Tetrahedron Letters No. 46, ?p 4587 - 4590. @Pergwon Press Ltc& 1978. Printed in Great Britain.

A NEW METHOD FOR THE SYNTHESIS OF<-AMINO-&LACTAMS

S.D. Sharma* and P.K. Gupta

Department of Chemistry, Panjab University, Chandigarh-160014, INDIA.

Presence of an&amid0 side chain on a p-lactam is an essential

feature for the antibacterial activity of the Penicillins and Cephalosporins.

Several years ago Sheehan’ demonstrated the use adphthalimidoacetyl chloride

for the formationof whalimido- B

lactams where phthalimido group serves as

the progenitor of the amino- or amido function. Later, Dose and associates*

demonstrated the use of azidoacetyl chloride for making+axido-glactams.

‘fhe asldo group could then be reduced to an amino function. An alternative

to this was then reported by these workers3 mentioning the use of benzyloxy-

oarbonylglycyl chloride for the preparation of<-amido#lactams. However,

the yields of the products in many oases were reported to be in the range of

lo-2% only.

During the course of our investigations towards@ctam antibiotics,

we have explored a new and convenient method for the synthesis ofo(-amino-

8- lactams . An<-aaylamino acid when converted into the corresponding chloride,

always tends to form the azalactone. So, direct synthesis of O(-amido- p-

lactams from imines is not possible. We, therefore, planned to use the enamlne

derivative (1) of an amino acid. Glycine on condensation4 with a 13-

dicarbonyl

compound leads to a product of high stability due to hydrogen bonding. We

have been successful in using this enamine derivative of the amino acid for the

annelation of imines to the corresponding B

-1actams

developed POCl3 method. ’

through our recently

CH I 3

H-f: ~c~N-CH,C06 it RO-CH=N-R9 I

R-C\O...H 2

I (0) R0=kH5 ; R=sH5

I

(a) R=OC2H5

(b) R=CH3

(b) R+-CH30$$$; R%-CH3sH4

(cl RG j R+CH3CgH4

4587

4588

R CH I 3

(a) - C=CHCOOC2H5

(b) H

% (cl - h =CHCOOC2H5

(d) H

(e) PhOCH2C0

(f) fH3

- C = CHCOOC2H5

(9) H

(h) PhOCH2C0

(i) 7”3

-C=CHCOCHf

CH I 3

t u _ RNH-e--E-R’

R’

b-CH30C6H4

No. 46

Ii*

kH3C6H4

bcH3c6H4

b-cH3c6H4

b- cH3c6H4

b-CH3C6H4

One step synthesis of 3-eaamlno-2-azetldinone (3a) was achieved by the

reaction of POClg on a mixture of the potassium salt (la) and the imine (2a)

in the presence of triethylamlne. Thus the reaction is carried out by the slow

addition of POC13 (one mole) to a mixture of one mole each of the potassium

salt and the imine alongwith two moles of triethylamlne in dichloromethane.

Obviously there is no need of making any acid chloride or mixed anhydride

of the acid component. Moreover, the yields of the products are in the range

of 35 to 4% or higher. Similarly the enamido-glactams (3~) and (3f) could be obtained from the salt (la) and imines (2b) and (2~) respectively. We were

also suocessful in reacting (lb) with (2b) to obtain (31) in 35% yield. In

all of these cases we obtained the cis stereochemistry of the I3 -1actams as

shown by the NMR spectrum. The CI-H appeared as a doublet in the range of

w.8505.02 with the required cls coupling (J=5-6 Hs). Further eonfirmatlon of their structures as well as 01s stereochemls-

try became apparent by converting them into the aorrespondlng 3-amino- or

3-amide-p-lactams. Thep-dicarbonyl function in (3a, 3c, 3f and 31) was easily cleaved by stirring the compounds In a mixture of ethanol-HCl (2:l) at room

temperature. Thus (3a) gave (3b) In high yield and was found identical to

the one already reported.2 Theo&amino-~ lactam (36) obtained after removing

the proteoting group from (3e) or (31) was acylated with phenoxyacetyl &lorMe to give phenoxyacetamido- -1actam B

(38). The aom ound E

(30) is identical in

all respects to the compound synthesised earlier having a cis stereochemistry

of H-3 and E-4.

This method was also successful in synthesising the bicyclic systems.

The cepham (4) lsas obtained from the oorresponding 3,4-dihydroisoqulnollne7

and (la) in 45% yield. Its structure was confirmed by IR and NMR spectra.

Treatment of (4) with HCl in ethanol easily converted this compound into the

l+llno-cepham (5). The oepham (5) obtained by this method was identical with one prepared through the azidoacetyl ahloride method.8 By using

different N-protected amino aoids the present method should result in the

stereospecifio synthesis of a variety of new B -1actams.

All the new compounds reported In this communication showed satisfactory

elemental and spectral analysis.

Aoknovledgementr We are thankful to CSIR, New Delhi for the award of JRP

to (Pm).

REFERENCES

1. J.C. Sheehan and P.A. Crulckshank, J.Am. Chem. Sot., & 3680 0956).

2. A.K. Dose, B. Anjaneyulu, S.K. Bhattaoharya and M.S. Wanhas,

Tetrahedron,_& 4769 0.967).

4590 No.

3.

4.

5.

6.

7.

8.

A.K. Bose, H.P.S. Chawla, B. Dayal and M.S; Manhas, Tetrahedron Lett.,

2503 (1973).

Elisabeth Dane, Fritz Dress and Peter Konard, Chemical Abstracts,

59, 1754 (1963).

S.D. Sharma, Gurdlal Singh and P.K. Gupta, Indian J. Chem.,

12, 740978).

A.& Bose, M.S. Manhas, H.P.S. Chawla and B. Dayal, J. Chern* sot** Perkin 1, 1880 (1975).

S.D.

16B,

A.K.

2193

(Received in USC 12 September 1978)

46

Sharma, (Miss) Usha Mehra and P.K. Gupta, Indian J. Chem.,

461 (1978).

Bose, S.G. Amln, J.C. Kapur and M.S. Manhas, J. Chem. Soc.,Perkin 1,

(1976).