S. Bruce Wild

Resolutions of tertiary phosphines and arsines with orthometallated palladium (II)—amine complexes

Abstract The use of the homochiral forms of chloro-bridged palladium (II) complexes containing orthometallated N , N -dimethyl(α-methylbenzyl)amines and related naphthylamines for the resolution of trivalent phosphines and arsines chiral at phosphorus and arsenic is reviewed. Work with a wide variety of ligands is discussed and references to applications of the ligands as probes of inorganic stereochemistry and as auxiliaries for asymmetric synthesis are given. Most examples have been taken from work carried out in the authors laboratories.

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.

Facile interconversions between diastereomers of chloro-bridged palladium(II) dimers of orthometallated (±)-dimethyl[1-(1-naphthyl)ethyl]amine

Abstract The important chloro-bridged dipalladium(II) resolving agents (R,R)- and (S,S)-cis-di-μ-chlorobis[1-[1-(dimethylamino)-ethyl]-2-naphthalenyl-C,N]dipalladium, (R,R)- and (S,S)-cis-1, undergo facile rearrangements into unequal mixtures of cis and trans diastereomers upon dissolution in chloroform or dichloromethane, although concentration of the solution in each case affords in high yield the pure cis diastereomer of the dinuclear metal complex as the corresponding mono-solvate in a typical second-order asymmetric transformation. When equimolar solutions of (R,R)-cis- and (S,S)-cis-1 CH2Cl2 in dichloromethane are mixed together, however, an equilibrium is rapidly established between the cis and trans diastereomers of the (R ∗ ,R ∗ )-(±) and ( R ∗ ,S ∗ ) forms of 1 and from which solution configurationally homogeneous (R ∗ ,S ∗ )-trans- 1 · CH 2 Cl 2 crystallizes in high yield by second-order asymmetric transformation. The crystal and molecular structures of (R,R)-cis- 1 · CH 2 Cl 2 and (R ∗ ,S ∗ )-trans- 1 · CH 2 Cl 2 have been determined. The optical purities of the individual enantiomers of (R ∗ ,R ∗ )-(±)- 1 · CH 2 Cl 2 have been determined by reaction with (1R,2S,5R)-menthyldiphenylphosphine or (1S, 2S, 5R)-neomenthyldiphenylphosphine in chloroform-d1 and analysis of the 31P1H NMR spectra of the resulting solutions of the corresponding bridge-split palladium(II)-phosphine epimers.

Configurationally homogeneous diastereomers of a linear hexa(tertiary phosphine): Enantioselective self-assembly of a double-stranded parallel helicate of the type (P)-(Cu 3 (hexaphos) 2 )(PF 6 ) 3

Three configurationally homogeneous diastereomers of the linear hexa(tertiary phosphine) Ph2PCH2CH2P(Ph)CH2CH2P(Ph)CH2CH2P(Ph)CH2CH2P(Ph)CH2CH2PPh2 (hexaphos) have been isolated in enantiomerically pure form, namely (R,S,S,R)-, (R,S,S,S)-, and (S,S,S,S)-hexaphos. The strongly helicating (R,S,S,R)-(−) form of the ligand combines with copper(I) ions to generate by stereoselective self-assembly the P enantiomer of a parallel helicate of the type [Cu3(hexaphos)2](PF6)3, which has been characterized by x-ray crystallography. Theoretical modeling of the cation indicates that it is the relationship between the helicities of the two 10-membered rings containing the three copper ions, each of which has the twist-boat–chair–boat conformation, and the configurations of the three chiral, tetrahedral copper stereocenters of P configuration that determines the stereochemistry of the parallel and double α-helix conformers of the double-stranded trinuclear metal helicate.

Facile syntheses and interconversions between simple phosphiranium and phosphirenium salts

Abstract The first phosphiranium salt, 1-methyl-1-phenylphosphiranium triflate ( 1 ), has been isolated in 73% yield from the reaction between 1-phenylphosphirane and methyl triflate in benzene. The crystal and molecular structures of 1 have been determined. The phosphiranium ion in 1 undergoes ring opening with water to give (±)-ethylmethylphenylphosphine oxide, and reacts with primary alcohols to give (±)-alkoxyethylmethylphenylphosphonium ions. Treatment of 1 with dimethyl- or methylphenylacetylene in dichloromethane affords over one week the corresponding substituted phosphirenium salts in high yield. Phosphirenium salts can also be prepared in high yields by reacting a chloroalkylaryl- or chlorodiarylphosphine and an alkyne with thallium(I) triflate in dichloromethane. The crystal and molecular structures of 1,2,3-trimethyl-1-phenylphosphirenium triflate have been determined. The reaction of chloromethylphenylphosphine with thallium(I) triflate in the absence of an alkyne leads to an unstable phosphinophosphonium triflate that undergoes rapid chloride exchange and/or pyramidal inversion at phosphorus under ambient conditions, as determined by variable temperature NMR spectroscopy.

Convenient resolution of (±)-piperidine-2-carboxylic acid ((±)-pipecolic acid) by separation of palladium(II) diastereomers containing orthometallated (S)-(−)-1-[1-(dimethylamino)ethyl]naphthalene

Abstract (±)-Piperidine-2-carboxylic acid ((±)-pipecolic acid) has been resolved by the fractional crystallisation of diastereomeric palladium(II) complexes containing orthometallated ( S )-(−)-1-[1-dimethylamino)ethyl]naphthalene. The enantiomers of the acid were liberated from the individual configurationally homogeneous diastereomers of the complex in high yield with [ α ] D ± 26.0 ( c 1.00, H 2 O). The crystal and molecular structures of both diastereomers of the complex have been determined.

Atropisomerism in (±)-7-methyl- and -phenyl-substituted dinaphtho[2,1-b;1′,2′-d]phospholes and dinaphth[2,1-b;1′,2′-d]arsoles

Abstract The reaction of 2,2′-dilithio-1,1′-binaphthyl with RECl 2 (E = P or As; R = Me or Ph) affords the corresponding (±)-7-substituted dinaphtho[2,1- b ;1′,2′- d ]phospholes and dinaphth[2,1- b :1′,2′- d ]arsoles. The molecules are fluxional on the NMR time scale with similar barriers between the conformational isomers (atropisomers) for the four compounds, vis . † G ‡ = 56 ± 1 (243 K, ER = PMe), 56 ± 1 (254 K, ER = PPh), 65 ± 1 (287 K, ER = AsMe), 59 ± 1 (259 K, ER = AsPh) kJ mol −1 . An X-ray diffraction study of ( S )-7-phenyldinaphth[2,1- b ;1′,2′- d ]arsole which crystallized out by spontaneous resolution reveals appreciable bending of the distorted naphthyl residues away from each other. The asymmetric unidentates (±)-L coordinate to iron(II) in complexes of the type [(η 5 -C 5 H 5 )[1,2-C 6 H 4 (PMePh) 2 ]FeL]PF 6 with a small degree of enantioselection of one atropisomer of (±)-L. The complexes of the arsines are stable on the NMR time scale in CD 2 Cl 2 at 20°C, but the corresponding phosphine complexes require cooling for observation of diastereomerism. The 7-methyl substituted arsole is demethylated by bromine giving the corresponding 7-bromo compound, which, in turn, is converted by additional bromine into configurationally stable (±)-[2-(2′-bromo-1,1′-binaphthyl)]dibromoarsine.

Attempted resolution of free (±)-chlorophenylisopropylphosphine

Abstract (±)-Chlorophenylisopropylphosphine has been resolved in a palladium(II) complex containing the phosphine and ortho-metalated ( R )-1-[1-(dimethylamino)ethyl]naphthalene; the configurationally homogeneous ( R , R p ) diastereomer of the complex crystallises from the reaction mixture by typical second-order asymmetric transformation in overall 82% yield. The absolute configuration of the complex was determined by X-ray crystallography. The pure ( R , R p ) diastereomer of the complex reacts quantitatively with methanol in the presence of triethylamine to give the corresponding methoxyphosphine complex with complete stereoselectivity and inversion at phosphorus. All attempts at liberating optically active chlorophosphine from the palladium complex were unsuccessful.

ARE PI-LIGAND EXCHANGE REACTIONS OF THIIRENIUM AND THIIRANIUM IONS FEASIBLE? AN AB INITIO INVESTIGATION

Pi-ligand exchange is predicted to be experimentally feasible for thiirenium and thiiranium ions by a G2 ab initio investigation (see figure). The reaction is also predicted to be stereospecific with respect to the configuration at sulfur. Comparisons are made with the analogous phosphorus systems.

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.