Geoffrey Salem

Antitumor activity of gold(i), silver(i) and copper(i) complexes containing chiral tertiary phosphines.

The in vitro cytotoxicities of a number of gold(I), silver(I) and copper(I) complexes containing chiral tertiary phosphine ligands have been examined against the mouse tumour cell lines P815 mastocytoma, B16 melanoma [gold(I) and silver(I) compounds] and P388 leukaemia [gold(I) complexes only] with many of the complexes having IC50 values comparable to that of the reference compounds cis-diamminedichloroplatinum(ll), cisplatin, and bis[1,2-bis(diphenylphosphino) ethane]gold(I) iodide. The chiral tertiary phosphine ligands used in this study include (R)-(2-aminophenyl)methylphenylphosphine; (R,R)-, (S,S)- and (R*,R*)-1,2-phenylenebis(methylphenylphosphine); and (R,R)-, (S,S)- and (R*,R*)-bis{(2-diphenylphosphinoethyl)phenylphosphino}ethane. The in vitro cytotoxicities of gold(I) and silver(I) complexes containing the optically active forms of the tetra(tertiary phosphine) have also been examined against the human ovarian carcinoma cell lines 41M and CH1, and the cisplatin resistant 41McisR, CH1cisR and SKOV-3 tumour models. IC50 values in the range 0.01 - 0.04 μM were determined for the most active compounds, silver(I) complexes of the tetra(tertiary phosphine). Furthermore, the chirality of the ligand appeared to have little effect on the overall activity of the complexes: similar IC50 data were obtained for complexes of a particular metal ion with each of the stereoisomeric forms of a specific ligand.

Axially asymmetric metal alkyls. Part 6. Lithiation of 2,2′-dimethyl-1,1′-binaphthyl and its trimethylsilylated compounds, and of 2,2′,6,6′-tetramethyl-1,1′-biphenyl (asymmetric induction): X-ray crystal structures of monomeric [{Li(Me2NCH2CH2NMe2)}2{(2-CH2C10H6)2}] and [Li{(Me2NCH2CH2)2NMe}{2-CH2-6-Me(C6H3)2-2′,6′-Me2}]

The compound [{Li(tmen)}2{(2-CH2C10H6)2}], (6)(tmen =N,N,N′,N′-tetramethylenediamine), has been prepared via metallation, and structurally characterized using X-ray diffraction data. It is monomeric with two different lithium centres, one bridging the ipso-carbon atoms at 2.13(5) and 2.23(5)A, the other interacting with one ipso-carbon at 2.36(5)A and its adjacent ring carbon at 2.51(5)A, such that one ipso carbon is bridging the lithium centres. 7Li N.m.r. data are consistent with this structure in toluene, below ca.–28 °C. Treatment of (6) with AsMe2I then Mel yielded the arsonium salt [(2-Me3AsCH2C10H6)2]I2, and with SiMe3Cl it gave (2-Me3SiCH2C10H6)2. This afforded [2-(Me3Si)2CHC10H6]2 on treatment with LiBun(tmen) then SiMe3Cl. Metallation of 2,2′,6,6′-Tetramethyl-1,1′-biphenyl using LiBun(pmdien)(pmdien =N,N,N′,N′,N″-pentamethyldiethylenetriamine) in diethyl ether yielded a monolithiated species [{Li(pmdien)}{2-CH2-6-Me(C6H3)2-2′,6′-Me2}](13), also structurally characterized; the lithium centre is attached to only the ipso-carbon of the hydrocarbyl group at 2.14(2)A. Treatment of the same biphenyl with LiBun(sp)[sp =(–)sparteine] in Et2O yielded a dilithiated species based on the asymmetrical chiral dianion, (2-CH2-6-MeC6H3)22–. The degree of asymmetric induction in the metallation step was estimated to be ca. 40% using a 1H n.m.r.–chiral lanthanide shift reagent technique on the diol (2-HOCH2CH2-6-MeC6H3)2, formed by carboxylation then esterification and reduction of the dilithiated species.

Synthesis, resolution and reactions of (±)-(2-aminophenyl)methylphenylphosphine. Crystal and molecular structure of (R*,R*, S*, R*)-(±)-(1,3-bis{[2-(methylphenylphosphino)phenyl]amino}propane)nickel(II) perchlorate

Asymmetric bidentate (±)-(2-aminophenyl)methylphenylphosphine has been prepared in 80% yield from (2-aminophenyl)diphenylphosphine via the secondary phosphine (±)-(2-aminophenyl)phenylphosphine. The chiral tertiary phosphine has been resolved by the method of metal complexation via the separation by fractional crystallisation of a pair of internally diastereomeric palladium(II) complexes containing the racemic ligand and (S)-[1-(1-ethyl)naphthyl]dimethylamine. The optically pure antipodes of the phosphine have α± 160°(589 nm, CH2Cl2). A number of square-planar bis(bidentate ligand) complexes of bivalent nickel, palladium and platinum containing the various forms of the ligand have been prepared and their solution behaviour studied by 1H and 31P-{1H} NMR spectroscopy. Monodeprotonation of the co-ordinated amino groups in the complexes has also been achieved by reaction with anhydrous sodium carbonate in acetone. The palladium(II) and platinum(II) complexes form cis diastereomers exclusively, whereas trans diastereomers were observed for the nickel(II) analogues. Furthermore, most of the complexes are kinetically labile. Reaction of (±)-(2-aminophenyl)methylphenylphosphine with n-butyllithium and N,N,N′,N′-tetramethylethylenediamine in tetrahydrofuran followed by the addition of 1,3-bis(p-tolylsulfonyloxy)propane gave the quadridentate ligand (R*,R*)- and (R*,S*)-1,3-bis{[2-(methylphenylphosphino)phenyl]amino}propane. The (R*,R*) and (R*,S*) forms of the quadridentate ligand have been separated by complexation to nickel(II). The structure of the nickel(II) complex containing the (R*,R*) form of the quadridentate ligand, viz. (R*,R*,S*,R*)-(1,3-bis{[2-(methylphenylphosphino)phenyl]amino}propane)nickel(II) perchlorate, has been determined by X-ray crystallography.

Axially asymmetric metal alkyls. Part 4. Synthesis and X-ray crystal structure of the tungsten(V) metallabicyclic complex [{W[(2-CH2C6H4)2]2O}2Mg(C4H8O)4]·CH2Cl2

Reaction of the di-Grignard reagent [{Mg(thf)nCl}2{(2-CH2C6H4)2}], derived from [Mg(anth)(thf)3](anth = anthracene) and (2-CICH2C6H4)2, with WCI4O in tetrahydrofuran (thf) yields a paramagnetic species, shown by an X-ray diffraction study to be [{W[(2-CH2C6H4)2]2[graphic omitted]g(thf)4]. Within each molecule the bidentate alkyl ligands have the same chirality, the overall molecular symmetry being approximately 222. A two-fold axis containing the oxo-groups and metal centres is the only crystallographically imposed symmetry. Oxo-groups are trans in the octahedrally co-ordinated magnesium centre [Mg–O(oxo) 2.036(5), 2.029(5)A; Mg–O(thf) 2.080(3), 2.1 20(5)A] and occupy an apical position of square-pyramidally co-ordinated tungsten centres [W–01.744(5), 1.726(4) A; W–CH2 2.162(5)–2.191(4)A]. Important angles of the metallacycles are: CH2–W–CH2 83.7(2), 85.8(2)°; W–CH2 C(aryl)115.3(4)–121.1(4)°; and torsion angles along the biphenyl axes, 52.9 and 63.1°.

Chiral Birch reduced tertiary phosphines: precursors to asymmetric 1,2-cyclohexenebis(tertiary phosphines)

The first examples of an optically active Birch reduced tertiary phosphine, viz. (R(P))-(cyclohexa-2,5-dienyl)(3-pentyl)phenylphosphine, and successful hydrophosphination of the related racemic ligand (±)-(cyclohexa-2,5-dienyl)(2-propyl)phenylphosphine with PHPh(2) in the presence of KOBu(t) in thf to give a 1,2-cyclohexenebis(tertiary phosphine), viz. (±)-1,2-C(6)H(8)(PPh(2))(PPhPr(i)), are described; as confirmed by crystal structure determinations of [SP-4-4-(S(P),S)]-chloro[(cyclohexa-2,5-dienyl)(3-pentyl)phenylphosphine][2-{1-(dimethylamino)ethyl}phenyl-C,N]palladium(II) and [SP-4-3-(±)]-dimethyl[(1-diphenylphosphino)(2-isopropylphenylphosphino)cyclohexene]platinum(II).

Stereoselective methylation of co-ordinated phenylphosphine: crystal and molecular structure of [(R*,R*),(R*)]-[(η5-C5H5){{1,2-C6H4(PMePh)2}FePHMePh]PF6·0.5CH2Cl2

Reaction of (R*,R*)-[(η5-C5H5){{1,2-C6H4(PMePh)2}FePHMePh]PF6 with iodomethane in the presence of triethylamine at 20 °C produces a separable 4 : 1 mixture of [(R*,R*),(R*)]- and [(R*,R*),(S*)]-[(η5-C5H5){{1,2-C6H4(PMePh)2}FePHMePh]PF6η the crystal and molecular structure of the major [(R*,R*),(R*)] diastereoisomer is reported.

Synthesis, resolution and reactions of (±)-1-(dimethylarsino)-2-(methylphenylphosphino)benzene. Crystal and molecular structure of [(S), (S)]-(+)589-{2-[1-(dimethylamino)ethyl]phenyl-C1,N}[1-(dimethylarsino)-2-(methylphenylphosphino)benzene-As,P]palladium(II) hexafluorophosphate

Asymmetric bidentate (±)-1-(dimethylarsino)-2-(methylphenylphosphino)benzene has been prepared by the reaction of sodium dimethylarsenide with (±)-1-chloro-2-(methylphenylphosphino)benzene in tetrahydrofuran. Its resolution has been achieved by the separation by fractional crystallisation of a pair of internally diastereomeric palladium(II) complexes containing the racemic ligand and orthometallated (S)-dimethyl(1-phenylethyl)amine. The optically pure antipodes have α±32°(589 nm, dichloromethane). The absolute configuration of the R enantiomer of the ligand has been assigned by a crystal-structure determination of the least-soluble diastereomeric complex [(S),(S)]-(+)589-{2-[1-(dimethylamino)ethyl]phenyl-C1, N}[1-(dimethylarsino)-2-(methylphenylphosphino)benzene-As,P]palladium(II) hexafluorophosphate. Chemoselective cleavage of the dimethylarsino moiety of the free benzene derivative occurs in the presence of lithium metal in tetrahydrofuran.

Resolutions involving metal complexation. Optical resolution of (±)-methylphenylphosphine in the complex [(S),(S,S)]-(+)589-[PtCl(PHMePh){1,2-C6H4(PMePh)2}]PF6©H2Cl2

Abstract Cofigurationally homogeneous [( S ), ( S,S )]-(+) 589 -[PtCl(PHMePh){1,2-C 6 H 4 (PMePh) 2 }]PF 6 ·CH 2 Cl 2 has been isolated and its structure determined by X-ray diffraction.

Diastereoselective synthesis of a resolved secondary arsine complex: asymmetric synthesis of (R-(−)589-ethylmethylphenylarsine

Abstract The reaction of [ R -( R ★ , R ★ )]-(+) 589 -[(η 5 -C 5 H 5 ){1,2-C 6 H 4 (PMePh) 2 }Fe(NCMe)]PF 6 with (±)-AsHMePh in boiling methanol yields crystalline [ R -[( R ★ )-( R ★ , R ★ )]-(+) 589)-[(η 5 -C 5 H 5 ){1,2-C 6 H 4 (PMePh) 2 }Fe(AsHMePH) PF 6 , optically pure, in ca. 90% yield, in a typical second-order asymmetric transformation. This complex contains the first resolved secondary arsine. Deprotonation of the secondary arsine complex with KOBu t at −65°C gives the diastereomerically pure tertiary arsenido-iron complex [ R -[( R ★ ),( R ★ , R ★ )]]-[((η 5 -C 5 H 5 ){1,2-C 6 H 4 (PMePh) 2 }FeAsMePh] · thf, from which optically pure [ R -[( S ★ ),( R ★ , R ★ )]]-(+) 589 -[(η 5 -C 5 H 5 ){1,2-C 6 H 4 (PMePh) 2 }Fe(AsEtMePh)PF 6 is obtained by reaction with iodoethane. Cyanide displaces ( R )-(−) 589 -ethylmethylphenylarsine from the iron complex, thereby effecting the asymmetric synthesis of a tertiary arsine, chiral at arsenic, from (±)-methylphenylarsine and an optically active transition metal auxiliary.

Chemistry of 2,3-dihydro-2-metallaphenalenes. Part 2. Formation of [CHMMe2C(MMe3)C10H6]xvia base decomposition of [1,8-(Me3MCH2)2C10H6]y(M = Ge, x= 2–, y= 0; M = P, x= 0, y= 2+); crystal structures of the novel bis-ylide CHPMe2C(PMe3)C10H6 and of a distorted peri-ylide, 1-Me-8-(Me3PCH)C10H6

Treatment of 1,8-(Me3GeCH2)2C10H6, derived from a Grignard in situ trapping reaction, with Li(Me2NCH2CH2NMe2)Bun in hexane yields the germanium heterocyclic dianion [[graphic omitted]H6]2–, characterized as its protonolysis product. Potassium hydride and [1,8-(Me3PCH2)2C10H6]Cl2 in tetrahydrofuran affords the novel bis-ylide H[graphic omitted]H6, (4), and small amounts of the mono-ylide 1-Me-8-(Me3PCH)C10H6, (5). The ring system in (4) is planar, the heteroatom excepted (0.50 A deviation), with Cylide–P to P–Cylide to Cylide–P distances of 1.742(4), 1.700(5), and 1.726(5)A; cf. P–CMeca. 1.8 and P–Cylide 1.69(1)A in (5). The aromatic rings in (5) are twisted, the ylide carbon, which is almost ‘co-planar’ with the adjacent ring, and peri-methyl carbon being skewed in opposite directions.