J.C.S. CHEM.COMM.,1981 A New Rearrangement of a 4-Mercaptoazetidin-2-one oia a Thioaldehyde Intermediate By JACK E. BALDWIN,* JUNG, and JOHN KITCHIN MANKIL (Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY) Summary The 4-mercaptoazetidin- 2-one (4) was prepared by a short and efficient route from phthalimidopenicillin methyl ester, and its pyrolysis provided a new y-lactam (7a) stereospecifically via an ene reaction of a thio-aldehyde. DURINGthe course of studies on the biomimetic synthesis of penicillins we wished to examine the Michael closure of mercaptoazetidinones, such as (4), which was invoked in an early biosynthetic scheme for these substances.l To provide a suitable substrate for these studies we converted the sulphoxide (1) of methyl phthalimidopenicillinate, via the seco-thioester (2) (80y0, acetic anhydride, trimethyl phosphite) into the conjugated derivative (3) (65y0,triethyl-amine in CHCl,, m.p.210-211 0C).3 Deprotection of the thioester (3) was achieved by sequential treatment with mercury(I1) acetate (1 equiv., acetic acid) and then reduc- tive cleavage of the mercury derivative (hydrogen sulphide Allin CH,Cl,) to yield (4) [61%, m.p. 176 "C (de~omp.)].~ our attempts to effect ring closure of (4) to the known phthalimidopenicillin methyl ester (5),under acidic, basic, or free radical (azobis-isobutyronitrile) conditions have failed (limit of detection ca. 0.1%). The penicillin (5)was shown to be stable under all reaction conditions tested.However in the course of these experiments we uncovered an interesting reaction of this mercaptan (4) as follows. On pyrolysis (1 76 "C, under N,, 10 min) it was cleanly converted into the y-lactam (7a) [60y0,m.p. 204-208 "C, i.r. (CHCl,) : 0-0 I C02Me 0 C02Me (3) H I IC02Me C02Me (5) 1.SCHEME Ft = phthalmido. Ft.y/fHH (41 J.C.S. CHEM. COMM., 1981 3400, 1700, 1730, and 1720 cm-l; lH n.m.r. (CDCl,, 300 MHz) :6 1-91 (d,J 9 Hz, lH, SH), 1.96 (s, 3H, vinyl-Me), 3.87 (s, 3H, ester Me), 4.49 (dd, J 11 and 9 Hz, lH, 4-H, 0F;* \c tram), 4-74 (d, J 11 Hz, lH, 3-H), 5.36 (m, 2H, =CH2), 6.44 (br s, lH, NH), and 7-79 (m, 4H, ArH);addition of D20 led to deuterium exchange of the peaks at 6 1-91 and 6.44, while the dd at 8 4.49 collapsed to a broadened d, J 11 Hz ; m.s.(70 eV), m/e 360 (M+)]. Acetylation of (7a) (acetyl bromide, 25 "C) gave the ester (7b) [98%, m.p. 247-249 OC, i.r. (CHC1,): 3400, 1770, and 1720 crn-l; lH n.m.r. (CHC1,): 6 1.93 (s, 3H, vinyl-Me), 2.35 (s, 3H, CH,COS), thioaldehyde 3.85 (s, 3H, CQCH,), 5-02 (m, 4H, =CH,, 3-and 4-H), 6.62 ene (br s, lH, NH), and 7.75 (m, 4H, ArH); m.s. (70 eV),m/e 402 (M+)]. The stereochemistry at C-4 and C-5 in these products was determined by a nuclear Overhauser effect Ft (n.0.e.) on 3-H (+13%) on irradiation of the vinyl methyl. There was no n.0.e. on 4-H under these conditions. We rationalize this result as depicted in Scheme 2. Thus preliminary thermal opening of (4) to the thioaldehyde (6) provides an intermediate which by an 'ene' type reaction directly yields the y-lactam (7a).6 The stereochemical out- (7) come is presumably the result of the directing effect of the a; R=H, C-3 phthalimido substituent. We thank Lady Richards for assistance with the n.0.e.b; R=Ac experiments. SCHEME (Received, 13th March 1981; Corn. 286.)2 1 H. V. R. Arnstein and J. C. Crawhall, Biochem. J., 1957,67, 180. However tracer experiments have disproved the in vivo validity of this suggestion: cf. P. A. Fawcett, J. J. Usher, J. A. Huddleston, R. C. Bleaney, J. J. Nisbet, and E. P. Abraham, Biochem. J., 1976, 157, 651. The realization of this Michael reaction from phthalimidoanhydropenicillin has been claimed: cf. S. Wolfe, R.N. Bassett, S. M. Caldwall, and F. I. Wasson, J. Am. Chem. SOC.,1969, 91, 7205. 3 L. D. Hatfield, J. Fisher, F. L. Jose, and R. D. G. Cooper, Tetrahedron Lett., 1970, 4897. 4 Similar mercaptoazetidinones have been made by other procedures: cf. R. Lattrell, Angew. Chem., Int. Ed. Engl., 1973, 12, 925; M. D. Bachi and 0.Goldberg, J. Chem. SOC.,Perkin Trans. 1, 1974, 1184; J. E. Baldwin and M. Christie, J. Chem. SOC.,Chem. Commun., 1978, 239; M. Narisada, H. Onoue, M. Ohtani, F. Watanabe, T. Okada, and W. Nagata, Tetrahedron Lett., 1978, 1755; T. E. Gunda, I. Lakatos, E. R. Farkas, J. Cs. JBszberhyi, J. Tam&, and M. MBk, ibid., 1979, 2929. 5A similar y-lactam was obtained by direct base-catalysed rearrangement of penicillin sulphoxides: cf. J. E. Baldwin, S. R. Herchen, G. Schulz, C. P. Falshaw, and T. J. King, J. Am. Chem. Soc., 1980, 102, 7815.