4324 debenzoylation of 4a a n d Sa with methanolic ammp >190" dec: picrate nip 145-147" (1it.I nip 143monium hydroxide followed by heating the resulting 144"); A ~ 259 ~ ~n n i ~ ( E " 15,000): nnir (pyridinenucleosides 4b and 5b in dimethylformamide at 140" d:) 5.03 (d, 2 , J H , I ; = 8.5 H z , C;,(HZ), 5.25 (9, 1, JIf,?. = for 16 hr. Under these conditions, 4b, like nucleocidin 2 Hz, J2',3' = 6 Hz, CStH), 5.56 (4,1, J?,,3! = 6 Hz, J3',I> itself, formed a n ionic N3,5' cyclonucleoside character= 17.5 Hz, C3!H), 6.94 (d, I , J l ! , ? ! = 2 Hz, CIcH), ized by its uv spectrum ,A,(, 274 nm) and its electro8.24 (br s, 2, C6NH2),8.49 a n d 8.51 ppm (s, 1, C,H a n d phoretic mobility, while 5b remained unchanged. C8H) as described for nucleocidin.? The antibacterial spectrum of synthetic 8 was very similar t o what has While the iodo function of 4a was readily removed by been reported for natural nucleocidin. catalytic hydrogenolysis giving the corresponding 5'deoxy-4'-fluoronucleoside with, , A, 250 ( E 22,300), 273 The above series of reactions has also been carried out i n the a-L-lyxofuranosyl series starting with 5. nm ( E 16,800); nmr (CDC13) 1.65 (d, 3. J H , F = 17 Hz, These results, together with the preparation of some C,/H,) 6.30 (br s, 1, J1),?t'v 1 Hz, CITH),8.13 and 8.69 analogs of nucleocidin, will be described in full at a (s, 1, C2H a n d CxH), its nucleophilic displacement later date. proved t o be very difficult. None of the oxygen nucleophiles tried proved satisfactory but reaction of 4a (1 1 ) Syntex Postdoctoral Fellow, 1969-1971. with lithium azide in dimethylformamide at 100" for 20 I. D. Jenkins," J. P. 11. Verheyden, J. C. Moffatt* hr followed by debenzoylation with methanolic amCoiitributioii No. 90 monia gave 5'-azido-5'-deoxy-4'-fluoro-2',3'-0-isolirstifirte of Molc,cular Biology, Syiitex Research propylideneadenosine (6) in 93 yield: 258 Ptrlo Alto, Coliforiritz 94304 nm ( E 13,300);, ,A, (KBr) 4.70 y (N3); ninr (CDCI3) Receiced Julie 17. 1971 3.61 (d, 2, J H , F = 13.5 Hz, CjIHC), 5.58 (9, l,JCl,B' = 6 Hz, J31,F = 12.5 Hz, C,(H), 6.38 (s, 1, C1/H), 7.93 and 8.41 ppm (s, 1, C 2 H and CsH).' While catalytic reduction 6-Methyl Penicillins and 7-Methyl Cephalosporins of the azido function of 6 and its N'i-benzoyl derivative t o the corresponding 5'-aniino-4'-fluoronucleosides Sir: was readily achieved, subsequent attempted deaniinaIt has been well established',? that penicillins and tion with nitrous acid led t o complex mixtures. cephalosporins inhibit bacterial cell-wall synthesis by Conversion of the azido function of 6 to the desired interfering with the final cross-linking process, which hydroxyl group was achieved by ultraviolet irradiation has been termed transpeptidation and involves an amino of a benzene solution of 6 in a Pyrex apparatus.8 The group i n a peptidoglycan molecule and the D-ahnylresulting intermediate 5'-imine was hydrolyzed t o the D-alanine end of the acetyl -muraniyl pentapeptide 5'-aldehyde by brief acidic treatment and then directly fragment i n another. It has been suggested that the reduced with sodium borohydride giving 4'-fluoro-2', chemical structures of both penicillins and cephalo3'-0-isopropylideneadenosine(7a) with nip 225-226" sporins can mimic this D-alanyl-o-alanine residue and from methanol: '';A:: 258 n n i ( E 13,200); O R D thereby inhibit (irreversibly) the enzyme transpeptidase (MeOH) negative Cotton effect with [@]?2$' - 2000", responsible for the cross-linking. 6-Methyl penicillins 0", and [@]2aoPk +3800"; nnir (pyridine-d,) 4.19 and 7-methyl cephalosporins have been proposed' as (d, 2, J H , F = 9.5 Hz, CA'H?), 5.90 (9, I , Jer,a, = 6 Hz, more analogous t o D-alanyl-o-alanine than their parent J3f,F= 12 Hz, Ca,H), 6.90 (s, I , C1!H), 8.45 and 8.56 molecules, since both classes bear a niethyl group in the ppni (s, I , C,H and CaH). same position a s is found i n the D-alanyl residue. It has The reactions of 7a with sulfamoyl chloride using been suggested that they may, therefore, show enhanced either pyridine or sodium hydride as baseg gave the 5'effectiveness as antibacterial agents. T o examine this sulfamate 7c in low yields. If, however, 7a was first hypothesis, we habe synthesized both a 6-methyl penitreated with an excess of bis(tributy1tin) oxide in recillin and a 7-methyl cephalosporin. fluxing benzene with azeotropic removal of water it was 6-Methyl-6-phenylacetamidopenicillanic acid, methyl converted into the corresponding 5'-0-tributyltin ether ester (V) was prepared by the following sequence of reac(7b). Without isolation this conipound was treated'O with sulfanioyl chloride at 5" for 10 min giving the 5 ' 0-sulfamate 7c i n 8 7 z yield as the hydrate with mp 162-165" from water: X ~ ~ ~ , "259 " nm ( E I5,SOO); nmr (pyridine-&) 4.9 (,ABX multiplet, 2, CjfHZ deI. R = a-H shielded 0.70 ppm relative t o 7a), 5.92 (q, l , J.f,a( = 11. R = a-CH 6 Hz, J3p,F= 12 Hz, C,.H), 6.86 (s, I , CIfH), 8.46 a n d Ill. R S-CH 8.51 ppm (s, 1, C ? H and C8H). Treatment of 7c with 9 0 % trifluoroacetic acid at 23" for 30 min gave 4'- tions. Treatment of N-benzylidene-6-aiilinopenicilfl u or 0-5 '- 0 - s ul fa m oy1a den osi ne (8) as the m on oh yd r a t e lanic acid, methyl ester ( I ) with 1 equiv of sodiunihydride in 6 0 % yield after two recrystallizations from water: and excess methyl iodide in dimethoxyethane at 0" gave a mixture of epimeric 6-methyl derivatives [II, 90% yield; ninr (CDCla) 522 (s, 1 H), 322 (s, 1 H), 108 (s, (8) Photochemical conversions of primary sugar azitlcs to aldehydes have been described: D. Horton, A . E. Luetzow, and J . C. Wease, 3 H) H z ; 111, 5 % yield; nmr (CDCI:,), 516 (s, 1 H), Carbohj d. Res., 8, 366 (1968). 329 (s, 1 H), 268 (s, 1 H) Hz]. Crystallization from (9) These methods have been successfully used for sulfamation of dichloromethane-hexane gave white, solid I 1 (nip 83.2',3'-O-isopropylideneadcnosine: D. A. Shuman, M. J. Robins, and R . I
