH). IR (KBr): m 3432 (br, COOH),

1736 (br, CON, COO), 1628, 1576, 1400, 1152, 792 cm^ꢀ1

.

4.15. (1R,2R,5S)-6-(4-Methoxyphenyl)-2-methyl-3-oxa-6-

azabicyclo[3.2.0]heptan-7-one 12a

¹H NMR (500 MHz, MeOD-d₄):

d

1.28 (3H, d,

J = 6.5 Hz, b-Me), 2.16 (3H, s, 3-Me), 2.84 (1H, m, 6-H),

3.48 (1H, m, 7-H), 3.66 (1H, m ꢂ t, 1-H_A), 4.21 (1H,

m ꢂ qui, a-H), 4.60 (1H, dd, J_gem= 10.7 Hz,

J_1HB= 3.7 Hz, 1-H_B). ¹³C NMR (75 MHz, MeOD-d₄): d

17.71 (b-Me), 22.08 (3-Me), 46.28 (6-C), 64.84 (7-C),

66.16 (a-C), 70.16 (1-C), 112.12 (4-C), 150.63 (3-C),

168.49 (CON). HRMS m/z measured as Na/K adduct

Mesyl chloride (0.25 mL; 3 mmol) was added dropwise to a

solution of 11a (0.5 g; 2 mmol) in pyridine (15 mL). After

3 h of stirring at rt (TLC: CH₂Cl₂–EtOAc 10:1, UV, Rf₁₁

0.05, Rf₁₂0.42, Rf₁₃0.19), pyridine was removed under re-

duced pressure. The oily residue was dissolved in dichloro-

methane, washed with water, then with 10% HCl and then

3118

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

with water again. After it was dried over MgSO₄, the oily

residue obtained after evaporation of solvent was triturated

with ether, the precipitating white crystals were ﬁltered to

aﬀord 13a (0.26 g; 32%). The mother liquor was puriﬁed

with prep. TLC (CH₂Cl₂–EtOAc 15:1, run twice) to give

(3H, d, J = 6.5 Hz, 2-Me), 3.47 (1H, dd, J_gem= 11 Hz,

J_5H= 3 Hz, 4-H_A), 3.69 (1H, dd, J_2H= 5.5 Hz,

J_5H= 4 Hz, 1-H), 3.88 (3H, s, OMe), 3.91 (1H, m ꢂ qui,

2-H), 3.96 (1H, d, J_gem= 11 Hz, 4-H_B), 5.01 (1H, m ꢂ t,

5-H), 7.04 (1H, s, Ar-3⁰-H), 7.84 (1H, s, Ar-6⁰-H). ¹³C

NMR (75 MHz): d 15.84 (2-Me), 56.94, 59.04 and 61.50

(1-C, 5-C, OMe), 67.90 (4-C), 75.36 (a-C), 111.33 (Ar-5⁰-

C), 115.97 (Ar-2⁰-C), 116.42 (Ar-3⁰-C), 128.29 (Ar-6⁰-C),

131.57 (Ar-1⁰-C), 152.22 (Ar-4⁰-C), 165.69 (CON).

C₁₃H₁₃Br₂NO₃requires C 39.9; H 3.3; N 3.6; Br 40.9;

found C 39.9; H 3.3; N 3.4; Br 40.8.

12a (0.20 g, 43%) as white crystals. Mp 161 ꢁC.

28

½aꢁ_D¼ ꢀ197:2. IR (KBr): m 1720 (CON), 1520 (Ar), 1400,

1

1384, 1248, 824 cm^ꢀ1. H NMR (300 MHz): d 1.54 (3H,

d, J = 6.3 Hz, 2-Me), 3.49 (1H, dd, J_gem= 10.8 Hz,

J_5H= 3.0 Hz, 4-H_A), 3.67 (1H, dd, J_2H= 5.5 Hz,

J_5H= 4.0 Hz, 1-H), 3.79 (3H, s, OMe), 3.85 (1H, m ꢂ qui,

2-H), 4.22 (1H, d, J_gem= 10.8 Hz, 4-H_B), 4.53 (1H, dd,

J_4HA= 3.0 Hz, J_1H= 4.0 Hz, 5-H), 6.87 (2H, d,

J_ortho= 9.0 Hz, Ar-3⁰,5⁰-H), 7.31 (2H, d, J_ortho= 9.0 Hz,

Ar-2⁰,6⁰-H). ¹³C NMR (75 MHz): d 15.84 (2-Me), 55.74,

57.54 and 58.25 (1-C, 5-C, OMe), 67.45 (4-C), 74.19

(2-C), 114.76 (Ar-3⁰,5⁰-C), 118.10 (Ar-2⁰,6⁰-C), 131.00

(Ar-1⁰-C), 156.37 (Ar-4⁰-C), 162.79 (CON). C₁₃H₁₅NO₃

requires C 66.9; H 6.5; N 6.0; found C 66.8; H 6.5; N 6.0.

4.17. (3R,4S)-3-[(1R)-1-(Methanesulfonyloxy)ethyl]-4-

[(methanesulfonyloxy)methyl]azetidin-2-one 16a

A solution of CAN (1.64 g; 3 mmol) in water (15 mL) was

added dropwise to a solution of 13a (0.41 g; 1 mmol) in

acetonitrile (10 mL) while the temperature was kept be-

tween ꢀ10 and 0 ꢁC during the addition and the mixture

was stirred at this temperature for an additional hour

(TLC: CH₂Cl₂–EtOAc 1:1, UV + PMA, Rf₁₃0.7, Rf₁₆

0.2 only PMA). Water (10 mL) was added and the mixture

was extracted with EtOAc (5 · 20 mL). The combined

organic layers were washed subsequently with 10% NaHCO₃

(15 mL), 10% NaHSO₃(15 mL), with 10% NaHCO₃

(15 mL) and with brine. All the aqueous phases were

extracted with EtOAc. The combined organic layers were

dried (MgSO₄). The solvent was removed under reduced

pressure. The resulting white solid was triturated with

EtOAc to give 16a (0.20 g, 66%). Mp 143–145 ꢁC. IR

(KBr): m 3328 (NH), 1764 (CON), 1384, 1352 (Ms), 1168

4.16. (1R,2R,5S)-6-(3-Bromo-4-methoxyphenyl)-2-methyl-3-

oxa-6-azabicyclo[3.2.0]heptan-7-one 14a and (1R,2R,5S)-6-

(2,5-Dibromo-4-methoxyphenyl)-2-methyl-3-oxa-6-

azabicyclo[3.2.0]heptan-7-one 15a

Bromine (0.04 mL; 0.8 mmol) was added dropwise to a

solution of 12a (0.18 g; 0.77 mmol) in acetic acid (2 mL)

and then stirred at rt for a day (TLC: CH₂Cl₂–EtOAc

10:2, UV, Rf₁₂0.45, Rf₁₄0.50). Because the reaction was

not completed, another 0.04 mL of bromine was added

and stirred again for a day. It was then poured onto the

mixture of ice (5 g) and Na₂S₂O₅(0.15 g; 0.8 mmol). The

precipitating yellowish crystals were ﬁltered, dried and

puriﬁed with prep. TLC (CH₂Cl₂–EtOAc 10:2), resulting

in 0.15 g (62%) of 14a and 60 mg (20%) of 15a as white

solids.

1

(Ms), 984, 968, 904, 824, 524 cm^ꢀ1. H NMR (500 MHz,

DMSO): d 1.46 (3H, d, J = 6.2 Hz, b-Me), 3.21 + 3.22

(2 · 3H, 2 · s, 2 · SMe), 3.61 (1H, m ꢂ t, 3-H), 3.93 (1H,

m, 4-H), 4.40 (1H, m ꢂ t, CH_2A), 4.51 (1H, dd,

J_gem= 10.5 Hz, J_4H= 3.5 Hz, CH_2B), 5.07 (1H, m ꢂ qui,

a-H), 7.35 (1H, s, NH). ¹³C NMR (125 MHz, DMSO): d

20.71 (b-Me), 36.83 and 38.78 (2 · SMe), 48.58 (3-C),

56.66 (4-C), 70.49 (CH₂), 74.93 (a-C), 166.03 (CON).

C₈H₁₅NO₇S₂requires C 31.9; H 5.0; N 4.65; S 21.3; found

C 32.1; H 4.9; N 4.6; S 21.0.

4.16.1. (1R,2R,5S)-6-(3-Bromo-4-methoxyphenyl)-2-methyl-

3-oxa-6-azabicyclo[3.2.0]heptan-7-one 14a. Mp 163–

28

165 ꢁC (MeOH). ½aꢁ_D¼ ꢀ169:2. IR (KBr):

m 1744,

(CON), 1504 (Ar), 1448, 1404, 1384, 1296, 1280, 1248,

1228, 1184, 1096, 1048, 1012, 872, 812, 672 cm^ꢀ^{1 1}H

.

NMR (500 MHz): d 1.53 (3H, d, J = 6.5 Hz, 2-Me), 3.49

(1H, dd, J_gem= 10.9 Hz, J_5H= 2.9 Hz, 4-H_A), 3.68 (1H,

dd, J_2H= 5.5 Hz, J_5H= 4.1 Hz, 1-H), 3.84 (1H, m ꢂ qui,

2-H), 3.87 (3H, s, OMe), 4.20 (1H, d, J_gem= 10.9 Hz, 4-

H_B), 4.52 (1H, dd, J_4HA= 2.9 Hz, J_1H= 4.1 Hz, 5-H),

6.87 (1H, d, J_ortho= 8.8 Hz, Ar-5⁰-H), 7.35 (1H, dd,

J_ortho= 8.8 Hz, J_meta= 2.5 Hz, Ar-3⁰-H), 7.51 (1H, d,

J_meta= 2.5 Hz, Ar-6⁰-H). ¹³C NMR (125 MHz): d 15.78

(2-Me), 56.79, 57.73 and 58.53 (1-C, 5-C, OMe), 67.40 (4-

C), 74.23 (a-C), 112.39 and 112.77 (Ar-3⁰-C, Ar-5⁰-C),

117.13 (Ar-6⁰-C), 121.61(Ar-2⁰-C), 131.62 (Ar-1⁰-C),

152.82 (Ar-4⁰-C), 162.94 (CON). C₁₃H₁₄BrNO₃requires

C 50.0; H 4.5; N 4.5; Br 25.6; found C 49.9; H 4.4; N

4.4; Br 25.65.

4.18. Benzyl (6S,7R)-7-[(1R)-1-(methanesulfonyloxy)-ethyl]-

3-methyl-2-iso-oxacephem-4-carboxylate 17a and benzyl

(6S,7Z)-7-ethylidene-3-methyl-2-iso-oxacephem-4-carboxyl-

ate 18a

Benzyl 2,3-dioxobutyrate¹¹(0.41 g) and NEt₃(0.05 mL)

were added to the solution of 16a (0.4 g; 1.3 mmol) in

THF (15 mL). The mixture was stirred at rt for 3 h, then

cooled down to ꢀ25 ꢁC. Pyridine (0.4 mL), then a solution

of thionyl chloride (0.27 mL) in 5 mL THF were added

dropwise. After 1 h of stirring the white precipitate was ﬁl-

tered oﬀ and the solvent was removed under reduced pres-

sure. Zinc (0.45 g) was slowly added at 5 ꢁC to the solution

of the yellow oily residue in the mixture of acetic acid

(15 mL) and water (3 mL). After 2 h of stirring the insolu-

ble materials were ﬁltered oﬀ, and the solvent was removed

under reduced pressure. The residue was dissolved in

dichloromethane, washed with water, dried over MgSO₄,

and the solvent was evaporated. The resulting oil was puri-

ﬁed by ﬂash chromatography (CH₂Cl₂!CH₂Cl₂–EtOAc

4.16.2.

methyl-3-oxa-6-azabicyclo[3.2.0]heptan-7-one

(1R,2R,5S)-6-(2,5-Dibromo-4-methoxyphenyl)-2-

15a. Rf₁₅

0.64. Mp 193–195 ꢁC (MeOH, recrystallises at 190 ꢁC).

28

½aꢁ_D¼ ꢀ109:3. IR (KBr): m 1744 (CON), 1492 (Ar), 1380,

1

1256, 1056, 1024, 840 cm^ꢀ1. H NMR (500 MHz): d 1.58

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

3119

1:1), and the fractions having an Rf 0.5 (TLC: CH₂Cl₂–

EtOAc 10:2) were collected. Starting material (0.05 g) was

also recovered. The aqueous layer of the extraction was

extracted with EtOAc. The organic phase was dried over

MgSO₄, the solvent was evaporated and resulted in 0.05 g

of starting material (total 25%). NEt₃(0.05 mL) was added

to the solution of the material with Rf 0.5 of the above

mentioned chromatography in chloroform (10 mL) and re-

ﬂuxed for 2 h (TLC: CH₂Cl₂–EtOAc 10:2, UV, Rf₁₈0.6,

Rf₁₉0.85). The mixture was washed with water, dried over

MgSO₄, the solvent was evaporated and the residue was

puriﬁed with ﬂash chromatography (CH₂Cl₂!CH₂Cl₂–

EtOAc 10:0.3) to give 80 mg (15%) of 17a and 40 mg

(10%) of 18a.

over MgSO₄, the solvent was evaporated to give 19a (1.4 g,

95%) as a beige solid material, which was pure enough for

30

further reactions. Mp 148–149 ꢁC. ½aꢁ_D¼ ꢀ60:4. IR (KBr):

m 1744 (br, CON, COO), 1516 (Ar), 1384, 1248, 1024, 904,

828 cm^ꢀ1. ¹H NMR (500 MHz): d 1.65 (3H, d, J = 6.8 Hz,

2-Me), 3.79 (3H, s, OMe), 4.04 (1H, dd, J_2H= 7.5 Hz,

J_5H= 4.5 Hz, 1-H), 4.62 (1H, d, J = 4.5 Hz, 5-H), 4.83

(1H, m ꢂ qui, 2-H), 6.88 (2H, d, J_ortho= 9.0 Hz, Ar-3⁰,5⁰-

H), 7.84 (2H, d, J_ortho= 9.0 Hz, Ar-2⁰,6⁰-H). ¹³C NMR

(125 MHz): d 18.18 (2-Me), 53.96, 54.77 and 55.71 (1-C,

5-C, OMe), 75.27 (2-C), 114.69 (3⁰,5⁰-C), 118.54 (2⁰,6⁰-C),

130.78 (1⁰-C), 156.99 (4⁰-C), 160.95 (CON), 170.62

(COO). C₁₃H₁₃NO₄requires C 63.15; H 5.3; N 5.7; found

C 62.9; H 5.4; N 5.2.

4.18.1.

Benzyl

(6S,7R)-7-[(1R)-1-(methanesulfonyl-

oxy)ethyl]-3-methyl-2-iso-oxacephem-4-carboxylate 17a.

4.20. (3R,4S)-3-[(1R)-1-Hydroxyethyl]-4-(hydroxymethyl)-

1-(4-methoxyphenyl)azetidin-2-one 11a

Yellow oil. IR (ﬁlm): m 1768 (CON), 1712 (COO), 1620

(Ar), 1356 (Ms), 1176 (Ms), 920 cm^ꢀ1

.

¹H NMR

NaBH₄(0.75 g; 0.02 mol) was added in small portions

under ice cooling to a solution of 19a (1.4 g; 5.7 mmol) in

methanol (25 mL) (gas generation). The suspension was

stirred at rt overnight (TLC: CH₂Cl₂–EtOAc 1:1, UV,

Rf₁₁0.15, Rf₁₉0.7). The solvent was evaporated under re-

duced pressure. The remaining solid material was sus-

pended in water and neutralized with 1 M HCl. The

white insoluble solid material was ﬁltered and then sus-

pended in CH₂Cl₂, the insoluble material was ﬁltered to

give 1.2 g (84%) of 11a as a white solid material, which

was pure enough for further reactions. Its physical proper-

ties are the same as those previously described.⁹

(500 MHz): d 1.55 (3H, d, J = 6.5 Hz, b-Me), 2.27 (3H, s,

3-Me), 3.15 (3H, s, SMe), 3.75 (1H, ddd, J_1HA= 10 Hz,

J_1HB= 3.5 Hz, J_cis= 5.5 Hz, 6-H), 3.92 (1H, dd,

J_cis= 5.5 Hz, J_aH= 8.0 Hz, 7-H), 4.07 (1H, m ꢂ t, 1-H_A),

4.58 (1H, dd, J_gem= 10.5 Hz, J_1HB= 3.5 Hz, 1-H_B), 5.03

(1H, qd, J_7H= 8.0 Hz, J_CH¼ 6:5 Hz, a-H), 5.27 (2H,

3

AB, J_gem= 12.5 Hz, CH₂Ph), 7.32–7.40 (3H, m, Ar-

3⁰,4⁰,5⁰-H), 7.45 (2H, d, J_ortho= 7.2 Hz, Ar-2⁰,6⁰-H). ¹³C

NMR (125 MHz): d 18.17 (b-Me), 21.90 (3-Me), 39.62

(SMe), 45.32 (6-C), 58.43 (7-C), 66.71, 67.03 and 73.31

(a-C, CH₂Ph, 1-C), 106.56 (4-C), 128.34, 128.50 and

128.67 (Ar-2⁰,3⁰,4⁰-C), 135.95 (Ar-1⁰-C), 155.65 (3-C),

162.94 (COOBn), 164.21 (CON).

4.21. (3R,4S)-4-(Acetoxymethyl)-3-[(1R)-1-hydroxyethyl]-1-

(4-methoxyphenyl)azetidin-2-one 20a and (3R,4S)-3-[(1R)-1-

acetoxyethyl]-4-(acetoxymethyl)-1-(4-methoxyphenyl)azeti-

din-2-one 21a

4.18.2. Benzyl (6S,7Z)-7-ethylidene-3-methyl-2-iso-oxace-

phem-4-carboxylate 18a. Yellow oil. IR (ﬁlm): m 1752

(CON), 1720 (COO), 1612 (Ar), 1352, 1212, 1120, 1080,

1

1032, 736, 696 cm^ꢀ1. H NMR (500 MHz): d 2.06 (3H, d,

AcCl (0.28 mL; 4 mmol), then NEt₃(0.32 mL, 4 mmol)

were added dropwise at 0 ꢁC to a suspension of compound

11a (0.4 g; 1.6 mmol) in THF (15 mL). The mixture was

stirred for 2 h at that temperature, then for an additional

day (TLC: CH₂Cl₂–EtOAc 10:2, UV, Rf₁₁0.05, Rf₂₀

0.15, Rf₂₁0.55) at rt. It was diluted with water, neutralized

with 1 M HCl, then extracted with EtOAc (3 · 15 mL). It

was washed with brine, dried over MgSO₄and the solvent

evaporated under reduced pressure. The remaining solid

was triturated with ether, the insoluble white solid was ﬁl-

tered oﬀ to give 0.2 g of 20a. The ethereal mother liquor

was puriﬁed by prep. TLC (CH₂Cl₂–EtOAc 10:2) to give

21a (0.15 g, 28%) and an additional 0.05 g of 20a (total

53%).

J = 7.2 Hz, b-Me), 2.25 (3H, s, 3-Me), 3.55 (1H, m ꢂ t,

1-H_A), 3.86 (1H, dd, J_1HA= 9 Hz, J_1HB= 3.7 Hz, 6-H),

4.60 (1H, dd, J_gem= 10.6 Hz, J_6H= 3.7 Hz, 1-H_B), 5.29

(2H, AB, J_gem= 12.5 Hz, CH₂Ph), 5.81 (1H, q,

J = 7.2 Hz, a-H), 7.30–7.46 (5H, m, ArH). ¹³C NMR

(125 MHz): d 15.16 (b-Me), 18.12 (3-Me), 49.39 (6-C),

66.96 and 69.06 (CH₂Ph, 1-C), 107.47 (4-C), 128.20,

128.45 and 128.65 (Ar-2⁰,3⁰,4⁰-C), 129.29 (a-C), 136.27

(Ar-1⁰-C), 139.45 (7-C), 153.85 (3-C), 163.22 and 163.65

(COOBn, CON).

4.19. (1R,2R,5S)-6-(4-Methoxyphenyl)-2-methyl-3-oxa-6-

azabicyclo[3.2.0]heptane-4,7-dione 19a

A solution of AcCl (0.65 mL; 9 mmol) in THF (5 mL) was

added dropwise to a suspension of (2S,3R)-3-[(1R)-1-

hydroxyethyl]-1-(4-methoxyphenyl)-4-oxoazetidine-2-carb-

oxylic acid 10a⁹(1.6 g; 6 mmol) in THF (30 mL) under salt-

ice cooling. Then a solution of pyridine (1.2 mL; 15 mmol)

in THF (5 mL) was added dropwise to it. The suspension

was stirred at ꢀ5 ꢁC for 2 h, then at rt for another 2 h

(TLC: CH₂Cl₂–EtOAc 10:2, UV, Rf₁₉0.5). The insoluble

material was dissolved in water and the mixture was

extracted with EtOAc (3 · 30 mL). The organic phase

was washed with 1 M HCl, then with brine and then dried

4.21.1. (3R,4S)-4-(Acetoxymethyl)-3-[(1R)-1-hydroxyethyl]-

1-(4-methoxyphenyl)-azetidin-2-one 20a. White solid.

28

Mp 125 ꢁC. ½aꢁ_D¼ ꢀ77:8. IR (KBr): m 3472 (OH), 1736

(br, CON, COO), 1520 (Ar), 1384, 1252, 1224, 1036,

824 cm^ꢀ1

.

¹H NMR (500 MHz):

d

1.46 (3H, d,

J = 6.5 Hz, b-Me), 1.68 (1H, br s, OH), 2.09 (3H, s,

MeCO), 3.42 (1H, m ꢂ t, 3-H), 3.79 (3H, s, OMe), 4.28

(1H, m, a-H), 4.33 (1H, m ꢂ q, 4-H), 4.60 (2H, dAB,

J_gem= 10 Hz, J_4H= 5.5 Hz, CH₂), 6.87 (2H, d,

J_ortho= 9.0 Hz, Ar-3⁰,5⁰-H), 7.40 (2H, d, J_ortho= 9.0 Hz,

Ar-2⁰,6⁰-H). ¹³C NMR (75 MHz): d 21.08 (b-Me), 23.24

3120

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

(MeCO), 53.62, 55.72 and 58.07 (2-C, 3-C, OMe), 62.32

and 64.66 (CH₂, a-C), 114.60 (Ar-3⁰,5⁰-C), 119.21 (Ar-

2⁰,6⁰-C), 130.76 (Ar-1⁰-C), 156.63 (Ar-4⁰-C), 165.25

(CON), 170.66 (MeCO). C₁₅H₁₉NO₅requires C 61.4; H

6.5, N 4.8; found C 61.3; H 6.4; N 4.7.

0.1 mmHg. All the fractions boiling below 160 ꢁC were

collected and used again for the next charge. The fraction

having a boiling point of 165–173 ꢁC consisted of the title

compound and gave 19.2 g (42%) of the title compound

as a colourless liquid. n_D1.5542. IR (ﬁlm): m 1736

(COO), 1456, 1332, 1272, 1148 (COC), 1008, 748,

1

4.21.2. (3R,4S)-3-[(1R)-1-Acetoxyethyl]-4-(acetoxymethyl)-

1-(4-methoxyphenyl)azetidin-2-one 21a. White solid. Mp

696 cm^ꢀ1. H NMR (300 MHz): d 3.46 (2H, s, CCH₂C),

5.16 (4H, s, CH₂Ar), 7.32 (10H, ꢂs, ArH).

24

114–115 ꢁC. ½aꢁ_D¼ ꢀ58:5. IR (KBr): m 1732 (br, CON,

1

COO), 1516 (Ar), 1400, 1384, 1252, 1028, 832 cm^ꢀ1. H

4.24. Dibenzyl bromomalonate

NMR (500 MHz): d 1.51 (3H, d, J = 6.5 Hz, b-Me), 2.09

(6H, s, 2 · MeCO), 3.53 (1H, m ꢂ t, 3-H), 3.79 (3H, s,

OMe), 4.30 (1H, dd, J_gem= 11.5 Hz, J_4H= 6.5 Hz, CH_2A),

4.36 (1H, m ꢂ q, 4-H), 4.53 (1H, dd, J_gem= 11.5 Hz,

J_3H= 4 Hz, a-H), 6.88 (2H, d, J_ortho= 9.0 Hz, Ar-3⁰,5⁰-

H), 7.38 (2H, d, J_ortho= 9.0 Hz, Ar-2⁰,6⁰-H). ¹³C NMR

(125 MHz): d 19.80 (b-Me), 20.91 and 21.56 (2 · MeCO),

53.06, 55.75 and 55.83 (2-C, 3-C, OMe), 62.35 and 66.68

(CH₂, a-C), 114.66 (Ar-3⁰,5⁰-C), 119.00 (Ar-2⁰,6⁰-C),

130.83 (Ar-1⁰-C), 156.65 (Ar-4⁰-C), 163.64 (CON), 170.44

and 170.57 (2 · MeCO). C₁₇H₂₁NO₆requires C 60.9; H

6.3; N 4.2; found C 61.1; H 6.1; N 4.0.

Bromine (7.3 mL; 0.142 mol) was added dropwise to the

solution of dibenzyl malonate (38 g; 0.135 mol) in CCl₄

(100 mL), always waiting for its colour to disappear. It

was stirred for 2 h, then washed with water, 2 · 50 mL sat-

urated Na₂CO₃, then with brine. It was then dried over

Na₂SO₄, and the solvent was evaporated under reduced

pressure to give 45 g light yellow oil, which was distilled

at 0.1 mmHg. The fraction boiling under 60 ꢁC was dis-

carded and the remaining material (37 g) was used without

further puriﬁcation (at this pressure it cannot be distilled

without decomposition). Caution: the compound is very

lachrymatory, all of the glassware should be washed with

alcoholic ammonia. n_D1.5590. IR (ﬁlm): m 1744 (COO),

J_4H= 5.5, CH_2B), 5.33 (1H, qd, J_CH¼ 6:5 Hz,

3

1

4.22. Tritylation/acetylation/detrytilation of 11a

1456, 1376, 1232, 1140 (COC), 1004, 748, 696 cm^ꢀ1. H

NMR (300 MHz): d 4.46 (1H, s, CHBr), 5.19 (4H, s,

CH₂), 7.31 (10H, ꢂs, ArH).

A solution of trityl chloride (0.3 g; 1.1 mmol) and 11a (0.2 g,

0.8 mmol) in pyridine (2 mL) was boiled for 4 h (TLC:

CH₂Cl₂–acetone 10:0.5, UV, Rf 0.4, Rf₁₁0.05). It was then

concentrated under reduced pressure and dissolved in

CH₂Cl₂. If it consisted of an insoluble material, then it

was ﬁltered oﬀ. The ﬁltrate was washed with water and

dried (MgSO₄). AcCl (0.07 mL, 1 mmol) and pyridine

(0.07 mL, 1 mmol) were added to the solution of the residue

obtained after evaporation of the solvent in THF (5 mL) at

0 ꢁC. The mixture was stirred for 2 h (TLC: CH₂Cl₂–ace-

tone 10:0.5, UV, Rf 0.85), concentrated under reduced pres-

sure and the residue dissolved in CH₂Cl₂. It was washed

with water, dried (MgSO₄) and the solvent evaporated

under reduced pressure. The residue was puriﬁed by ﬂash

chromatography (CH₂Cl₂) to give 0.3 g white solid mate-

rial. Mp 158 ꢁC. 0.1 g of it was reﬂuxed for 3 h in 90% acetic

acid. The residue obtained after concentration under

reduced pressure was dissolved in EtOAc, washed with

water, dried over MgSO₄, the solvent was evaporated under

reduced pressure. The residue was puriﬁed by prep. TLC

(CH₂Cl₂–acetone 10:2) to give 30 mg of white solid material

with an Rf 0.2, with all of its physical properties being the

same as 20a, and 30 mg of white solid material with an Rf

0.5, with all of its physical properties the same as 21a.

4.25. Dibenzyl [(4-methoxyphenyl)amino]malonate 22

The solution of dibenzyl bromomalonate (37 g; 0.1 mol)

and freshly distilled p-anisidine (25 g; 0.2 mol) in 100 mL

ether was stirred for two 2 days at rt under an N₂atmo-

sphere. The precipitation was ﬁltered oﬀ (p-anisidineÆHBr)

and washed with ether. The ﬁltrate was concentrated under

reduced pressure and the dark brown-black solid recrystal-

lized from ethanol to give 22 (25.1 g, 46% calcd for di-

benzyl malonate) as a white crystalline solid. Mp 92 ꢁC.

IR (KBr): m 3376 (NH), 1752 (CO), 1728 (CO), 1520,

1320, 1280, 1240, 1224, 1160 (COC), 824, 744, 696 cm^ꢀ1

.

¹H NMR (500 MHz): d 3.35 (1H, br s, NH), 3.73 (3H, s,

OMe), 4.82 (1H, s, NCH), 5.17 (4H, s, CH₂O), 6.63 (2H,

d, J_ortho= 8.7 Hz, PMP-3⁰,5⁰-H), 6.74 (2H, d, J_ortho

=

8.6 Hz, PMP-2⁰,6⁰-H), 7.22–7.31 (10H, m, benzyl-ArH).

¹³C NMR (75 MHz): d 55.87 (OMe), 62.22 (CHN), 68.14

(CH₂Ph), 115.13 and 115.76 (PMP-2⁰,3⁰,5⁰,6⁰-C), 128.47

and 128.80 (benzyl-2⁰,3⁰,5⁰,6⁰-C), 128.74 (benzyl-4⁰-C),

135.00 (benzyl-1⁰-C), 139.15 (PMP-1⁰-C), 153.64 (PMP-4⁰-

C), 167.70 (COO). C₂₄H₂₃NO₅requires C 71.1; H 5.7; N

3.45; found C 71.1; H 5.7; N 3.2.

4.23. Dibenzyl malonate

4.26. Dibenzyl {[(2S,3R)-3-acetoxy-2-bromobutyryl](4-

methoxyphenyl)amino}malonate 23a

Diethyl malonate (25 mL; 0.16 mol), benzyl alcohol

(35 mL; 0.34 mol) and a catalytic amount of DMAP were

heated in a 150 ꢁC oil bath by using a Dean–Stark trap.

The amount of the ethanol distillating out of the reaction

was measured. After 1 day of heating, another 5 mL

(0.05 mol) of benzyl alcohol was added, then after another

day another 5 mL was added. When the distillation speed

of the outdistillating ethanol slowed down (after 4–5 days

of heating), the mixture was distilled through a column at

The solution of 22 (14.4 g; 36 mmol) and (2S,3R)-3-acetoxy-

3-bromobutyryl chloride¹¹(8.7 g; 36 mmol) in toluene

(40 mL) was stirred at 80 ꢁC for 2.5 days (till the evolution

of HCl gas ceased). TLC: toluene–acetone 10:0.5, UV,

Rf₂₂0.9, Rf₂₃0.5. The mixture was washed with water, dried

over Na₂SO₄and the solvent was evaporated under reduced

pressure to give 22 g brown oil (99%), which was used with-

out further puriﬁcation, but was puriﬁed by prep. TLC (tol-

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

3121

uene–EtOAc 15:2) for analytical investigations resulting in a

NMR (500 MHz): d 1.48 (3H, d, J = 6.5 Hz, b-Me), 1.98

(3H, s, MeCO), 3.75 (3H, s, OMe), 3.99 (1H, d,

J_aH= 2.4 Hz, 3-H), 4.93 + 5.29 and 5.05 + 5.13 (2 · 2H,

2 · AB, J_gem= 12 Hz, 2 · CH₂), 5.33 (1H, qd,

30:5

yellow oil. ½aꢁ_D¼ þ54. IR (ﬁlm): m 2936 (CH), 1748 (br,

CON, COO), 1672, 1512 (Ar), 1456, 1376, 1236, 1168, 748,

696 cm^ꢀ1. ¹H NMR (500 MHz): d 1.25 (3H, d, J = 6.5 Hz,

4-Me), 1.98 (3H, s, MeCO), 3.80 (3H, s, OMe), 4.08 (1H,

d, J_CHOAc= 9.5 Hz, CHBr), 5.02 + 5.08 and 5.15 + 5.20

(2 · 2H, 2 · AB, J_gem= 12 Hz, 2 · CH₂), 5.34 (1H, qd,

J_CH¼ 6:5 Hz, J_3H= 2.4 Hz, a-H), 6.73 (2H, d,

3

J_ortho= 9.0 Hz, PMP-3⁰,5⁰-H), 7.07 (2H, d, J_ortho= 7.2 Hz,

benzyl-2⁰-H), 7.23–7.34 (8H, m, benzyl-ArH), 7.39 (2H, d,

J_ortho= 9.0 Hz, PMP-2⁰,6⁰-H). ¹³C NMR (125 MHz): d

18.50 (b-Me), 21.05 (MeCO), 55.54 (OMe), 62.26, 66.63,

67.69, 68.46 and 68.82 (3-C, 2-C, 2 · CH₂, a-C), 114.19

(PMP-3⁰,5⁰-C), 121.02 (PMP-2⁰,6⁰-C), 128.68, 128.76,

128.78, 128.89, 128.93, 129.11 (benzyl-2⁰,3⁰,4⁰,5⁰,6⁰-C),

129.99 (PMP-1⁰-C), 134.15 and 134.31 (2 · benzyl-1⁰-C),

157.16 (PMP-4⁰-C), 163.28 (CON), 165.82 and 166.90

(2 · COOBn), 170.31 (MeCO). C₃₀H₂₉NO₈requires C

67.8; H 5.5; N 2.6; found C 67.6; H 5.4; N 2.6.

J_CH¼ 6:5 Hz, J_CHBr= 9.5 Hz, CHOAc), 5.43 (1H, s,

3

CHN), 6.81 (2H, br, PMP-3⁰,5⁰-H), 7.21–7.31 (12H, m,

PMP-2⁰,6⁰-H, benzyl-ArH). ¹³C NMR (125 MHz): d 17.66

(4-Me), 21.01 (MeCO), 44.98 (CHBr), 55.54 (OMe), 65.31

(CHN), 68.13 (CH₂), 71.15 (CHOAc), 114.84 and 115.13

(PMP-3⁰,5⁰-C), 128.58 and 128.63 (benzyl-2⁰,3⁰,4⁰,5⁰,6⁰-C),

130.09 and 130.41 (PMP-2⁰,6⁰-C), 131.42 (PMP-1⁰-C),

134.65 and 134.85 (benzyl-1⁰-C), 160.23 (PMP-4⁰-C),

164.88, 165.24 168.04 and 169.65 (CON, MeCO,

2 · COOBn). C₃₀H₃₀NO₈Br requires C 58.8; H 4.9; N 2.3;

Br 13.05; found C 58.9; H 4.8; N 2.1; Br, 13.5.

4.29. Dibenzyl (3S)-3-[(1S)-1-acetoxyethyl]-1-(4-methoxy-

phenyl)-4-oxoazetidine-2,2-dicarboxylate 24b

4.27. Dibenzyl {[(2R,3S)-3-acetoxy-2-bromobutyryl]-

(4-methoxyphenyl)amino}malonate 23b

Prepared analogously to 24a from 23b (36 g; 59 mmol)

gave 30.6 g brown oil, which was puriﬁed by ﬂash chroma-

Prepared analogously to 23a from (2R,3S)-3-acetoxy-3-

bromobutyryl chloride¹¹(14.8 g; 61 mmol) and 22 (24.6 g;

61 mmol) and gave a brown oil (36 g, 97%), which was used

without further puriﬁcation, but was puriﬁed with prep.

tography (CH₂Cl₂) to give 24b (25.2 g, 79%) as a yellow oil.

22

½aꢁ_D¼ þ48:6. IR (ﬁlm): m 1770 (COO), 1744 (CON), 1512

(Ar), 1456, 1376, 1240, 1128, 1036, 952, 832, 736, 696 cm^ꢀ1

.

¹H NMR (500 MHz): d 1.49 (3H, d, J = 6.5 Hz, b-Me),

1.99 (3H, s, MeCO), 3.77 (3H, s, OMe), 3.98 (1H, d,

J_aH= 2.4 Hz, 3-H), 4.93 + 5.29 and 5.05 + 5.13 (2 · 2H,

2 · AB, J_gem= 12 Hz, 2 · CH₂), 5.34 (1H, qd,

TLC (toluene–acetone 10:0.5) for analytical investigations

24

resulting in a yellow oil. ½aꢁ_D¼ ꢀ54:9. IR (ﬁlm): m 2940

(CH), 1752 (br, CON, COO), 1676, 1512 (Ar), 1456,

1376, 1232, 1184, 1168, 748, 696 cm^ꢀ1

.

¹H NMR

J_CH¼ 6:5 Hz, J_3H= 2.4 Hz, a-H), 6.73 (2H, d,

3

(500 MHz): d 1.25 (3H, d, J = 6.4 Hz, 4-Me), 2.00 (3H, s,

MeCO), 3.81 (3H, s, OMe), 4.06 (1H, d, J_CHOAc= 9.5 Hz,

CHBr), 5.03 + 5.09 and 5.16 + 5.21 (2 · 2H, 2 · AB,

J_ortho= 9.0 Hz, PMP-3⁰,5⁰-H), 7.08 (2H, d, J_ortho= 7.3 Hz,

benzyl-2⁰-H), 7.23–7.34 (8H, m, benzyl-ArH), 7.39 (2H, d,

J_ortho= 9.0 Hz, PMP-2⁰,6⁰-H). ¹³C NMR (75 MHz): d

18.58 (b-Me), 21.16 (MeCO), 55.64 (OMe), 62.31, 66.70,

67.73, 68.53 and 68.91 (3-C, 2-C, 2 · CH₂, a-C), 114.25

(PMP-3⁰,5⁰-C), 121.06 (PMP-2⁰,6⁰-C), 128.67, 128.77,

128.85, 128.97, 129.01, 129.19 (benzyl-2⁰,3⁰,4⁰,5⁰,6⁰-C),

130.06 (PMP-1⁰-C), 134.19 and 134.35 (2 · benzyl-1⁰-C),

157.21 (PMP-4⁰-C), 163.35 (CON), 165.89 and 165.98

(2 · COOBn), 170.42 (MeCO). C₃₀H₂₉NO₈requires C

67.8; H 5.5; N 2.6; found C 67.7; H 5.7; N 2.3.

J_gem= 12 Hz, 2 · CH₂), 5.33 (1H, qd, J_CH¼ 6:4 Hz,

3

J_CHBr= 9.4 Hz, CHOAc), 5.43 (1H, s, CHN), 6.81 (2H,

br, PMP-3⁰,5⁰-H), 7.21–7.31 (12H, m, PMP-2⁰,6⁰-H, benz-

yl-ArH). ¹³C NMR (125 MHz): d 17.78 (4-Me), 21.14

(MeCO), 45.06 (CHBr), 55.66 (OMe), 65.40 (CHN),

68.26 (CH₂), 71.29 (CHOAc), 114.87 and 115.24 (PMP-

3⁰,5⁰-C), 128.70 and 128.75 (benzyl-2⁰,3⁰,4⁰,5⁰,6⁰-C),

130.25 and 130.57 (PMP-2⁰,6⁰-C), 131.54 (PMP-1⁰-C),

134.76 and 134.98 (2 · benzyl-1⁰-C), 160.33 (PMP-4⁰-C),

165.01, 165.39, 168.17 and 169.79 (CON, MeCO,

2 · COOBn). C₃₀H₃₀NO₈Br requires C 58.8; H 4.9; N

2.3; Br 13.05; found C 58.7; H 4.9; N 2.1; Br 12.9.

4.30. (3R)-3-[(1R)-1-Acetoxyethyl]-2-(benzyloxycarbonyl)-

1-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylic acid 25a

4.28. Dibenzyl (3R)-3-[(1R)-1-acetoxyethyl]-1-(4-methoxy-

phenyl)-4-oxoazetidine-2,2-dicarboxylate 24a

NaOH (1 M, 16 mL) was added dropwise at 5 ꢁC to a solu-

tion of 24a (8.5 g; 16 mmol) in pyridine (6 mL). The mixture

was stirred at this temperature for 3 h (TLC: CH₂Cl₂–

EtOAc 10:2, UV, Rf₂₄0.75, Rf₂₅0.05), then diluted with

10% HCl (10 mL) and extracted with EtOAc. The organic

phase was washed with 10% HCl again, dried over MgSO₄

and the solvent was evaporated under reduced pressure to

give 7.2 g of a brown oil (containing also some benzyl alco-

hol). The aqueous phase was cooled down, saturated with

NaCl, and acidiﬁed with cc. HCl to pH 2–3. The separating

oil was extracted with EtOAc and dried over MgSO₄. The

solvent was evaporated under reduced pressure to give a

light brown oil (0.7 g). The two fractions were collected

and used without further puriﬁcation. IR (ﬁlm): m 3500–

3300 (COOH), 1770 (COO), 1752 (CON), 1512 (Ar),

A solution of DBU (8.2 mL; 54 mmol) in toluene (30 mL)

was added dropwise under an ice bath cooling to a solution

of 23a (33 g; 54 mmol) in toluene (200 mL). The mixture

was stirred for a day at rt (TLC: CH₂Cl₂–EtOAc 10:2,

UV, Rf₂₄0.75, Rf₂₃0.57). The precipitate (DBUÆHBr)

was ﬁltered oﬀ and washed with EtOAc. The ﬁltrate was

washed subsequently with 10% HCl, with satd NaHCO₃,

water and brine and dried over Na₂SO₄. The solvent was

evaporated under reduced pressure to give 24.8 g brown

oil, which was puriﬁed by ﬂash chromatography (CH₂Cl₂)

30

and gave 24a (20.0 g, 70%) as a yellow oil. ½aꢁ_D¼ ꢀ48:0.

IR (ﬁlm): m 1770 (COO), 1744 (CON), 1512 (Ar), 1456,

1

1376, 1248, 1188, 1128, 1036, 952, 832, 752, 696 cm^ꢀ1. H

1456, 1376, 1248, 1128, 1032, 832, 748, 700 cm^ꢀ1

.

3122

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

4.31. (3S)-3-[(1S)-1-Acetoxyethyl]-2-(benzyloxycarbonyl)-1-

(4-methoxyphenyl)-4-oxoazetidine-2-carboxylic acid 25b

4.32.2. Benzyl (2R,3R)-3-[(1R)-1-acetoxyethyl]-1-(4-meth-

oxyphenyl)-4-oxoazetidine-2-carboxylate 27a. A sample

was puriﬁed from the tert-butyl alcoholic mother liquor

for analytical investigations with prep. TLC (CH₂Cl₂–

EtOAc 10:1), then crystallized from hexane/EtOAc to give

Prepared analogously to 25a from 24b (25.2 g; 47 mmol).

The evaporation of the solvent from the organic phase

resulted in 23.7 g of a brown oil, the acidiﬁcation of the aque-

ous phase resulted in 2.3 g of 25b, as a light brown oil. The

two fractions were collected. IR (ﬁlm): m 3500–3300

(COOH), 1770 (COO), 1752 (CON), 1512 (Ar), 1456,

pure 27a as a white solid. Mp 67–68 ꢁC (hexane/EtOAc).

26

½aꢁ_D¼ þ60:8. IR (KBr): m 1770 (COO), 1752 (CON),

1516 (Ar), 1456, 1400, 1376, 1240, 1176, 1048, 1024, 912,

1

824, 760, 704 cm^ꢀ1. H NMR (500 MHz): d 1.42 (3H, d,

1376, 1248, 1128, 1032, 832, 752, 700 cm^ꢀ1

.

¹H NMR

J = 6.5 Hz, b-Me), 1.98 (3H, s, MeCO), 3.57 (1H, dd,

J_aH= 4.5 Hz, J_trans= 2.5 Hz, 3-H), 3.78 (3H, s, OMe),

4.32 (1H, d, J_trans= 2.5 Hz, 2-H), 5.21 (2H, AB,

(500 MHz): d 1.45 (3H, d, J = 6.5 Hz, b-Me), 1.96 (3H, s,

MeCO), 3.76 (3H, s, OMe), 3.91 (1H, d, J_aH= 2.5 Hz, 3-

H), 4.97 + 5.31 (2H, AB, J_gem= 12 Hz, CH₂), 5.30 (1H, m,

a-H), 6.80 (2H, d, J_ortho= 9.0 Hz, PMP-3⁰,5⁰-H), 7.33 (5H,

ꢂs, benzyl-ArH), 7.47 (2H, d, J_ortho= 9.0 Hz, PMP-2⁰,6⁰-

H). ¹³C NMR (75 MHz): d 18.50 (b-Me), 21.11 (MeCO),

55.67 (OMe), 62.47, 66.84, 67.22, 68.69 (3-C, 2-C, CH₂, a-

C), 114.35 (PMP-3⁰,5⁰-C), 120.85 (PMP-2⁰,6⁰-C), 128.84,

128.99, 129.02 (benzyl-2⁰,3⁰,4⁰,5⁰,6⁰-C), 130.10 (PMP-1⁰-C),

134.26 (benzyl-1⁰-C), 157.20 (PMP-4⁰-C), 163.48 (CON),

165.87 and 169.43 (COOH, COOBn), 170.69 (MeCO).

J_gem= 12 Hz, CH₂), 5.30 (1H, qd, J_CH¼ 6:5 Hz,

3

J_3H= 4.5 Hz, a-H), 6.82 (2H, d, J_ortho= 9.0 Hz, PMP-

3⁰,5⁰-H), 7.21 (2H, d, J_ortho= 9.0 Hz, PMP-2⁰,6⁰-H), 7.33

(5H, m, benzyl-ArH). ¹³C NMR (75 MHz): d 17.54 (b-

Me), 21.15 (MeCO), 53.68, 55.70 and 58.71 (3-C, 2-C,

OMe), 67.19 and 67.83 (CH₂, a-C), 114.65 (PMP-3⁰,5⁰-C),

118.36 (PMP-2⁰,6⁰-C), 128.59, 128.87, 129.01 (benzyl-

2⁰,3⁰,4⁰,5⁰,6⁰-C), 130.78 (PMP-1⁰-C), 134.97 (benzyl-1⁰-C),

156.81 (PMP-4⁰-C), 162.26 (CON), 169.60 (COOBn),

170.52 (MeCO). C₂₂H₂₃NO₆requires C 66.5; H 5.8; N

3.5; found C 66.2; H 5.75; N 3.4.

4.32. cis/trans Benzyl (3R)-3-[(1R)-1-acetoxyethyl]-1-

(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate 26a, 27a

4.33. cis/trans Benzyl (3S)-3-[(1S)-1-acetoxyethyl]-1-

(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate 26b, 27b

The solution of 25a (7.9 g) in a-picoline (30 mL) was heated

in an 140 ꢁC oil bath for 3 h (TLC: CH₂Cl₂–EtOAc 10:0.5,

UV, Rf_26,270.5, Rf₂₅0.05). The picoline was removed by dis-

tillation at 15 mmHg. The remaining material was dissolved

in EtOAc (150 mL), washed with 10% HCl (20 mL), with

10% NaHCO₃(20 mL), then with brine. The organic phase

was dried over Na₂SO₄and concentrated till about 30 mL

solvent remained. The precipitating white solid was ﬁltered

to give 1.2 g of pure 26a as a white solid, which was recrys-

tallized from MeOH. The ﬁltrate was concentrated under

reduced pressure; the benzyl alcohol was removed by

distillation at 0.1 mmHg to give a brown oil (3.2 g), which

was puriﬁed by ﬂash chromatography. The fractions

(2.5 g) containing the title compounds were triturated with

tert-butyl alcohol. The insoluble white crystals were ﬁltered

to give 0.2 g of 26a. The mother liquor containing 27a was

used without further puriﬁcation in the next step.

Prepared analogously to 26a, 27a from 25b (26 g), and gave

8 g material, containing 27b, and 6.3 g (34% from 24b) of

26b.

4.33.1. Benzyl (2R,3S)-3-[(1S)-1-acetoxyethyl]-1-(4-meth-

oxyphenyl)-4-oxoazetidine-2-carboxylate

26b. White

23:5

solid. Mp 164 ꢁC (MeOH). ½aꢁ_D¼ þ73:4. IR (KBr): m

1740 (br, CON, COO), 1520 (Ar), 1248, 1212, 1152,

1

11032, 832, 736 cm^ꢀ1. H NMR (500 MHz): d 1.46 (3H,

d, J = 6.5 Hz, b-Me), 2.00 (3H, s, MeCO), 3.69 (1H, dd,

J_aH= 3 Hz, J_cis= 6.5 Hz, 3-H), 3.79 (3H, s, OMe), 4.60

(1H, d, J_cis= 6.5 Hz, 2-H), 4.99 + 5.21 (2H, AB,

J_gem= 12 Hz, CH₂), 5.30 (1H, qd, J_CH¼ 6:5 Hz,

3

J_3H= 3 Hz, a-H), 6.86 (2H, d, J_ortho= 9.0 Hz, PMP-3⁰,5⁰-

H), 7.30 (2H, d, J_ortho= 9.0 Hz, PMP-2⁰,6⁰-H), 7.25–7.35

(5H, m, benzyl-ArH). ¹³C NMR (75 MHz): d 18.72 (b-

Me), 21.04 (MeCO), 53.89, 55.54 and 56.89 (3-C, 2-C,

OMe), 66.09 and 67.78 (CH₂, a-C), 114.35 (PMP-3⁰,5⁰-C),

118.45 (PMP-2⁰,6⁰-C), 128.76, 128.86, 128.97 (benzyl-

2⁰,3⁰,4⁰,5⁰,6⁰-C), 130.87 (PMP-1⁰-C), 134.50 (benzyl-1⁰-C),

156.52 (PMP-4⁰-C), 162.41 (CON), 167.66 (COOBn),

170.46 (MeCO). C₂₂H₂₃NO₆requires C 66.5; H 5.8; N

3.5; found C 66.5, H 5.9, N 3.7.

4.32.1. Benzyl (2S,3R)-3-[(1R)-1-acetoxyethyl]-1-(4-meth-

oxyphenyl)-4-oxoazetidine-2-carboxylate 26a. Yield: 1.4 g

(22% from 24a) of a white solid. Mp 164 ꢁC (MeOH).

23

½aꢁ_D¼ ꢀ74:8. IR (KBr): m 1740 (br, CON, COO), 1520

(Ar), 1248, 1212, 1152, 1032, 832, 736 cm^ꢀ^{1 1}H NMR

.

(500 MHz): d 1.46 (3H, d, J = 6.5 Hz, b-Me), 2.00 (3H, s,

MeCO), 3.69 (1H, dd, J_aH= 3.1 Hz, J_cis= 6.5 Hz, 3-H),

3.79 (3H, s, OMe), 4.60 (1H, d, J_cis= 6.5 Hz, 2-H),

4.99 + 5.21 (2H, AB, J_gem= 12 Hz, CH₂), 5.30 (1H, qd,

4.33.2. Benzyl (2S,3S)-3-[(1S)-1-acetoxyethyl]-1-(4-meth-

27b. White

J_CH¼ 6:5 Hz, J_3H= 3.1 Hz, a-H), 6.86 (2H, d,

oxyphenyl)-4-oxoazetidine-2-carboxylate

3

21:5

J_ortho= 9.0 Hz, PMP-3⁰,5⁰-H), 7.30 (2H, d, J_ortho= 9.0 Hz,

PMP-2⁰,6⁰-H), 7.35 (5H, m, benzyl-ArH). ¹³C NMR

(75 MHz): d 18.91 (b-Me), 21.21 (MeCO), 54.12, 55.73

and 57.11 (3-C, 2-C, OMe), 66.27 and 67.95 (CH₂, a-C),

114.55 (PMP-3⁰,5⁰-C), 118.66 (PMP-2⁰,6⁰-C), 128.94,

129.03, 129.13 (benzyl-2⁰,3⁰,4⁰,5⁰,6⁰-C), 131.08 (PMP-1⁰-

C), 134.73 (benzyl-1⁰-C), 156.73 (PMP-4⁰-C), 162.59

(CON), 167.86 (COO), 170.60 (MeCO). C₂₂H₂₃NO₆

requires C 66.5; H 5.8; N 3.5; found C 66.5; H 5.8; N 3.4.

solid. Mp 68–69 ꢁC (hexane/EtOAc). ½aꢁ_D¼ ꢀ61:3. IR

(KBr): m 1770 (COO), 1752 (CON), 1516 (Ar), 1456,

1400, 1380, 1240, 1176, 1048, 1024, 912, 824, 760,

704 cm^ꢀ1

.

¹H NMR (500 MHz):

d

1.42 (3H, d,

J = 6.5 Hz, b-Me), 1.98 (3H, s, MeCO), 3.57 (1H, dd,

J_aH= 4.5 Hz, J_trans= 2.5 Hz, 3-H), 3.78 (3H, s, OMe),

4.32 (1H, d, J_trans= 2.5 Hz, 2-H), 5.21 (2H, AB,

J_gem= 12 Hz, CH₂), 5.31 (1H, qd, J_CH¼ 6:5 Hz,

3

J_3H= 4.5 Hz, a-H), 6.82 (2H, d, J_ortho= 9.0 Hz, PMP-

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

3123

3⁰,5⁰-H), 7.21 (2H, d, J_ortho= 9.0 Hz, PMP-2⁰,6⁰-H), 7.26–

7.34 (5H, m, benzyl–ArH). ¹³C NMR (75 MHz): d 17.59

(b-Me), 21.21 (MeCO), 53.66, 55.72 and 58.74 (3-C, 2-C,

OMe), 67.18 and 67.84 (CH₂, a-C), 114.65 (PMP-3⁰,5⁰-C),

118.33 (PMP-2⁰,6⁰-C), 128.63, 128.90, 129.01 (benzyl-

2⁰,3⁰,4⁰,5⁰,6⁰-C), 130.82 (PMP-1⁰-C), 134.99 (benzyl-1⁰-C),

156.80 (PMP-4⁰-C), 162.21 (CON), 169.62 (COOBn),

170.48 (MeCO). C₂₂H₂₃NO₆requires C 66.5; H 5.8; N

3.5; found C 66.3; H 5.5, N 3.4.

4.37. (2R,3S)-3-[(1S)-1-Acetoxyethyl]-1-(4-methoxyphenyl)-

4-oxoazetidine-2-carboxylic acid 29b

Prepared analogously to 29a from 26b (2.15 g; 5.4 mmol)

and gave 29b (1.6 g, 96%) as a white solid. Mp 233 ꢁC.

IR (KBr): m 3500–3300 (COOH), 1740 (br, CON, COO),

1696, 1512 (Ar), 1392, 1288, 1248, 1176, 1028, 832 cm^ꢀ1

.

¹H NMR (500 MHz, DMSO): d 1.34 (3H, d, J = 6.5 Hz,

b-Me), 1.90 (3H, s, MeCO), 3.72 (3H, s, OMe), 3.87 (1H,

dd, J_aH= 3.7 Hz, J_cis= 6.5 Hz, 3-H), 4.76 (1H, d,

J_cis= 6.5 Hz, 2-H), 5.07 (1H, qd, J_CH¼ 6:5 Hz,

3

4.34. (3R,4R)-3-[(1R)-1-Acetoxyethyl]-4-(hydroxymethyl)-

1-(4-methoxyphenyl)azetidine-2-one 28a

J_3H= 3.5 Hz, a-H), 6.92 (2H, d, J_ortho= 8.9 Hz, Ar-3⁰,5⁰-

H), 7.30 (2H, d, J_ortho= 8.9 Hz, Ar-2⁰,6⁰-H). ¹³C NMR

(125 MHz, DMSO): d 19.08 (b-Me), 21.55 (MeCO),

54.30, 56.15 and 56.44 (3-C, 2-C, OMe), 67.11 (a-C),

114.94 (Ar-3⁰,5⁰-C), 118.92 (Ar-2⁰,6⁰-C), 132.10 (Ar-1⁰-C),

156.38 (Ar-4⁰-C), 164.14 (CON), 170.38 and 170.56

(COOH, MeCO). C₁₅H₁₇NO₆requires C 58.6; H 5.5; N

4.6; found C 58.2; H 5.1; N 4.4.

NaBH₄(0.38 g; 10 mmol) was added to a solution of 27a

(1.6 g; 4 mmol) in tert-butyl alcohol (30 mL) under cooling

with cold water. After 2 h of stirring (TLC: CH₂Cl₂–EtOAc

10:0.5, UV, Rf_26,270.5, Rf₂₈0.1), the insoluble inorganics

were ﬁltered oﬀ on a G4 ﬁlter and washed several times

with EtOAc. The ﬁrst ﬁltrate (containing only tert-butyl

alcohol) was concentrated at 50 mmHg. The residue was

dissolved in the EtOAc used for washing the inorganics.

It was washed with brine, dried (MgSO₄) and the residue

obtained after evaporation of the solvent was puriﬁed by

ﬂash chromatography (CH₂Cl₂!CH₂Cl₂–EtOAc 10:2) to

give 28a (0.45 g, 14% from 24a) as a light yellow oil. All

of its physical properties were the same as those previously

described.^9,11If the starting material contains cis impurity,

it can be recovered unreacted during chromatography.

4.38. (3R,4S)-3-[(1R)-1-Acetoxyethyl]-4-(hydroxymethyl)-1-

(4-methoxyphenyl)azetidine-2-one 30a

NEt₃(0.75 mL; 5.5 mmol) was added to a suspension of

29a (0.9 g; 2.9 mmol) in THF (150 mL). Then a solution

of ethyl chloroformate (0.55 mL; 5.5 mmol) in THF

(5 mL) was added to it dropwise at ꢀ20 ꢁC. The mixture

was stirred for 1.5 h at this temperature (TLC: CH₂Cl₂–

MeOH 10:3, UV, Rf₂₉0.3, Rf₃₁0.9), then an additional

0.75 mL (5.5 mmol) of triethylamine and a 0.55 mL

(5.5 mmol) of ethyl chloroformate were added. It was stir-

red for 1 h at this temperature. NaBH₄(0.6 g; 16 mmol)

was added to it, then a solution of MeOH (2 mL) and

THF (10 mL) was added dropwise at ꢀ20 ꢁC (gas genera-

tion) (TLC: CH₂Cl₂–EtOAc 10:2, UV, Rf₃₁0.6, Rf₃₀0.2).

Because the reaction was not complete, an additional

0.3 g (8 mmol) of NaBH₄and a solution of 1 mL of MeOH

and 5 mL of THF were added dropwise at the same tem-

perature. After the reaction was complete, the mixture

was neutralized with 1 M HCl. The residue obtained after

evaporation of the solvent was taken up in a mixture of

water and EtOAc. The two phases were separated. The

aqueous phase was extracted with EtOAc, and the com-

bined organic layers were washed with brine and dried over

MgSO₄. The solvent was evaporated under reduced pres-

sure. The remaining material was triturated ﬁrst with

CH₂Cl₂, then the insoluble material was ﬁltered oﬀ. The

remaining solid obtained after evaporation of the solvent

was triturated with ether to give a white crystalline solid

(0.78 g), which proved to be (NMR) the 10:1 mixture of

the title compound 30a and its regioisomer 20a. The ether

mother liquor was puriﬁed by ﬂash chromatography

(CH₂Cl₂!CH₂Cl₂–EtOAc 10:0.2) to give an additional

0.05 g (total 97%) of the title compound (and its isomer).

Mp 147–150 ꢁC. IR (KBr): m 3488 (OH), 1732 (br, CON,

COO), 1512 (Ar), 1456, 1392, 1296, 1280, 1248, 1164,

4.35. (3S,4S)-3-[(1S)-1-Acetoxyethyl]-4-(hydroxymethyl)-1-

(4-methoxyphenyl)azetidine-2-one 28b

Prepared analogously to 28a from 27b (8 g; 20 mmol) and

gave 28b (2.2 g, 14% from 24b) as a light yellow oil. All

of its physical properties are the same as those previously

described.^9,11

4.36. (2S,3R)-3-[(1R)-1-Acetoxyethyl]-1-(4-methoxyphenyl)-

4-oxoazetidine-2-carboxylic acid 29a

Compound 26a (1.93 g; 4.9 mmol) dissolved in DMF

(120 mL) was hydrogenolyzed at normal pressure in the

presence of 10% Pd/C (0.5 g). After 20 min the reaction

was completed. The catalyst was ﬁltered oﬀ and the result-

ing white solid obtained after removal of the solvent by dis-

tillation at 0.1 mmHg was triturated with ether. The

insoluble white solid was ﬁltered and gave 29a (1.34 g,

90%). Mp 233 ꢁC. IR (KBr): m 3500–3300 (COOH), 1740

(br, CON, COO), 1696, 1512 (Ar), 1392, 1292, 1248,

1176, 1028, 832 cm^ꢀ^{1 1}H NMR (500 MHz, DMSO): d

.

1.33 (3H, d, J = 6.5 Hz, b-Me), 1.90 (3H, s, MeCO), 3.72

(3H, s, OMe), 3.83 (1H, dd, J_aH= 3.7 Hz, J_cis= 6.5 Hz,

3-H), 4.72 (1H, d, J_cis= 6.5 Hz, 2-H), 5.08 (1H, qd,

J_CH¼ 6:5 Hz, J_3H= 4 Hz, a-H), 6.91 (2H, d,

3

J_ortho= 9.0 Hz, Ar-3⁰,5⁰-H), 7.29 (2H, d, J_ortho= 9.0 Hz,

Ar-2⁰,6⁰-H). ¹³C NMR (75 MHz, DMSO): d 18.25 (b-

Me), 20.64 (MeCO), 53.63, 55.25 and 55.49 (3-C, 2-C,

OMe), 66.24 (a-C), 114.03 (Ar-3⁰,5⁰-C), 117.98 (Ar-2⁰,6⁰-

C), 131.27 (Ar-1⁰-C), 155.45 (Ar-4⁰-C), 163.26 (CON),

169.44 and 169.59 (COOH, MeCO). C₁₅H₁₇NO₆requires

C 58.6; H 5.5; N 4.6; found C 58.4; H 5.3; N 4.4.

1

1136, 1112, 1064, 1028, 832 cm^ꢀ1. H NMR (500 MHz):

d 1.46 (3H, d, J = 6.5 Hz, b-Me), 2.08 (3H, s, MeCO),

3.49 (1H, m ꢂ t, 3-H), 3.78 (3H, s, OMe), 3.97 + 4.03

(2H, dAB, J_gem= 12 Hz, J_4H= 5 Hz, CH₂), 4.27 (1H,

m ꢂ q, 4-H), 5.41 (1H, qd, J_CH¼ 6:5 Hz, J_3H= 5.5 Hz,

3

a-H), 6.86 (2H, d, J_ortho= 9.0 Hz, Ar-3⁰,5⁰-H), 7.44 (2H,

3124

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

d, J_ortho= 9.0 Hz, Ar-2⁰,6⁰-H). ¹³C NMR (75 MHz): d

20.14 (b-Me), 21.60 (MeCO), 55.67, 55.71 and 56.19 (3-C,

4-C, OMe), 60.77 (CH₂), 66.63 (a-C), 114.59 (Ar-3⁰,5⁰-C),

119.04 (Ar-2⁰,6⁰-C), 131.20 (Ar-1⁰-C), 156.47 (Ar-4⁰-C),

164.15 (CON), 170.81 (MeCO).

4.40. (3R,4S)-3-[(1R)-1-Acetoxyethyl]-4-[(methanesulfonyl-

oxy)methyl]-1-(4-methoxyphenyl)azetidine-2-one 33a

Mesyl chloride (0.55 mL; 7.4 mmol) was added to a solu-

tion of the mixture of 30a and 20a (1.4 g; 4.8 mmol) in

THF (50 mL) at ꢀ5 ꢁC. A solution of triethylamine

(1 mL; 7.5 mmol) in THF (5 mL) was added to the reaction

mixture at this temperature. It was stirred for 1 h (TLC:

CH₂Cl₂–EtOAc 10:2, Rf₃₀0.2, Rf₃₃0.55), then neutralized

with 1 M HCl, the solvent was evaporated under reduced

pressure. The residue was taken up in EtOAc and water.

The two phases were separated and the aqueous phase

was extracted with EtOAc. The combined organic layers

were washed with brine, dried over MgSO₄and the residue

obtained after evaporation of the solvent was triturated

4.38.1. (3S,4S)-3-Ethyl-4-(hydroxymethyl)-1-(4-methoxy-

phenyl)azetidine-2-one 32a. From the chromatography,

20 mg (1.3%) of 32a was also isolated. TLC: CH₂Cl₂–

EtOAc 7:4, UV, Rf₃₂0.48, Rf₃₀0.38. Mp 108–110 ꢁC (hex-

ane), white, needle like crystals. IR (KBr): m 3424 (OH),

1

1708 (CON), 1520 (Ar), 1252, 1024, 824 cm^ꢀ1. H NMR

(500 MHz): d 1.14 (3H, t, J = 7.4 Hz, b-Me), 1.74 + 1.91

(2 · 1H, 2 · m, CH₂Me), 1.94 (1H, s, OH), 3.26 (1H,

m ꢂ q, 3-H), 3.78 (3H, s, OMe), 3.97 + 4.04 (2H, dAB,

J_gem= 12 Hz, J_4H= 4.8 Hz, CH₂O), 4.21 (1H, m ꢂ q,

4-H), 6.85 (2H, d, J_ortho= 8.9 Hz, Ar-3⁰,5⁰-H), 7.42 (2H,

d, J_ortho= 8.9 Hz, Ar-2⁰,6⁰-H). ¹³C NMR (125 MHz): d

13.02 (b-Me), 18.44 (CH₂Me), 53.32, 55.70 and 56.19 (3-

C, 4-C, OMe), 60.86 (CH₂O), 114.58 (Ar-3⁰,5⁰-C), 118.91

(Ar-2⁰,6⁰-C), 131.52 (Ar-1⁰-C), 156.28 (Ar-4⁰-C), 168.27

(CON). HRMS m/z 235.1210 (C₁₃H₁₇NO₃calcd 235.1208).

with ether to give 33a (1.5 g, 85%) as white crystals. Mp

25:5

121 ꢁC. ½aꢁ_D¼ ꢀ67:2. IR (KBr): m 1752 (COO), 1736

(CON), 1520 (Ar), 1384, 1352, 1296, 1236, 1176, 1152,

1

1032, 976, 960, 848, 832, 528 cm^ꢀ1. H NMR (500 MHz):

d 1.51 (3H, d, J = 6.4 Hz, b-Me), 2.10 (3H, s, MeCO),

3.00 (3H, s, SMe), 3.59 (1H, dd, J_aH= 3.7 Hz,

J_cis= 5.5 Hz, 3-H), 3.80 (3H, s, OMe), 4.46 (2H, m, 4-

H + CH_2A), 4.62 (1H, dd, J_gem= 10 Hz, J_4H= 5 Hz,

4.39. (3S,4R)-3-[(1S)-1-Acetoxyethyl]-4-(hydroxymethyl)-1-

(4-methoxyphenyl)azetidine-2-one 30b

CH_2B), 5.32 (1H, qd, J_CH¼ 6:4 Hz, J_3H= 3.7 Hz, a-H),

3

6.90 (2H, d, J_ortho= 9.0 Hz, Ar-3⁰,5⁰-H), 7.36 (2H, d,

J_ortho= 9.0 Hz, Ar-2⁰,6⁰-H). ¹³C NMR (75 MHz): d 19.79

(b-Me), 21.64 (MeCO), 37.92 (SMe), 53.10, 55.76 and

56.00 (3-C, 4-C, OMe), 66.41 and 66.61 (CH₂, a-C),

114.80 (Ar-3⁰,5⁰-C), 119.10 (Ar-2⁰,6⁰-C), 130.40 (Ar-1⁰-C),

156.88 (Ar-4⁰-C), 163.21 (CON), 170.50 (MeCO).

C₁₆H₂₁NO₇S requires C 51.7; H 5.7; N 3.8; S 8.6; found

C 51.5; H 5.6; N 3.6; S 8.85.

Prepared analogously to 30a from 29b (1.6 g; 5.2 mmol) and

gave a mixture of the title compound and its regioisomer

(10:1) (1.4 g, 92%) as a white solid. Mp 148–150 ꢁC. IR

(KBr): m 3488 (OH), 1736 (CON), 1712 (COO), 1704,

1512 (Ar), 1456, 1392, 1296, 1280, 1252, 1164, 1136, 1112,

1

1064, 1028, 832 cm^ꢀ1. H NMR (500 MHz): d 1.47 (3H,

d, J = 6.5 Hz, b-Me), 2.09 (3H, s, MeCO), 3.49 (1H,

m ꢂ t, 3-H), 3.79 (3H, s, OMe), 3.97 + 4.04 (2H, m ꢂ AB,

J_3H= 5.5 Hz, a-H), 6.87 (2H, d, J_ortho= 9.0 Hz, Ar-3⁰,5⁰-

H), 7.45 (2H, d, J_ortho= 9.0 Hz, Ar-2⁰,6⁰-H). ¹³C NMR

(125 MHz): d 19.95 (b-Me), 21.40 (MeCO), 55.50, 55.52

and 55.96 (3-C, 4-C, OMe), 60.61 (CH₂), 66.42 (a-C),

114.41 (Ar-3⁰,5⁰-C), 118.85 (Ar-2⁰,6⁰-C), 131.00 (Ar-1⁰-C),

156.29 (Ar-4⁰-C), 163.90 (CON), 170.58 (MeCO).

4.41. (3S,4R)-3-[(1S)-1-Acetoxyethyl]-4-[(methanesulfonyl-

oxy)methyl]-1-(4-methoxyphenyl)azetidine-2-one 33b

CH₂), 4.27 (1H, m ꢂ q, 4-H), 5.42 (1H, qd, J_CH¼ 6:5 Hz,

3

Prepared analogously to 33a from the mixture of 30b and

20b (1.2 g; 4 mmol) and gave 33b (1.24 g, 84%) as

25:5

white crystals. Mp 121 ꢁC. ½aꢁ_D¼ þ66:6. IR (KBr): m

1752 (COO), 1736 (CON), 1516 (Ar), 1384, 1352, 1296,

1236, 1176, 1152, 1032, 976, 960, 848, 832 cm^ꢀ^{1 1}H

.

NMR (500 MHz): d 1.52 (3H, d, J = 6.4 Hz, b-Me), 2.11

(3H, s, MeCO), 3.00 (3H, s, SMe), 3.59 (1H, dd,

J_aH= 3.6 Hz, J_cis= 5.5 Hz, 3-H), 3.80 (3H, s, OMe), 4.46

(2H, m, 4-H + CH_2A), 4.63 (1H, dd, J_gem= 10.5 Hz,

4.39.1. (2R,3S)-3-[(1S)-1-Acetoxyethyl]-1-(4-methoxyphen-

yl)-4-oxoazetidine-2-carboxylic anhydride 31b. A small

sample was taken out of the reaction mixture before the

addition of NaBH₄. The solvent was evaporated under

reduced pressure. The remaining material was solved in

CH₂Cl₂, washed with water, dried over MgSO₄and pro-

vided 31b after evaporation of the solvent. Mp: decom-

poses at 220 ꢁC. IR (KBr): m 1832 (COanh), 1768 (COO),

1736 (CON), 1516 (Ar), 1456, 1396, 1376, 1248, 1240,

J_4H= 5 Hz, CH_2B), 5.32 (1H, qd, J_CH¼ 6:5 Hz, J_3H

=

3

3.6 Hz, a-H), 6.89 (2H, d, J_ortho= 9.0 Hz, Ar-3⁰,5⁰-H),

7.36 (2H, d, J_ortho= 9.0 Hz, Ar-2⁰,6⁰-H). ¹³C NMR

(75 MHz): d 19.76 (b-Me), 21.59 (MeCO), 37.88 (SMe),

53.11, 55.73 and 55.99 (3-C, 4-C, OMe), 66.41 66.58

(CH₂, a-C), 114.78 (Ar-3⁰,5⁰-C), 119.10 (Ar-2⁰,6⁰-C),

130.39 (Ar-1⁰-C), 156.87 (Ar-4⁰-C), 163.20 (CON), 170.45

(MeCO). C₁₆H₂₁NO₇S requires C 51.7; H 5.7; N 3.8; S

8.6; found C 51.7; H 5.85; N 4.1; S 8.65.

1200, 1184, 1160, 1064, 1040, 960, 944, 824 cm^ꢀ1

NMR (500 MHz): d 1.57 (6H, d, J = 6.5 Hz, b-Me), 2.00

(6H, s, MeCO), 3.80 (6H, s, OMe), 3.82 (2H, dd, J_aH

.

¹H

=

2.5 Hz, J_cis= 6.5 Hz, 3-H), 4.27 (2H, d, J_cis= 6.5 Hz,

2-H), 5.37 (2H, qd, J_CH¼ 6:5 Hz, J_3H= 2.5 Hz, a-H),

4.42. (3R,4S)-3-[(1R)-1-Acetoxyethyl]-4-[(methanesulfonyl-

oxy)methyl]azetidine-2-one 34a

3

6.90 (4H, d, J_ortho= 9.0 Hz, Ar-3⁰,5⁰-H), 7.40 (4H, d,

J_ortho= 9.0 Hz, Ar-2⁰,6⁰-H). ¹³C NMR (75 MHz): d 18.62

(b-Me), 21.26 (MeCO), 53.77, 55.73 and 57.17 (3-C, 2-C,

OMe), 66.10 (a-C), 114.60 (Ar-3⁰,5⁰-C), 118.53 (Ar-2⁰,

6⁰-C), 130.67 (Ar-1⁰-C), 156.91 (Ar-4⁰-C), 161.67 and

161.97 (CON, COOCO), 171.64 (MeCO).

A solution of CAN (7.6 g; 14 mmol) in water (80 mL) was

added dropwise to the solution of 33a (1.64 g; 4.6 mmol) in

acetonitrile (60 mL), while the temperature was kept

between ꢀ10 and 0 ꢁC. It was stirred at this temperature

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

3125

for two h (TLC: CH₂Cl₂–EtOAc 1:1, UV + PMA, Rf₃₄0.2

(only PMA), Rf₃₃0.7). The reaction mixture was diluted

with water (80 mL) and extracted with 5 · 100 mL EtOAc.

The combined organic layers were washed subsequently

with 10% NaHCO₃, 10% NaHSO₃, again with 10% NaH-

CO₃and brine. All of the aqueous phases were extracted

back with EtOAc and these were combined with the organ-

ic phase. It was then dried over Na₂SO₄. Evaporation

of the solvent followed by ﬂash chromatography

(CH₂Cl₂!CH₂Cl₂–EtOAc 10:1) gave a yellowish solid that

by ﬂash chromatography (CH₂Cl₂!CH₂Cl₂–EtOAc 1:1).

Fractions having an Rf 0.5 (TLC: CH₂Cl₂–EtOAc 10:2)

were collected. Starting material (0.15 g) was also recov-

ered. The aqueous layer was extracted with EtOAc, dried

over MgSO₄. The solvent was evaporated, and resulted in

0.15 g of starting material (total 30%). NEt₃(0.3 mL) was

added to the solution of the material with Rf 0.5 in chloro-

form (30 mL) and it was reﬂuxed for 4 h (TLC: CH₂Cl₂–

EtOAc 10:2, UV, Rf₁₇0.5, Rf₃₅0.7). The mixture was

washed with water and dried over MgSO₄. The residue ob-

tained after evaporation of the solvent was puriﬁed by ﬂash

was triturated with ether and provided 34a (0.95 g, 83%) as

22:5

a white solid. Mp 104 ꢁC. ½aꢁ_D¼ ꢀ31:0. IR (KBr): m 3320

chromatography (CH₂Cl₂!CH₂Cl₂–EtOAc 10:0.3) to give

28

(NH), 1764 (COO), 1736 (CON), 1384, 1352, 1248, 1172,

35a (0.6 g, 48%) as a yellow oil. ½aꢁ_D¼ þ96:6 (c 3). IR

1136, 1033, 984, 976, 968, 824 cm^ꢀ1

.

¹H NMR

(ﬁlm): m 1772 (COO), 1740 (CON), 1710 (COO), 1616

(500 MHz): d 1.44 (3H, d, J = 6.5 Hz, b-Me), 2.11 (3H, s,

MeCO), 3.07 (3H, s, SMe), 3.51 (1H, m ꢂ t, 3-H), 4.06

(1H, m, 4-H), 4.35 (1H, dAB, J_gem= 11 Hz,

J_4H= 4.5 Hz, CH_2A), 4.43 (1H, dAB, J_gem= 11 Hz,

(Ar), 1456, 1392, 1240, 1188, 1144, 1072, 1040, 952, 740,

696 cm^ꢀ1

.

¹H NMR (500 MHz):

d

1.35 (3H, d,

J = 6.4 Hz, b-Me), 2.08 (3H, s, MeCO), 2.23 (3H, s, 3-

Me), 3.68 (1H, m, 6-H), 3.82 (1H, dd, J_aH= 6.7 Hz,

J_cis= 5.8 Hz, 7-H), 4.04 (1H, m ꢂ t, 1-H_A), 4.49 (1H, dd,

J_gem= 10.4 Hz, J_6H= 3.6 Hz, 1-H_B), 5.25 (3H, m, a-

H+CH₂Ph), 7.29 (1H, m ꢂ t, Ar-4⁰-H), 7.36 (2H, m ꢂ t,

Ar-3⁰,5⁰-H), 7.45 (2H, d, J_ortho= 7.1 Hz, Ar-2⁰,6⁰-H). ¹³C

NMR (125 MHz): d 18.12 (b-Me), 20.39 (3-Me), 21.51

(MeCO), 45.60 (6-C), 58.34 (7-C), 65.30 (a-C), 66.69

(CH₂Ph), 67.00 (1-C), 106.75 (4-C), 128.28 (Ar-4⁰-C),

128.53 and 128.67 (Ar-2⁰,3⁰,5⁰,6⁰-C), 136.08 (Ar-1⁰-C),

155.25 (3-C), 163.18 and 164.80 (CON, COOBn), 170.30

(MeCO). C₁₉H₂₁NO₆requires C 63.5; H 5.9; N 3.9; found

C 63.4; H 5.9; N 3.85.

J_4H= 8 Hz, CH_2B), 5.20 (1H, qd, J_CH¼ 6:5 Hz, J_3H

=

3

4 Hz, a-H), 6.18 (1H, s, NH). ¹³C NMR (75 MHz):

d 19.62 (b-Me), 21.58 (MeCO), 37.98 (SMe), 50.01 and

57.27 (3-C, 4-C), 66.19 (CH₂), 68.61 (a-C), 166.27

(CON), 170.42 (MeCO). C₉H₁₅NO₆S requires C 40.75; H

5.7; N 5.3; S 12.1; found C 40.6; H 5.6; N 5.1; S 12.1.

4.43. (3S,4R)-3-[(1S)-1-Acetoxyethyl]-4-[(methanesulfonyl-

oxy)methyl]azetidine-2-one 34b

Prepared analogously to 34a from 33b (2.5 g; 7 mmol) and

gave 34b (1.33 g, 72%) as a white solid. Mp 105 ꢁC.

24:5

½aꢁ_D¼ þ31:4. IR (KBr): m 3320 (NH), 1764 (AcO), 1736

.

968, 824 cm^ꢀ^{1 1}H NMR (500 MHz): d 1.44 (3H, d,

4.45. Benzyl (6R,7S)-7-[(1S)-1-acetoxyethyl]-3-methyl-2-

iso-oxacephem-4-carboxylate 35b

(CON), 1384, 1352, 1248, 1172, 1136, 1032, 984, 976,

J = 6.4 Hz, b-Me), 2.11 (3H, s, MeCO), 3.07 (3H, s,

SMe), 3.51 (1H, m ꢂ t, 3-H), 4.06 (1H, m, 4-H), 4.35

(1H, dAB, J_gem= 10.6 Hz, J_4H= 4.2 Hz, CH_2A), 4.43

(1H, dAB, J_gem= 10.5 Hz, J_4H= 8.1 Hz, CH_2B), 5.20

Prepared analogously to 35a from 34b (1.3 g; 4.9 mmol)

28

and gave 35b (0.7 g, 40%) as a yellow oil. ½aꢁ_D¼ ꢀ97:8.

IR (ﬁlm): m 1772 (COO), 1740 (CON), 1712 (COO), 1620

(Ar), 1456, 1392, 1352, 1304, 1240, 1188, 1144, 1072,

(1H, qd, J_CH¼ 6:4 Hz, J_3H= 4.1 Hz, a-H), 6.33 (1H,

3

1

1040, 740, 696 cm^ꢀ1. H NMR (500 MHz): d 1.35 (3H, d,

s, NH). ¹³C NMR (75 MHz): d 19.63 (b-Me), 21.57

(MeCO), 37.95 (SMe), 49.97 and 57.24 (3-C, 4-C), 66.19

(CH₂), 68.64 (a-C), 166.44 (CON), 170.43 (MeCO).

C₉H₁₅NO₆S requires C 40.75; H 5.7; N 5.3; S 12.1; found

C 40.7, H 5.5; N 5.1; S 12.25.

J = 6.4 Hz, b-Me), 2.08 (3H, s, MeCO), 2.23 (3H, s, 3-

Me), 3.68 (1H, m, 6-H), 3.82 (1H, dd, J_aH= 6.7 Hz,

J_cis= 5.8 Hz, 7-H), 4.04 (1H, m ꢂ t, 1-H_A), 4.49 (1H, dd,

J_gem= 10.4 Hz, J_6H= 3.6 Hz, 1-H_B), 5.25 (3H, m, a-

H + CH₂Ph), 7.29 (1H, m ꢂ t, Ar-4⁰-H), 7.36 (2H, m ꢂ t,

Ar-3⁰,5⁰-H), 7.45 (2H, d, J_ortho= 7.1 Hz, Ar-2⁰,6⁰-H). ¹³C

NMR (125 MHz): d 18.12 (b-Me), 20.39 (3-Me), 21.51

(MeCO), 45.62 (6-C), 58.35 (7-C), 65.31 (a-C), 66.70

(CH₂Ph), 67.00 (1-C), 106.76 (4-C), 128.28 (Ar-4⁰-C),

128.53 and 128.67 (Ar-2⁰,3⁰,5⁰,6⁰-C), 136.09 (Ar-1⁰-C),

155.24 (3-C), 163.17 and 164.80 (CON, COOBn), 170.29

(MeCO). HRMS m/z 359.1397 (C₁₉H₂₁NO₆calcd

359.13957).

4.44. Benzyl (6S,7R)-7-[(1R)-1-acetoxyethyl]-3-methyl-2-

iso-oxacephem-4-carboxylate 35a

Benzyl 2,3-dioxobutyrate (1.15 g; 5 mmol) and NEt₃

(0.3 mL; 2 mmol) were added to the solution of 34a

(0.93 g; 3.5 mmol) in THF (50 mL). The mixture was stir-

red at rt for 3 h, then cooled down to ꢀ25 ꢁC. Pyridine

(1.0 mL; 12 mmol), then a solution of thionyl chloride

(0.7 mL; 10 mmol) in 5 mL dry THF were added dropwise.

After 1 h stirring, the white precipitate (Py HCl) was ﬁl-

4.46. Benzyl (6S,7R)-7-[(1R)-1-hydroxyethyl]-3-methyl-2-

iso-oxacephem-4-carboxylate 36a and benzyl (6S,7Z)-7-

ethylidene-3-methyl-2-iso-oxacephem-4-carboxylate 18a

*

tered oﬀ and the ﬁltrate was evaporated under reduced

pressure. Zinc (1.0 g; 15 mmol) was added slowly at 5 ꢁC

to a solution of the yellow oily residue in a mixture of acetic

acid (40 mL) and water (6 mL). After 2 h of stirring, the

insoluble materials were ﬁltered oﬀ. The residue obtained

after evaporation of the solvent was dissolved in CH₂Cl₂,

washed with water, dried over MgSO₄and the resulting

oil obtained after evaporation of the solvent was puriﬁed

NaOMe/MeOH (0.2 M) was added hourly in 1 mL por-

tions at 0 ꢁC to a solution of 35a (0.45 g; 1.25 mmol) in

methanol (30 mL) until the starting material disappeared

(4 h) (TLC: CH₂Cl₂–EtOAc 10:2, UV + PMA, Rf₁₈0.7,

Rf₃₆0.15). After completion, the mixture was neutralized

3126

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

1

with 1 M HCl and the methanol was evaporated under re-

duced pressure. The residue was dissolved in EtOAc

(30 mL), washed with water and brine and dried over

MgSO₄. The yellow crude oil (0.37 g) obtained after evap-

oration of the solvent was puriﬁed by prep. TLC (CH₂Cl₂–

EtOAc 10:1.5) to give 36a (160 mg, 40%), 18a (90 mg, 24%)

and 37a (15 mg, 4%).

1072, 1048, 740, 696 cm^ꢀ1. H NMR (500 MHz): d 1.30

(3H, d, J = 6.5 Hz, b-Me), 2.24 (3H, s, 3-Me), 2.40 (1H,

br s, OH), 3.63 (1H, m, 7-H), 3.70 (1H, m, 6-H), 4.14

(1H, m ꢂ qui, a-H), 4.24 (1H, m ꢂ t, 1-H_A), 4.51 (1H,

dd, J_gem= 10.7 Hz, J_6H= 3.8 Hz, 1-H_B), 5.26 (2H, AB,

J_gem= 12.5 Hz, CH₂Ph), 7.30 (1H, t, J_ortho= 7.3 Hz, Ar-

4⁰-H), 7.36 (2H, t, J_ortho= 7.3 Hz, Ar-3⁰,5⁰-H), 7.45 (2H,

d, J_ortho= 7.2 Hz, Ar-2⁰,6⁰-H). ¹³C NMR (125 MHz): d

18.18 (b-Me), 23.18 (3-Me), 45.55 (6-C), 60.80 (7-C),

63.69 (a-C), 66.75 and 66.99 (CH₂Ph, 1-C), 106.55 (4-C),

128.31 (Ar-4⁰-C), 128.51 and 128.68 (Ar-2⁰,3⁰,5⁰,6⁰-C),

136.08 (Ar-1⁰-C), 155.65 (3-C), 163.17 (CON), 167.21

(COOBn). HRMS m/z 317.1271 (C₁₇H₁₉O₅N calcd

317.1263).

4.46.1. Benzyl (6S,7R)-7-[(1R)-1-hydroxyethyl]-3-methyl-2-

iso-oxacephem-4-carboxylate

36a. Yellow

oil.

26

½aꢁ_D¼ þ103:5. IR (ﬁlm): m 3448 (OH), 2976 (CH), 1752

(CON), 1708, 1616 (Ar), 1456, 1392, 1308, 1224, 1152,

1072, 1048, 740, 696 cm^ꢀ1. H NMR (500 MHz): d 1.30

1

(3H, d, J = 6.5 Hz, b-Me), 2.24 (3H, s, 3-Me), 2.36 (1H,

br s, OH), 3.63 (1H, m, 7-H), 3.70 (1H, m, 6-H), 4.15

(1H, m ꢂ qui, a-H), 4.24 (1H, m ꢂ t, 1-H_A), 4.51 (1H,

dd, J_gem= 10.7 Hz, J_6H= 3.7 Hz, 1-H_B), 5.26 (2H, AB,

J_gem= 12.5 Hz, CH₂Ph), 7.30–7.46 (5H, m, ArH). ¹³C

NMR (125 MHz): d 18.17 (b-Me), 23.17 (3-Me), 45.54 (6-

C), 60.79 (7-C), 63.66 (a-C), 66.76 and 66.98 (CH₂Ph, 1-

C), 106.52 (4-C), 128.30 (Ar-4⁰-C), 128.50 and 128.67

(Ar-2⁰,3⁰,5⁰,6⁰-C), 136.08 (Ar-1⁰-C), 155.66 (3-C), 163.18

(CON), 167.22 (COOBn). HRMS m/z 317.1281

(C₁₇H₁₉O₅N calcd 317.1263).

4.47.2. Benzyl (6S,7Z)-7-ethylidene-3-methyl-2-iso-oxace-

24:5

phem-4-carboxylate 18b. Yellow oil. ½aꢁ_D¼ ꢀ121:2. IR

(ﬁlm): m 1752 (CON), 1712, 1612 (Ar), 1456, 1384, 1352,

1292, 1208, 1120, 1080, 1028, 736, 696 cm^ꢀ^{1 1}H NMR

.

(500 MHz): d 2.07 (3H, d, J = 7.2 Hz, b-Me), 2.25 (3H, s,

3-Me), 3.55 (1H, dd, J_6H= 9.3 Hz, J_gem= 10.6 Hz, 1-

H_A), 3.86 (1H, dd, J_1HA= 9.3 Hz, J_1HB= 3.8 Hz, 6-H),

4.60 (1H, dd, J_gem= 10.6 Hz, J_6H= 3.8 Hz, 1-H_B), 5.29

(2H, AB, J_gem= 12.5 Hz, CH₂Ph), 5.81 (1H, q,

J = 7.1 Hz, a-H), 7.30–7.41 (3H, m, Ar-3⁰,4⁰,5⁰-H), 7.48

(2H, d, J_ortho= 7.2 Hz, Ar-2⁰,6⁰-H). ¹³C NMR

(125 MHz): d 15.17 (b-Me), 18.12 (3-Me), 49.40 (6-C),

66.98 and 69.07 (CH₂Ph, 1-C), 107.49 (4-C), 128.21 (Ar-

4⁰-C), 128.46 and 128.65 (Ar-2⁰,3⁰,5⁰,6⁰-C), 129.29 (a-C),

136.28 (Ar-1⁰-C), 139.47 (7-C), 153.86 (3-C), 163.23 and

163.65 (COOBn, CON). HRMS m/z 299.1168

(C₁₇H₁₇NO₄calcd 299.1158).

4.46.2. Benzyl (6S,7Z)-7-ethylidene-3-methyl-2-iso-oxace-

25:5

phem-4-carboxylate 18a. Yellow oil. ½aꢁ_D¼ þ121:0.

HRMS m/z 299.1139 (C₁₇H₁₇NO₄calcd 299.1158), the

spectra were the same as cited above (see Section 4.19.2).

4.46.3. Benzyl (6S,7E)-7-ethylidene-3-methyl-2-iso-oxace-

phem-4-carboxylate 37a. Needle-like white crystals.

34

Rf_37a0.65. ½aꢁ_D¼ þ196:1 (c 0.4). Mp 119–120 ꢁC. IR

4.48. (6S,7R)-7-[(1R)-1-Hydroxyethyl]-3-methyl-2-iso-oxace-

phem-4-carboxylic acid 38a

(KBr): m 1752 (CON), 1712 (COO), 1608 (Ar), 1456,

1384, 1348, 1320, 1288, 1204, 1116, 1080, 1048, 992, 748,

700 cm^ꢀ1

.

¹H NMR (500 MHz):

d

1.80 (3H, d,

Compound 36a (150 mg; 0.47 mmol) was hydrogenated un-

der normal pressure in the presence of 10% Pd/C catalyst

(20 mg) in methanol (40 mL) for an hour (TLC: CH₂Cl₂–

EtOAc 1:1, UV, Rf₃₆0.3, Rf₃₈0; CH₂Cl₂–MeOH 10:3,

UV, Rf₃₇0.3). The catalyst was ﬁltered oﬀ and washed with

methanol. The ﬁltrate was evaporated under reduced pres-

J = 6.7 Hz, b-Me), 2.26 (3H, s, 3-Me), 3.60 (1H, m ꢂ t,

1-H_A), 4.00 (1H, dd, J_1HA= 9 Hz, J_1HB= 3.6 Hz, 6-H),

4.69 (1H, dd, J_gem= 10.7 Hz, J_6H= 3.6 Hz, 1-H_B), 5.28

(2H, AB, J_gem= 12.5 Hz, CH₂Ph), 6.33 (1H, q,

J = 6.7 Hz, a-H), 7.30 (1H, t, J_ortho= 7.1 Hz, Ar-4⁰-H),

7.36 (2H, t, J_ortho= 7.1 Hz, Ar-3⁰,5⁰-H), 7.48 (2H, d,

J_ortho= 7.1 Hz, Ar-2⁰,6⁰-H). ¹³C NMR (125 MHz): d

15.31 (b-Me), 18.17 (3-Me), 49.21 (6-C), 67.06 and 68.70

(CH₂Ph, 1-C), 107.51 (4-C), 125.94 (a-C), 128.25 (Ar-4⁰-

C), 128.53 and 128.66 (Ar-2⁰,3⁰,5⁰,6⁰-C), 136.17 (Ar-1⁰-C),

140.78 (7-C), 153.91 (3-C), 162.71 and 163.60 (COOBn,

CON). HRMS m/z 299.1143 (C₁₇H₁₇NO₄calcd 299.1158).

sure. The resulting colourless oil solidiﬁed on ether to give

25:5

38a (75 mg, 70%) as a white solid. ½aꢁ_D¼ þ175:8

(MeOH). IR (KBr): m 3500–3400 (br, OH, COOH), 1748

(CON), 1628, 1396, 1228, 1160, 1048 cm^ꢀ^{1 1}H NMR

.

(300 MHz, MeOD-d₄): d 1.26 (3H, d, J = 6.5 Hz, b-Me),

2.15 (3H, s, 3-Me), 3.30 (1H, s, OH), 3.65 (2H, m, 6-

H+7-H), 4.11 (1H, m ꢂ qui, a-H), 4.26 (1H, m ꢂ t, 1-

H_A), 4.50 (1H, dd, J_gem= 10.8 Hz, J_6H= 3.5 Hz, 1-H_B).

¹³C NMR (75 MHz, MeOD-d₄): d 17.89 (b-Me), 23.81 (3-

Me), 47.29 (6-C), 61.73 (7-C), 64.31 (a-C), 67.77 (1-C),

111.25 (4-C), 151.94 (3-C), 169.10 (CON). HRMS m/z

227.0810 (C₁₀H₁₃NO₅calcd 227.0794).

4.47. Benzyl (6R,7S)-7-[(1S)-1-hydroxyethyl]-3-methyl-2-

iso-oxacephem-4-carboxylate 36b and benzyl (6R,7Z)-7-

ethylidene-3-methyl-2-iso-oxacephem-4-carboxylate 18b

Prepared analogously to 36a and 18a from 35b (0.35 g;

1 mmol) and gave 36b (120 mg, 38%) and 18b (80 mg,

27%).

4.49. (6R,7S)-7-[(1S)-1-Hydroxyethyl]-3-methyl-2-iso-oxace-

phem-4-carboxylic acid 38b

4.47.1.

Benzyl

(6R,7S)-7-[(1S)-1-hydroxyethyl]-3-

Prepared analogously to 38a from 36b (60 mg; 0.19 mmol)

27

methyl-2-iso-oxacephem-4-carboxylate 36b. Yellow oil.

and gave 38b (30 mg, 70%) as white solid. ½aꢁ_D¼ ꢀ176:7

25:5

½aꢁ_D¼ ꢀ102:7. IR (ﬁlm): m 3448 (OH), 2976 (CH), 1752

(MeOH). IR (KBr): m 3500–3400 (br, OH, COOH), 1748

1

(CON), 1712, 1616 (Ar), 1456, 1392, 1304, 1224, 1152,

(CON), 1628, 1576, 1376, 1228, 1160, 1048, 788 cm^ꢀ1. H

Z. Sa´nta et al. / Tetrahedron: Asymmetry 17 (2006) 3111–3127

3127

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2333–2342.

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NMR (300 MHz, MeOD-d₄): d 1.26 (3H, d, J = 6.5 Hz, b-

Me), 2.15 (3H, s, 3-Me), 3.30 (1H, s, OH), 3.65 (2H, m, 6-

H+7-H), 4.11 (1H, m ꢂ qui, a-H), 4.28 (1H, m ꢂ t, 1-H_A),

4.50 (1H, dd, J_gem= 11 Hz, J_6H= 3.4 Hz, 1-H_B). ¹³C

NMR (75 MHz, MeOD-d₄): d 17.90 (b-Me), 23.78 (3-

Me), 47.29 (6-C), 61.79 (7-C), 64.34 (a-C), 67.82 (1-C),

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Acknowledgements

The authors wish to thank the Hungarian Scientiﬁc Foun-

dation (OTKA T 14200 and 37875) for ﬁnancial support

´

8. Diaz, N.; Suarez, D.; Merz, K. M., Jr.; Sordo, T. L. J. Med.

Chem. 2005, 48, 780–791.

and are also indebted to Dr. Aron Szo¨llo¨ssy and Dr. Pa´l

Kolonits for their contribution in measuring NMR spectra,

to Csaba Peltz, Dr. Gyula Parlagh and Attila Mako´ for

´

9. Santa, Z.; Nagy, J.; Parkanyi, L.; Nyitrai, J. Monatsh. Chem./

Chem. Monthly 2004, 135, 671–684.

´

HRMS spectra and K. Ofalvi for recording IR spectra.

´

10. Madarasz, Z.; Nemeth, I.; Toscano, P.; Welch, J.; Nyitrai, J.

Our thanks go to H. Medzihradszky–Schweiger for per-

forming micro-analysis. We are very grateful to Dr. Klaus

Thirring (Novartis/Nabriva Therapeutics/Vienna) and

Tetrahedron Lett. 1995, 36, 8303–8306.

´

11. Santa, Z.; Parkanyi, L.; Nemeth, I.; Nagy, J.; Nyitrai, J.

Tetrahedron: Asymmetry 2001, 12, 89–94.

´

Jean-Marc Paris (Laboratoire Biochimie Ecole Nationale

´

12. Greﬀ, Z.; Horvath, Z.; Nyitrai, J.; Kajtar-Peredy, M.; Brlik,

Superieure de Chimie de Paris) for antibacterial screening

and beta-lactamase assay of our compounds.

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´

Nyitrai, J.; Kajtar-Peredy, M.; Brlik, J. J. Chem. Res. (M)

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13. Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1978, 647–

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Synthesis of thienamycin-like 2-iso-oxacephems with optional stereochemistry

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