Keith W. Lumbard

A stable and long-lived germaimine

Abstract Spectroscopic identification of the first reported stable germaimine is provided, together with an analysis of its bond structure; it exists in cisoid and transoid forms.

Glucuronide and sulfate conjugates of ICI 182,780, a pure anti-estrogenic steroid. Order of addition, catalysis and substitution effects in glucuronidation

Abstract The 3-sulfate 4 and 3- and 17-glucuronide conjugates 5 and 6 of the pure anti-estrogenic steroid ICI 182,780 1 , which is expected to be an effective agent for the treatment of breast cancer, have been prepared. The synthesis of 6 could only be satisfactorily achieved using an inverse addition technique, not previously employed in the glucuronic acid series: the value of this technique for some other aglycones is discussed.

Formation of germanium–nitrogen double bonds in reactions of the electron-rich germylene bis[bis(trimethylsilyl)amido]germanium(II) with a range of diazo-compounds

The electron-rich germylene Ge[N(SiMe3)2]2 reacts with the diazo-compounds R1CH2COC(N2)R2[R1= H, R2= CO(OEt), SO2C6H4Me-p, or COPh; R1, R2=–CMe2CH2C(O)–], which contain an enolisable function, to yield the heterocycles [graphic omitted]; the weakly acidic diazo-compounds ethyl diazoacetate and diazoacetophenone yield bis-adducts Ge[N(SiMe3)2]2[C(N2)COR][NHNC(H)COR](R = OEt or Ph). Diazo-compounds containing two non-enolisable substituents yield mono-adducts with Ge[N(SiMe3)2]2 which can be hydrolysed to yield the diol Ge(OH)2[N(SiMe3)2]2 and, in one example, the corresponding hydrazone H2NNC(COPh)CO(OEt). These adducts appear to be thermodynamically stable in an aprotic solvent, but can be trapped by addition of ethanol, to yield Ge[N(SiMe3)2]2(OEt){NHNC[CCO(OMe)]2}, or of diazoacetophenone to yield Ge[(SiMe3)2]2[C(N2)COPh]{NHNC[CO(OMe)]2}. All the reactions of the germylene with diazo-compounds can be rationalised in terms of the initial formation of a germyleneazine [(Me3Si)2N]2GeN–NC(X)Y, which readily adds any available protic species to give a germane derivative. MNDO calculations on model systems are in accord with the experimental findings and also explain their differences from results previously obtained using the simpler germylene GePh2.

Structure-activity relationships of some opiate glycosides

A number of analogues of morphine-6-glucuronide 1 have been prepared and evaluated as potential analgesic agents by competitive mu-receptor binding assay and in vivo antinociceptive activity. The analogues show variation in the nature of the carbohydrate residue, the N-substituent, the O(3)-substituent and saturation of the 7,8-double bond compared to 1. In general, only the 6beta-glucoside or beta-glucuronide carbohydrate residues showed potent agonism; other modified carbohydrates were less active or exhibited potential antagonism. Variations in N-substituent led to either reduced agonism (N-H) or potential antagonism [N-allyl, N-(cyclopropyl)methyl]; a polar N-substituent, carboxymethyl, failed to bind. Saturation of the 7,8-double bond led to increased agonism compared to the parent compound in all three examples studied.

FLASH VACUUM PYROLYSIS OF STABILISED PHOSPHORUS YLIDES. PART 16. MODEL STUDIES FOR THE CONSTRUCTION OF CONJUGATED POLYMERS

Abstract Reaction of a range of bis(ylides) with acid chlorides has been used to prepare the bis(oxoylides) 11–15 . Similarly a range of simple ylides react with bis(acid chlorides) to give bis(oxoylides) 19–27 with the isomeric structure. Flash vacuum pyrolysis (FVP) of one example of the first type results in extrusion of Ph 3 P rather than the expected Ph 3 PO while six examples of the second type do extrude Ph 3 PO upon FVP at 500 °C to afford the bis(alkynes) 28 . Examples of the corresponding bis(tributylphosphonium ylides) have also been prepared but attempts to construct a tetrakis(oxoylide) 31 using a stepwise approach were unsuccessful. Fully assigned 13 C NMR spectra are presented for six of the bis(oxoylides).

Reactions of diazo-compounds with the electron-rich germylene Ge[N(SiMe3)2]2. Characterisation and some addition reactions of [(Me3Si)2N]2GeNNC(COOMe)2: crystal and molecular structure of [(Me3Si)2N]2Ge[NHNC(COOMe)2][C(N2)COPh]

Two forms of the stable germyleneazine [(Me3Si)2N]2GeNNC(COOMe)2, formed by addition of the diazo-compound N2C(COOMe)2 to the electron-rich germylene Ge[N(SiMe3)2]2 have been characterised in solution by 1H and 13C n.m.r. spectroscopy. MNDO calculations on the simpler analogue [(H3Si)2N]2GeNNC(COOMe)2 indicate that the two forms have planar transoid and cisoid GeNNC groups respectively, with the cisoid isomer as the more stable: the calculations also indicate that charge-controlled additions of electrophiles will occur at N1, adjacent to germanium, while all nucleophilic addition will occur at Ge. Some adducts of [(Me3Si)2N]2GeNNC(COOMe)2 with weak acids HX are described; in all cases 1,2-addition of HX occurs across the Ge–N1 bond to yield [(Me3Si)2N]2Ge(X)[NHNC(COOMe)2]. Crystals of one such adduct [(Me3Si)2N]2Ge[NHNC(COOMe)2][C(N2)COPh] are triclinic, space group P, with a= 9.627(2), b= 12.672(19), c= 15.702(3)A, α= 101.66(4), β= 85.02(2), γ= 77.65(5)°, and Z= 2. The structure was refined from diffractometer data (5 173 observed reflections) to an R value of 0.046. The structure determination confirms the 1,2-addition of HC(N2)COPh across the Ge–N1 bond of [(Me3Si)2N]2-GeNNC(COOMe)2 and reveals a free diazo-group, sterically unconstrained. Reaction of tosyl azide with Ge[N(SiMe3)2] follows a different course from the reactions involving diazo-compounds; nitrogen is lost and the product is a polygermazane {[(Me3Si)2N]2GeNSO2C6H4Me-p}n, which is insoluble in aqueous media and all common organic solvents, wholly resistant to hot 50% aqueous alkali, but readily hydrolysed by concentrated hydrochloric acid.

Putative metabolites of fulvestrant, an estrogen receptor downregulator. Improved glucuronidation using trichloroacetimidates

Following regioselective protection of the estrogen receptor downregulator fulvestrant (ICI 182,780) 1 as its 17-acetate 2 or 3-benzoate 4, the 3-sulfate 5 and 3- and 17-glucuronide conjugates 8 and 12 were prepared. Satisfactory preparation of 12 required use of the tri-O-isobutyryl imidate derivative 10 in conjunction with an inverse-addition technique not previously employed in glucuronidation. The value of this method for simpler aglycones is discussed together with a study of variations in donor acyl substituent and catalyst. Another putative metabolite, the 17-ketone 19, was prepared by direct oxidation of 1.

Aspects of the inorganic chemistry of rubber vulcanisation. Part 3. Anionic cadmium complexes derived from dialkyldithiocarbamates, 2-mercaptobenzothiazole and its derivatives, and dialkyl dithiophosphates, and the crystal and molecular structures of [NBun4][Cd(S2CNEt2)3], [NEt4][Cd(C7H4NS2)3], and [NMe4][Cd{S2P(OPri)2}3]

The reactions of [Cdl2{(S2CNEt2)2}] with certain Lewis bases are described, and the complexes [NBun4][Cdl2(S2CNEt2)], [NR4][Cd(S2CNR′2)3](R = Me or Bun; R′= Me, Et, Bun, or NHNMe2), [NR4][Cd(OCOMe)(S2CNEt2)2], (R = Me or Bun), [{Cd(S2CNHNMe2)2}n], [Cd(py)2(6-RC7H3NS2)2](R = H or EtO, py = pyridine), [Cd(6-EtOC7H3NS2)2], [NBun4][Cd(C7H4NS2)n(6-EtOC7H3NS2)3–n](n= O–3), [NBun4][Cd(C7H4NS2)2(S2CNEt2)], and [NMe4][Cd{S2P(OPri)2}3] have been prepared. The structures of the title compounds have been determined crystallographically. All three anions have geometries intermediate between trigonalprismatic and octahedral; in the second, the C7H4NS2– ligand is bound to the metal via the N and the exocyclic S (thiolate) atoms. These structures are compared with those of the corresponding zinc complexes and [Cd(S2COEt)3]–.

Synthesis of a cyclic sulphonated prostaglandin analogue

Abstract Ethyl 8-nonenoate was converted into a new heterocyclic (sultam) prostanoid by a simple procedure involving photocatalysed addition of N-bromo-N-methylmethanesulphonamide to the olefin and cyclization of the adduct to a sultam, which was formylated and ketovinylated to provide two methods of introducing the β-side chain.

Reaction of an enolisable diazo-compound with the electron-rich stannylene Sn[N(SiMe3)2]2: preparation of a novel spiro[1,3,4,2-oxadiazastannine-6,4′-pyrazole] derivative

The reaction of the enolisable diazo-compound MeCOC(N2)CO(OEt) with the electron-rich stannylene Sn[N(SiMe3)2]2 yields a 2 : 1 adduct {in contrast to its reaction with the analogous germylene Ge[N(SiMe3)2]2, which gives a 1 : 1 adduct}, shown spectroscopically to be diethyl 3′-acetyl-2,2-di[bis(trimethylsilyl)amino]-3,6,3′,5′-tetrahydrospiro[1,3,4,2-oxadiazastannine-6,4′-pyrazole]-5,3′-dicarboxylate.