Michael J. McGlinchey

Tamoxifen Derivatives for Delivery of the Antitumoral (DACH)Pt Group: Selective Synthesis by McMurry Coupling, and Biochemical Behaviour†

The goal of our study was to potentiate the effects of the ((R,R)‐trans‐1,2‐diaminocyclohexane)‐platinum(II) fragment [(DACH)Pt], known for its cytotoxic properties, either with tamoxifen (Tam), the most widely used antiestrogen in the treatment of hormone‐dependent breast cancers, or with its active metabolite hydroxytamoxifen (hydroxy‐Tam). We coupled Tam or hydroxy‐Tam derivatives bearing a malonato group at the para position of the β aromatic ring with the (DACH)Pt fragment. The malonato‐Tam and malonato‐hydroxy‐Tam compounds were prepared through McMurry coupling of the appropriate ketones. The presence of the malonate group resulted in a pronounced stereospecificity in the reaction, since malonato‐Tam was obtained only as the Z isomer, while malonato‐hydroxy‐Tam was obtained as an 80/20 E/Z mixture. Attribution of the isomeric structures was achieved by 2D NMR spectroscopy. The platinum complexes (DACH)Pt‐malonato‐Tam and (DACH)Pt‐malonato‐hydroxy‐Tam were then prepared by coupling the barium salts derived from the malonato‐Tam and malonato‐hydroxy‐Tam with the nitrate derived from (DACH)PtCl2. Study of the biochemical properties of these two platinum complexes showed that, while the hydroxy‐Tam complex is satisfactorily recognized by the estrogen receptor (relative binding affinity, RBA=6.4 %), the Tam complex is less well recognized (RBA=0.5 %). The effects of these complexes on two hormone‐dependent breast cancer cell lines (MCF7 and MVLN) were studied in vitro. Both complexes showed an antiproliferative effect on MCF7 cells, and an antiestrogenic effect on MVLN cells. The observed effects appear to be essentially antihormonal, since incorporation of the (DACH)Pt fragment into the tamoxifen skeleton did not cause an increase in the cytotoxicity of the complexes.

Synthesis, oxidation chemistry and cytotoxicity studies on ferrocene derivatives of diethylstilbestrol

A series of compounds is described in which one of the ethyl groups in diethylstilbestrol has been replaced by a ferrocenyl substituent. Only those derivatives incorporating phenol moieties underwent isomerisation from the Z to the E form, and some of them could be chemically oxidized to a quinone species. The compounds were less cytotoxic against hormone-independent MDA-MB-231 breast cancer cell lines than their corresponding ferrocenyl phenyl or phenol isomers in which the ferrocene and ethyl moieties are linked to the same carbon atom. The biochemical results were evaluated in conjunction with information obtained from electrochemical and chemical oxidation experiments.

Joining the rings: the preparation of 2- and 3-indenyl-triptycenes, and curious related processes.

The indenyltriptycenes, and , where the 3- or 2-indenyl, respectively, is attached at the 9-position of the triptycene, are attractive prototypes of molecular gearing systems that can also incorporate a brake. These molecules have been prepared from their respective indenylanthracenes, and , by the [4 + 2] cycloaddition of benzyne to the anthracene fragment, and the rotational barriers about the indenyl-triptycenyl single bonds in (12 kcal mol(-1)) and (<9 kcal mol(-1)) have been measured. The precursor anthracenes, and , were prepared by using palladium-catalysed coupling reactions. Unexpectedly, the Heck-type reaction of 9-bromoanthracene, , with indene leads to the formation of 3-indenylanthracene ; moreover, this process is accompanied by a novel palladium-catalysed carbocyclisation reaction leading to the indenophenanthrylene . The addition of benzyne to 9-(3-indenyl)anthracene, , yields the corresponding indenyltriptycene, , and, surprisingly, the anthracenyl methano-bridged phenanthrene . It has been demonstrated that 2-arylindenes can act as 1,3-dienes in the [4 + 2] cycloadditions of benzyne. The products , , and have been characterised by X-ray crystallography.

Synthesis, characterization, structure, molecular modeling studies and biological activity of sterically crowded Pt(II) complexes containing bis(imidazole) ligands

The syntheses, structures and biological evaluation of a series of cisplatin-like complexes containing bis(imidazole) derivatives - the so-called Joseph ligands - are described. Their cytotoxicity is discussed in terms of their polar surface area, rate of aquation, and lipophilicity. The X-ray crystal structure of the platinum diiodido derivative of dimethyl 2-(di(1H-imidazol-2-yl)methyl)malonate) is reported and compared to those of related systems. Molecular modeling studies are focused on the hydrogen bonding properties of such systems, and their relevance to antitumor activity.

Solvent-mediated generation of cobalt-cluster-stabilised propargyl cations and radicals: allyl migration versus peroxide formation.

The protonation of [Co(2)(CO)(6){9-[(allyldimethylsilyl)ethynyl]-9H-fluoren-9-ol}] (4), with HBF(4) in CH(2)Cl(2) led to migration of the allyl group from silicon to the cobalt-stabilised cationic site to furnish [Co(2)(CO)(6){9-allyl-9-[(dimethylfluorosilyl)ethynyl]-9H-fluorene}] (17). However, under the same conditions, [Co(2)(CO)(6){9-[(benzyldimethylsilyl)ethynyl]-9H-fluoren-9-ol}] (5) underwent desilylation and rearrangement of the resulting terminal alkyne-dicobalt complex to give [Co(3)(CO)(9)(9H-fluorenylmethylcarbynyl)] (24); moreover, dimerisation of the (benzyldimethylsilyl)ethynyl-9H-fluorenyl moiety led to the propargyl-allene 26. In contrast, protonation of 5 in THF yielded [{Co(2)(CO)(6){[(benzyldimethylsilyl)ethynyl-9H-fluorenyl])}(2)peroxide] (27) through a radical coupling process. Analogously, protonation of [Co(2)(CO)(6){9-[(vinyldimethylsilyl)ethynyl]-9H-fluoren-9-ol}] (6) yields the corresponding peroxide 28. X-ray crystallographic data are reported for, among others, complexes 17, 24, 26, 27 and 28.

Reciprocal polyhedra and the Euler relationship: cage hydrocarbons, CnHn and closo-boranes [BxHx]2−

Summary The closo-boranes BxHx +2, or their corresponding anions [BxHx]2− (where x = 5 through 12) and polycycloalkanes CnHn (where n represents even numbers from 6 through 20) exhibit a complementary relationship whereby the structures of the corresponding molecules, e.g., [B6H6]2− and C8H8 (cubane), are based on reciprocal polyhedra. The vertices in the closo-boranes correspond to faces in its polycyclic hydrocarbon counterpart and vice versa. The different bonding patterns in the two series are described. Several of these hydrocarbons (cubane, pentagonal dodecahedrane and the trigonal and pentagonal prismanes) are known while others still remain elusive. Synthetic routes to the currently known CnHn highly symmetrical polyhedral species are briefly summarized and potential routes to those currently unknown are discussed. Finally, the syntheses of the heavier element analogues of cubane and the prismanes are described.

Different Rearrangement Behaviour of the Cation or Anion Derived from the Diels–Alder Adduct of 9‐Ferrocenylanthracene and 1,4‐Benzoquinone: Ring‐Opening or Paddlewheel Formation

Prototropic rearrangement of the Diels-Alder adduct (3a) of 9-ferrocenylanthracene and 1,4-benzoquinone potentially furnishes 9-ferrocenyl-1,4-dihydroxytriptycene (3b) incorporating a C(2v) symmetrical paddlewheel moiety. However, reaction of 3a with HBF(4) unexpectedly yields instead 9-ferrocenyl-10-(2,5-dihydroxyphenyl)anthracene (4) via cleavage of the C9-C12 bond to generate initially a ferrocenyl-stabilized cation. Treatment of 3a with sodium hydride and iodomethane yields 1,4-dimethoxy-9-ferrocenyltriptycene (3c) in high yield but, surprisingly, also leads to fission of the C9-C12 bond resulting, after methylation, in the formation of 9-hydroxy-9-ferrocenyl-10-(2-hydroxy-5-methoxyphenyl)dihydroanthracene (12), which readily dehydrates on silica to form 9-ferrocenyl-10-(2-hydroxy-5-methoxyphenyl)anthracene (8). The X-ray crystal structures of 3a, 3c and 4 are reported.

A Ferrocenyl Kaleidoscope: Slow Interconversion of Six Diastereo‐atropisomers of 2,6‐Di‐tert‐butyl‐9,10‐diferrocenyltriptycene

The title triptycene, 6, has been isolated as the product of 9,10-cycloaddition of benzyne to 9,10-diferrocenyl-2,6-di-tert-butylanthracene, 5, whose X-ray crystal structure is reported. Each ferrocenyl unit in 6 has access to the same three non-equivalent molecular environments, and their rotations relative to the molecular paddlewheel give rise to six slowly interconverting atropisomers. Their dynamic behaviour in solution is a challenging NMR puzzle that can be successfully solved by taking advantage of the recently described very large diamagnetic anisotropy of the ferrocenyl moiety, together with the C2 symmetry of particular atropisomers. Application of one- and two-dimensional NMR techniques over a range of temperatures together, with a detailed analysis of the homo- and heteronuclear correlations in 6, resulted in unequivocal mapping of the 99 (1)H and 162 (13)C positions in the six interconverting systems. Variable-temperature 2D-EXSY measurements revealed that, while the stability of the atropisomers is almost identical, they are separated by energy barriers which the ferrocenyls must overcome in the course of their interconversions. The heights of two different rotational barriers have been identified and these experimental findings are in good agreement with DFT calculations.

Chromium Compounds with CO or Isocyanides

A review with 684 references covering the period 1993–2004 summarising the syntheses, structures and reactivity of molecules possessing a chromium carbonyl or chromium isonitrile linkage. The major topics discussed are complexes in which there is a chromium–main group element bond, and arene chromium tricarbonyl complexes with emphasis on the stereochemical and electronic effects of complexation on the chemistry of the arene. Recent work on chromium hydrides and on (cyclopentadienyl)Cr(CO)3 radicals and the formation of fulvalene complexes is also discussed. The use of carbene complexes as precursors to polycyclic aromatics is summarised, and the interconversion of chromium isonitriles and their isomeric nitrogen-stabilised Fischer-type carbenes is outlined. Potential applications such as chromium-containing conducting polymers, materials with novel non-linear optical properties, biological labelling, and molecular machines are discussed.

Organometallic derivatives of natural products: dicobalt hexacarbonyl complexes of geranyl-alkynes

Treatment of methyl geranyl ether with diiron nonacarbonyl leads to hydrogen migration to form previously unknown E and Z 1-methoxy-3,7-dimethyl-1,6-octadiene in low yield. Sodium propargyl alkoxide and geranyl bromide yield propargyl geranyl ether, 13; subsequent reaction with dicobalt octacarbonyl and then bis(diphenylphosphino)methane furnishes the corresponding alkyne–Co2(CO)4(dppm) tetrahedral cluster, 16. Reaction of geranylacetone with phenylethynyl-lithium, and then with Co2(CO)8, forms (1-phenyl-3,7,11-trimethyldodeca-6,10-dien-1-yn-3-ol)Co2(CO)6, 19. The carbynyltricobaltnonacarbonyl clusters RC(O)CCo3(CO)9, where R = geranyl, 23, or farnesyl, 25, are preparable in very good yield either by reaction of the appropriate alcohol with trichloroacetyl chloride and then Co2(CO)8, or by reaction with the metal-stabilized acylium ion [Co3(CO)9CCO]+, 24. Potential use of these (η2-alkyne)dicobalt complexes in Pauson–Khand or Nicholas cyclizations is discussed.