Tetrahedron Letters NO. 5, _W 409 - 412, 1978. PerZa?on ?ress. Printed in Great BAtaiR.

ClmfICAL TRANSPORXATIOU O? A CEPHALOSPORIN TO A 6-EPI-l-OXACRPRRH1~

C. U. Ri& wui D. 1. McGregor

Research Division, Bristol Lebomtorier Mvision of Bristol-Myerr Comply

Syracuse, New York 13201 USA

(Received in USA 3 October 1977; received in UK for .whlication 6 December 1977)

Replacmt of the sulfur atom at position 1 of the cepblorporia nucleus with oxygen

showed vrable bioactivity to their natural 1-this counterpartr. ‘** lb We demribe

here a very efficient chemical transfonmtion of the dihydrothierine ring of l

cephalosporin 1 into the dihydroonrine ring

The reection of the cephloeporin eater

chloride (1:l) Swe the 2-methoxy cephem k2,

from ether. Treetment of 4 with chlorine in

2 co2R

2 with N-chlororuccioiuide in methenol-methylene

mp 132-133' in 85% yield after recrystallization

cmboo tetrmhloride (2.5 eq, -20°, 60 pi33

followed by 8x1 equeoue work-up gave a quantiative conversion to the aldehyde 2 l II a mixture

of cia and trens isomers (CY chloro@ chloro Z -1 l/9) [ I.R. (RBr) 1795, 1730, 1710 end 1690 cm ;

NNR (CDC13) of zb 6 2.20 (I, 3R, methyl), 4.60 (6, 2?I, $0(X2), 5.70 (q, HI, 34.2, 11.5 Ez,

C-7li), 6.30 (d, lR, J4.2E2, C-6@, 6.8-7.5 (IO, 16E), 10.4 (a, la, Cm); mR (CDC13) of jg

6 2.10 (6, 3H, methyl), 4.60 (I, 2H, a&), 5.10 (q, lR, J-1.2, 10 Rz C-7H), 6.21 (d, lH,

J-l. 282, C-6E), 6.8-7.5 (a, 168) 10.5 (a, lR, CR@].

5 a - a chloro

b - B chloro

410 No. 5

Prcsumbly the chlorinolysis includes initial S-chlorination to give the sulfenyl

chloride 6 followed by further chlorinolysis to the dichloride land subsequeut hydrolysis

to the l ldehyde & In fact, intermediate 2 could be isolated by anhydrous work-up and

quantitatively converted into the aldehyde 2 by contact with uter. It ir uot claar why the

themodymaically less stable S-chloro isomer & is predominant in the reaction mixture.

I Schems Cl-

Cl

4 leq. Cl

>

> 4 1 _ +-cl

1 eq. Cl2 Yl 'u"

A J vl l

t-i / -ad” H3

2l=2

1

+ SC12 "2O > CRC

'ia-

-P / h3

5 2=2

The reaction of the isomsric mixture 2 with ngBF4-414~0 (l:l)la in aethylene chloride

gave the oxaxoloue & in 852 yield [I.B. (XC&) 1780, 1720 and 1680 cm"; mm (CDC13) 6 2.10

(s, 3E, methyl) 4.81 (broad 8, 2H, WA), 5.40 (d, lH, 54.5 Fls, C-7Ii), 6.30 (d, lli, 514.5

Es, C-6E), 6.9-7.8 (m, 16E)3. Treatment of a methylene chloride solution of g with HCl gas

at 0' Save quantitatively the a-chloro isomer &by a stereospecific ring opening. 4

Reduction of l ldehyde 2 with sodium cyanoborohydride5 in THP-acetic acid produced the

alcohol 2 in over 90% yield [I.R. (KBr) 1785, 1700 and 1685 cm -l; turn (CW13) of 9& 6 2.35

(I, 3E, rthyl), 4.21 (d, lH, J-1282, Q+OH) 4.40 (d, lli, J-lZEs, m20H), 4.51 (s, 2H, @WA),

No. 5 411

5.62 (q, lH, 513.9, 9.5Rz, C-7H), 5.90 (d, III, J-3.9Rs, C-6R), 6.7-7.5 (m, 16R)].

closure of &or a mixture of !&and Ewith AgBF4-Ag20 (1:l) in methylene chloride

E"

mve

the 6-epi-l-oxacephem m in 87% yield after silica gel chraatography [I.R. (ICBr) 1785,

1735 and 1685 cm -1

; RMR (CDC13) 6 1.95 (II, 3R, methyl), 4.42 (broad s, SR, C-2@, 4.65 (8;

2?I, ea2), 4.80 (q, ill, J=O.S, 8.7Rs, C-7@, 5.20 (d, lIi, J-O.EHe, C-6R), 6.9-7.8 (m,

17H)]. No trace of the cis isomer m was detected in the resction products by examination

with 100 MRz nmr. This indicates that the intermediate ion 116 generated by Ag+ cyclizes

only from the less sterically hindered a-side and produces exclusively the tram isomer.

Rydrogeuation of m over W/C in dioxane-water gave the free acid m mp 139-141'

[I.R. (RBr) 1785, 1720 and 1670 cm"], which displayed significantly diminished anti-

bacterial activity when compared with 1 (R = WCR2).

CC2CR@2

e a = a chloro

b -B chloro

LpL R-ClW2 (aSa)

robR=CRt+2 (B6a)

m R-H (a 6a)

&& R=H (I3 6rr)

IJo. 5

RHFHHBwcHs:

1. a. L. D. Cam and B. G. Christeneen, & Ika &g+ &g., s 7582 (1974).

b. S. Wolfe, J. B. Ducep, K C. Tin and S. L. Lee, Can J. Chem., a 3996 (1974).

c. Raymnui A. Firestone, J. L. Fahey, N. S. Mwiejewicz, C. S. Patel, and

B. G. Chrirtenren, & M&&. m, & 551 (1977).

2. D. 0. Spry, Tetrahedron Letters, 3717 (1972).

3. S. Kukolja, & APer. ca_gL. &., & 6267 (1971).

4. a. D. F. Cobett and R. J. Stoodley, & &g. &g., Perkin I 185 (1974).

b. Ibid., 432 (1975).

5. IL F. Borch, M. D. Bernstein and H. D. Duret, & Amer. Chem. a, & 2897 (1971).

6. Azetinium ions, analogous to & have been proposed In my instancea.

a. S. Kukolja, & &g. &g. &., & 6270, 7590 (1972).

b. S. Wolfe and M, P. Goeldner, Tetrahedron Letters, 5131 (1973).

c. Also lee references la,3, and 4b.