D-Glucosamine propanedithioacetal, an efficient chiral auxiliary in β-lactam chemistry

Bioorganic & Medicinal Chemistry 7 (1999) 837±850

D-Glucosamine Propanedithioacetal, an Ecient Chiral Auxiliary

in ꢀ-Lactam Chemistry^y

Josefa Anaya,^a,* Stephane D. Gero,^bManuel Grande,^aJose Ignacio M. Hernando^a

and Nieves M. Laso^a

a

Â

Departamento de Quõmica Organica, Universidad de Salamanca, E-37008 Salamanca, Spain

^bInstitut de Chimie des Substances Naturelles, C.N.R.S., 91198 Gif-sur-Yvette, France

Received 31 August 1998; accepted 2 November 1998

AbstractÐThe synthesis of some monocyclic b-lactams (monobactams) by the Staudinger reaction using d-glucosamine propane-

0

dithioacetal as chiral auxiliary is reported. The in¯uence of several radicals at C₃, C₄, and C₁(sugar moiety) as well as other

Introduction

modi®cations at C-3 and C-4 on the 2-azetidinone ring

and at C-1 and C-2 on the sugar moiety, in order to

clarify the relationship between the structure and the

inhibition of HLE by these monocyclic b-lactams.

For the last few years we have been developing an

enantioselective approach to the synthesis of b-lactams,¹

which relies on the use of 3,4;5,6-di-O-isopropylidene-d-

glucosamine propanedithioacetal (1)²as chiral auxiliary

in the Staudinger reaction.³This methodology let us

obtain the monocyclic azetidin-2-ones (monobactams )

required to prepare bicyclic b-lactam antibiotics.

In this article, we wish to give a full account of the

enantioselective preparation of compounds 1±28

(Scheme 1) extended by the synthesis of compounds

29±45 (Schemes 2±4), as well as discuss their inhibitory

activities to HLE.

The discovery that monocyclic azetidin-2-ones with

appropriate substituents at 1, 3, and 4 positions are

inhibitors of human leukocyte elastase⁴(HLE) promp-

ted us to study the inhibitory activity of the mono-

Results and Discussion

Chemistry

bactams , , and

, showed in Scheme 1,⁵against

three dierent elastases: pancreatic porcine, rat leuko-

cyte and human leukocyte, in order to design potent

and speci®c HLE inhibitors.

As shown in Scheme 1, the synthesis of monobactams

started from 3,4;5,6-di-O-isopropylidene-d-glucosamine

propane dithioacetal (1) which was available from d-

glucosamine in two steps. Condensation of 1 with var-

ious aldehydes (see Experimental) yielded the chiral

Schi-bases 2. These crude reaction products were used

without further puri®cation in the Staudinger reaction

by using triethylamine as a base and toluene as solvent.

The cis-monobactams 3, 4, 5, and 6 (3a,4a+3b,4b dia-

stereomers) were obtained by cycloaddition of 2 with

methoxyacetyl chloride at room temperature, in a short

reaction time and with good yields. From this reaction

mixture the pure diastereomers could be easily sepa-

rated by column chromatography or by recrystalliza-

tion. In contrast, when the imines 2 were reacted with

caproyl chloride no reaction was observed even after

24 h at room temperature but in re¯uxing toluene the

cis-monobactams 7±10 were the only diastereomers

obtained.

We found⁵that all the 3,4-disubstituted 2-azetidinones

(monobactams ) do not show elastase inhibition; in

contrast, the introduction of an acyl group on the

nitrogen atom (monobactams ) activates the b-lactam

ring and shows non-selective antielastase activity; how-

ever, some monobactams that have a butyl or a meth-

oxy group at C-3 and a styryl or a-methylstyryl group at

C-4, give selective inhibition to HLE.

Encouraged by this promising results, we turned our

attention to the preparation of new monobactams with

Key words: b-Lactams; synthesis; structure/circular dichroism; anti-

elastase activity.

*Corresponding author. Fax: +34-923-294574; e-mail: janay@gugu.

usal.es and/or mgrande@gugu.usal.es

y

Dedicated to Professor Sir Derek H. R. Barton.

PII: S0968-0896(98)00264-8

838

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

Scheme 1. Reagents: (a) HCl (g), 1,3-propanedithiol, HCl, 60 ^ꢀC; (b) 2,2-dimethoxypropane, p-TsOH, 60 ^ꢀC, 30 cmHg; (c) R²CHO, toluene, re¯ux;

(d) TEA, R¹CH₂COCl, toluene, 70 ^ꢀC or re¯ux; (e) n-BuLi, THF, 40 ^ꢀC; (f) CH₃COCl, Et(iPr)₂N, DMAP, CH₃CN, rt; (g) O₃, CH₂Cl₂, 78 ^ꢀC;

Me₂S, rt; (h) m-CPBA, CH₂Cl₂, rt; (i) tBuMe₂SiCl, Et(iPr)₂N, CH₂Cl₂, rt.

The N-unsubstituted monobactams , 11±17, were pre-

pared in very good yields and in a short reaction time

(20±40 min) by treatment of monobactams with 2.2

equiv of n-butyllithium in tetrahydrofurane at 40 ^ꢀC.

The cis-relationship of the C-3 and C-4 substituents in

compounds 3a±17 was deduced from the vicinal coupling

constants of the hydrogen atoms H-3 and H-4

(J_3,4ꢁ4.8 Hz) and the absolute con®guration at C-3 and

C-4 was deduced from the [a]_ddata, the CD curves

(Table 1) and the X-ray crystal structure of compounds

3b and 10.⁶

for 10), according to the X-ray data. These mono-

bactams have negative [a]_d, which suggests the 3b,4b

con®guration for the remaining levorotatory mono-

bactams 4b±6b, 7, 8, and 9 (major diastereomeric reac-

tion products) and the 3a,4a con®guration for the

monobactams 3a±6a.

The CD measurements also con®rm this absolute con-

®guration. Two empirical rules have been proposed by

Ogura et al. (lactam rule)⁷and by Schellman et al.

(amide quadrant rule)⁸to correlate the Cotton eect

with the absolute con®guration of the lactams. There

are nevertheless some exceptions and the predictions are

not always in agreement.⁹In our case, the lactam rule

The absolute con®guration of monobactams 3b and

10 was established as 3b,4b (3S,4R for 3b and 3S,4S

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

839

Scheme 2. Reagents: (a) PhCHC(R³)CHO, toluene, re¯ux; (b) TEA, R¹R²CHCOCl, toluene (or CH₂Cl₂), re¯ux; (c) n-BuLi, THF, 40 ^ꢀC.

applied to 2-azetidinones predict a negative Cotton

eect for the 3b,4b isomers, which is consistent with the

sign of the experimental curves. However, in the case of

The N-unsubstituted monobactams

does not show

the same regularity in the optical rotation as their par-

ent monobactams (Table 1). However, the CD curves

show a negative ®rst Cotton eect for compounds 3b,4b

and positive for 3a,4a, which also con®rm the proposed

absolute con®gurations.

monobactams

the CD curves are more complex

because of the presence of an aromatic chromophore

which could be responsible for the strong Cotton eects

observed. The aromatic ¹L_babsorption band (220±

230 nm) and the n±p* amide bands (ca. 210 and/or

220 nm) can overlap and produce an exciton coupling of

both chromophores that give rise to a Davido split-

ting.¹⁰The intensity of the coupling depends on the

degree of overlapping, the intensity of the excitons and

the orientation of the chromophores: in the case of

monobactams , the splitting reaches the maximum

amplitude in 6b (ÁÁe_210/230=35) but the exciton split-

ting is not so clear in other monobactams.

Compounds 19±23 (monobactams ) were prepared by

with acetyl

acylation of the respective monobactams

chloride in acetonitrile using diisopropylethylamine and

4-dimethylaminopyridine as base.

Conversion of the monobactams ,

and

into the

respective derivatives 24±28 was carried out by usual

chemical manipulations. Ozonolysis of compound 4b

gave the 4b-acetyl derivative 24, which was transformed

into the 4b-acetoxyazetidinone 25 by Baeyer±Villiger

reaction. On the other hand, silylation of 16 followed by

ozonolysis and treatment with m-chloroperbenzoic acid

gave 26. Finally, the compounds 27 and 28 were

obtained by ozonolysis of monobactams 20 and 23,

respectively.

According to the exciton chirality rule,¹⁰a positive

splitting (positive ®rst and negative second Cotton

eects) is related to a positive chirality of the transition

moments in the chromophores. The compounds 3a±6a

show positive splitting which corresponds to the 4a

con®guration (positive dihedral angle) while the

remaining compounds display a negative splitting and

should have 4b con®guration.

Monobactams 29±31, which have dierent alkyl groups

at C-3, were prepared as shown in Scheme 2. Con-

densation of 1 with trans-cinnamaldehyde or trans-a-

methylcinnamaldehyde, followed by treatment of b,b-

dimethylacryloyl chloride or 2-ethylbutyroyl chloride

in the presence of triethylamine, provided two cis-

monobactams 29 or 30 as a diastereomeric mixture. In

contrast, the Staudinger reaction between butyroyl

chloride and the condensation product of amine 1 and

trans-a-methylcinnamaldehyde yielded exclusively the

monobactam 31.

The cis-orientation of the substituents at C-3 and C-4 in

compounds 29 and 31 was also evident from the NMR

data (J_4,3ꢁ5.5 Hz) and the absolute con®guration was

deduced from the [a]_dand the X-ray crystal structure of

compound 10.⁶Moreover, the structures of mono-

bactams 30 were rigorously established on the basis of

the NMR spectra and con®rmed by CD-curve analysis

of the N-unsubstituted monobactams 32a and 32b,

which were prepared by treatment with n-butyllithium

from 30a and 30b, respectively.

Scheme 3. Reagents: (a) PhCHC(Me)CHO, toluene, re¯ux; (b)

TEA, CH₃(CH₂)₂COCl, toluene, re¯ux; (c) PhI(COCF₃)₂, MeOH, rt;

(d) CBZ, MeOH, Na₂CO₃, rt; (e) H₂/Pd-C(5%), EtOH, rt.

In order to clarify the role played by the dithianyl group

in the HLE inhibition, we have also prepared the

840

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

Scheme 4. Reagents: (a) PhICl₂, CH₂Cl₂, 40 ^ꢀC; (b) O₃, CH₂Cl₂, 78 ^ꢀC; Me₂S, rt; (c) m-CPBA, CH₂Cl₂, rt.

monobactams 35 and 36 (Scheme 3) which have on the

sugar moiety at C-1 an open chain thioacetal and acetal,

respectively.

Finally, we have carried out the preparation of com-

pounds 38±43 (Scheme 4) in order to synthesise the

monobactams 44 that have the sugar moiety trans-

formed into an electron-withdrawing group and better

leaving groups at C-4 of the monobactam ring. These

1,4 substituents on b-lactam ring would increase the

Preparation of 35 was carried out starting from amine

34¹¹by condensation with trans-a-methylcinnamalde-

hyde, followed by Staudinger reaction of the inter-

mediate imine with butyroyl chloride. A small amount of

the Z-isomer (35⁰) was also obtained due to the presence

of cis-a-methylcinnamaldehyde in the starting material.

reactivity and hence the antielastase activity of the ®rst

5

monobactams

have been reported as important elements to design

,

since both structural requirements

monocyclic b-lactam HLE inhibitors.^4a

In a ®rst approach to obtain the monobactam 36, which

have an acetal group at C-1 on the sugar moiety, we used

the Stork procedure.¹²Thus, treatment of compounds

31 and 35 with [bis(tri¯uoroacetoxy)iodo]benzene in

methanol furnished the monobactam 36 in 54 and 71%

yield, respectively. Alternatively, this compound was

also prepared by Staudinger reaction of butyroyl chlor-

ide with the condensation product of trans-a-methyl-

cinnamaldehyde and the amine 37, which was available

from 34 in a three-step sequence (i.e. carbamoylation¹³

of the amine group, transacetalyzation with [bis(tri-

¯uoroacetoxy)iodo]benzene¹²and hydrogenolysis).

Conversion of 31 into the intermediate monobactam 41

was carried out by extended ozonolysis (45 min) of the

monobactam 39. A shorter ozonolysis time (20 min)

gave the monobactam 40 only. Compound 39 along

with 38, was obtained by treatment of monobactam 31

with dichloroiodobenzene.^1cThe sulfoxide 38 was

nevertheless transformed into 39 by Pummerer rearran-

gement.¹⁴The intermediate monobactam 43 was also

synthesised from 36, by ozonolysis and Baeyer±Villiger

reaction.

Unfortunately, we did not succeed in the preparation of

the desired monobactam 44. Since all attempts to pre-

pare the 4b-acetoxy derivatives from 41 or to transform

the 4b-acetoxy monobactam 43 into the acylesters 44

were unproductive.

Table 1. Chiroptical data^afor monobactams and

[a]_d

Áe_(l)

[a]_d

Áe_(l)

C₃,C₄

3a +115

+29.3₍₂₆₀₎

11a

12a

13a

10

40

112

a,a

b,b

4a

5a

6a

3b

4b

5b

6b

7

+47

+13

+30

102

53

109

111

67

Biological properties

+4.5₍₂₃₀₎

+3.1₍₂₃₉₎

17.0₍₂₅₀₎

+10.2₍₂₂₆₎

The antielastase activity of monobactams 29±31, 35±36,

39, 41±43, and the readily available 1,3,4-trisubstituted

azetidin-2-one 45¹⁵was evaluated in vitro.¹⁶It was found

that only monobactams 30b, 35, and 45 showed sig-

ni®cant bioactivity against HLE, whose inhibition per-

centage at 10 ⁵M were 27, 31, and 21%, respectively.

11b +10

12b +40

13b +112

17.7₍₂₂₇₎

18.3₍₂₃₂₎

18.3₍₂₂₁₎

4.3₍₂₂₈₎

11.6₍₂₂₀₎

20.8₍₂₃₀₎

15.4₍₂₂₆₎

14

15

16

17

66

+12

46

10.2₍₂₁₅₎

3.0₍₂₂₀₎

2.6₍₂₃₆₎

23.2₍₂₄₆₎

8

9

10

42

43

170

53

If we compare the structure±activity relationship of the

tested b-lactams⁵and take into account that mono-

bactams 3a and 9 showed ca. 50% inhibition rate (IC₅₀)

^a[a]_d: c&1 in CHCl₃. Áe_(l)in MeOH. See Experimental for other CD

maxima.

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

841

at 10 ⁶M, we can draw the following conclusions: (1)

The n-butyl radical at C-3 seems to be more eective

than the isopropenyl and diethyl substituents (i.e. the

monobactams 29a, 29b, 30a, and 30b showed

IC₅₀ꢂ270 mM). (2) The dithiane protecting group in the

sugar side chain at N-1 seems to be much more eective

than the dipropylthioacetal and the dimethylacetal

groups (i.e. the monobactams 35 and 36 showed

IC₅₀ꢂ310 mM). (3) The eect of the substituents on

C-4 is not clear. The tested substances showed

IC₅₀ꢂ210 mM, but they have dierent functionalization

in the sugar moiety.

which was dissolved in warm EtOH. After ®ltration of

the solution, concentration and crystallization in EtOH,

the d-glucosamine hydrochloride was isolated (27 g,

92%). A solution of this crystalline compound (24 g,

93 mmol) in 2,2-dimethoxypropane and a catalytic

amount of p-toluenesulfonic acid (150 mL) was stirred

for 3 h at 60 ^ꢀC and 300 mmHg in Rotavapor¹. The

reaction mixture was poured over a cold saturated

NaHCO₃solution and extracted with hexane. The

organic layers were dried (Na₂SO₄), ®ltered and evapo-

rated to dryness. After crystallization in hexane the

amine 1 was obtained as a white solid (29 g, 90%). MS

(EI, m/z): 350 (MH)⁺. mp: 79±80 ^ꢀC (hexane). [a]_d+89

1

The above data suggest that the 2-deoxy-2-dithianyl-

3,4;5,6-di-O-isopropylidene-d-2-glucosyl group may be

related to the selective HLE inhibition. In conclusion, it

would be interesting to synthesise a monobactam with

the dithiane protecting group in the sugar chain at N-1,

a butyl group at C-3 and a halogen, ether, sulphur, or

sulphone as leaving group at C-4 in order to increase the

HLE inhibition, according to the mechanism proposed

by Doherty et al. for the inhibition of the L-680,833

monobactam.¹⁷

(c 1.3, CHCl₃). IR (KBr): 3393, 3323, 1228. H NMR

(200 MHz) d: 1.33, 1.37, 1.41, 1.43 (4s, 12H, C(CH₃)₂),

1.90±2.10 (m, 2H, H9), 2.70±3.00 (m, 4H, H8), 3.16 (dd,

J_2,1=8.5 Hz, J_2,3=2.0 Hz, 1H, H₂), 3.96 (d,

J_2,1=8.5 Hz, 1H, H₁), 4.00±4.20 (m, 4H, H_4-6), 4.50 (dd,

J_3,2=2.0 Hz, J_3,4=8.5 Hz, 1H, H₃); ¹³C NMR

(50.3 MHz) d: 25.1, 26.5, 26.7, 26.9 (C(CH₃)₂), 25.6 (C₉),

27.8, 28.2 (C₈), 51.5, 53.5 (C₁, C₂), 67,6 (C₆), 77.1, 78.0,

79.1 (C₃, C₄, C₅), 109.2, 109.3 (C₇).

3,4;5,6-Di-O-isopropylidene-1,1-dimethoxy-^D-glucosamine

(37). To a stirred solution of 34 (10 g, 25.5 mmol) in

methanol (100 mL), benzyl chloroformate (5.6 g, 1.3

equiv) and sodium carbonate (3.6 g) in water (5 mL)

were added. The reaction mixture was stirred at room

temperature for a period of 4 h and then poured over 2

N hydrochloric acid, extracted with chloroform, washed

with water, and then with a saturated sodium chloride

solution. The organic layers were dried (Na₂SO₄), ®l-

tered, and evaporated to dryness. The residue was pur-

i®ed on a silica gel column (hexane:ethyl acetate, 9:1) to

yield the carbobenzyloxy derivative of 34 (10.7 g, 80%).

To a solution of this compound (2.0 g, 3.8 mmol) in dry

methanol (10 mL), [bis(tri¯uoroacetoxy)iodo]benzene

(2.5 g, 1.5 equiv) was added. The mixture was stirred at

room temperature for 15 min. Once the methanol was

evaporated, the residue was dissolved in ethyl acetate

and the solution was washed with saturated sodium

bicarbonate solution. The organic layers were dried

(Na₂SO₄), ®ltered and evaporated to dryness. The resi-

due was puri®ed on a silica gel column (hexane:ethyl

acetate, 8:2) to yield the carbobenzyloxy derivative of 37

(1.25 g, 75%). Next, a solution of this derivative (1.1 g,

2.4 mmol) and cyclohexene (2.4 mL, 24 mmol) was added

to a stirred suspension of palladium on activated carbon

(454 mg, 5%) in anhydrous ethanol (60 mL). After 1.5 h

re¯ux under hydrogen atmosphere, the solution was ®l-

tered through a Celite pad and the ®ltrate was evapo-

rated to dryness. The residue gave the amine 34 (664 mg,

91%). MS (EI, m/z): 306 (MH)⁺. [a]_d+32 (c 1, CHCl₃).

Experimental

General methods

Flash chromatographies were run on silica gel (Merck

60 230±400 mesh) and thin-layer chromatographies

(TLC) on commercial silica gel plates (Merck F-254).

Microanalyses were performed by the Analytical

Department, C.N.R.S., Gif-sur-Yvette. Mass spectra

(MS), were recorded on AEI MS 50 (EI) and Kratos

MS 80 (FAB) spectrometers. Melting points were mea-

sured with a Reichert hot stage apparatus and are

uncorrected. Optical rotations were recorded in CHCl₃

solution in a 1 dm cell on a Perkin±Elmer 243 polari-

meter. IR spectra were recorded as neat ®lms or in KBr

pellets on a Bomem MB-100 or on a Nicolet 205 FT-IR

instruments. H and ¹³C NMR spectra were obtained

1

on Bruker instruments WP200SY, AC250 or AM 400

(200, 250, and 400 MHz, respectively) as solutions in

CDCl₃with tetramethylsilane as internal standard (d,

ppm). Curves of circular dichroism were obtained on

Jobin Yvon Dichrograph Mark-III instrument as solu-

tions in MeOH (HPLC), Fissons. Solvents and reagents

were puri®ed according to standard techniques.

Preparation of amines

3,4;5,6-Di-O-isopropylidene-1-(1⁰,3⁰-propanedithio)-D-glucos-

amine (1). A solution of d-glucosamine hydrochloride

(25 g, 116 mmol) in hydrochloric acid (100 mL) was

cooled at 0 ^ꢀC and saturated with a HCl(g) ¯ow for 2 h.

1,3-Propanedithiol (15 g, 1.2 equiv) and CH₂Cl₂(25 mL)

were added to this solution and the reaction mixture

was stirred for 12 h at 60 ^ꢀC. Then, the excess of dithiol

was eliminated by extraction with CH₂Cl₂and the aqu-

eous solution was neutralized to pH 7 by addition of

PbCO₃. Filtration through a Buchner funnel and eva-

poration of water under reduced pressure gave a residue

1

IR: 3389, 1228. H NMR (200 MHz) d: 1.30, 1.35, 1.38,

1.39 (4s, 12H, C(CH₃)₂), 1.50 (br s, 2H, NH₂), 2.95 (dd,

J_2,1=7.8 Hz, J_2,3=2.0 Hz, 1H, H₂), 3.39, 3.41 (2s, 6H,

OCH₃), 3.91±4.14 (m, 5H, H_3-6), 4.21 (d, J_1,2=7.8 Hz,

1H, H₁); ¹³C NMR (62.5 MHz) d: 25.5, 26.7, 27.1, 27.2

(4C, C(CH₃)₂), 52.5 (C₂), 53.9, 54.6 (CH₃O), 67.9 (C₆),

77.5, 77.6, 79.1 (C₃, C₄, C₅), 106.5 (C₁), 109.3 (2C, C₇).

General procedure for preparation of imines. A solution

of amine 1, 34, or 37 (1 mmol) and trans-cinnamaldehyde

842

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

0

(A), trans-1-methylcinnamaldehyde (B), benzaldehyde

(C), or p-methoxybenzaldehyde (D) (1 mmol) in toluene,

under the conditions showed in Table 2, yielded after

solvent evaporation, the respective imines 2(amine/

aldehyde) which were used without further puri®cation

in the Staudinger reaction.

78.5 (C₃, C₄, C₅), 85.3 (C₃), 109.1, 109.4 (C₇), 123.1,

126.6, 128.1 (5C, CH_Ph, C₅), 135.8 (C₆), 136.2 (C_Ph), 167.8

(C₂).

3b (63%): Anal. calcd for C₂₇H₃₇O₆NS₂: C, 60.53; H,

6.96; N, 2.61; S, 11.97. Found: C, 60.41; H, 6.80; N,

2.63; S, 12.06. MS (IE, m/z): 536 (MH)⁺. mp 206±

207 ^ꢀC (hexane:CH₂Cl₂). [a]_d102 (c 1, CHCl₃). IR

(KBr): 1768 (NCO). ¹H NMR (200 MHz) d: 1.20,

1.28, 1.36, 1.53 (4s, 12H, C(CH₃)₂), 1.90±2.21 (m, 2H,

General procedure for preparation of monobactams

To a solution of the imine 2 (1 mmol) and dry TEA

(2.5 mmol) in dry toluene (10 mL), a solution of the

carboxylic acid chloride (1.5 mmol) in dry toluene

(8 mL) was added dropwise under argon atmosphere.

The reaction mixture was stirred for the time and tem-

perature speci®ed in each case, until the starting mate-

rial disappeared in TLC. The solution was poured into

cold ammonium chloride solution, neutralised to pH 7

by addition of acetic acid and extracted with dichloro-

methane. The organic layers were dried (Na₂SO₄), ®l-

tered and evaporated to dryness. The residues were

puri®ed by silica gel column chromatography.

0

H₉), 2.70±2.90 (m, 4H, H₈), 3.46 (s, 3H, OCH₃), 3.80±

0

4.40 (m, 7H, H_{1 -6}), 4.57 (dd, J_4,3=5.0 Hz, J_4,5=9.0 Hz,

1H, H₄), 4.76 (d, J_3,4=5.0 Hz, 1H, H₃), 6.45 (dd,

J_5,4=9.0 Hz, J_5,6=16.0 Hz, 1H, H₅), 6.71 (d, J_6,5=

16.0 Hz, 1H, H₆), 7.30±7.60 (m, 5H, H_Ph); ¹³C NMR

(50.3 MHz) d: 25.2 (C(CH₃)₂), 25.6 (C₉), 26.4, 27.1, 27.2

0

(C(CH₃)₂), 27.3 (C₈), 44.4 (C₂), 54.2 (C₄), 58.7 (OCH₃),

0

62.4 (C₁), 67.7 (C₆), 76.9, 77.3, 79.0 (C₃C₄, C₅), 85.4

0

(C₃), 109.0, 110.0 (C₇), 126.0, 126.9, 128.1 (5C, CH_Ph

C₅) 135.0 (C₆), 136.4 (C_Ph), 168.9 (C₂).

,

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3ꢁ-methoxy-4ꢁ-(ꢁ-methyl-

styryl)-2-azetidinone (4a) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-

di-O-isopropylidene-1⁰(1,3-propanodithio))-D-2⁰-glucosyl]-

3ꢀ-methoxy-4ꢀ-(ꢁ-methylstyryl)-2-azetidinone (4b).

They were obtained by Staudinger reaction of imine 2

(1/B) and methoxyacetyl chloride, after 2 h at 25 ^ꢀC, via

the general procedure in 75% yield from 1. The reaction

mixture was puri®ed on a silica gel column (hexane:

ethyl acetate, 7:3).

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3ꢁ-methoxy-4ꢁ-styryl-2-aze

tidinone (3a) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopro-

pylidene-1⁰(1,3-propanodithio))-D-2⁰-glucosyl]-3ꢀ-methoxy-

4ꢀ-styryl-2-azetidinone (3b). They were obtained by

Staudinger reaction of imine 2(1/A) and methoxyacetyl

chloride after 30 min at 25 ^ꢀC, via the above general

procedure, in 94% yield from 1. The reaction mixture

was puri®ed on a silica gel column (hexane:ethyl ace-

tate, 8:2).

4a (24%): Anal. calcd for C₂₈H₃₉NO₆S₂: C, 61.18; H,

7.15; N, 2.55; S, 11.66. Found: C, 60.93; H, 7.03; N,

2.47; S, 11.60. MS (IE, m/z): 549 (M)⁺. mp 97±99 ^ꢀC

(hexane:EtOAc). [a]_d+47 (c 1, CHCl₃). IR (KBr): 1758

3a (31%): Anal. calcd for C₂₇H₃₇NO₆S₂: C, 60.53; H,

6.96; N, 2.61; S, 11.97. Found: C, 60.51; H, 7.25; N,

2.53; S, 12.04. MS (IE, m/z): 536 (MH)⁺. mp 156±

157 ^ꢀC (hexane:EtOAc). [a]_d+115 (c 1, CHCl₃). IR

(KBr): 1770 (NCO). ¹H NMR (200 MHz) d: 1.35,

1.36, 1.49, 1.58 (4s, 12H, C(CH₃)₂), 1.93±2.13 (m, 2H,

1

(NCO). H NMR (250 MHz) d: 1.50, 1.55, 1.60, 1.65

0

(4s, 12H, C(CH₃)₂), 1.95±2.30 (m, 2H, H₉), 2.25 (s, 3H,

0

CH₃), 2.88±3.10 (m, 2H, H_{8 ax}), 2.9±3.20 (m, 2H,

0

H₉), 2.51±2.78 (m, 2H, H_{8 ax}), 2.93±3.26 (m, 2H, H_{8 eq}),

0

H_{8 eq.}), 3.60 (s, 3H, OCH₃), 4.10±4.45.(m, 6H, H_{1 ±2},

0

3.46 (s, 3H, OCH₃), 3.62 (t, J_{4 ,3}=J_{4 ,5}=8.0 Hz, 1H, H₄)

0

0 0

H_{4 ±6}), 4.85 (d, J_4,3=4.6 Hz, 1H, H₄), 4.90 (d, J_3,4=

0

3.91±4.22 (m, 4H, H₁, H₅,H₆), 4.60 (dd, J_{2 ,3}=1.5 Hz,

0

5.0 Hz, 1H, H₃), 5.00 (dd, J_{3 ,2}=3.5 Hz, J_{3 ,4}=8.0 Hz,

0

J_{2 ,1}=11.0 Hz, 1H, H₂), 4.69 (dd, J_4,3=5.0 Hz, J_4,5

10.0 Hz, 1H, H₄), 4.78 (d, J_3,4=5.0 Hz, 1H, H₃), 4.91

(dd, J_{3 ,2}=1.5 Hz, J_{3 ,4}=8.0 Hz, 1H, H₃), 6.61 (dd,

J_5,4=10.0 Hz, J_5,6=15.5 Hz, 1H, H₅), 6.72 (d, J_6,5

15.5 Hz, 1H, H₆), 7.32±7.60 (m, 5H, H_Ph); ¹³C NMR

=

1H, H₃), 6.85 (s, 1H, H₆), 7.40±7.50 (m, 5H, H_Ph); ¹³C

NMR (62.5 MHz) d: 16.3 (CH₃), 25.4, 25.6 (C(CH₃)₂),

0 0

26.5 (C₉), 27.4 (2C, C₈), 28.5, 28.7 (C(CH₃)₂), 47.0

0 0 0

(C₂), 54.5 (C₄), 57.8 (OCH₃), 56.3 (C_l), 67.9 (C₃), 68.7

0

(C₆), 76.6, 76.7, 79.3 (C₃, C₄, C₅), 85.3 (C₃), 110.0 (2C,

0

=

0

C₇), 126.9, 128.3, 129.2 (5C, CH_Ph), 131.7 (C₆), 133.5

(C_Ph), 137.5 (C₅), 168.8 (C₂).

(50.3 MHz), d: 25.0 (C(CH₃)₂), 25.3(C₉), 25.6 (C₈), 25.9

0

(C(CH₃)₂), 26.1 (C₈), 26.3, 27.5 (C(CH₃)₂), 43.7 (C₂),

0

51.8 (C₄), 58.6 (OCH₃), 63.0 (C₁), 67.5 (C₆), 77.1, 77.7,

0

4b (51%): Anal. calcd for C₂₈H₃₉NO₆S₂: C, 61.17; H,

7.15; N, 2.55; S, 11.66. Found: C, 61.32; H, 6.99; N,

2.66; S, 11.25. MS (IE, m/z): 549 (M)⁺. mp 147±149 ^ꢀC

(hexane:EtOAc). [a]_d53 (c 1, CHCl₃). IR (KBr): 1757

Table 2. Formation of imines 2

Amine

Aldehyde

t (^ꢀC)

Time (h)

Imine

1

(NCO). H NMR (400 MHz) d: 1.16, 1.26, 1.36, 1.53

1

34

37

A

B

C

D

B

70^a

2

5

3

7

12

5

2 (1/A)

2 (1/B)

2 (1/C)

2 (1/D)

2 (34/B)

2 (37/B)

(4s, 12H, C(CH₃)₂), 2.06 (s, 3H, CH₃(C=)), 2.06±2.10

0

(m, 2H, H₉), 2.58±2.78 (m, 2H, H_{8 ax}), 2.98±3.15 (m,

0

70^a

0

2H, H_{8 eq}), 3.47 (s, 3H, OCH₃), 3.82 (t, J_{4 ,3}=

110^b

70^a

0

J_{4 ,5}=7.2 Hz, 1H, H₄), 3.98±4.22 (m, 4H, H₁, H₅, H₆),

0

4.48 (d, J_4,3=5.7 Hz, 1H, H₄), 4.65 (dd, J_{2 ,1}=10.7 Hz,

0

J_{2 ,3}=2.8 Hz, 1H, H₂), 4.80 (dd, J_{3 ,2}=2.7 Hz, J_{3 ,4}=

^aUnder reduced pressure (100 mmHg). Toluene was added several

times.

^bUnder re¯ux with azeotropical removal of water.

0

7.3 Hz, 1H, H₃), 4.83 (d, J_3,4=5.0 Hz, 1H, H₃), 6.72 (s,

1H, H₆), 7.19±7.38 (m, 5H, H_Ph); ¹³C NMR (62.5 MHz)

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

843

0

d: 16.0 (CH₃(C=)), 25.3 (2C, C(CH₃)₂), 25.5 (C₉), 26.1,

70% yield, from 1. The reaction mixture was puri®ed on

a silica gel column (hexane:ethyl acetate, 7:3).

0

26.5 (C(CH₃)₂), 26.9 (C₈), 44.7 (C₂), 53.9 (C₄), 58.8

0

(OCH₃), 66.8 (C_l), 67.9 (C₃), 67.6 (C₆), 76.7, 77.2, 78.8

0

(C₃, C₄, C₅), 85.4 (C₃), 109.0, 110.0 (C₇), 126.8, 128.2,

129.2 (5C, CH_Ph), 130.4 (C₆), 134.7 (C_Ph), 137.4 (C₅),

171.2 (C₂).

6a (6%): Anal. Calcd for C₂₇H₃₇NO₇S₂: C, 57,88; H,

6,86; N, 2,60; S, 11,87. Found: C, 57.42; H, 6.92; N,

2.39; S, 11.94. mp 164±166 ^ꢀC (hexane:EtOAc). [a]_d

1

+30 (c 1, CHCl₃). IR (KBr): 1767 (NCO). H NMR

1[(1⁰,2⁰-Deoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3ꢁ-methoxy-4ꢁ-phenyl-2-aze-

tidinone (5a) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopro-

pylidene-1⁰(1,3-propanodithio))-D-2⁰-glucosyl]-3ꢀ-methoxy-

4ꢀ-phenyl-2-azetidinone (5b). They were obtained by

Staudinger reaction of imine 2 (1/C) and methoxyacetyl

chloride after 5 h at 50 ^ꢀC, using dichloromethane as

solvent, in 85% yield from 1. The reaction mixture was

puri®ed on a silica gel column (hexane:ethyl acetate, 7:3).

(200 MHz) d: 1.33, 1.36, 1.43, 1.57 (4s, 12H, C(CH₃)₂),

0

1.91±2.03 (m, 2H, H₉), 2.46±2.68 (m, 2H, H_{8 ax}), 2.82±

0

3.09 (m, 2H, H_{8 eq}), 3.15 (s, 3H, OCH₃), 3.58 (t,

0

J_{4 ,3}=J_{4 ,5}=7.8 Hz, 1H, H₄), 3.64 (d, J_{1 ,2}=10.0 Hz,

0

1H, H₁), 3.82 (s, 3H, OCH₃), 3.85 (dd, J_{5 ,4}=7.8 Hz,

0

J_{5 ,6 a}=5.4 Hz, 1H, H₅), 4.00±4.20 (m, 2H, H₆), 4.35

0

(dd, J_{2 ,3}=2.4 Hz, J_{2 ,1}=9.8 Hz, 1H, H₂), 4.75 (d,

0

J_4,3=4,7 Hz, lH, H₄), 4.82 (dd, J_{3 ,2}=2.4 Hz, J_{3 ,4}=

0

7.8 Hz, 1H, H₃), 5.05 (d, J_3,4=5.0 Hz, 1H, H₃), 6.88 (d,

J=8.3 Hz, 2H, H_Ph), 7.51 (d, J=8.7 Hz, 2H, H_Ph); ¹³C

NMR (50.3 MHz) d: 25.2, 26.1, 26.5, 27.4 (C(CH₃)₂),

5a (4%): Anal. calcd for C₂₅H₃₅NO₆S₂: C, 58.94; H,

6.88; N, 2.75; S, 12.57. Found: C, 58.65; H, 7.28; N,

2.39; S, 12.16. mp 112±114 ^ꢀC (Hexane:EtOAc). [a]_d

0

25.5 (C₉), 27.1, 27.4 (C₈), 45.2 (C₂), 54.2 (C₄), 55.2

0

(OCH₃), 58.2 (OCH₃), 64.13 (C_l), 67.8 (C₆), 77.3, 78.1,

0

1

0

+13 (c 1, CHCl₃). IR (KBr): 1755 (NCO). H NMR

78.7 (C₃, C₄, C₅), 85.1 (C₃), 109.8, 110.0 (C₇), 113.3,

126.0 (CH_Ph), 131.2 (C_Ph), 160.0 (C_Ph), 168.2 (C₂). Áe

(l): 14.42 (204), 3.55 (225), +3.13 (239), +2.51 (276),

+2.30 (282).

(200 MHz) d: 1.33, 1.35, 1.42, 1.58 (4s, 12H, C(CH₃)₂),

0

1.90±2.00 (m, 2H, H₉), 2.48±2.70 (m, 2H, H_{8 ax}), 2.81±

0

3.06 (m, 2H, H_{8 eq}), 3.12 (s, 3H, OCH₃), 3.58 (t,

0

J_{4 ,3}=J_{4 ,5}=7.8 Hz, 1H, H₄), 3.71 (d, J_{1 ,2}=9.6 Hz,

0

1H, H₁), 3.83 (dd, J_{5 ,4}=7.8 Hz, J_{5 ,6 a}=4.6 Hz), 4.00±

0

6b (64%): Anal. calcd for C₂₇H₃₇NO₇S₂: C, 57.88; H,

6.86; N, 2.60; S, 11.87. Found: C, 57.62; H, 6.87; N,

2.55; S, 11.75. MS (EI, m/z) 540 (MH)⁺. mp 133±135 ^ꢀC

(hexane:EtOAc). [a]_d111 (c 1, CHCl₃). IR (KBr):

0

4.18 (m, 2H, H₆), 4.30 (dd, J_{2 ,3}=2.6 Hz, J_{2 ,1}

0

=

0

9.6 Hz), 4.78 (d, J_4,3=4.6 Hz, 1H, H₄), 4.81 (dd, J_{3 ,2}

0

2.6 Hz, J_{3 ,4}=7.8 Hz, 1H, H₃), 5.09 (d, J_3,4= 4.7 Hz,

1H, H₃), 7.34±7.37 (m, 3H, H_Ph), 7.57±7.62 (m, 2H,

H_Ph); ¹³C NMR (62.5 MHz, C₆D₆) d 25.3 (C(CH₃)₂),

1

1755 (NCO). H NMR (200 MHz) d: 0.61, 1.15, 1.33,

0

1.50 (4s, 12H, C(CH₃)₂), 2.00±2.12 (m, 2H, H₉), 2.55±

0

0 0

2.74 (m, 2H, H_{8 ax}), 2.95±3.11 (m, 2H, H_{8 eq}), 3.03 (s,

25.6 (C₉), 26.2, 26.9; 30.0 (C(CH₃)₂), 27.5, 27.9 (C₈),

0

46.4 (C₂), 54.5 (C₄), 57.8 (OCH₃), 64.9 (C_l), 68.1 (C₆),

0

0 0 0 0 0

3H, OCH₃), 3.72 (t, J_{4 ,3}=J_{4 ,5}=7.4 Hz, 1H, H₄), 3.77

0

78.1, 79.0, 79.1 (C₃, C₄, C₅), 85.9 (C₃), 109.7, 110.3

0 0 0 0 0

(dd, J_{2 ,3}=2.5 Hz, J_{2 ,1}=10.1 Hz, 1H, H₂), 3.82 (s, 3H,

0

0 0 0 0

OCH₃), 3.96±4.16 (m, 3H, H_{5 ±6}), 4.21 (d, J_{1 ,2}=9.8 Hz,

(C₇), 127.7, 130.3 (CH_Ph), 135.5 (C_Ph), 168.2 (C₂). Áe

0

1H, H₁), 4.57 (dd, J_{3 ,2}=2.4 Hz, J_{3 ,4}= 7.8 Hz, 1H,

0

(l): 4,17(214), +4,49(232).

0

H₃), 4.76 (d, J_4,3=4.9 Hz, lH, H₄), 4.82 (d, J_3,4=5.0Hz,

5b (81%): Anal. calcd for C₂₅H₃₅NO₆S₂: C, 58.94; H,

6.88; N, 2.75; S, 12.57. Found: C, 58.88; H, 6.84; N,

2.72; S, 12.58. MS (IE, m/z): 510 (MH)⁺. mp 175±

176 ^ꢀC (Hexane:CH₂Cl₂). [a]_d109 (c 1, CHCl₃). IR

(KBr): 1757 (NCO). ¹H NMR (200 MHz) d: 0.46,

1.14, 1.34, 1.50 (4s, 12H, C(CH₃)₂), 2.00±2.17 (m, 2H,

1H, H₃), 6.89 (d, J=10.0 Hz, 2H, H_Ph), 7.38 (d,

J=10.0 Hz, 2H, H_Ph); ¹³C NMR (50.3 MHz) d: 25.5,

0

25.7 (C(CH₃)₂), 25.8 (C₉), 26.4, 26.7 (C(CH₃)₂), 26.8,

0

27.1 (C₈), 44.6 (C₂), 54.2 (C₄), 55.6 (OCH₃), 58.1

0

(OCH₃), 62.4 (C_l), 67.7 (C₆), 76.7, 76.9, 79.1 (C₃, C₄,

0

C₅), 85.4 (C₃), 108.9, 110.2 (C₇), 113.8, 127.5, 130.9

(CH_Ph), 160.2 (C_Ph), 170.8 (C₂). Áe (l): +19.11 (206),

18.32 (232), 2.92 (275), 2.12 (282).

0

H₉), 2.53±2.73 (m, 2H, H_{8 ax}), 2.97 (s, 3H, OCH₃),

0

2.93±3.17 (m, 2H, H_{8 eq}), 3.72 (dd, J_{4 ,3}=6.5 Hz, J_{4 ,5}=

0

8.6 Hz, 1H, H₄), 3.93±4.13 (m, 4H, H₂, H₅, H₆), 4.18

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panodithio))-^D-2⁰-glucosyl]-3ꢀ-butyl-4ꢀ-phenyl-2-azetid-

inone (7) and n-(2-dideoxy-2⁰-dithianyl-3⁰,4⁰;5⁰,6⁰-di-O-

isopropylidene-^D-glucosyl)-hexanamide (7⁰). They were

obtained by Staudinger reaction of imine 2 (1/C) and

caproyl chloride after 40 h at 110 ^ꢀC in 75% yield from

1. The reaction mixture was puri®ed on a silica gel col-

umn (hexane:ethyl acetate, 7:3).

0

(d, J_{1 ,2}=10.1 Hz, 1H, H₁), 4.60 (d, J_4,3=3.4 Hz, 1H,

0

H₄), 4.63 (dd, J_{3 ,2}=2.3 Hz, J_{3 ,4}=6.4 Hz, 1H, H₃),

0

4.68 (d, J_4,3=3.4 Hz, 1H, H₃), 7.26±7.46 (m, 5H, H_Ph);

13

0

C NMR (50.3 MHz) d: 25.4 (C(CH₃)₂), 25.6 (C₉),

0

26.6, 26.7 (C(CH₃)₂), 26.8, 26.9 (C₈), 44.5 (C₂), 54.0

0

(C₄), 58.0 (OCH₃), 62.7 (C_l), 67.7 (C₆), 76.7, 77.4, 78.9

0

(C₃, C₄, C₅), 85.4 (C₃), 108.8, 110.1 (C₇), 128.2, 128.5,

129.7, (CH_Ph), 135.6 (C_Ph), 170.8 (C₂). Áe (l): +10.11

(208), 17.66 (227).

7 (55%): MS (EI, m/z): 536 (MH)⁺; 520 [(MH)⁺CH₃].

1[(1⁰,2⁰-Deoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3ꢁ-methoxy-4ꢁ-(4-methoxy-

phenyl)-2-azetidinone (6a) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰

-di-O-isopropylidene-1⁰(1,3-propanodithio))-D-2⁰-glucosyl]

- 3ꢀ-methoxy-4ꢀ-(4-methoxyphenyl)-2-azetidinone (6b).

They were obtained by Staudinger reaction of imine 2

(1/D) and methoxyacetyl chloride, after 3 h at 25 ^ꢀC in

[a]_d67 (c 1, CHCl₃). IR: 1745 (NCO). H NMR

1

(200 MHz) d: 0.63 (t, J_8,7=6.8 Hz, 3H, H₈), 0.76, 1.21,

1.30, 1.36 (4s, 12H, C(CH₃)₂), 0.80±1.60 (m, 6H, H_5±7),

0

1.94±2.10 (m, 2H, H₉), 2.60±2.76 (m, 2H, H_{8 ax}), 2.90±

0

3.08 (m, 2H, H_{8 eq}), 3.52 (dt, J_3,4=6.0 Hz, J_3,5=6.7 Hz,

0

1H, H₃), 3.78 (t, J_{4 ,3}=J_{4 ,5}=7.6 Hz, 1H, H₄), 3.90±

0

4.42 (m, 5H, H₁, H₂, H_{4 ±6}), 4.55 (dd, J_{3 ,2}=2.8 Hz,

0

844

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

0

_{8 ax}), 2.72±3.10 (m, 2H, H_{8 eq}), 3.50 (dt, J_3,7=6.7 Hz,

0

J_{3 ,4}=7.8 Hz, 1H, H₃), 4.88 (d, J_4,3=6.0 Hz, lH, H₄),

7.26±7.39 (m, 5H, H_Ph); ¹³C NMR (50.3 MHz) d: 13.5

(C₈), 22.1 (C₇), 24.5 (C₆), 25.1, 25.6, 26.2 (C(CH₃)₂),

H

J_3,4=5.3 Hz, 1H, H₃), 3.87 (t, J_{4 ,3}=J_{4 ,5}=7.0 Hz, 1H,

0

H₄), 3.97±4.22 (m, 3H, H_{5 ±6}), 4.35 (dd, J_{2 ,1}=8.5 Hz,

0

25.4 (C₅), 27.0 (C₉), 27.4, 29.1 (C₈), 45.3 (C₂), 54.8

0 0 0 0 0 0

J_{2 ,3}=4.6 Hz, lH, H₂), 4.55 (d, J_{1 ,2}=8.5 Hz, 1H, H₁),

0

(C₃), 55.3 (C₄), 59.7 (C_l), 67.3 (C₆), 77.0, 78.8 (C₃, C₄,

0

0 0

4.72 (d, J_4,3=5.1 Hz, lH, H₄), 4.75 (dd, J_{3 ,2}=4.6 Hz,

0

C₅), 108.8, 109.7 (C₇), 127.8, 128.0, 128.4 (CH_Ph), 136.9

(C_Ph), 174.2 (C₂). Áe (l): +9.39 (203), 6.24 (208),

18.13 (221), +0.74 (252).

J_{3 ,4}=7.2 Hz, lH, H₃), 6.83 (s, 1H, H₆), 7.32±7.39 (m,

5H, H_Ph); ¹³C NMR (50.3 MHz) d: 14.0 (C₁₀), 17.7

(CH₃), 22.8 (C₉), 25.0 (C₈), 25.5, 26.8, 27.0 (C(CH₃)₂),

0

27.9 (C₇), 28.3 (C₉), 28.7, 30.4 (C₈), 46.6 (C₂), 54.9

0 0 0

(C₃), 56.3 (C₄), 63.1 (C_l), 67.6 (C₆), 77.3, 77.8, 79.6 (C₃,

0

1

7 (20%): IR: 1730 (HNCO). H NMR (200 MHz) d:

0.84 (t, J=6.8 Hz, 3H, CH₃(CH₂)₂CH₂CH₂CO), 1.06±

1.30 (m, 4H, CH₃(CH₂)₂CH₂CH₂CO), 1.27, 1.31, 1.32,

1.43 (4s, 12H, C(CH₃)₂), 1.60±1.75 (m, 2H, CH₃(CH₂)₂

0

C₄, C₅), 109.0, 109.9 (C₇), 126.7, 128.3, 129.2 (CH_Ph),

129.3, 133.9 (C₅, C₆), 137.7 (C_Ph), 173.7 (C₂). Áe (l):

7.48 (208), 1.60 (220), +1.81 (255).

0

CH₂CH₂CO), 1.87±2.09 (m, 2H, H₉), 2.20 (t, J=7.0 Hz,

0

3H, CH₃(CH₂)₂CH₂CH₂CO), 2.45±2.68 (m, 2H, H_{8 ax}),

10 (7%): Anal. calcd for C₃₁H₄₅NO₅S₂: C, 64.70; H,

7.83; N, 2.43; S, 11.13. Found: C, 64.25; H, 7.86; N,

2.38; S, 11.31. mp 118±120 ^ꢀC (Hexane). [a]_d170 (c 1,

CHCl₃). IR: 1755 (NCO). ¹H NMR (250 MHz) d: 0.90

(t, J_10,9=6.8 Hz, 3H, H₁₀), 1.30±1.73 (m, 6H, H_7±9),

1.32, 1.34, 1.42, 1.53 (4s, 12H, C(CH₃)₂), 1.72±2.00 (m,

0

2.86±3.10 (m, 2H, H_{8 eq}), 3.52 (t, J_{4 ,3}=J_{4 ,5}=7.9 Hz,

0

1H, H₄), 3.72 (d, J_{1 ,2}=8.9 Hz, 1H, H₁), 3.85±4.15 (m,

0

4H, H₂, H_{4 ±6}), 4.65 (dd, J_{3 ,4}=7.8 Hz, J_{3 ,NH}=10.1 Hz,

0

1H, H₃), 5.90 (d, J_{3 ,NH}=10.1 Hz, 1H, NH).

0

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3ꢀ-butyl-4ꢀ-styryl-2-azetidi-

none (8). It was obtained by Staudinger reaction of

imine 2 (1/A) and caproyl chloride after 30 h at 110 ^ꢀC

in 50% yield from 1. The reaction product was puri®ed

on a silica gel column (hexane:ethyl acetate, 8:2) and

also the amide 7⁰was isolated in 15% yield. MS (EI,

m/z): 562 (MH)⁺; 548 [(MH)⁺CH₃]. [a]_d42 (c 1,

CHCl₃). IR: 1768 (NCO). ¹H NMR (200 MHz) d: 0.85

(t, J_10,9=6.8 Hz, 3H, H₁₀), 1.23, 1.30, 1.34, 1.48 (4s,

12H, C(CH₃)₂), 1.25±1.78 (m, 6H, H_7±9), 2.01±2.03 (m,

2H, H₉), 2.06 (s, 3H, CH₃), 2.46±2.67 (m, 2H, H_{8 ax}),

0

2.88±3.30 (m, 2H, H_{8 eq}), 3.50 (dt, J_3,7=8.0 Hz, J_3,4

0

=

5.0 Hz, 1H, H₃), 3.72 (dd, J_{4 ,3}=8.0 Hz, J_{4 ,5}=7.0 Hz,

0

1H, H₄), 3.90±4.20 (m, 3H, H_{5 ±6}), 4.00 (d, J_{1 ,2}

0

10.1 Hz, 1H, H₁), 4.36 (dd, J_{2 ,1}=10.1 Hz, J_{2 ,3}

0

3.0 Hz, lH, H₂), 4.80 (d, J_4,3=5.0 Hz, lH, H₄), 4.81 (dd,

J_{3 ,2}=3.0 Hz, J_{3 ,4}=8.0 Hz, lH, H₃), 6.60 (s, 1H, H₆),

7.10 (d, J=7.0 Hz, 2H, H_Ph), 7.24±7.40 (m, 3H, H_Ph);

¹³C NMR (62.9 MHz) d: 13.9 (C₁₀), 21.3 (CH₃), 23.0

(C₉), 25.1 (C₈), 25.2, 26.3, 26.6 (C(CH₃)₂), 25.6 (C₇),

0

=

0

27.0 (C₉), 27.3, 30.1 (C₈), 45.3 (C₂), 54.9 (C₃), 55.1

0

2H, H₉), 2.66±2.71 (m, 2H, H_{8 ax}), 2.95±3.02 (m, 2H,

0

0 0 0 0 0

(C₄), 55.6 (C_l), 67.7 (C₆), 76.9, 77.4, 78.7 (C₃, C₄, C₅),

0

H_{8 eq}), 3.36 (dt, J_3,7=6.7 Hz, J_3,4=5.5 Hz, 1H, H₃), 3.79

0

109.8, 110.2 (C₇), 126.8, 128.3, 128.6 (5CH_Ph), 131.7

0

(dd, J_{4 ,3}=7.2 Hz, J_{4 ,5}=6.1 Hz, 1H, H₄), 4.01±4.20 (m,

0

(C₆), 136.0 (C₅), 137.2 (C_Ph), 175.4 (C₂). Áe (l): 10.47

(207), 20.77 (230).

0

3H, H_{5 ±6}), 4.28 (dd, J_{2 ,1}=10.1 Hz, J_{2 ,3}=2.0 Hz, lH,

0

H₂), 4.38 (d, J_{1 ,2}=10.1 Hz, 1H, H₁), 4.46 (dd, J_4,3

0

=

5.6 Hz, J_4,5=9.5 Hz, lH, H₄), 4.70 (dd, J_{3 ,2}=2.0 Hz,

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3ꢁ-isopropenyl-4ꢁ-styryl-2-

azetidinone (29a) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-

isopropylidene-1⁰(1,3-propanedithio))-D-2⁰-glucosyl]-3ꢀ-

isopropenyl-4ꢀ-styryl-2-azetidinone (29b). They were

obtained by Staudinger reaction of imine 2 (1/A) and

b,b-dimethylacryloyl chloride after 10 h at 50 ^ꢀC and

dichloromethane as solvent, in 20% yield from 1.

0

J_{3 ,4}=7.8 Hz, lH, H₃), 6.34 (dd, J_5,6=16.0 Hz, J_5,4

0

=

9.7 Hz, lH, H₅), 6.60 (d, J_6,5=16 Hz, 1H, H₆), 7.24±7.39

(m, 5H, H_Ph); ¹³C NMR (50.3 MHz) d: 13.7 (C₁₀), 22.4

(C₉), 25.2, 25.5 (C₈, C₇), 25.2, 26.4, 27.0 (C(CH₃)₂), 27.1

0

(C₉), 27.2, 29.6 (C₈), 44.7 (C₂), 54.2 (C₃), 54.4 (C₄),

0

59.0 (C_l), 67.5 (C₆), 76.9, 77.5, 78.9 (C₃, C₄, C₅),

0

109.0, 109.5 (C₇), 126.5, 127.1, 127.8 (CH_Ph), 128.5,

134.2 (C₅, C₆), 137.0 (C_Ph), 172.5 (C₂). Áe (l): 4.33

(202), +3.07 (205), 4.29 (228), +2 (262).

1

29a (6%): IR: 1765 (NCO). H NMR (200 MHz) d:

1.35, 1.37, 1.51, 1.59 (4s, 12H, C(CH₃)₂), 1.65 (s, 3H,

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3ꢀ-butyl-4ꢀ-(trans-ꢁ-methyl-

styryl)-2-azetidinone (9) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-

di-O-isopropylidene-1⁰(1,3-propanedithio))-D-2⁰-glucosyl]-

3ꢀ-butyl-4ꢀ-(cis-ꢁ-methylstyryl)-2-azetidinone (10). They

were obtained by Staudinger reaction of imine 2 (1/B)

and caproyl chloride after 26 h at 110 ^ꢀC in 65% yield

from 1. The reaction mixture was puri®ed on a silica gel

column (hexane:ethyl acetate, 8:2). The amide 7⁰was

also obtained in 7% yield.

0

H₈), 1.95±2.15 (m, 2H, H₉), 2.51±2.72 (m, 2H, H_{8 ax}),

0

2.90±3.30 (m, 2H, H_{8 eq}), 3.70 (t, J_{4 ,3}=J_{4 ,5}=7.8 Hz,

0

1H, H₄), 3.96 (d, J_{1 ,2}=9.8 Hz, 1H, H₁), 4.00±4.22 (m,

0

4H, H₃, H₅, H₆), 4.61 (dd, J_{2 ,1}=9.8 Hz, J_{2 ,3}=2.3 Hz,

0

1H, H₂), 4.72 (dd, 1H, H₄, J_4,5=10.0 Hz, J_4,3=5.5 Hz),

4.91 (dd, J_{3 ,2}=2.3 Hz, J_{3 ,4}=7.9 Hz, 1H, H₃), 5.08 (s,

1H, H_9a), 5.26 (s, 1H, H_9b), 6.46 (dd, J_5,6=16.0 Hz,

J_5,4=10.0 Hz, 1H, H₅), 6.68 (d, J_6,5=15.9 Hz, 1H, H₆),

7.27±7.36 (m, 5H, H_Ph).

0

29b (14%): Anal. calcd for C₂₉H₃₉NO₅S₂: C, 63.82; H,

7.20; N, 2.57; S, 11.75. Found: C, 63.90; H, 7.31; N,

2.53; S, 11.99. [a]_d109 (c 1, CHCl₃). IR: 1748

9 (59%): MS (EI, m/z): 575 (M)⁺; 561 [(M)⁺CH₃].

1

[a]_d43 (c 1, CHCl₃). IR: 1745 (NCO). H NMR

1

(200 MHz) d: 0.82 (t, J_10,9=6.8 Hz, 3H, H₁₀), 1.23±1.77

(m, 6H, H_7±9), 1.30, 1.37, 1.47 (4s, 12H, C(CH₃)₂), 1.90±

(NCO). H NMR (250 MHz) d: 1.20, 1.28, 1.35, 1.50

(4s, 12H, C(CH₃)₂), 1.65 (s, 3H, H₈), 1.90±2.15 (m, 2H,

0 0 0

H₉), 2.60±2.70 (m, 2H, H_{8 ax}), 2.92±3.01 (m, 2H, H_{8 eq}),

0

2.13 (m, 2H, H₉), 1.97 (s, 3H, CH₃), 2.63±2.72 (m, 2H,

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

845

0

3.82 (t, J_{4 ,3}=J_{4 ,5}=7.5 Hz, 1H, H₄), 4.00±4.38 (m, 6H,

0

31 (60%): Anal. calcd for C₂₉H₄₁NO₅S₂: C, 63.60; H,

7.55; N, 2.56; S, 11.69. Found: C, 63.87; H, 7.44; N,

2.86; S, 11.69. MS (EI, m/z) 547 (M⁺), 530 (M⁺

CH₃). mp 103±105 ^ꢀC (hexane:EtOAc). [a]_d72 (c 1,

0

H₃, H₁, H₂, H₅, H₆), 4.53 (dd, J_4,5=9.5 Hz, J_4,3=5.8Hz,

0

1H, H₄), 4.67 (dd, J_{3 ,2}=2.2 Hz, J_{3 ,4}=7.7 Hz, 1H, H₃),

5.05 (s, 1H, H_9a), 5.15 (s, 1H, H_9b), 6.28 (dd, J_5,6

=

1

15.9 Hz, J_5,4=9.8 Hz, 1H, H₅), 6.61 (d, J_6,5=15.9 Hz,

1H, H₆), 7.26±7.34 (m, 5H, H_Ph); ¹³C NMR (62.5 MHz)

d: 22.2 (C₈), 25.0, 26.2, 26.3 (4C(CH₃)₂), 25.3, 26.9 (3C;

CHCl₃). IR(KBr): 1742 (NCO). H NMR (250 MHz)

d: 0.93 (t, J_10,9=6.8 Hz, 3H, H₈), 1.27, 1.30, 1.32, 1.41

(4s, 12H, C(CH₃)₂), 1.67±1.83 (m, 2H, H₇), 1.85±2.10

0

(m, 2H, H₉), 1.94 (s, 3H, CH₃), 2.61±2.80 (m, 2H,

C₈, C₉), 44.3 (C₂), 53.9 (C₃), 59.1 (C₄), 60.5 (C₁), 67.4

0

0 0

H_{8 ax}), 2.85±3.03 (m, 2H, H_{8 eq}), 3.38 (dt, J_3,7=7.8 Hz,

(C₆), 76.7, 77.2, 78.9 (C₃, C₄, C₅), 109.1, 109.6 (C₇),

115.0 (C₉), 126.5 (C₅), 126.7, 127.7, 128.3 (5CH_Ph),

134.0 (C₆), 136.2 (C_Ph), 137.0 (C₇), 169.3 (C₂).

0

J_3,4=5.8 Hz, 1H, H₃), 3.85 (dd, J_{4 ,3}=7.1 Hz, J_{4 ,5}=

0

6.8 Hz, 1H, H₄), 3.94±4.13 (m, 3H, H_{5 ±6}), 4.27 (dd,

0

J_{2 ,1}=8.5 Hz, J_{2 ,3}=4.3 Hz, lH, H₂), 4.51 (d, J_{1 ,2}=

0

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3,3-diethyl-4ꢁ-(ꢁ-methylsty-

ryl)-2-azetidinone (30a) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-

O-isopropylidene-1⁰(1,3-propanedithio))-D-2⁰-glucosyl]-

3,3-diethyl-4ꢀ-(ꢁ-methylstyryl)-2-azetidinone (30b). They

were obtained by Staudinger reaction of imine 2 (1/B)

and 2-ethylbutyroyl chloride after 20 h at 50 ^ꢀC, and

dichloromethane as solvent, in 28% yield from 1.

8.5 Hz, 1H, H₁), 4.53 (d, J_4,3=5.8 Hz, lH, H₄), 4.63 (dd,

0

J_{3 ,2}=4.5 Hz, J_{3 ,4}=7.1 Hz, lH, H₃), 6.77 (s, 1H, H₆),

7.17±7.30 (m, 5H, H_Ph); ¹³H NMR (50.3 MHz) d: 13.0

(C₈), 17.9 (CH₃), 19.0 (C₇), 25.7, 27.1, 27.3 (C(CH₃)₂),

0

26.2 (C₉), 28.7, 29.0 (C₈), 46.9 (C₂), 56.6 (C₃), 56.8

0

(C₄), 63.3 (C_l), 67.9 (C₆), 77.6, 78.2, 79.9 (C₃, C₄, C₅),

0

110.0, 111.0 (C₇), 127.0, 128.6 (5CH_Ph), 129.4 (C₆),

133.5 (C₅), 137.9 (C_Ph), 174.5 (C₂). Áe (l): 14.42 (206),

11.48 (220), +2.54 (252).

0

30a (11%): MS (EI, m/z): 576 (MH)⁺. [a]_d6 (c 1,

CHCl₃). IR: 1743 (NCO). ¹H NMR (250 MHz) d:

0.94, 1.06 (2t, J=7.4 Hz, 6H, H₈), 1.37, 1.46, 1.50 (3s,

12H, C(CH₃)₂), 1.70±2.00 (m, 4H, H₇), 1.91 (s, 3H,

31⁰(10%): MS (EI, m/z) 419 (M⁺), 404 (M⁺CH₃).

1

IR: 1732 (HNCO). H NMR (200 MHz) d: 0.94 (t,

J=6.8 Hz, 3H, CH₃CH₂CH₂CO), 1.33, 1.35, 1.38, 1.46

(4s, 12H, C(CH₃)₂), 1.63 (sex, J=6.8 Hz, 2H, CH₃CH₂

0

CH₃(C=)), 2.01±2.10 (m, 2H, H₉), 2.90±3.10 (m, 4H,

0

H₈), 3.77 (dd, J_{2 ,1}=7.6 Hz, J_{2 ,3}=3.5 Hz, 1H, H₂),

0

CH₂CO), 1.90±2.10 (m, 2H, H₉), 2.20 (t, J=6.8 Hz, 2H,

0

3.97±4.27 (m, 5H, H₁, H_{4 ±6}), 4.38 (s, 1H, H₄), 5.05

0

CH₃CH₂CH₂CO), 2.50±2.70 (m, 2H, H_{8 ax}), 2.76±3.01

0

0 0 0 0 0 0

(m, 2H, H_{8 eq}), 3.55 (t, J_{4 ,3}=J_{4 ,5}=7.9 Hz, 1H, H₄),

(dd, J_{3 ,2}=3.6 Hz, J_{3 ,4}=7.8 Hz, 1H, H₃), 6.84 (s, 1H,

H₆), 7.20±7.38 (m, 5H, H_Ph); ¹³C NMR (62.5 MHz) d:

8.9, 9.4 (C₈), 18.1 (CH₃(C=)), 20.9 (2C₇), 25.6, 26.2,

0

3.75 (d, J_{1 ,2}=8.9 Hz, 1H, H₁), 3.90±4.15 (m, 4H, H₂,

0

H_{4 ±6}), 4.70 (dd, J_{3 ,4}=7.8 Hz, J_{3 ,NH}=10.1 Hz, 1H,

0

26.7, 27.4 (C(CH₃)₂), 25.8 (C₉), 28.2, 28.6 (C₈), 47.8

0

H₃), 5.87 (d, J_{3 ,NH}=10.1 Hz, 1H, NH).

0

(C₂), 55.3 (C₄), 63.5 (C₃), 67.9 (C₆), 70.8 (C₁), 77.6,

0

78.0, 79.4 (C₃, C₄, C₅), 109.5, 110.2 (C₇), 126.6, 128.3,

128.4 (5CH_Ph), 129.1 (C₆), 133.3 (C₅), 137.8 (C_Ph), 175.1

(C₂).

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰,1⁰-di-

propylthio)-^D-2⁰-glucosyl]-3ꢀ-ethyl-4ꢀ-(trans-ꢁ-methyl-

styryl)-2-azetidinone (35) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-

di-O-isopropylidene-1⁰,1⁰-dipropylthio)-D-2⁰-glucosyl]-3ꢀ-

ethyl-4ꢀ-(cis-ꢁ-methylstyryl)-2-azetidinone (35⁰). They

were obtained by Staudinger reaction of imine 2 (34/B)

and butyroyl chloride after 4 h at re¯ux in toluene in

72% yield from 34. The reaction mixture was puri®ed

on a silica gel column (hexane:ethyl acetate, 9:1).

0

30b (17%): Anal. Calcd for C₃₁H₄₅NO₅S₂: C, 64.66; H,

7.88; N, 2.43; S, 11.14. Found: C, 64.21; H, 7.29; N,

2.02; S, 11.04. mp 156±157 ^ꢀC (hexane:EtOAc). [a]_d

25 (c 1, CHCl₃). IR: 1749 (NCO). ¹H NMR

(250 MHz) d: 0.94, 1.04 (2t, J=7.4 Hz, 6H, H₈), 1.33,

1.34, 1.38, 1.47 (4s, 12H, C(CH₃)₂), 1.65±2.00 (m, 4H,

0

H₇), 1.96 (s, 3H, CH₃(C=)), 2.02±2.18 (m, 2H, H₉),

35 (60%): Anal. calcd for C₃₂H₄₉NO₅S₂: C, 64.94; H,

8.34. Found: C, 65.01; H, 8.42. [a]_d94^ꢀ(c 1, CHCl₃).

IR: 1753 (NCO). ¹H NMR (200MHz) d: 0.92±1.02 (m,

0

2.80±2.95 (m, 4H, H₈), 3.89 (dd, J_{2 ,1}=7.0 Hz, J_{2 ,3}=

0

3.8 Hz, 1H, H₂), 3.97±4.16 (m, 4H, H_{4 ±6}), 4.42 (s, 1H,

0

H₄), 4.57 (t, J_{4 ,3}=J_{4 ,5}=6.8 Hz, 1H, H₄), 4.85 (d, 1H,

0

9H, H₈, H₁₀), 1.29, 1.31, 1.36, 1.38 (4s, 12H, C(CH₃)₂),

0

1.50±1.86 (m, 6H, H₇, H₉), 1.95 (s, 3H, CH₃(C=)),

H₁, J_{1 ,2}=6.8 Hz), 7.00 (s, 1H, H₆), 7.15±7.32 (m, 5H,

H_Ph); ¹³C NMR (62.5 MHz) d: 9.0, 9.4 (C₈), 18.2 (CH₃

(C=O)), 20.9, 25.3 (C₇), 25.6, 26.9, 27.2, 27.3

0

2.60±2.80 (m, 4H, H₈), 3.39 (dt, J_3,4=5.8Hz, J_3,7

=

0

7.2 Hz, 1H, H₃), 3.80 (t, J_{4 ,3}=J_{4 ,5}=7.2 Hz, 1H, H₄),

0

(C(CH₃)₂), 26.2 (C₉), 30.4, 30.6 (C₈), 48.1 (C₂), 57.8

0

0 0 0 0 0

3.90±4.25 (m, 4H, H₂, H_{5 ±6}), 4.46 (d, J_{1 ,2}=7.8 Hz,

0

(C₄), 63.2 (C₃), 67.6 (C₆), 70.0 (C₁), 77.2, 78.7, 80.3 (3C;

0

1H, H₁), 4.56 (d, J_4,3=5.8 Hz, 1H, H₄), 4.68 (dd,

0

C₃, C₄, C₅), 109.7 (2C₇), 126.6, 128.4, 129.0 (5CH_Ph),

0

J_{3 ,2}=2.3 Hz, J_{3 ,4}=6.9 Hz, 1H, H₃), 6.85 (s, 1H, H₆),

7.20±7.40 (m, 5H, H_Ph); ¹³C NMR (62.5 MHz) d: 12.7

0

(C₈), 13.7, 13.8 (C₁₀), 17.7 (CH₃(C=)), 18.8 (C₇), 22.5,

0

128.3 (C₆), 133.0 (C₅), 137.9 (C_Ph), 175.1 (C₂).

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰(1,3-pro-

panedithio))-^D-2⁰-glucosyl]-3ꢀ-ethyl-4ꢀ-(ꢁ-methylstyryl)-

2-azetidinone (31) and N-(2-dideoxy-2⁰-dithianyl-3⁰,4⁰;

5⁰,6⁰-di-O-isopropylidene-D-glucosyl)-butananamide (31⁰).

They were obtained by Staudinger reaction of imine 2

(1/B) and butyroyl chloride after 20h at room tempera-

ture in 70% yield from 1. The reaction mixture was pur-

i®ed on a silica gel column (hexane:ethyl acetate, 7:3).

22.7 (C₉), 25.6, 26.7, 27.0, 27.2 (4C(CH₃)₂), 32.7, 34.7

0

(2C₈), 52.8 (C₂), 56.4 (C₃), 57.1 (C₄), 63.4 (C₁), 67.7

0

(C₆), 77.3, 78.8, 80.0 (C₃, C₄, C₅), 109.5, 110.0 (2C₇),

126.6, 128.3, 129.1 (5CH_Ph), 129.0 (C₆), 133.6 (C₅),

138.1 (C_Ph), 173.0 (C₂).

35⁰(12%): [a]_d103 (c 1.5, CHCl₃). IR: 1758 (NCO).

¹H NMR (200 MHz) d: 0.88, 0.95 (2t, 6H, H₁₀

,

0

846

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

J=7.4 Hz), 1.12 (t, 3H, H₉, J=7.4 Hz), 1.32, 1.37, 1.42,

0

1.47 (4s, 12H, C(CH₃)₂), 1.35±1.92 (m, 6H, H₇, H₉),

General procedure for preparation of monobactams

0

2.04 (s, 3H, CH₃(C=)), 2.35±2.70 (m, 4H, H₈), 3.42

To a solution of monobactam (1 mmol) in dry THF

(25 mL) a 1.6 M solution of n-butyllithium (1.5 mL, 2.2

equiv) in hexane was slowly added under an inert

atmosphere at 40 ^ꢀC. The mixture was stirred for 20±

40 min, poured into cold ammonium chloride solution

and extracted with dichloromethane. The organic layers

were dried (Na₂SO₄), ®ltered, and evaporated to dry-

ness. After puri®cation by silica gel column chromato-

graphy (hexane:ethyl acetate, 9:1), the compound 18

was obtained as a brown oil in 95±100% yield, ¹H

NMR (200 MHz) d: 1.01, 1.50 (2s, 12H, C(CH₃)₂), 2.20±

2.45 (m, 2H, H₉), 2.80±3.00 (m, 4H, H₈), 3.90±4.20 (m,

3H, H_5±6), 4.85 (dd, J_3,2=8.8 Hz, J_3,4=7.8 Hz, 1H, H₃),

5.84 (d, J_2,3=8.8 Hz, 1H, H₂).

0

(dd, J_3,4=6.2 Hz, J_3,7=7.0 Hz, 1H, H₃), 3.70 (t, J_{4 ,3}

0

=

0

J_{4 ,5}=7.9 Hz, 1H, H₄), 3.88±4.14 (m, 5H, H₁, H₂,

0

H_{5 ±6}), 4.85 (d, J_4,3=6.2 Hz, 1H, H₄), 4.87 (dd, J_{3 ,2}=

0

2.2 Hz, J_{3 ,4}=7.9 Hz, 1H, H₃), 6.57 (s, 1H, H₆), 7.13 (d,

J=9.0 Hz, 2H, H_Ph), 7.26±7.32 (m, 3H, H_Ph); ¹³C NMR

0

(62.5 MHz) d: 13.1 (C₈), 13.8, 14.2 (2C, C₁₀), 18.9 (C₇),

0

21.4 (CH₃(C=)), 22.4, 22.5 (C₉), 25.3, 26.3, 26.4, 26.6

0

(4C(CH₃)₂), 31.5, 33.3 (2C₈), 53.6 (C₂), 55.8 (C₃), 56.4

0

(C₄), 57.0 (C₁), 67.9 (C₆), 77.7, 78.5 (3C; C₃, C₄, C₅),

0

109.5, 110.0 (2C₇), 126.8, 128.3, 128.7 (5CH_Ph), 131.5

(C₆), 135.9 (C₅), 137.5 (C_Ph), 174.8 (C₂).

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰,1⁰-di-

methoxy)-^D-2⁰-glucosyl]-3ꢀ-ethyl-4ꢀ-(trans-ꢁ-methyl-

styryl)-2-azetidinone (36) and 1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-

di-O-isopropylidene-1⁰,1⁰-dimethoxy)-D-2⁰-glucosyl]-3ꢀ-

ethyl-4ꢀ-(cis-ꢁ-methylstyryl)-2-azetidinone (36⁰). They

were obtained by Staudinger reaction of imine 2 (37/ B)

and butyroyl chloride after 12 h at re¯ux in toluene, in

70% yield from 37. The reaction mixture was puri®ed

on a silica gel column (hexane:ethyl acetate, 8:2). The

monobactam 36 was also obtained by reaction of 31 or

35 with [bis(tri¯uoroacetoxy)iodo]benzene in methanol

according to the procedure reported by Stork et al.¹²in

54 and 71% yield, respectively.

3ꢁ-Methoxy-4ꢁ-styryl-2-azetidinone (11a) and 3ꢀ-meth-

oxy-4ꢀ-styryl-2-azetidinone (11b). They were obtained

from 3a (3 mmol) and 3b (4.8 mmol) via the above

general procedure in 85 and 90% yield, respectively,

after chromatography on silica gel (hexane:ethyl acetate,

7:3).

Anal. calcd for C₁₂H₁₃O₂N: C, 70.91; H, 6.45; O, 15.75;

N, 6.89. Found: C, 70.66; H, 6.20; O, 15.82 for 11a and

C, 70.87; H, 6.35; N, 6.57 for 11b. mp 125±127 ^ꢀC (hep-

tane:CH₂Cl₂). [a]_d10 (c 1, CHCl₃) for 11a and [a]_d

1

+10 (c 1, CHCl₃) for 11b. IR(KBr): 1768 (NCO). H

36 (58%): Anal. calcd for C₂₈H₄₁NO₇: C, 66.77; H,

8.20; N, 2.78 . Found: C, 66.11; H, 8.58; N, 3.01. [a]_d

130 (c 1.9, CHCl₃). IR: 1755 (NCO). ¹H NMR

(200 MHz) d: 0.99 (t, J_8,7=7.4 Hz, 3H, H₈), 1.29, 1.32,

1.36, 1.40 (4s, 12H, C(CH₃)₂), 1.45±1.80 (m, 2H, H₇),

1.69 (s, 3H, CH₃(C)), 3.27 (ddd, J_3,4=J_3,7a=5.6 Hz,

J_3,7b=8.6 Hz, 1H, H₃), 3.44, 3.53 (2s, 6H, OCH₃),

NMR (200 MHz) d: 3.44 (s, 3H, OCH₃), 4.38 (dd,

J_4,3=4.8 Hz, J_4,5=8.3 Hz, 1H, H₄), 4.64 (dd,

J_3,4=4.8 Hz, J_3,1=2.0 Hz, 1H, H₃), 6.26 (dd, J_5,4=

8.3 Hz, J_5,6=16.0 Hz, 1H, H₅), 6.56 (br.s, 1H, NH), 6.65

(d, J_6,5=16.0 Hz, 1H, H₆), 7.20±7.50 (m, 5H, H_Ph). ¹³C

NMR (50.3 MHz) d: 56.9 (C₄), 58.5 (OCH₃), 86.8 (C₃),

125.0 (C₆), 126.7, 128.1, 128.7 (5CH_Ph), 134.8 (C₅),

136.4 (C_Ph), 168.0 (C₂). Áe (l): +53 (226) for 11a and

101.6 (226) for 11b.

0

3.65 (dd, 1H, H₂, J_{2 ,1}=7.8 Hz, J_{2 ,3}=3.4 Hz), 3.86 (t,

0

J_{4 ,3}=J_{4 ,5}=7.4 Hz, 1H, H₄), 3.91±4.18 (m, 3H, H_{5 ±6}),

0

4.25 (dd, J_{3 ,2}=3.2 Hz, J_{3 ,4}=7.4 Hz, 1H, H₃), 4.40 (d,

0

J_4,3=5.6 Hz, 1H, H₄), 5.20 (d, J_{1 ,2}=7.8 Hz, 1H, H₁),

6.90 (s, 1H, H₆), 7.20±7.31 (m, 5H, H_Ph); ¹³C NMR

(50.3 MHz) d: 12.6 (C₈), 17.3 (CH₃(C)), 18.6 (C₇),

25.3, 26.7, 27.3, 27.4 (4C(CH₃)₂), 54.2, 56.0 (2OCH₃),

3ꢁ-Methoxy-4ꢁ-(trans-ꢁ-methylstyryl)-2-azetidinone (12a)

and 3ꢀ-methoxy-4ꢀ-(trans-ꢁ-methylstyryl)-2-azetidinone

(12b). They were obtained from 4a (1 mmol) and 4b

(1 mmol) via the general procedure above in 97 and

95% yield, respectively, after chromatography on silica

gel (hexane:ethyl acetate, 7:3). Anal. Calcd for

C₁₃H₁₅O₂N: C, 71.86; H, 6.96; N, 6.44. Found: C,

71.64; H, 6.80; N, 6.23 for 12a and C, 71.52; H, 6.98; N,

6.33 for 12b. MS (EI, m/z): 217 (M⁺), 402 (M⁺CH₃).

mp 91±93 ^ꢀC (heptane:CH₂Cl₂). [a]_d40 (c 1, CHCl₃)

for 12a and [a]_d+40 (c 1, CHCl₃) for 12b. IR(KBr):

1756 (NCO). ¹H NMR (250 MHz) d: 3.44 (s, 3H,

OCH₃), 4.38 (dd, J_4,3=4.8 Hz, J_4,5=8.3 Hz, 1H, H₄),

4.64 (dd, J_3,4=4.8 Hz, J_3,1=2.0 Hz, 1H, H₃), 6.26 (dd,

J_5,4=8.3 Hz, J_5,6=16.0 Hz, 1H, H₅), 6.56 (br.s, 1H,

NH), 6.65 (d, J_6,5=16.0 Hz, 1H, H₆), 7.20±7.50 (m, 5H,

H_Ph); ¹³C NMR (62.5 MHz) d: 15.5 (CH₃(C)), 58.9

(OCH₃), 61.3 (C₄), 86.6 (C₃), 127.2, 128.5, 129.5

(5CH_Ph), 134.7 (C₆), 137.1 (2C, C5, C_Ph), 169.1 (C₂).

0

56.2 (C₃), 57.1 (C₄), 63.6 (C₂), 67.7 (C₆), 77.3, 78.8, 79.5

0

(C₃, C₄, C₅), 102.6 (C₁), 109.8, 109.9 (2C₇), 126.6,

128.3, 129.1 (5CH_Ph), 129.0 (C₆), 132.6 (C₅), 137.8

(C_Ph), 171.5 (C₂).

0

1

36 (12%): IR: 1755 (NCO). H NMR (250 MHz) d:

1.09 (t, J_8,7=7.2 Hz, 3H, H₈), 1.28, 1.30, 1.38 (3s, 12H,

C(CH₃)₂), 1.50±2.00 (m, 2H, H₇), 2.03 (s, 3H, CH₃

(C=)), 3.22 (ddd, J_3,4=J_3,7a=6.0 Hz, J_3,7b=8.2 Hz, 1H,

0

H₃), 3.32, 3.35 (2s, 6H, OCH₃), 3.59 (dd, J_{2 ,1}=7.7 Hz,

0

J_{2 ,3}=3.6 Hz, 1H, H₂), 3.65±3.80 (m, 2H, H_{4 ±5}), 3.92±

0

4.10 (m, 2H, H₆), 4.16 (dd, J_{3 ,2}=3.6 Hz, J_{3 ,4}=7.5 Hz,

0

1H, H₃), 4.83 (d, J_4,3=6.0 Hz, 1H, H₄), 4.87 (d, J_{1 ,2}=

7.7 Hz, 1H, H₁), 6.63 (s, 1H, H₆), 7.12 (d, J=7.0 Hz,

2H, H_Ph), 7.20±7.40 (m, 3H, H_Ph); ¹³C NMR

(62.5 MHz) d: 12.9 (C₈), 19.0 (C₇), 20.9 (CH₃(C)),

25.3, 26.5, 26.9 (4C(CH₃)₂), 53.8, 55.5 (OCH₃), 56.6

0

3ꢁ-Methoxy-4ꢁ-phenyl-2-azetidinone (13a) and 3ꢀ-

methoxy-4ꢀ-phenyl-2-azetidinone (13b). They were

obtained from 5a (0.2 mmol) and 5b (2.3 mmol) accord-

ing to the general procedure in 80 and 87% yield,

0

(2C; C₃, C₂), 57.2 (C₄), 67.3 (C₆), 77.2, 78.1, 78.5 (C₃,

C₄, C₅), 102.2 (C₁), 109.7 (2C₇), 126.9, 128.3, 128.6

(5CH_Ph), 131.9 (C₆), 135.4 (C₅), 137.0 (C_Ph), 172.8 (C₂).

0

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

847

respectively, after chromatography on silica gel (hexane:

ethyl acetate, 7:3). Anal. calcd for C₁₀H₁₁O₂N: C, 67.80;

H, 6.21; N, 7.91. Found: C, 67.55; H, 6.27; N, 8.11 for

13b. mp 46±48 ^ꢀC (hexane:EtOAc). [a]_d112 (c 1,

CHCl₃) for 13a and [a]_d+112 (c 1, CHCl₃) for 13b.

IR(KBr): 1765 (NCO). ¹H NMR (200 MHz) d: 3.15 (s,

3H, OCH₃), 4.73 (br.s, 1H, H₄), 4.83 (d, J_3,4=4.3 Hz,

1H, H₃), 6.56 (br.s, 1H, NH), 7.37 (br.s, 5H, H_Ph); ¹³C

NMR (50.3 MHz) d: 58.2 (2C, C₄, OCH₃), 86.8 (C₃),

127.7, 128.4 (5C, CH_Ph), 135.8 (C_Ph), 169.1 (C₂). Áe (l):

4.87 (209), +10.18 (226) for 13a and +4.60 (211),

15.40 (226) for 13b.

H₃), 4.70 (d, J_4,3=5.6 Hz, 1H, H₄), 6.28 (br.s, 1H, NH),

6.60 (s, 1H, H₆), 7.08±7.13 (m, 2H, H_Ph), 7.23±7.38 (m,

3H, H_Ph); ¹³C NMR (50.3 MHz) d: 13.7 (C₁₀), 21.7

(CH₃), 22.5 (C₉), 25.2 (C₈), 29.9 (C₇), 52.3 (C₃), 56.4

(C₄), 126.7, 128.2, (5C, CH_Ph), 129.9 (C₆), 134.9 (C₅),

136.5 (C_Ph), 171.9 (C₂). Áe (l): 15.07 (210), 23.33

(246).

3,3-Diethyl-4ꢁ-(trans-ꢁ-methylstyryl)-2-azetidinone (32a)

and 3,3-diethyl-4ꢀ-(trans-ꢁ-methylstyryl)-2-azetidinone

(32b). They were obtained from 30a (0.5 mmol) and

30b (0.8 mmol) in 84 and 85% yield, respectively, after

chromatography on silica gel (hexane:ethyl acetate, 6:4).

MS (EI, m/z): 243 (M⁺), 215 (M⁺CO) for 32a. [a]_d

+47^ꢀ(c 1, CHCl₃) for 32a and [a]_d47 (c 1, CHCl₃)

for 32b. IR: 1766 (NCO). ¹H NMR (200 MHz) d: 0.92

(t, J_7,8=6.8 Hz, 3H, H₈), 1.41±1.65 (m, 2H, H₇), 1.78 (s,

3H, CH₃), 3.90 (s, 1H, H₄), 6.18 (br.s, 1H, NH), 6.44 (s,

1H, H₆), 7.24±7.40 (m, 5H, H_Ph). Áe (l): +1.3 (220) for

32a and 1.4 (220) for 32b.

3ꢀ-Butyl-4ꢀ-phenyl-2-azetidinone (14). It was obtained

from 7 (2.3 mmol) in 70% yield after chromatography

on silica gel (hexane:ethyl acetate, 8:2). MS (EI, m/z):

203 (M⁺), 175 (M⁺CO).[a]_d66 (c 1, CHCl₃). IR:

1756 (NCO). ¹H NMR (200 MHz) d: 0.70 (t, J_8,7

=4.6 Hz, 3H, H₈), 1.02±1.38 (m, 6H, H_5±7), 3.43±3.47

(m, 1H, H₃), 4.86 (d, J_4,3=5.4 Hz, 1H, H₄), 6.02 (br.s,

1H, NH), 7.29±7.37 (m, 5H, H_Ph); ¹³C NMR

(50.3 MHz) d: 13.5 (C₈), 22.2 (C₇), 25.2 (C₆), 29.0 (C₅),

54.9 (C₃), 56.2 (C₄), 126.3, 127.9, 128.3 (5C, CH_Ph), 137.4

(C_Ph), 171.5 (C₂). Áe (l): 7.82 (207), 10.15 (215).

3ꢀ-Ethyl-4ꢀ-(trans-ꢁ-methylstyryl)-2-azetidinone (33).

It was obtained from 31 (0.65 mmol) in 87% yield after

chromatography on silica gel (hexane:ethyl acetate, 8/2).

mp 78±80 ^ꢀC (Hexane:ether). [a]_d11 (c 1, CHCl₃). IR

1

3ꢀ-Butyl-4ꢀ-styryl-2-azetidinone (15). It was obtained

from 8 (0.35 mmol) in 85% yield after chromatography

on silica gel (hexane:ethyl acetate, 8:2). MS (EI, m/z):

229 (M⁺), 201 (M⁺CO). mp 77±79 ^ꢀC (heptane:

CH₂Cl₂). [a]_d+12 (c 1, CHCl₃). IR (KBr): 1755

(KBr): 1755 (NCO). H NMR (200 MHz) d: 1.07 (t,

J_7,8=6.8 Hz, 3H, H₈), 1.46±1.80 (m, 2H, H₇), 1.90 (s,

3H, CH₃), 3.34 (m, 1H, H₃), 4.32 (d, J_4,3=5.0 Hz, 1H,

H₄), 5.94 (br.s, 1H, NH), 6.56 (s, 1H, H₆), 7.25±7.41 (m,

5H, H_Ph); ¹³C NMR (50.3 MHz) d: 12.1 (C₈), 16.8

(CH₃), 18.7 (C₇), 56.7 (C₃), 57.2 (C₄), 126.4, 126.6, 128.2

(5C, CH_Ph), 128.8 (C₆), 134.3 (C₅), 137.1 (C_Ph), 171.5

(C₂). Áe (l): 4.05 (198), 7.59 (215), 4.04 (237).

1

(NCO). H NMR (200 MHz) d: 0.93 (t, J_10,9=6.8 Hz,

3H, H₁₀), 1.30±1.82 (m, 6H, H_7±9), 3.41 (m, 1H, H₃),

4.45 (dd, J_4,3=5.4 Hz, J_4,5=7.5 Hz, 1H, H₄), 5.95 (br.s,

1H, NH), 6.29 (dd, J_5,4=7.4 Hz, J_5,6=15.9 Hz, 1H, H₅),

6.69 (d, J_6,5=16.0 Hz, 1H, H₆), 7.33±7.47 (m, 5H, H_Ph);

¹³C NMR (50.3 MHz) d: 13.9 (C₁₀), 22.6 (C₉), 25.2 (C₈),

29.7 (C₇), 53.5 (C₃), 55.9 (C₄), 126.2, 126.6, 128.1 (5C,

CH_Ph), 128.8 (C₆), 133.7 (C₅), 136.3 (C_Ph), 17.15 (C₂).

Áe (l): +4.01 (212), 3.89 (215), 2.98 (220), 2.12

(242).

General procedure for preparation of monobactams

To a solution of monobactam

(1 mmol), N,N⁰-diiso-

propylethylamine (2.2 mmol) and a catalytic amount of

4-dimethylaminopyridine in dry acetonitrile (5 mL),

acetyl chloride (2.2 mmol) at 25 ^ꢀC was added under

inert atmosphere. The mixture was stirred at room

temperature overnight, poured into cold ammonium

chloride solution and extracted with dichloromethane.

The organic layers were dried (Na₂SO₄), ®ltered and

evaporated to dryness. After puri®cation by silica gel

column chromatography some starting material was

recovered, as well as the pure compounds 19±23 (hex-

ane:ethyl acetate, 9:1).

3ꢀ-Butyl-4ꢀ-(trans-ꢁ-methylstyryl)-2-azetidinone (16).

It was obtained from 9 (13 mmol) in 95% yield after

chromatography on silica gel (hexane:ethyl acetate, 8:2).

Anal. calcd for C₁₆H₂₁ON: C, 79.01; H, 8.64; N, 5.76.

Found: C, 79.00; H, 8.59; N, 5.45. [a]_d46 (c 1,

CHCl₃). IR: 1754 (NCO). ¹H NMR (200 MHz) d: 0.90

(t, J_10,9=6.8 Hz, 3H, H₁₀), 1.27±1.70 (m, 6H, H_7±9), 1.90

(s, 3H, CH₃), 3.38 (m, 1H, H₃), 4.30 (d, J_4,3=5.4 Hz,

1H, H₄), 6.30 (br.s, 1H, NH), 6.58 (s, 1H, H₆), 7.23±7.43

(m, 5H, H_Ph); ¹³C NMR (50.3 MHz) d: 13.9 (C₁₀), 16.9

(CH₃), 22.8 (C₉), 25.1 (C₈), 29.9 (C₇), 53.4 (C₃), 57.4

(C₄), 126.7, 128.3, (5C, CH_Ph), 128.9 (C₆), 134.5 (C₅),

137.3 (C_Ph), 171.5 (C₂). Áe (l): 8.20 (210), 4.98

(215), 2.55 (236).

1-Acetyl-3ꢁ-methoxy-4ꢁ-styryl-2-azetidinone (19a) and

1-acetyl-3ꢀ-methoxy-4ꢀ-styryl-2-azetidinone (19b). They

were obtained from 11a (1 mmol) and 11b (1.5 mmol)

via the general procedure above in 45% and 50% yield,

respectively. Anal. calcd for C₁₄H₁₅NO₃: C, 68.55; H,

6.16; N, 5.71. Found: C, 68.42; H, 6.06; N, 5.71 for 19a

and C, 68.21; H, 6.14; N, 5.82 for 19b. MS (EI, m/z):

245 (M⁺), 202 [(M⁺) CO±CH₃]. mp 121±123 ^ꢀC

(heptane:CH₂Cl₂). [a]_d+103 (c 1, CHCl₃) for 19a and

[a]_d103^ꢀ(c 1, CHCl₃) for 19b. IR (KBr): 1805 (CO±

3ꢀ-Butyl-4ꢀ-(cis-ꢁ-methylstyryl)-2-azetidinone (17). It

was obtained from 10 (1.4 mmol) in 88% yield after

chromatography on silica gel (hexane:ethyl acetate,

8:2). MS (EI, m/z): 243 (M⁺). mp 121±123 ^ꢀC (hep-

tane). [a]_d53 (c 1, CHCl₃). IR (KBr): 1747 (NCO).

¹H NMR (200 MHz) d: 0.90 (t, J_10,9=6.8 Hz, 3H, H₁₀),

1.30±1.73 (m, 6H, H_7±9), 1.97 (s, 3H, CH₃), 3.42 (m, 1H,

1

N), 1709 (N-CO-CH₃). H NMR (250 MHz) d: 2.45 (s,

3H, CH₃CO), 3.55 (s, 3H, OCH₃), 4.60 (d, J_3,4=4.8 Hz,

1H, H₃), 4.85 (dd, J_4,3=4.8 Hz, J_4,5=8.2 Hz, 1H, H₄),

6.25 (dd, J_5,4=8.2 Hz, J_5,6=16.0 Hz, 1H, H₅), 6.85 (d,

848

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

J_6,5=16.0 Hz, 1H, H₆), 7.25±7.50 (m, 5H, H_Ph); ¹³C

NMR (62.5 MHz) d: 24.4 (CH₃CO), 59.0 (C4), 59.3

(OCH₃), 84.4 (C₃), 121.1 (C₅), 126.9, 128.4, 128.6

(5CH_Ph), 136.1 (C₆), 137.0 (C_Ph), 164.8 (CH₃CO), 168.0

(C₂).

the solution was brought to room temperature and stir-

red for 30 min. Evaporation of solvent under reduced

pressure gave a crude product which was puri®ed by

silica gel column chromatography using hexane:ethyl

acetate mixtures as eluents.

1-Acetyl-3ꢀ-methoxy-4ꢀ-(trans-ꢁ-methylstyryl)-2-azeti-

dinone (20). It was obtained from 12b (2.5 mmol) via the

above general procedure in 55% yield. Anal. calcd for

C₁₅H₁₅NO₃: C, 69.91; H, 6.69; N, 5.40. Found: C,

69.50; H, 6.62; N, 5.32. MS (EI, m/z): 259 (M⁺). mp 51±

4ꢀ-Acetyl-3ꢀ-methoxy-1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-iso-

propylidene-1⁰(1-sul®nyl-3-thiopropane))-D-2⁰-glucosyl]-2-

azetidinone (24). It was obtained from 4a (3 mmol) in

70% yield (hexane:ethyl acetate, 3:7). Anal. calcd for

C₂₁H₃₃O₈NS₂: C, 51.33; H, 6.77; N, 2.85; S, 13.07.

Found: C, 51.17; H, 6.61; N, 2.86; S, 13.21. MS (EI, m/

z): 491 (M⁺), 486 [(M⁺) -CH₃]. mp 76±78 ^ꢀC (heptane:

EtOAc). [a]_d+47 (c 1, CHCl₃). IR (KBr): 1768 (CO-

53 ^ꢀC (pentane:ether). [a]_d

134 (c 1, CHCl₃). IR

(KBr): 1795 (CO-N), 1700 (CO-CH₃). ¹H NMR

(200 MHz) d: 1.90 (s, 3H, CH₃(C)), 2.50 (s, 3H,

CH₃CO), 3.60 (s, 3H, OCH₃), 4.70 (d, J_4,3=6.0 Hz, 1H,

H₄), 4.80 (d, J_3,4=6.0 Hz, 1H, H₃), 6.50 (s, 1H, H₆),

7.30±7.50 (m, 5H, H_Ph); ¹³C NMR (50.3 MHz) d: 15.1

(CH₃(C)), 24.2 (CH₃CO), 59.6 (OCH₃), 63.5 (C₄), 84.7

(C₃), 127.0, 128.3, 129.2, 130.0 (5CH_Ph), 131.2 (C₆),

136.0 (2C; C5, C_Ph), 165.3 (CH₃CO), 168.2 (C₂).

1

N), 1735 (CO-CH₃). H NMR (400 MHz) d: 1.30, 1.45

0

(2s, 12H, C(CH₃)₂), 1.95±2.37 (m, 1H, H_{10 a}), 2.25 (s,

0

3H, CH₃CO), 2.50±2.80 (m, 4H, H_{8 a}, H₉, H_{10 b)}, 3.10±

0

3.60 (m, 1H, H_{8 b}), 3.50 (s, 3H, OCH₃), 3.85±4.05 (m,

0

2H, H₆), 4.10 (dd, J_{5 ,4}=8.0 Hz, J_{5 ,6 a}=6.0 Hz, 1H,

0

H₅), 4.15 (dd, J_{4 ,3}=6 Hz, J_{4 ,5}=8.0 Hz, 1H, H₄), 4.25

0

(d, J_{1 ,2}=6 Hz, 1H, H₁), 4.50 (d, J_4,3=6.0 Hz, 1H, H₄),

0

1-Acetyl-3ꢀ-methoxy-4ꢀ-phenyl-2-azetidinone (21). It

was obtained from 13b (0.13 mmol) in 53% yield. Anal.

calcd for C₁₅H₁₅NO₃: C, 65.75; H, 5.94; N, 6.39. Found:

C, 65.75; H, 5.85; N, 6.30. mp 83±84 ^ꢀC (Hexane). IR

(KBr): 1796 (CO-N), 1713 (CO-CH₃). ¹H NMR

(200 MHz) d: 2.47 (s, 3H, CH₃CO), 3.23 (s, 3H, OCH₃),

4.80 (d, J_4,3=5.0 Hz, 1H, H₄), 5.20 (d, J_3,4= 5.1 Hz, 1H,

H₃), 7.27±7.40 (m, 5H, H_Ph); ¹³C NMR (50.3 MHz) d:

24.4 (CH₃CO), 58.0 (OCH₃), 60.1 (C₄), 84.5 (C₃),

127.7, 128.6 (5CH_Ph), 133.0 (C_Ph), 170.1 (CH₃CO),

172.0 (C₂).

4.51±4.70 (m, 2H, H₂, H₃), 4.80 (d, J_3,4=6.0 Hz, 1H,

H₃); ¹³C NMR (62.5 MHz) d: 22.3, 25.3 (4C(CH₃)₂),

0

26.2 (C₁₀), 27.4 (C₉), 28.0 (CH₃CO), 28.5 (C₈), 51.5

0

(OCH₃), 53.1 (C₂), 64.5 (C_l), 66.5 (C₄), 67.7 (C₆), 76.6,

77.9, 79.0 (C₃, C₄, C₅), 85.3 (C₃), 107.4, 109.9 (C₇),

168.3 (C₂), 203.5 (CH₃CO).

0

1,4-Diacetyl-3ꢀ-methoxy-2-azetidinone (27). It was

obtained from 20 (3 mmol) in 62% yield (hexane:ethyl

acetate, 7:3). Anal. Calcd for C₈H₁₁NO₄: C, 51.88; H,

6.15; N, 7.49. Found: C, 51.88; H, 5.98; N, 7.56.

[a]_d= 197 (c=1, CHCl₃). IR (KBr): 1805 (CO-N),

1714 (CO-CH₃). H NMR (250 MHz) d: 2.25 (s, 3H,

CH₃CO), 2.50 (NCOCH₃), 3.60 (OCH₃), 4.75 (d, J_4,3

6.0 Hz, 1H, H₄), 4.80 (d, J_3,4=6.0 Hz, 1H, H₃); ¹³C

NMR (62.5 MHz) d: 24.0 (NCOCH₃), 28.1 (CH₃CO),

59.9 (OCH₃), 62.1 (C₄), 83.5 (C₃), 163.5 (2C; C₂,

NCOCH₃), 200.2 (COCH₃).

1

1-Acetyl-3ꢀ-butyl-4ꢀ-styryl-2-azetidinone (22). It was

obtained from 15 (0.5 mmol) in 20% yield. IR: 1796

=

1

(CO-N), 1720 (CO-CH₃). H NMR (200 MHz) d: 0.81

(t, J_10,9=6.8 Hz, 3H, H₁₀), 1.17±1.69 (m, 6H, H_7±9), 2.38

(s, 3H, CH₃CO), 3.22±3.31 (m, 1H, H₃), 4.25 (dd, J_4,3=

6.0 Hz, J_4,5=6.3 Hz, 1H, H₄), 6.06 (dd, J_5,4=6.3 Hz,

J_5,6=16.2 Hz, 1H, H₅), 6.81 (d, J_6,5=16.3 Hz, 1H, H₆),

7.09±7.28 (m, 5H, H_Ph).

3ꢀ-Butyl-1,4-diacetyl-2-azetidinone (28). It was obtained

from 23 (3 mmol) in 89% (hexane:ethyl acetate, 8:2).

Anal. calcd for C₁₁H₁₇NO₃: C, 62.56; H, 8.06; N,

6.64. Found: C, 62.56; H, 7.94; N, 6.20. IR: 1800

1-Acetyl-3ꢀ-butyl-4ꢀ-(trans-ꢁ-methylstyryl)-2-azetidi-

none (23). It was obtained from 17 (4.7 mmol) in 25%

yield. Anal. calcd for C₁₈H₂₃NO₂: C, 75.79; H, 8.07; N,

4.91. Found: C, 75.50; H, 8.26; N, 5.16. MS (EI, m/z):

285 (M⁺), 243 [(M⁺)-CO-CH₃]. IR: 1782 (CO-N), 1709

1

(CO-N), 1727 (NCO-CH₃), 1710 (CO-CH₃). H NMR

(200 MHz) d: 0.64 (t, J_7±8=6.8 Hz, 3H, H₈), 1.07±1.39

(m, 6H, H_5±7), 2.01, 2.15 (2s, 6H, CH₃CO), 3.25 (t, 1H,

J_3,7=J_3,4=6.5 Hz, H₃), 4.36 (d, J_4,3=6.5 Hz, 1H, H₄);

¹³C NMR (62.5 MHz) d: 13.8 (C₈), 22.4 (C₉), 23.7

(CH₃CO), 24.8 (C₈), 29.1 (CH₃CO), 29.7 (C₇), 52.5 (C₃),

58.5 (C₄), 168.2 (NCOCH₃), 169.0 (C₂), 202.4 (COCH₃).

(CO-CH₃). ¹H NMR (200 MHz) d: 0.89 (t, J_10,9

=

6.8 Hz, 3H, H₁₀), 1.24±1.74 (m, 6H, H_7±9), 1.88 (s, 3H,

CH₃(C)), 2.46 (s, 3H, CH₃CO), 3.45 (m, 1H, H₃), 4.68

(d, J_4,3=6.0 Hz, 1H, H₄), 6.40 (s, 1H, H₆), 7.23±7.40 (m,

5H, H_Ph); ¹³C NMR (50.3 MHz) d: 13.9 (C₁₀), 16.4

(CH₃(C)), 22.7 (C₉), 24.1 (CH₃CO), 24.5 (C₈), 30.1

(C₇), 53.9 (C₃), 59.6 (C₄), 126.9, 128.1, 128.3 (5CH_Ph),

129.1 (C₆), 131.6 (C₅), 137.0 (C_Ph), 168.5 (CH₃CO),

168.9 (C₂).

4ꢀ-Acetyl-3ꢀ-ethyl-1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-iso-

propylidene-1⁰(1-sul®nyl-3-thiopropane))-D-2⁰-glucosyl]-2-

azetidinone (40). It was obtained from 39 (3 mmol) in

70% yield (hexane:ethyl acetate, 3:7), after 20 min ozo-

nolysis. Anal. Calcd for C₂₂H₃₅NO₇S₂: C, 53.98; H,

7.20; N, 2.86; S, 13.07. Found: C, 54.02; H, 7.02; N,

2.83. mp 58±60 ^ꢀC (hexane:MeOH). IR (KBr): 1770

General procedure for ozonolysis

1

A solution of diene (1 mmol) in dichloromethane

(20 mL) was cooled to 78 ^ꢀC and a ozone current was

bubbled through it until permanent blue coloration of

the solution. Dimethyl sul®de (2 mmol) was added and

(CO-N), 1720 (CO-CH₃). H NMR (200 MHz) d: 1.07

(t, J=7 Hz, 3H, H₈), 1.21, 1.29, 1.36, 1.51 (4s, 12H,

C(CH₃)₂), 1.63 (m, 2H, H₇), 2.03 (s, 3H, H₆), 2.15 (m,

0

2H, H₁₀), 2.61 (m, 2H, H₉), 3.12 (m, 2H, H₈), 3.42±4.20

0

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

849

0

(m, 5H, H3, H_{4 ±6}), 4.72 (m, 4H, H_{4 ±6}), 4.72 (d, J_4,3

0

=

(0.5 mmol) according to the procedure reported for 25.

MS (EI, m/z): (M)⁺449. [a]_d52 (c 1, CHCl₃). IR:

6.6 Hz, 1H, H₄), 5.24 (d, J_{3 ,4}=8 Hz, 1H, H₃); ¹³C

NMR (50.3 MHz) d 12.0 (C₈), 16.0 (C₁₀), 19.6 (C₇),

0

25.2, 27.3, 28.6 (C(CH₃)₂), 29.0 (C₆), 31.2 (C₉), 48.3

0

1

0

1760 (NCO), 1745 (CO-CH₃). H NMR (200 MHz) d:

1.03 (t, J_6,7=7.2 Hz, 3H, H₇), 1.32, 1.41, 1.48 (3s, 12H,

C(CH₃)₂), 1.62±1.85 (m, 2H, H₆), 3.20±3.85 (m, 2H,

0

(C₈), 56.5 (C₃), 63.5 (C₄), 67.7 (C₆), 76.5, 77.8; 80.0

0

0 0

H₃), 3.38, 3.40 (2s, 6H, OCH₃), 3.80±4.20 (m, 6H, H_{2 ±6}),

(C₃, C₄, C₅), 109.5; 110.8 (C₇), 133.4 (C₁), 137.2 (C₂),

169.3 (C₂), 205.4 (C₅).

0

4.78 (d, J_{1 ±2}=8.5 Hz, 1H, H₁), 6.24 (d, J_6,7=4.5 Hz,

0

1H, H₄).

4ꢀ-Acetyl-1[(2⁰,3⁰;4⁰,5⁰-di-O-isopropylidene)-D-1⁰-arabino-

syl)]-3ꢀ-ethyl-2-azetidinone (41). It was obtained from

39 (3 mmol) in 60% yield (hexane:ethyl acetate, 7:3)

after 45 min ozonolysis. MS (FAB, m/z): 376 (M+Li)⁺,

370 (MH)⁺. IR: 1800 (CO-N), 1732 (NCO-CH₃), 1713

(CO-CH₃). ¹H NMR (200 MHz) d: 1.07 (t, J=7 Hz, 3H,

H₈), 1.34, 1.39, 1.46 (3s, 12H, C(CH₃)₂), 1.61 (m, 2H,

4ꢀ-Acetoxy-3ꢀ-butyl-2-azetidinone (26). A solution of

monobactam 16 (587 mg, 2.4 mmol), N,N⁰-diisopropyl-

ethylamine (1.3 mL, 7.6 mmol) and tert-butyldimethyl-

silyl chloride (1.18 g, 3.7 mmol) in dichloromethane

(20 mL) was stirred at room temperature for 19 h and

then poured into cold ammonium chloride solution and

extracted with dichloromethane. The organic layers

were dried (Na₂SO₄), ®ltered and evaporated to dryness.

Column chromatography (hexane:ethyl acetate, 8/2)

gave the silyl derivative of 16 (462 mg, 54%): IR: 1755

0

H₇), 2.26 (s, 3H, H₆), 3.30±3.55 (m, 2H, H₃, H_{5 a}), 4.10±

0

4.40 (m, 3H, H_{3 ±4}, H_{5 b}), 4.62 (d, J_{2 ,3}=7.2 Hz, 1H,

0

H₂), 5.09 (d, J_4,3=6.6 Hz, 1H, H₄).

4ꢀ-Acetyl-1[(2⁰-didesoxi-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-

1⁰,1⁰-dimethoxy)-D-2(-glucosyl]-3ꢀ-ethyl-2-azetidinone

(42). It was obtained from 36 (0.5 mmol) in 80% yield

(hexane:ethyl acetate, 6:4). IR: 1770 (CO-N), 1726 (CO-

(NCO). H NMR (200 MHz) d: 0.10, 0.32 (2s, 6H,

1

CH₃Si), 0.89 (t, J_10,9=6.8 Hz, 3H, H₁₀), 0.99 (s, 9H,

CH₃Bu), 1.18±1.68 (m, 6H, H_7±9), 1.87 (s, 3H, CH₃

t

(CO)), 3.44 (c, J_3,4=J_3,7=6.2 Hz, 1H, H₃), 4.20 (d,

J_4,3=6.0 Hz, 1H, H₄), 6.54 (s, 1H, H₆), 7.23±7.40 (m,

5H, H_Ph). This compound (462 mg, 1.3 mmol) gave

by ozonolysis a residue which was diluted with

dry dichloromethane (6 mL) and m-CPBA (420 mg,

2.4 mmol) was added. The mixture was stirred under

argon atmosphere for 10 h at room temperature and

then diluted with dichloromethane, washed with a solu-

tion of sodium bicarbonate and with water. The organic

layers were dried (Na₂SO₄), ®ltered, and evaporated to

dryness. The residue was diluted with methanol (15 mL)

and with a 0.5 N HCl (10 mL) solution . This solution

was stirred for 5 h at room temperature and then neu-

tralised with IRA-68 resin and ®ltered. The ®ltrate was

evaporated to dryness and the residue was diluted in

ethyl acetate and washed with water. The organic layers

were dried (Na₂SO₄), ®ltered and evaporated to dryness.

Column chromatography (hexane:ethyl acetate, 1:1) on

Florisil¹yielded 26 as an oil (84 mg, 35%): Anal. calcd

for C₉H₁₅O₃N: C, 58.36; H, 8.16; N, 7.56. Found: C,

58.20; H, 8.11; N, 7.86. MS (IE, m/z): 186 (MH)⁺; 170

[(MH)⁺-CH₃). [a]_d35 (c 1, CHCl₃). IR: 3200 (NH),

1773 (N-C=O), 1727 (OOC-CH₃). ¹H NMR (200 MHz)

d: 0.89 (t, J_10,9=6.8 Hz, 3H, H₁₀), 1.26±1.56 (m, 6H,

H_7±9), 2.23 (s, 3H, CH₃CO), 3.56 (dd, J_3,7=6.4 Hz,

J_3,4=6.0 Hz, 1H, H₃), 4.32 (d, J_4,3=6.0 Hz, 1H, H₄),

6.80 (br.s, 1H, NH); ¹³C NMR (50.3 MHz) d: 13.8 (C₁₀),

22.7 (C₉), 25.9 (C₈), 28.2 (CH₃CO), 29.5 (C₇), 56.1 (C₃),

58.7 (C₄), 171.0 (CO), 172.1 (C₂).

1

CH₃). H NMR (200 MHz) d: 0.97 (t, J=7.5 Hz, 3H,

H₈), 1.30, 1.33, 1.34, 1.43 (4s, 12H, C(CH₃)₂), 1.50±1.70

(m, 2H, H₇), 2.21 (s, 3H, H₆), 3.36, 3.41 (2s, 6H,

0

CH₃O), 3.30±3.50 (m, 1H, H₃), 3.93±4.13 (m, 6H, H_{2 ±}

0

₆), 4.40 (d, J_4,3=6.3 Hz, 1H, H₄), 4.75 (d, J_{1 ,2}=7.2 Hz,

0

1H, H₁). ¹³C NMR (62.5 MHz) d: 12.2 (C₈), 18.8 (C₇),

25.3, 26.3, 26.4, 26.7 (4C, C(CH₃)₂), 29.5 (C₆), 53.2, 54.0

0

(2C, CH₃O), 55.0 (C₃), 56.2 (C₂), 61.6 (C₄), 67.6 (C₆),

0

77.3, 77.9 (3C; C₃, C₄, C₅), 101.3 (C₁), 109.1, 110.0

0

(2C, C₇), 171.4 (C₂), 205.1 (C₅).

4ꢀ-Acetoxy-3ꢀ-methoxy-1[(1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-

isopropylidene-1⁰(3-sul®nyl-1-sulfonyl))-D-2⁰-glucosyl]-2-

azetidinone (25). A solution of 24 (442 mg, 0.9 mmol) in

dry dichloromethane (10 mL) containing m-CPBA (1.2

equiv) was stirred under argon atmosphere at room

temperature overnight. The reaction mixture was dilu-

ted with dichloromethane, washed with a solution of

sodium bicarbonate and water. The organic layers were

dried (Na₂SO₄), ®ltered and evaporated to dryness.

Column chromatography (hexane:ethyl acetate, 4:6)

gave 25 as a white solid (377 mg, 77%). Anal. calcd for

C₂₁H₃₃NO₁₁S₂+2/3 H₂O: C, 45.72; H, 6.27; N, 2.54; S,

11.63. Found: C, 45.51; H, 6.34; N, 2.27; S, 11.41. MS

(EI, m/z): (M)⁺539. mp 186±220 ^ꢀC (EtOAc). [a]_d22

(c 1, CHCl₃). IR (KBr): 1795 (NCO), 1735 (OCO-

CH₃). ¹H NMR (250 MHz) d: 1.20, 1.45 (2s, 12H,

C(CH₃)₂), 2.25 (s, 3H, CH₃CO), 2.55±2.70 (m, 2H,

0

H₁₀), 2.85±3.20 (m, 2H, H_{8 ax}, H_{9 ax}), 3.25±3.75 (m, 2H,

1[(1⁰,2⁰-Dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰-(1-sulf-

inyl-3-thiopropane))-^D-2⁰-glucosy]-3ꢀ-ethyl-4ꢀ-(trans-ꢁ-

methylstyryl)-2-azetidinone (38) and 1[(1⁰,2⁰-dehydro-

1⁰,2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-1⁰-(1,3-prop-

anedithio)-^D-2(-glucosyl]-3ꢀ-ethyl-4ꢀ(trans-ꢁ-methylsty-

ryl)-2-azetidinone (39). To a solution of 31 (547 mg,

1 mmol) in dry dichloromethane (2 mL) cooled to

40 ^ꢀC, a solution of iodobenzene dichloride (1.2 equiv)

and dry pyridine (3.5 equiv) in dry dichloromethane

(2 mL) was added. The reaction mixture was stirred for

1 h and brought to room temperature. After 30 min the

0

H_{8 eq}, H_{9 eq}), 3.45 (s, 3H, OCH₃), 3.85±4.25 (m, 4H,

0

H_{4 ±6}), 4.65±5.40 (m, 5H, H_{1 ±3}, H_3±4); ¹³C NMR

(62.5 MHz) d: 26.5, 26.7 (4C(CH₃)₂), 27.4 (CH₃CO),

0

28.2 (C₁₀), 49.5 (C₉), 51.5 (OCH₃), 52.4 (C₈), 52.5

0

(C₂), 67.4 (C₁), 68.1 (C₆), 78.7, 79.1, 79.2 (C₃, C₄C₅),

0

84.4 (2C; C₃, C₄), 109.7, 110.3 (C₇), 168.2 (C₂), 205.4

(OCOCH₃).

0

4ꢀ-Acetoxy-1[(2⁰-dideoxy-3⁰,4⁰;5⁰,6⁰-di-O-isopropylidene-

1⁰,1⁰-dimethoxy)-D-2⁰-glucosyl]-3ꢀ-ethyl-2-azetidinone

(43). This compound was prepared in 30% from 42

850

J. Anaya et al. / Bioorg. Med. Chem. 7 (1999) 837±850

mixture was poured into cold ammonium chloride

solution and extracted with dichloromethane. The

organic layers were dried (Na₂SO₄), ®ltered and evapo-

rated to dryness. Column chromatography (hex-

ane:ethyl acetate, 1:1) gave the compounds 39 (54 mg,

10%) and 38 (338 mg, 60%). Monobactam 39 was also

obtained in 65% yield by treatment of 38 (300 mg,

0.53 mmol) with tri¯uoroacetic anhydride (1.7 equiv)

and dry TEA (3 mmol) in dry dichloromethane (30 mL)

for 6 h.

Cleophax, J.; Gero, S. D.; Chiaroni, A.; Riche, C. J. Chem.

Soc., Perkin Trans. 1 1990, 3211.

3. Georg, G. I.; Ravikumar, V. T. in The Organic Chemistry of

b

Lactams; Georg, G. I. Ed.; VCH: New York, 1993; p 295.

4. (a) Firestone, R. A.; Barker, P. L.; Pisano, J. M.; Ashe,

B. M.; Dahlgren, M. E. Tetrahedron 1990, 46, 2255. (b) Maillard,

J. L.; Favreau, C.; Reboud-Ravaux, M.; Kobaiter, R.;

Joyeau, R.; Wakselman, M. Eur. J. Cell. Biology 1990, 213. (c)

Mascaretti, O. A.; Boschetti, C. E.; Danelon, G. O.; Mata, E.

G.; Roveri, O. A. Current Med. Chem. 1995, 1, 441.

5. Adonias, M.; Anaya, J.; Camara, J.; Canet, E.; Gateau-

Olesker, A.; Gero, S. D.; Grande, M.; Hernando, J. I. M.

Bioorg. Med. Chem. Lett. 1993, 3, 2547.

1

(38): MS (IE, m/z): 563 (M)⁺. IR: 1763 (NCO). H

6. Chiaroni, A.; Riche, C.; Anaya, J.; Gateau-Olesker, A.;

Gero, S. D.; Hernando, J. I. M. Acta Crystallogr., Sect. C

1994, C50, 1474.

7. Ogura, H.; Takayanagi, H.; Kerbo, K.; Furuhata, K. J.

Am. Chem. Soc. 1973, 95, 8056.

8. Schellman, J. A. Acc. Chem. Res. 1968, 1, 144.

9. Kefurt, K.; Kefurtova, Z.; Trska, P.; Blaha, K.; Fric, I.;

Jary, J. Collect. Czech. Chem. Commun. 1989, 54, 256.

10. Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy.

Exciton Coupling in Organic Stereochemistry. University Sci-

ence Books: Mill Valley, 1983.

11. Anaya, J.; Barton, D. H. R.; Caballero, M. C.; Gero, S.

D.; Grande, M.; Laso, N. M.; Hernando, J. I. M., Tetra-

hedron: Asymmetry 1994, 5, 2137.

NMR (200 MHz) d: 0.98 (t, J=7 Hz, 3H, H₈), 1.33,

1.37, 1.43, 1.45 (4s, 12H, C(CH₃)₂), 1.70±1.82 (m, 3H,

0

H₇), 1.92 (s, 3H, CH₃(C=)), 2.21±2.40 (m, 2H, H₁₀),

0

2.50±2.72 (m, 2H, H₉), 3.21±3.40 (m, 2H, H₈), 3.41±

0

3.51 (m, 1H, H₃), 3.81±4.20 (m, 5H, H₂, H_{4 ±6}), 4.35 (d,

0

J_{1 ,2}=12 Hz, 1H, H₁), 4.40 (d, J_4,3=5.9 Hz, 1H, H₄),

0

4.84 (dd, J_{3 ,2}=2 Hz, J_{3 ,4}=8.8 Hz, 1H, H₃), 6.82 (s,

1H, H₆), 7.35±7.50 (m, 5H, H_Ph).

1

(39): MS (IE, m/z): 545 (M)⁺. IR: 1752 (NCO). H

NMR (200 MHz) d: 1.06 (t, J=7 Hz, 3H, H₈), 1.18,

1.29, 1.38, 1.51 (4s, 12H, C(CH₃)₂), 1.65±1.70 (m, 2H,

0

H₇), 1.90 (s, 3H, CH₃(C)), 2.05±2.12 (m, 1H, H_{9 ax}),

12. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 1989.

13. Dutcher, J. D.; Walters, D. R.; Wintersteiner, O. J. Org.

Chem. 1963, 28, 995.

14. Bakuzis, P.; Bakuzis, M. L. F. J. Org. Chem. 1985, 50,

2569.

0

2.70±2.85 (m, 1H, H_{9 eq}), 3.05±3.36 (m, 5H, H₈, H₃),

0

3.80±4.11 (m, 4H, H_{4 ±6}), 4.74 (d, J_4,3=5.7 Hz 1H, H₄),

0

5.20 (d, J_{3 ,4}=8 Hz, 1H, H₃), 6.72 (s, 1H, H₆), 7.25±

0

7.30 (m, 5H, H_Ph).

15. Hernando, J. I. H.; Laso, N. M.; Anaya, J.; Gero, S. D.;

Grande, M. Synlett 1997, 281.

Acknowledgements

16. The tests were performed by Dr. Canet, E., Institut Ser-

vier. 11, Rue des Moulineaux; 92150-Suresnes, France.

17. Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.;

Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K.

R.; Brause, K. A.; Chandler, G. O.; Knight, W. B.; Maycock,

A. L.; Ashe, B. M.; Weston, H.; Gale, P.; Mumford, R. A.;

Andersen, O. F.; Williams, H. L.; Nolan, T. E.; Franken®eld,

D. L.; Underwood, D. J.; Vyas, K. P.; Kail, P. H.; Dahlgren,

M. E.; Mao, J.; Fletcher, D. S.; Dellea, P. S.; Hand, K. M.;

Osinga, D. G.; Peterson, L. B.; Williams, D. T.; Metzger, J.

M.; Bonney, R. J.; Humes, J. L.; Pacholock, S. P.; Hanlon, W.

A.; Opas, E.; Stolk, J.; Davies, P. E. Proc. Natl. Acad. Sci.

USA 1993, 90, 8727.

Financial support of this work by the Junta de Castilla y

Leon (SA22/97) is gratefully acknowledged.

References and Notes

1. (a) Barton, D. H. R.; Anaya, J.; Gateau-Olesker, A.; Gero,

S. D. Tetrahedron Lett. 1992, 6641. (b) Anaya, J.; Barton,

D. H. R.; Gero, S. D.; Grande, M.; Martõn, N.; Tachdjian,

C. Angew. Chem., Int. Ed. Engl. 1993, 32, 867. (c) Anaya,

J.; Barton, D. H. R.; Gero, S. D.; Grande, M.; Hernando,

J. I. M., Laso, N. M.; Tetrahedron: Asymmetry 1995, 6, 609.

2. Barton, D. H. R.; Gateau-Olesker, A.; Anaya-Mateos, J.;

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D-Glucosamine propanedithioacetal, an efficient chiral auxiliary in β-lactam chemistry

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