A novel synthetic approach to N-unsubstituted β-lactams

Tetrahedron Printed in

Letters,Vol.26,No.35,pp Great Britain

A NOVEL SYNTHETIC

APPROACH

Fernando Kimika Organikako

-B-lactams

Synthesis

P. Cossio and Claudio Palomo* Kimika Fakultatea.

Altza.

simple route to N-unsubstituted

of N-unsubstituted

B-lactams

of the third generation

easily synthesized

Bose’ have reported

Donostia.

B-lactams

monocyclic

that permanganate

have received

of 8-lactam

Euskal Herriko

Spain.

is described.

6-lactams

RL.Ph

RbR2

Formation

CrN+Ph

attention

of unusual N-styryl-

of 6-lactams

approach

6-lactams

prepared

by reaction

Schiff base 12, formed

ethanolamine

was treated

trate/DBU

= l/2) and the resulting

off. After

in benzene

B-lactam -lla was of phenoxyacetic acid fi and from anisaldehyde

silyl ether

with sodium iodide/trimethylchlorosilane

as solvent mixture

with 1,8-diazabicyclo was refluxed

work-up the crude N-styryl-8-lactam

free hydroxy

B-lactam

in refluxing

affording

the N-unsubstituted

R1

B-lactam 2

acetonitrile

for 25 min,

-10a in 88% yield. The crude iodo(5.4.0)undec-7-ene (DBU) (molar ratio, subswas fil-

& was “in situ” oxfdized by means of potassium

Ph 3

4235

Only

8-lactam

for 30 min; then, the DBU.HI precipitated

(40% overall

R2

v o-N.&

reagent.

lla or its trimethyl5 (molar ratio

yield -11+5 after recrystallization m.p. 167-168QC, NMR Gppm: 8.5,5.6 and 5.1 JAB = 5 Hz, JAX = 2 Hz, JBX z 0 Hz).

ganate

and 2-phenyl-

yield (m.p. 175-177gC).

of the resulting

gives the corresponding -compound

example

in 91% isolated

= l/3/3)

(Analysis 21,

from the readily available

Treatment

substrate/NaI/C1SiMe3

the

we have found that

13, induced by phenyl dichlorophosphate

a single isomer was obtained

6-lac-

2 leads to an unusual

group interconversion,

13. In a typical

by our method4,

4-carboxy-

2. Unfortunately,

8-lactams

3 can be easily synthesized

2-phenylethanolamine

the silylated

B-lactams

of these

9 (Analysis 1). However,

the vinylamine

in conManhas and

that under the same conditions

by means of a simple functional these

therefore,

derivatives.

of type 1 give the corresponding

the N-unsubstituted

disconnection

synthon,

N-unsubstituted

2. We expected

tams 3 afforded

in the past few years and specially

We have been interested,

to the corresponding

oxidation

direct

increased

antibiotics’.

-azetidinones

tered

B-LACTAhd

is the key of the method.

with the advent verting

TO N-UNSUBSTITUTED

Departamendua,

Unibertsitatea. Abstract: A convenient

0040-4039/85 $3.00 + .oo al.985 Perqamon Press Ltd.

4235-4238,1985

perman-

from ethanol,

4236

Table

. 8-lactams

Compound g

prepared

% Yield

lH-N.M.R.

M;ls;‘“,C) a

data (6 ppm, CDC13)

1.

-10a

85

146-150

7.4-6.6(m,14H,arom.); 5.3(d,J= 5 Hz,lH,COCH); 5.4-4.8(m,lH,CHBr) 5.l(d,J= 5 Hz,lH,NCH); 4.3-3.4(m,2H,CH2); 3.7(s,3H,OCH3)

3a

90

168-171

7.4-6.7(m,15H,=CH,arom.); 5.8(d,J= 14 Hz,lH,=CH); lH,CH); 5.2(d,J= 5 Hz,lH,CH); 3.7(s,3H,OCH3)

5a

62

165-166 (166-167)

-lob

86

184-185

7.3-6.5(m,15H,arom.); 5.5-4.8(m,lH,CHBr);

3b

98

160-164

7.3-6.6(m,16H,arom,=CH);

sb

77

-1OC

64

193-196

94c

syrup

c

b

5 Hz,

see text

5.2(d,J= 174-176

5.4(d,J=

5.4(d,J= 5 Hz,lH,CH); 5.l(d,J= 4.4-4.0,3.7-3.2(m,2H,CH2Br) 5.8(d,14H,=CH);

5.4(d,J=

5 Hz,lH,CH); 5 Hz,lH,CH);

5 Hz,lH,CH)

7.3-6.4(m,llH,arom,NH);

5.4(dd,J=

2 Hz,J’= 5 Hz,lH,CH);

4.9(&J=

5 Hz,lH,CH) 7.6-6.5(m,13H,arom.); 5.5-4.9(m,lH,CHBr);

5.3(d,J= 5 Hz,lH,CH); 4.5-3.4(m,2H,CH2CBr);

5.l(d,J= 5 Hz,lH,CH); 3.6(s,3HVOCH3)

7.6-6.5(m,14H,arom,=CH); 5.9(d,J= 14 Hz&H); 5.5(d,J= 5 Hz,lH, CH 2); 5.2(sb,2H,CH E; lH,CH Z); 3.7(s,3H,OCH3 E); 3.5 (s, 3H, OCH3 Z)

4oc

8.3(sb,lH,NH); 7.5-6.3(m,8H,arom.); Z); 4.7(d,J= 2 Hz,lH,CH E); 4.6(d,J=

5.l(dd,J= 5 Hz, J’= 2 Hz,lH,CH, 2 Hz,lH,CH E); 4.5-4.7(unresol-

ved signal,lH,CH

E); 3.2(s,3HFOCH3

Z); 3.4(s,3H,OCH3

Z)

-17d

50 d

142-144

7.3-6.4(m,16H,arom,NH); 5.5(dd,J= 5 Hz,J’= 10 Hz,lH,CHCO); 4.8 d,J= 5 Hz,lH,CH); 5.1-4.7(m,lH,CH); 4.2(d,J= - 14 Hz,lH,OCHCO); 3.9(d,J= - 14 Hz,lH,OCHCO); 4.0-2.9(m,2H,NCH2)

-19d

64e

165-167

7.6-6.3(m,17H,arom,NH,=CH); 5.8(d,J= 16 Hz,lH,=CH); Hz,J’= 10 Hz,lH,CHCO); 5.2(d,J= 5 Hz,lH,CH); 4.3(d,J= OCHCO); 4.0(d,J= - 14 Hz,lH,OCHCO)

-20d

80

-17e

47d

128-130

-19e

53e

146-147

-20e

75

5.6(dd,J= 5 - 14 Hz,lH,

7.3-6.4(m,12H,arom,NH,NH); 5.6(dd,J= 5 Hz,J’= 10 Hz,lH,CH), 5.6 d,J= 5 Hz,lH,CH); 4.3(d,J= - 14 Hz,lH,OCHCO); 4Nd,J= - 14 Hz, lH,OCHCO) 7.4-6.5(m,15H,arom,NH); 5.5(dd,J= 5 Hz,J’= 16 Hz,lH,CHCO); 4.8 d,J= 5 Hz,lH,CH); 5.2-4.7(m,lH,CH); 4.3(d,J= - 14 Hz,lH,OCHCO); 4.2(d,J= - 14 Hz,lH,OCHCO); 3.7(s,3H,OCH3); 4.3~29(m,2H,NCH2); 2.2(Sb,lH,OH) 7.3-6.5(m,l6H,arom,NH,=CH);

5.8(d,J=

16 Hz,lH,=CH);

Ly(dd,J= 5

Hz,J’= 10 Hz,lH,CHCO); 5.2(d,J= 5 Hz,lH,CH); 4.3(&J= -14 Hz,lH, OCHCO); 4.l(d,J= - 14 Hz,lH,OCHCO); 3.7(s,3H,OCH3) 154-155

7.3-6.4(m,llH,arom,NH,NH); 5.5(dd,J= 5 Hz,J’= 19 Hz,iH,CH); 4.9 (d,J= 5 Hz,lH,CH); 4.3(d,J= -14 Hz,lH,OCHCO); 4.l(d,J= -14 Hz,lH, OCHCO);

3.7(s,3H,OCH3)

a) A single spot was detected by tic analysis except for & which showed two spot corresonding to Z and E c) both isomers Z (25%) and E (75%) were obisomers; b) A.K. Bose et al. Tetrahedron Lett. 3851 (1973); d) overall yield from the correspontained after work-up. The Z-E ratio was determined by pmr analysis; ding imine 14; e) overall yield from 17 ; f) A.K. Bose et al. Synthesis 543 (1979); g) for preparation of 6-lactams 11 see ref. 4.

4231

Analysis

2

FGI

. .. ... 1,11,1*1

+

iv,v

-11

,fl.

vi

vii

)3

H 5

12

RI Rl

i: C1SiMe3/NEt3/CH2C12/r.t.;

& R2 : C6H5 : C6H50 a R2 : ‘bCH30C& : Phthalimidoyl 2 R2 : 4-CH30C6Hq iii: H20;

ii: R’CH2COOH/NEt3/PhOP(0)C12;

iv: C1SiMe3/NEt3/CH3CN/r.t.;

v:NaX/ClSiMeS/reflux;

vizDBU/Bz/reflux;

vii: Mn0,K/(CH,)2CO/H20. An alternative treatment

analogous

of 8-lactam

the corresponding

procedure

can be also developed

11 with phosphorus

bromide g

vent gave the expected

tribromide

from the corresponding

molar ratio 1:2, in refluxing

in 60-85% yield. Dehydrobromination

N-styryl

8-lactam

2 in 95% yield. Selected

of g

bromides

benzene

by means of DBU in the same sol-

examples

were prepared

by this

as shown in the Table. It is worthy of note that, Schiff bases 12 involving

a bulky silyl ether

groups’

of the N-unsubstituted

allows an stereospecific

The wide utility none, a compound

-1actam

reported

15 as single stereoisomer.

predominated.

trimethylsiloxy The vinylamino

E which was directly

However,

we have found that the desired dibromide’

thus, the potassium

B-lactams

2.

salt of (cr-methyl-B-metho-

with phenyl dichlorophosphate4

group of 15 was cleaved acylated

method

and phenyl

of 3-phenoxyacetamido-4-phenyl-2-azetidi-

Shiff base 14 to form the corresponding

very low yield of the corresponding

ment of 17 with triphenylphosphine mination

activity7;

acid 13 was allowed to react

of the corresponding

tribromide

1_1as precursors

by the synthesis

to show anti-9-lactamase

ce the free amino compound phosphorus

of 9-lactams

of our method is exemplified

xycarbonyl)-vinylaminoacetic in the presence

formation

lfJ(X:Br),thus,

for 15 min affords

bromides

a-vinylamino+

under mild acid condition

to 17. When 11 was subjected bromo compound

and triethylamine

18 was obtained

18 can be obtained

at OQC for 30 min in dichloromethane

to produ-

to bromination

with

and side reactions

in high yields by treatas solvent.

Dehydrobro-

of -17 by means of DBU and permanganate oxidation of the N-styryl-6-la&am -19 affords the N-unsubstituted a-lactam s in excellent yield. An additional important aspect is that analytically pure products

4238

2 E- CH2 -COOK +

2) NaOH

1)PhOPOC12/NEt3/CH2C12

(>ze3

2) H20

‘t -

-16

-17

Mn04

d R: PhOCH2

are obtained

R2: C H

6 5

_e R: PhOCH 2

by very easy work-up in all sequences

prove to be a useful alternative

REFERENCES

strategy

2

R : C6H40CH34

of the method.

to other recent

methods

Therefore, developed

the method

described

here may

for the same purpose’.

AND NOTES

1. Considered as Reagents and Synthetic Methods 50. This work was in part supported by GEMA S.A.-LIESSA S.A. (Spanish). A grant from Ministerio de Education y Ciencia to F.P. Cossio is gratefully acknowledged. We are grateful to BASF S.A. (Spanish) for financial support (supply of triphenylphosphine). 2. a) R.B. Morin, H. German, Ed. “Chemistry and Biology of 8-Lactam Antibiotics” Academic Press, Vol. 1, New York, 1982; b) P.G. Sammes, Ed. “Topics in Antibiotic Chemistry” Vol. 3, Ellis Howood Ltd. 1980; c) J. O’Sullivan, E.P. Abraham, “Antibiotics” Vol. IV, Ed. J.W. Corcoran, Springer-Verlag, Berlin, 1981. 3. A.K. Bose, M.S. Manhas, S.G. Amin, J.C. Kapur, J. Kreder, L. Mukkavilli, B. Ram, J.E. Vicent, Tetrahedron Lett. 2771 (1979). 4. a) J.M. Aizpurua, I, Ganboa, F.P. Cossio, A. Gonzalez, A. Arrieta, C. Palomo, Tetrahedron Lett. 25, 3905 (1984); b) A. Arrieta, F.P. Cossio, C. Palomo, Tetrahedron, 41, 1703 (1985). 5. a) G.A. Olah, S.C. Narang, G.B. Gupta, R. Malhotra, J.Org.Chem. 44, 1247 (1979); b) idem, J.Org.Chem. 45, 1638 (1980). 6. We are continuing to study the scope of the method and its utility from bulky chiral Schiff bases 12 according to the observations of Manhas and Bose; see A.K. Bose, M.S. Manhas, J.M. Van der Veen, S.S. Bari, D.R. Wagle, Tetrahedron Lett. 26, 33 (1985) and ibid “Recent Advances in the Chemistry of E-Lactam Antibiotics” Third International Symposium, 1984, The Royal Society of Chemistry,Burlington House, London. 7. British Patent, 1301’720 (1973); Chem. Abs. 76, 723809 (1973). 8. L.Horner, H.Oediger, H.Hoffman, Justus Liebigs.Ann.Chem. 626, 26 (1959). 9. a) D.R.Kronenthal, C.Y.Han, M.K.Taylor, J.Org.Chem. 47, 2765(1982); b) A.K.Bose, M.S.Manhas, J.E.Vincent, K.Gala, I.F.Fernandez, J.Org.Chem. 47, 4075(1982); c) T.Fukuyama, A.A. Laird, C.A. Schimdt, Tetrahedron Lett. 42, 4709 (1984).

(Received

in

UK 25 June

1985)