1697crystals which had formed were separated by fitration and washed with a little cold cyanomethane. Chromatography on a 1 in. X 18 in. CC-7 silica gel column (CH2C12) gave yellow needles from the yellow-orange band. Recrystallization from cyanomethanewater afforded 420 mg (68%) of 10: mp 173-174 "C; NMR (CDClJ 6 7.67 (m,5, CsH5), 8.72 (d, 1, 8.80 (d, 1, H-4); UV max (ether) 268 nm (t 38600), 295 (43400), 322 (sh, 9650), 422 (3380); mass spectrum, m / z 383.8676 (M' calcd for C1&7N279Br23SC1: 383.8666), with the natural abundances of %r, 81Br, %C1, and 37Cl. 7-Bromo-and 5,7-Dibromo-2H-cyclopenta[ dlpyridazine (11). To a stirred solution of 230 mg (1.95 mmol) of 2H-cyclopenta[d]pyridazine8 in 60 mL of cyanomethane cooled by a dry ice bath was added a solution of 357 mg (2.01 mmol) of NBS7 in ca. 15 mL of cyanomethane over a period of 1 h. TLC (9:l CH2C12-ether) showed three components, one corresponding to starting material. NMFt indicated a 253 ratio for starting material and the two products, respectively. Additional NBS solution was added slowly with periodic TLC monitoring until no starting material was present [ca. 200 mg (1.12 "01) of NBS]. A mixture of the products was isolatd by solvent removal (rotary evaporator) and chromatography 011 a 1 in. X 2 in. CC-7 silica gel column (CH2C1J. The separation of the products was accomplished with difficulty on an analytical TLC plate with %lo CH2C12-acetone. The 7-bromo compound was removed with ether and amounted to 29.
The general problem of the synthesis of compounds containing chiral methyl groups adjacent to an asymmetric centre is addressed for the specific case of valine having such groups exclusively at the 3 -pro ( R ) posit ion.The formation of the penam and cephem ring systems from the Arnstein tripeptide (1) remains a classic problem in bioorganic chemistry? It now appears certain,2 however, that penicillin N [3, R = 8-(~-0!-aminoadipyl)] in protoplast lysate systems of Cephnlosporium acremonium is the direct precursor of deacetoxycephalosporin C [4, R = a-(D-cc-arninoadipyl), X = HI. In an attempt to understand more fully the details of the in vivo ring expansion, we have sought to examine the stereochemical fate of specimens of valine bearing chiral methyl groups in the 3-pro(R) position (2, * = CHDT) in conversion into the p methyl group3 of penicillin N (3) and
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