Structure and absolute configuration of a penam derivative

Abstract

p-Nitrobenzyl 6-(1-tert-butyldimethylsiloxyethyl)-3-methylthio-3-nitromethyl7-oxo-4-thia1-azabicyclo[3.2.0]heptane-2-carboxylate, C23HaaN3OsS2Si, M r = 571.75, monoclinic, P2 l, a = 8.6734 (16), b = 10.420 (7), c = 16.785 (4)A, t = 93.75 (2) °, V = 1513.7/~ 3, Z = 2 , D x = l . 2 5 4 M g m -3, ,;L(CuKet)= * To whom correspondence should be addressed. 0108-2701/86/040442-04501.50 1.54178 A,/2 = 2.33 mm -~, F(000) = 604, T = 293 K, R = 0.061 for 1548 observed reflections. The absolute configuration was established. The main feature of this molecule is the bicyclic system related to that of penicillin. The five-membered ring, in the envelope conformation, shows a strong distortion when compared to carpetimycin or thienamycin. The fourmembered ring is not planar and has torsion angles of + 10 ° as in the other two related compounds. © 1986 International Union of Crystallography ANGELO BEDESCHI et al. 443 Introduction. The fl-lactam group of antibiotics continues to offer veritable challenges in chemistry, biology and medicine. The discovery of thienamycin (AlbersSch6nberg, Arison, Kaczka, Kahan, Kahan, Lago, Maiese, Rhodes & Smith, 1976; Kahan, Kahan, Goegelman, Currie, Jackson, Stapley, Miller, Hendlin, Mocharles, Hernandez & Woodruff, 1976), one of a potent class of novel fl-lactams possessing unique structural and functional features, has fostered many new efforts in the synthesis of related types (Kametani, 1982; Ratcliffe & Albers-Sch6nberg, 1982). Concurrently, the pioneering work of the late R. B. Woodward (1977, 1978) and his coworkers (Ernest, Gosteli, Greengrass, Holick, Jackman, Pfandler & Woodward, 1978) has led to the synthesis of an unsaturated penicillin nucleus called penem. Combining the functional features of the carbapenems such as thienamycin, with the Woodward penam structure led intuitively to a 'hybrid penem', exemplified by expression (1) (FCE 22101) (Franceschi, Foglio, Alpegiani, Battistini, Bedeschi, Perrone, Zarini, Arcamone, Della Bruna & San Fillipo, 1983) (Scheme 1). Several approaches and syntheses of this and related penems have been reported recently (Battistini, Scarafile, Foglio & Franceschi, 1984; Perrone, Alpegiani, Bedeschi, Giudici & Franceschi, 1984; Afonso, Hon, Weinstein, Ganguly & McPhail, 1982). Our synthesis of (1) (Hanessian, Bedeschi, Battistini & Mongelli, 1985) represented a tactically and operationally novel approach in which one of the crucial steps involved an intramolecular Michael reaction to produce the chiral bicyclic derivative (2). Interestingly, not only had this eyelization taken place with high stereoselection, but the seemingly more stericaUy demanding isomer had been formed as was evidenced from the X-ray analysis. Experimental. Recrystallization from a diisopropyl ether solution, m.p. 376-378 K, crystal size 0.04 x 0.20 x 0 .50mm, unit-cell dimensions from 25 well centered reflections, 13 1.96tr(/) retained for structure determination and refinement. Lp correction, no absorption correction, direct methods ( M U L T A N ) , * block-diagonal least squares based on F, anisotropic for all non-H atoms, H atoms found on difference Fourier synthesis, H atoms held at a fixed distance, 0.95 A, from their respective C atoms and given an isotropic temperature factor of 6.0 A 2 (B = 8.0 A 2 for methyl H atoms). Function minimized Y w( I F o I I F c I )2. Final R = 0.061, wR =0 .066 and S = 1.97 using weights derived from counting statistics. Maximum (A/a)=0.40 , average (A / t r )=O.12 , electron density fluctuation on final difference Fourier synthesis -0 .21 and +0.28 e A -a. The real and imaginary parts of the anomalous dispersion for Si and S were included in the structurefactor calculation. The absolute configuration which was thus established corresponds to the set atomic coordinates presented in Table 1 since for the antipode of structure (2) the above indicators take the values of R = 0 . 0 6 2 , w R = 0 . 0 6 8 and S = 2 . 0 1 . Scattering curves for non-H atoms from Cromer & Mann (1968), those for H from Stewart, Davidson & Simpson (1965). Anomalous-dispersion coefficients f ' and f for Si and S given by Cromer & Liberman (1970).