9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and

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9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin Raja Mitra, Richard Goddard, and Klaus-Richard Pörschke* Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany S Supporting Information *

ABSTRACT: As part of a comprehensive study of Nunsubstituted bispidines, the novel 9,9-difluorobispidine (D) has been synthesized. The compound crystallizes from pentane below 0 °C in the ordered-crystalline phase D-II and undergoes at 0−30 °C a stepwise endothermic phase transition to a dynamically disordered crystalline phase D-I; melting occurs at 227 °C. Single crystalline D-II has been subjected to X-ray structure analysis, revealing association of the molecules to form chains. Reaction of (1,5-hexadiene)PtCl2 with D affords {C7H10F2(NH)2}PtCl2 (D1), which can be converted by conventional routes to {C7H10F2(NH)2}Pt(cbdca)·5H2O (D2) and {C7H10F2(NH)2}Pt(C2O4) (D3). Compound D1 crystallizes solvent-free from water and is isomorphous to the solvent-free parent bispidine analogue (A1). The pentahydrate D2 is isomorphous to the bispidine and 9-oxabispidine homologues (A2 and C2), as shown by X-ray structure analyses. An increased polarity of the bispidine skeleton as a consequence of the high electronegativity of fluorine is seen as the reason for low cytotoxic potency of D1−D3.

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INTRODUCTION Cancers are among the most obnoxious diseases afflicting humanity.1 Although enormous progress has been made in the treatment of some of its varieties such as testicular cancer, where an almost 100% cure rate can be achieved, others such as the small and nonsmall cell lung cancers, pancreatic cancer, and certain neck and head cancers appear incurable by current treatments.2 In addition to malignant tumors (cancers) which spread to form metastases, benign (noncancer) tumors at difficult-toaccess locations (e.g., tumors of the brain or spinal cord) also call for chemotherapy as a preferential treatment. Serendipity led Rosenberg and co-workers3 in the mid-1960s to discover the antiproliferative action of cis-di(ammine) platinum dichloride, commonly known as cisplatin (Chart 1).

and oxaliplatin which mitigate some of the side effects have also gained worldwide approval, while their scope of application is more limited.5 Over time thousands of platinum compounds have been screened for their cytostatic properties, and empirical structure−activity rules/relationships (SAR) have been established.6 According to SAR, activity can be expected for neutral planar Pt(II) complexes of the general formula cis-Pt(II)A2X2 in which A represents a neutral amine ligand bearing 1−3 protons and X (X2, respectively) represents an anionic leaving group such as halide, oxalate, and malonate, which slowly hydrolyzes. Compounds which conform to these rules are termed “classical” or “traditional” platinum cytostatics. The amine plays an important role in the efficacy of these complexes. It is believed that the amine remains coordinated to the platinum atom during the whole action time of the drug and is considered as a “carrier ligand” for the transport of the drug from the bloodstream through the cell membrane of the tumor cell. In its function as a “carrier ligand”, the amine may determine selectivity of the drug for tumor cells and assist in accumulation of the drug. Clearly, if it were possible by choice of amine to optimize the way that the drug passes the cell membranes of a wider spectrum of tumor cells, more cancers could be treated effectively. Moreover, sparing healthy tissue should minimize side effects. There are several other functions associated with the amine ligand. Once inside the cell the drug must find its way through the cytoplasm and progress along DNA, ending up at a purine base.7 This migration is thought to proceed by a multitude of H-bond equilibria involving the NH

Chart 1. Worldwide Approved Platinum Drugs for Cancer Therapy

Cisplatin emerged as the most important anticancer drug ever developed, and until today about 50% all cancer patients are treated with this metal-containing drug. The numerous serious adverse effects associated with the treatments, its narrow profile of responding cancers, and an inherent or acquired resistance to the treatment (“platinum resistance”) have spurred an enduring search for alternative platinum cytostatics.4 As such, carboplatin © XXXX American Chemical Society

Received: March 31, 2017

A

DOI: 10.1021/acs.inorgchem.7b00836 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry functions. Finally, after the anionic ligands are cleaved off by hydrolysis, the remaining amino-Pt(II) part latches itself onto the DNA and causes denaturation of the DNA strand by intraand interstrand cross-linking. As DNA repair enzymes responsible for “Pt resistance” come into action to repair damaged sections, the amino-Pt(II) group by its shape and bulk must additionally hinder these enzymes so that they cannot proceed with their repair function. A more detailed description of the functions of the amine ligand is given in a companion report.8 The ammine ligand in cisplatin and carboplatin provides three protons at each N atom, which allows for utmost stereochemical flexibility in N−H···X hydrogen bonding. This flexibility is reduced for bidentate primary amines,9 and the rather rigid DACH ligand in oxaliplatin (DACH = 1,2diaminocyclohexane) uses only one of the four NH functions to form a specific N−H···O6 bond in the crystal.10 As one turns to secondary amines, steric effects become even more important, and in addition the inductive effects of the alkyl substituents are expected to reduce the acidity of the amine protons for hydrogen bonding. As a consequence, platinum complexes of secondary amines are predicted by SAR to be less potent. Since the traditional platinum cytostatics are not free of the side effects and limitations of the Pt-based anticancer therapy, current interest focuses on “non-classical” or “non-traditional” platinum antineoplastic agents that are exceptions to the SAR approach. Such species are, inter alia, complexes of transPt(II)A2X2 structure,11 octahedral Pt(IV) complexes,12 Pt(II) complexes lacking NH protons,13 multi-Pt(II) agents,14 and ionic Pt(II) complexes.15 This topic has also been reviewed.16 Some years ago we studied complexes of nickel(0) with 3,7dimethylbispidine (bispidine = 3,7-diazabicyclo[3.3.1]nonane).17 Bispidine−metal complexes feature four sixmembered rings in an adamantane-type rigid structural unit. The unexpected properties of the Ni(0) complexes raised the question whether N-unsubstituted bispidines, despite being secondary amines and thus disfavored by the SAR approach, could possibly act as useful “carrier ligands” for platinum cytostatics. Bispidine ligands are related to the DACH ligand in that both ligands are bidentate, with the obvious distinction that N-unsubstituted bispidines are secondary amines whereas DACH is a primary amine. The volumes of the unsubstituted bispidine and DACH ligands in the Pt(II) complexes are quite similar;18 however, the bispidine ligands appear pulvinate, whereas the DACH ligand is flat-discoid. An additional feature of the bispidine ligand is that substitution at the bridging 9position may provide a handle to alter the properties of the complexes without further enlarging the bulk of the ligand. Following an improvement of the synthesis of parent bispidine, (C7H12(NH)2, A), by Miyahara et al.,19,20 we synthesized the series of bispidine-modified analogues of cisplatin, carboplatin, and oxaliplatin (A1−A3).21 These bispidine-Pt(II) complexes exhibited cytostatic potency in the micromolar concentration range. The results encouraged us to modify the bispidine skeleton (Chart 2) by first introducing two hydroxy substituents in 9-position in an attempt to improve the solubility of the platinum complexes in water. While the uncoordinated bispidin-9,9-diol B is not a stable compound, its ketal B′ could actually be prepared. After coordinating B′ at PtCl2 the ketal in (B′)PtCl2 was cleaved, and the series of bispidin-9,9-diol−Pt(II) complexes B1−B3 became accessible (Chart 3).22 In a companion study, we revisited the synthesis of

Chart 2. Isolated N-Unsubstituted Bispidines

Chart 3. Previously Studied Bispidine-type Cisplatin Analogues

9-oxabispidine, (OC6H10(NH)2, C),23 and synthesized complexes C1−C3.8 These complexes show likewise high hydrophilicity, but their solubility is low since the oxygen atom participates in intermolecular hydrogen bonding. Recently, the (bispidine)Pt(II) system has been subjected to a theoretical investigation.24 Since the 1970s an ever increasing number of pharmaceuticals contain fluorine.25 Replacement of C−H by C−F or deoxofluorination has a significant impact on the properties of the pharmaceuticals, such as increased metabolic stability, reduced toxicity, conformational effects, increased acidity,26 and an altered lipophilicity,27,28 and some of these factors may also affect selectivity for cancer cells and other tissues.29 Although lipophilicity of compounds is often increased for fluorinated aromatic substrates, the reverse effect is frequently observed when partially fluorinated aliphatic groups are concerned, since the high polarity of the C−F bonds effectuates molecular polarity.30,31 A particularly unfavorable situation appears to prevail in the presence of gem-difluoro moieties, but at least one drug containing such a moiety (Ledipasvir) has received recent FDA approval.25c Fluorine (van der Waals radius 1.47 Å) is only slightly larger than hydrogen (1.20 Å)32a and thus sterically unobtrusive, although with respect to polarity and size the C−F bond appears comparable with C−OH (“bioisosterism”).27a Previous investigations into fluorinated cisplatin-related compounds led to the isolation of (cis-1,2-DACH)Pt(C6F5)2,33a {C2H4−nRn(NH2)2}PtCl2-type compounds (R = p-C6H4F),33b (dmba)Pt{P(p-C6H4CF3)3}Cl,33c and various amine complexes prepared from {(μ-SEt2)Pt(p-C6H4F)2}2,33d all bearing aryl groups. We became interested in studying the effect of selective fluorination of bispidine and set out to synthesize 9,9difluorobispidine (D), thus complementing the series of already existing simple N-unsubstituted bispidines A−C (Chart 2). With D the Pt(II) complexes D1−D3 (Chart 4) have been prepared which represent homologues of the complexes shown B


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Inorganic Chemistry

pure 2a with DAST in CH2Cl2 to afford 9,9-difluorinated 3 as a viscous liquid in 75% yield. Compound 3 crystallized from pentane (4 °C) with only slight loss of material. Cleavage of the N-carbamate substituents in 3 by refluxing with aqueous KOH gave C7H10F2(NH)2 (D) in 83% yield (Scheme 1). Dissolution of D in CH3OD and low-temperature evaporation of the solvent afforded partially deuterated C7H10F2(ND)2 (D-d2).

Chart 4. New 9,9-Difluorinated Bispidine-type Cisplatin Analogues

Scheme 1. Synthesis of 9,9-Difluorobispidine (D)

in Chart 3. The concept of “bioisosterism” suggested that introduction of two fluorine substituents at 9-position of the bispidine would cause for D1−D3 a sterically and electronically similar situation as for the 9,9-diols B1−B3, with the distinction of the absence of the oxygen atoms as possible base sites and much reduced hydrophilicity of the compounds. The new compounds have been characterized in their physical properties, including the determination of their crystal structures, and tested for their antiproliferative properties.

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RESULTS AND DISCUSSION Synthesis and Properties of 9,9-Difluorobispidine (D). Miyahara et al.19 have described a viable synthesis of the parent bispidine C7H12(NH)2, which involves 3,7-diallyl-bispidin-9one (1) as an intermediate. Intermediate 1 undergoes Wolff− Kishner reduction of the ketone to afford the C-unsubstituted 3,7-diallyl-bispidine. The N-allyl groups can then be replaced by carbamate34 and the latter cleaved by KOH to eventually yield the parent bispidine. Making use of the N-allyl functionality (as opposed, e.g., to the inert N-benzyl group) provided a notable improvement over alternative synthesis routes. While Miyahara et al. considered 1 to be unstable and handled it in situ,19a we isolated the pure 1 and found it to be stable at ambient temperature for years when protected from oxidation.20a In the search for a route to the synthesis of the 9,9-difluoro derivative D, we reasoned that 1 might also be a useful starting material for this reaction, as ketones are known to be susceptible deoxydifluorination under mild conditions. Once 9,9-difluorination was achieved, cleavage of the N-allyl groups was expected to proceed as for the parent bispidine. However, in attempting this route we discovered that reacting 1 directly with diethylaminosulfur trifluoride (DAST; in pentane or THF) or diethylaminodifluorosulfinium tetrafluoroborate (XtalFluorE; in CH2Cl2),35 as effective fluorination agents, gave undefined mixtures of products, as evident from the multitude of 19F NMR signals subsequently observed. Possible explanations for this behavior were substitution of the SF3 or SF2 moieties by the bispidine nitrogen in 1 via its lone electron pair and also fluorination of the allyl groups. Therefore, at the outset we replaced the allyl groups in 1 by carboxylate to afford the novel 2,36 which then was subjected to fluorination. Since carboxylate substitution at nitrogen activated the 9-keto group with respect to hydration, (slightly impure) 3,7-di(ethylcarboxylate)-bispidin-9,9-diol (2b) was isolated. Dehydration of diol 2b with toluene by azeotropic distillation allowed retrieval of the desired ketone to afford now pure crystalline 3,7-di(ethylcarboxylate)bispidin-9-one (2a). In 2a,b the N lone electron pair is in resonance with the carboxylate group so it no longer affected the fluorination agent, and the carboxylate group also did not interfere with the reagent. The fact that the yield was slightly higher when reacting the ketone 2a instead of gem-diol 2b could be attributed to the contained water equivalent. While the reaction also worked for XtalFluor-E, it was faster for DAST. Thus, deoxyfluorination was best performed by reacting the

The novel compounds 2a,b, 3, and D deserve closer inspection. The presence of the 9,9-diol 2b as an isolated intermediate is confirmed by the IR spectrum (see SI). When heated the compound liquefies at 90−100 °C, which may be attributed to elimination of water and subsequent dissolution, rather than to typical melting. The compound dissolves only poorly in most solvents. In solution, the nature of the solute depends on the properties of the solvent as indicated by the 1H and 13C NMR spectra. In DMSO the 9,9-diol 2b (δ(C) 90.7) is largely retained unchanged (90%), together with a minor amount (10%) of 9-ketone 2a (δ(C) 211.3). However, in CDCl3 solution almost exclusively 2a (99%) is present. Intermediate situations are observed for acetone and THF solutions. Apparently, solvents such as DMSO stabilize the diol moiety by serving as a hydrogen bond acceptor to the diol protons, whereas without such interaction 2b eliminates water. The 1H and 13C NMR spectra of 2b are best resolved for solutions in D2O where, however, no C(OH)2 1H signal is observed owing to H/D exchange. In addition, most 1H and 13 C signals are split, which is attributed to the presence of σ and C2 symmetrical conformers of 2b as will be described for 2a and 3 in more detail below. The formation of 2b suggests that the 3,7-dicarboxylate substituents stabilize the 9,9-diol function by removal of electron density from the N atoms, similar to protonation and metal coordination. Interestingly, the 9,9-diol stabilization is not effected by 1,5-dicarboxylate substitution at the bispidin-9-one C atoms,22 as will be described elsewhere in detail.36 In contrast to the diols, the prototypical 9-ketone 2a (mp 61 °C), obtained by dehydration of 2b via azeotropic distillation of toluene, is very soluble in toluene, diethyl ether, and warm pentane from which it can be recrystallized. There are no IR absorptions above 3000 cm−1 but a weak CO stretching band at 1727 cm−1. While the 13C spectrum (CDCl3 solution) is inconspicuous, the 1H NMR signals are less well resolved and appear to be partially split. The geminal coupling of NCHeqHax is about 2J = 12 Hz, while the vicinal coupling with the bridgehead CH is estimated to be 2J = 2−3 Hz and thus within the line width. Thus, the 1H signal of CH is a pseudosinglet and NCHeqHax gives rise to an AB-type spectrum. These latter signals are doubled to pairs, with the signals at low field (δ(H) 4.70, 4.60) being distinctly apart from one another, whereas the C


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Inorganic Chemistry higher field signals (δ(H) 3.34, 3.29) partially overlap. The spectrum is attributed to the presence of two conformers resulting from restricted rotation about the N−C bonds of the planar C2N−CO2 moieties. Depending on same or opposing orientations of the N−CO2Et functional groups with respect to one another, CS or C2 symmetrical conformers are present.37 Since the N−carboxylate groups are closer to Heq than to Hax, the former appear more influenced, allowing an assignment of Heq to the lower field doublets and Hax to those at higher field. The order of the signals NCHeqHax is thus the same as for parent A and in contrast to that for 9-oxabispidine (C) which represents an exception.8,38 In addition, the 1H signal observed for CO2CH2Me, instead of the expected two quartets, is also an unresolved heap of multiplets. This signal can again be explained by the presence of the two conformers and, moreover, diastereotopic splitting due to prochirality of the methylene group. The latter confirms that rotation about the N−CO2 bond is slow. The electron ionization and electrospray ionization (ESI) mass spectra of 2a,b are identical and solely water-free ions were found. In the EI mass spectrum of bispidin-9-one 2a (50 °C), M+ (m/e = 284, 33%) fragments by splitting-off one CO2C2H5 substituent (211, 21%); further fragmentation follows the pattern described for 1 (see ref 20a, there eq 5, for R′ = H) to afford the 2,3,6-dehydro-4-piperidonium cation [OC5H5N(CO2C2H5)]+ (m/e = 168) as the base ion. The melting point of the 9,9-difluoride 3 is as low (60 °C) as for 2a. The existence of two conformers is most clearly evident for 3. In the 19F NMR spectrum39 of 3 at low temperature (−40 °C) two sharp signals at δ(F) − 108.6 and −108.8 are found in the ratio of 1:0.45. Likewise, in the 1H and 13C NMR spectra unresolved sets of signals are also observed. With increasing temperature the signals coalesce and the limiting high temperature spectra are observed at 65 °C (toluene-d8 solution). As for 2a,b, we anticipate that the 9,9-difluorobispidine skeleton has a flattened chair−chair conformation with a temperature-dependent restricted rotation of the carboxylate moieties. In each conformer both F atoms are equivalent. As is the case for 2a, 13C NMR is less sensitive with respect to resolution of the two conformers. For the bridging CF2 (δ(C) 121.7, 1J(FC) = 248 Hz) and the bridgehead CH (δ(C) 36.4, 2 J(FC) = 19 Hz) clear triplets were observed due to 19F coupling, and we note only a shoulder for the NCH2 signal. In the 1H NMR spectrum of 3 the signal of the bridgehead CH is a pseudosinglet as no couplings are resolved. However, for each NCHeqHax and NCO2CH2Me two sets of signals are found, corresponding to two conformers. The protons of NCHeqHax show the typical geminal coupling 2J = 12 Hz but no resolved 3J coupling with the bridgehead CH. Nevertheless, we assign the pair of larger separated signals at lower field (δ(H) 4.40, 4.29) to Heq since these protons should more sensitively reflect the different conformers, so the pair of close signals at higher field (δ(H) 3.30, 3.23) is attributed to Hax of both conformers, similar as found for 2a. Instead of two NCO2CH2Me quartets, we found two unresolved multiplets which can be explained by diastereotopy of the prochiral protons. None of the 1H signals show any resolved 19F coupling. The EI mass spectrum of difluorinated 3 (50 °C) provides the molecular ion M+ (m/e = 306, 45%) and [M − CO2Et]+ (233) as the base peak. Otherwise, the spectrum suggests a similar degradation pattern as for D, after cleavage of the CO2Et substituents.

9,9-Difluorobispidine (D) has been obtained according to Scheme 1 in 90−100% purity. Cleavage of the carboxyl substituents proceeds stepwise via 3a as an intermediate (Scheme 2). Intermediate 3a apparently partially undergoes Scheme 2. Details of the Conversion of 3 into D

intramolecular nucleophilic attack of one N atom at the neighboring N−CO2Et group, resulting in EtOH elimination and formation of the urea derivative 3b.40 Thus, D may contain traces of byproducts 3a,b which are often invisible in the 1H and 13C spectra, but detectable by the more sensitive 19F NMR, gas chromatography (GC), and GC-MS. These byproducts do not interfere with the further reaction steps (see below). In the 1H NMR spectrum (THF-d8) of pure D, the axial and equatorial NCHaHe give rise to a pseudoquartet (600 MHz) owing to very similar chemical shifts, unlike the situation for the nonfluorinated bispidine A where distinct signals have been observed.20b The 1H signal of the bridgehead CH is a broad triplet, indicating 19F coupling. In the 13C NMR spectrum of D, all C atoms of the bispidine skeleton furnish triplets due to 19F coupling. As expected, the signal of CF2 is at a much lower field (δ(C) 124.2, 1J(FC) = 248 Hz) than the bridging 9-C in A (δ(C) 33.3). 19F NMR of D furnishes a sharp singlet (δ(F) − 102.9). The IR spectrum of D is discussed in the SI. The bispidine D sublimes under a vacuum at ambient temperature. For recording the EI mass spectrum, D was introduced into the EI mass spectrometer via GC-MS coupling because of its high volatility. The EI mass spectrum (20 °C) furnishes the molecular ion M+ (m/e = 162, 63%); the base ion is [C5H5FN]+ (m/e = 98) and a further prominent peak is assigned to the seven-membered ring [C6H7FN]+ (m/e = 112, 90%). Interestingly, there are two fragmentation routes, and both involve rupture of one C−F bond at an early stage, presumably by HF elimination. The suggested mechanism (Scheme S1, Supporting Information) is consistent with the mechanistic schemes we have proposed previously for other bispidines.20a In the ESI mass spectrum (positive ion mode) of a solution of D in MeOH, [M + H]+ is the exclusively observed ion, whereas in DMSO/MeOH solution [M + DMSO + H]+ (m/e = 241, 30%) is found as a further prominent ion. The high volatility of D is associated with a high melting temperature of about 227 °C (500 K), which is substantially higher than that of 2a and 3. These features already suggest that D might represent a plastic crystal, similar to that established for the parent bispidine A (mp 198 °C).20b In fact, differential scanning calorimetry (DSC) revealed that D undergoes a stepwise endothermic phase transition between 0 and 30 °C which is reversed between +10 and −40 °C in the cooling run. D


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Inorganic Chemistry

Table 1. Crystal Data for C7H10F2(NH)2 (D-II), {C7H10F2(NH)2)}PtCl2 (D1), and {C7H10F2(NH)2}Pt{C4H6(CO2)2}·5H2O (D2) compound internal identification CCSD no. empirical formula color formula wt (g mol−1) temp (K) wavelength (Å) cryst syst space group unit cell dimens a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z V/Z (Å3) calcd density (Mg·m−3) abs coeff (mm−1) F(000) (e) cryst size (mm3) θ range for data collecn (deg) index ranges

no. of rflns collected no. of indep rflns no. of rflns with I > 2σ(I) completeness (%) abs correction max/min transmission full-matrix least-squares no. of data/restraints/params goodness of fit on F2 final R indices (I > 2σ(I)) R1 wR2 R indices (all data) R1 wR2 ext coeff largest diff peak/hole (e Å−3)

D-II

D1

D2

9268 1515983 C7H12F2N2 colorless 162.19 223(2) 0.71073 monoclinic P21/c (No. 14)

9258 1515984 C7H12Cl2F2N2Pt colorless 428.18 100(2) 0.71073 monoclinic P21/n (No. 14)

9331 1515985 C13H28F2N2O9Pt colorless 589.46 100(2) 0.71073 triclinic P1̅ (No. 2)

10.730(2) 6.3910(13) 11.494(2) 90.0 103.55(3) 90.0 766.3(3) 4 191.6 1.406 0.120 344 0.02 × 0.25 × 0.27 3.647−35.072 −17 ≤ h ≤ 17 −10 ≤ k ≤ 10 −18 ≤ l ≤ 18 23455 3396 (Rint = 0.0793) 1538 99.9 (θ = 25.242°) Gaussian 0.99640/0.96265 F2 3396/0/108 1.029

12.1816(12) 7.0009(4) 12.3025(11) 90.0 97.712(8) 90.0 1039.7(2) 4 259.9 2.735 13.999 792 0.06 × 0.10 × 0.16 3.342−40.049 −22 ≤ h ≤ 22 −12 ≤ k ≤ 12 −22 ≤ l ≤ 22 84669 6458 (Rint = 0.0474) 5548 99.9 (θ = 25.242°) Gaussian 0.12486/0.45179 F2 6458/0/135 1.092

9.5631(5) 12.9477(8) 17.1155(5) 68.927(3) 89.019(3) 76.996(5) 1922.1(2) 4 480.5 2.037 7.367 1152 0.04 × 0.05 × 0.09 2.613−36.127 −15 ≤ h ≤ 15 −21 ≤ k ≤ 21 −28 ≤ l ≤ 28 68280 18261 (Rint = 0.0567) 15642 99.3 (θ = 36.127°)

0.0673 0.1587

0.0169 0.0315

0.0356 0.0902

0.1678 0.1929 0 0.221/−0.211

0.0254 0.0331 0 1.50/−1.54

0.0429 0.0955 0 2.39/−6.17

0.52594/0.78721 F2 18261/0/487 1.029

or below. We conclude from the above that D crystallizes under these conditions in its ordered-crystalline phase which we designate D-II and for which the crystal structure has been determined (see below). Between 0 and 20 °C a series of minor structural reorganizations take place with completion at 20−30 °C, ending up in the plastically crystalline (dynamically disordered) phase D-I which is present until melting. Thus, it is a common feature of 9,9-difluorinated D and parent A that they reversibly form a plastic phase I when heated, whereas the oxygen containing bispidines B and C (Chart 1) retain their ordered-crystalline phase up to melting. Considering that the ordered-crystalline phases II of parent A and the 9,9difluorinated D belong to different crystals systems and space

Although enthalpy and entropy of transition for the main thermal effect at 30 °C (ΔH303 K = 7 kJ mol−1, ΔS303 K = 23 J mol−1 K−1) were low, together with the preceding minor effects they reached a similar magnitude as for A (ΔH278 K = 10 kJ mol−1, ΔS278 K = 36 J mol−1 K−1).20b No further thermal effects, indicative of solid−solid phase transitions, were found between −20 and −100 °C. The enthalpy of melting of D was determined to be ΔH500 K ≈ 50 kJ mol−1 (mean of different batches) and entropy of melting ΔS500 K ≈ 100 J mol−1 K−1, but these values may be exaggerated due to partial evaporation of the compound. All in all, the thermal properties of D are quite similar to those of the parent A. Plate-like single-crystals of D have been obtained by cooling a saturated pentane solution from ambient temperature to 0 °C E


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Inorganic Chemistry

slightly bulbous geometry of the bispidine (as for A, whereas it is drawn in for C).8 In the crystal, molecules in alternating chiral environments are head−tail associated by intermolecular N2−H2···N1* hydrogen bonds (H2···N1* 2.34(3) Å, N2−H2···N1* 165(1)°; N2···N1* 3.192(3) Å) and are arranged to both sides of a glide plane. Thereby, racemic chains are formed which stretch in the direction of the c-axis (Figure 1b). The molecules in neighboring chains are related by the four 2-fold screw axes and eight inversion centers of the space group. Bonding between the chains in D appears to be based on van der Waals (vdW) H-bond contacts of one tertiary C−H group in one chain to F1 of the other chain, C2−H2A···F2**, with the H2A···F2** distance at 2.63 Å (angle C2−H2A···F1** is 142°) corresponding to the sum of the vdW radii of H (1.20 Å)32a and F (1.47 Å).32 These contacts can be seen as the equivalent to the C−H···O contacts in C.8 The molecular volume of a molecule of D in D-II has been determined from the unit cell volume at Vm = V/Z = 191.6 Å3. When compared with the structure of the parent bispidine A (Vm = 180.2 Å3),20b the volume of D-II is larger by ΔVm = 11.4 Å3, which nicely agrees with the value expected from the Hofmann atom volume increments42 of hydrogen (Vinc(H) = 5.08 Å3) and fluorine (Vinc(F) = 11.17 Å3) for the replacement of 2 H atoms by 2 F (ΔVinc = 12.2 Å3). Thus, there is an about equally effective packing of the chains of A and D. Synthesis of the Pt(II) Complexes D1−D3. The reaction of (1,5-hexadiene)PtCl243 with bispidine D is best carried out in dimethylformamide (DMF) (Scheme 3). When clear concen-

groups (see below), the plasticity of both bispidines appears to arise independently of the nature of the packing. Crystal Structure of D. For 9,9-difluorobispidine in its ordered-crystalline phase D-II an X-ray single-crystal structure analysis has been carried out at 223 K (Table 1). The crystals had to be selected and mounted in the cold to prevent transition to the plastic phase D-I. The crystals of D-II belong to the monoclinic crystal system, space group P21/c (No. 14), with four equivalent asymmetric molecules in the unit cell. Interestingly, the space group is the same as for 9-oxabispidine (C),8 but different from that of parent bispidine (A; orthorhombic crystal system; P212121 (No. 19)).20b,41 The main features of the molecules of D agree with those of A and C (Figure 1a). Thus, the molecules exhibit chair−chair

Scheme 3

Figure 1. Crystal and molecular structure of D-II. (a) Overlay of the molecules of D (red) and parent bispidine (A, black). (b) Excerpt from the chain structure of D-II, showing the intra- and intermolecular hydrogen bonding interactions. Selected distances (Å) and angles (deg): N1−H1 = 0.88(2), H1···N2 = 2.24(2), N2−H2 = 0.87(3), H2*···N1 = 2.34(3), N1···N2 = 2.830(3), N1···N2* = 3.192(3), C7− F1 = 1.377(2), C7−F2 = 1.380(2), F1−C7−F2 = 104.1(1), C2−C7− C5 = 109.6(1), N1−H1···N2 = 124(1), N2−H2···N1* = 165(2).

trated DMF solutions of the starting components are mixed at ambient temperature, a colorless precipitate forms. Heating to 40 °C affords an intense yellow solution from which colorless crystals are obtained. The product capriciously holds some DMF which cannot be removed under a vacuum. However, all crystals we selected for X-ray structure determination were devoid of solvent molecules. We therefore assume that the precipitate represents a mixture of well-formed crystals of (C7H12F2N2)PtCl2 (D1) and a variable amount of smaller DMF cocrystals (C7H12F2N2)PtCl2·DMF (D1-DMF) of undetermined nature. The situation may be compared to that of parent (C7H14N2)PtCl2 which crystallizes uniformly as a dimeric cocrystal {(C7H14N2)PtCl2·DMF}2 (A1-DMF) from DMF with the carbonyl oxygen serving as hydrogen bond acceptor toward the NH function, whereas from the weaker basic methylformamide the solvent-free dimeric (C7H14N2)PtCl2 (A1) is formed.21 X-ray structure analysis shows that crystalline D1 and A1 are isomorphous (see below). Compound D1 (with possibly D1-DMF) dissolves well in DMF and even more so in dimethyl sulfoxide (DMSO; see

conformation with the N1−H1 (0.88(2) Å) proton in an endo and the N2−H2 (0.87(3) Å) proton in an exo orientation with respect to the concave face of the molecule. This leads to an intramolecular N1−H1···N2 hydrogen bridge (H1···N2 2.24(2) Å; N1−H1···N2 124(1)°) with a rather short (nonbonding) N1···N2 distance at 2.830(3) Å (A: 2.849(2) Å; C: 2.875(3) Å). As for A and C, the piperidine ring involving N1 is more flattened at nitrogen (C−N−C−C torsion angles: 47.9°, mean) than the piperidine ring involving N2 (57.4°). Furthermore, as an effect of the fluorine substituents at C7, the bonds C2−C7 and C5−C7 (1.490(3) Å, mean) are shortened (A: 1.530(2) Å, mean), leading to some C2···C5 (2.435(3) Å) narrowing of the bispidine skeleton (A: 2.462(2) Å), although not as much as for 9-oxabispidine (C: 2.344(3) Å). Considering the smaller C1··· C6 and C3···C4 distances (2.407(3) Å, mean), D retains a F


Article

Inorganic Chemistry

the DMSO ligand and presumed formation of [(C7H12F2N2)PtCl(OD2)]Cl; this reaction has not been studied in detail. Similarly, when D1 is dissolved in D2O rapid partial hydrolysis is observed, and the 19F NMR signal of D1 at δ(F) −107.5 becomes joined by signals at δ(F) −107.7 and −107.8 attributed to cationic [(C 7 H 12 F 2 N 2 )PtCl(OD 2 )] + and [(C7H12F2N2)Pt(OD2)2]2+, respectively. When NaCl is added, the signal attributed to the dication is fully and that of the monocation is partially suppressed, suggesting the occurrence of equilibria (eq 2).

below), whereas it is insoluble in THF and CH2Cl2 and scarcely dissolves in water. Nevertheless, the dimeric D1 can be recrystallized from hot water without forming a hydrate. This behavior is different from that of parent A1 which from water forms the polymeric trihydrate {(C7H14N2)PtCl2·3H2O}n consisting of alternating chains of (C7H14N2)PtCl2 and water molecules embedded in a laminated (“lasagna”) structure. Thus, difluorinated D1 expectedly appears to be more hydrophobic than the parent A1. The NMR spectra of D1 are best recorded in DMF-d7 where sharp signals are observed, without indication of solvolysis. The NCHeqHax protons (eq/ax assignment with respect to the piperidine rings) give rise to a pair of doublets owing to geminal coupling (2J(HH) = 12.4 Hz); of these, the higher field doublet is flanked by a pair of satellites attributed to coupling with the antiperiplanar 195Pt (3J(195PtH) = 70 Hz). The 13C NMR spectrum of D1 is similar to that of uncoordinated D, with all C atoms delivering triplets due to coupling with 2 F (the NCH2 triplet is unanticipated). The 19F resonance of D1 is a sharp singlet (δ(F) −107.4), which is somewhat at higher field than for D (δ(F) −102.9) and quite similar to that of the carbamate 3 (δ(F) −108.7, mean). As a solution in DMSO, D1 reacts slowly with the solvent and after about 1 day microcrystals of the adduct D1-DMSO precipitate in 30−40% yield (eq 1). Clearly, the DMSO adduct

For the synthesis of the carboplatin and oxaliplatin analogues with 9,9-difluorobispidine as a carrier ligand, we reacted Pt(II)dichloride D1 (with possible D1-DMF) with Ag2(cbdca) (cbdca = 1,1-cyclobutanedicarboxylate) and Na2C2O4 according to Scheme 3. The reaction with Ag2(cbdca) was carried out as a suspension in water; after removal of the precipitated AgCl the solution was concentrated and cooled to 0−4 °C to yield colorless crystals of the pentahydrate (C 7 H 12 F 2 N 2 )Pt{C4H6(CO2)2}·5H2O (D2) in 53% yield. When dried under a vacuum D2 loses about four of the five water molecules. Compound D2 dissolves moderately in water at ambient temperature but increasingly so when gently warmed. It is quite soluble in DMSO and DMF. According to X-ray analysis, D2 is isomorphous to the parent (C7H14N2)Pt{C4H6(CO2)2}·5H2O (A2)21 and also the 9-oxabispidine derivative (OC6H12N2)Pt{C4H6(CO2)2}·5H2O (C2)8 (in contrast to the 9,9-diol {(HO)2C7H12N2}Pt{C4H6(CO2)2}·2H2O (B2) which forms a dihydrate).22 For the synthesis of the oxalate D3 hot aqueous solutions of equimolar amounts of D1 and Na2C2O4 were mixed at 70 °C, and the reaction solution was maintained at this temperature for 1 h. When the heating was turned off, colorless microcrystals of (C7H12F2N2)Pt(C2O4) (D3) precipitated in 66% yield. Even after slow cooling, extending over several days, no crystal suitable for X-ray structure analysis was found. The product is virtually insoluble in all typical solvents, including water and DMSO, and no 1H and 13C NMR characterization has been possible. Nevertheless, 19F NMR allowed observation of a clean singlet (δ(F) − 106.4). We assume that D3 features a polymeric structure similar to that of parent (C7H14N2)Pt(C2O4) (A3).21 IR Spectra of the Pt(II) Complexes D1−D3. A detailed description of the IR spectra of the pure C7H12(NH)2 (A), starting 1, and the new 2a,b, 3, and D is presented in the Supporting Information. Including complexes D1−D3, all compounds have the same bispidine skeleton and differ only in the substituents at the N atoms and/or at 9-C position, thus allowing interpretation of the spectra by comparison. All spectra have been included in the SI. The assignment of the IR bands of the Pt complexes D1−D3 is based on a recent vibrational analysis of oxaliplatin.45 According to this study, the symmetric and asymmetric Pt−N stretching vibrations are rather similar and are expected to appear as strong bands around 550 cm−1. Accordingly, we assign to υas(Pt−N) and υsy(Pt−N) for D1 predominantly a strong band at 532 cm−1, for D2 a triple combination centered at 555 cm−1, and for D3 a split band at 559/542 cm−1. For D3

D1-DMSO is less soluble in DMSO than D1. The reaction appears to involve displacement of one Cl− to give ionic [(C7H12F2N2)PtCl(DMSO)]Cl (D1-DMSO), possibly forming a tight ion-pair. The reaction (in DMSO-d6) can be monitored by highly sensitive 19F NMR where low solubility, in particular, of D1-DMSO, is less of a problem. Over time the singlet of starting D1 (δ(F) −106.2) is accompanied by a pair of signals for D1-DMSO (δ(F) −106.3, −106.4; no 2J(F,F) coupling visible in DMSO-d6) until an about 1:2 mixture is reached. The same mixture is obtained when D1-DMSO is dissolved in DMSO-d6. Thus, eq 1 represents an equilibrium and in DMSO neither D1, nor D1-DMSO can be independently observed, although both compounds can be synthesized in the pure state. Displacement reactions at Pt(II) by DMSO have been observed before.44 We have also characterized the components D1 and D1DMSO in DMSO-d6 solution by 1H (600 MHz) and 13C (150.9 MHz, 70000 scans) NMR, including COSY and HSQC spectra. The spectra of D1 in DMSO-d6 are similar to those in DMF-d7 and consistent with C2v symmetry. For D1-DMSO the 1H and 13 C signals of NH and NCHeqHax are split into pairs, indicating lower CS symmetry. The 13C signals of CF2 and CH remain as triplets, but the signals for both NCH2 and N′CH2 become doublets, attributed to marked coupling with only the antiperiplanar F (3J(FC) ≈ 5 Hz). In the ESI spectrum (positive operation mode) of D1-DMSO, the signal of [(C7H12F2N2)PtCl(DMSO)]+ (m/e = 470) is exclusively observed. The ionic D1-DMSO is insoluble in DMF, but sparingly soluble in D2O where it slowly reacts by partial displacement of G


Article

Inorganic Chemistry bands at 828(w) and 808(vs) cm−1 are attributed to υas(Pt−O) and υsy(Pt−O), in agreement with the situation reported for oxaliplatin.45 Pt−Cl stretching and O−Pt−O, N−Pt−N, and N−Pt−O bending vibrations are expected to occur well below 450 cm−1 beyond the range limits. The spectra of the malonate D2 and oxalate D3 are dominated by intense OCO stretching band combinations in the ranges 1660−1600 cm−1 (D2) and 1700−1650 cm−1 (D3). For D3 we find a strong uniform absorption at 1376 cm−1 assigned to υ(C−O) coupled with υ(C−C), and a related cluster of bands occurs for D2 around 1364 cm−1. For the dichloride D1 the spectral region 2950−1470 cm−1 is free of any bands. As for the uncoordinated 3 and D, complexes D1− D3 show a series of intense bands in the 1145−1040 cm−1 region which we attribute to υas(CF2), υsy(CF2), and υ(N−C). It can be expected that C−F vibrations will be hardly affected by the coordination of D to Pt(II) as present in D1−D3. All three Pt complexes display a pair of closely spaced sharp bands 473/ 458 cm−1 (D1), 473/460 cm−1 (D2), and 475/460 cm−1 (D3) attributed to unspecified bending vibrations. In contrast to the υ(N−H) hump at 3318/3257 cm−1 for uncoordinated D, for the Pt complexes the υ(PtN−H) bands are markedly shifted to lower wavenumbers to give rise for D1 to a remarkably sharp pair at 3194 and 3154 cm−1 and for D2 and D3 to weaker bands at 3169/3055 cm−1 and 3139/3055 cm−1, respectively. It must be borne in mind that for all compounds the N−H function is not free but involved in various forms of H-bonding, which for D2 includes water molecules. Unlike for uncoordinated D, any Bohlmann-type NC−H bands46 (see SI) are absent for D1−D3, since the nitrogen electron pairs are involved in Pt(II) coordination. Molecular Structures of (C7H12F2N2)PtCl2 (D1) and (C7H12F2N2)Pt{C4H6(CO2)2}·5H2O (D2). The structures of the 9,9-difluorobispidine complexes D1 and D2 have been determined by X-ray diffraction (Table 1). The structures are each isomorphous to their parent compounds A1 (solvent-free) and A2 and C2 (forming pentahydrates), so we refer to these for more detailed descriptions.8,21 Nevertheless, some features are particularly noteworthy. In D1 (monoclinic crystal system, space group P21/c, No.14), the molecules (Figure 2a) form centrosymmetric pairs by 2-fold mutual N1−H1···Cl1 hydrogen bonding (N1−H1 0.88(2) Å, H1···Cl1 2.41(2), N1···Cl1 3.217(2) Å, N1−H1···Cl1 153(2)°). While the distortion of the square-planar coordination geometry of the Pt atom is small (dihedral angle N1,N2,Pt1/Pt1,Cl1,C2 4°), the coordination planes of the two adjacent Pt centers are offset by 1.12(6) Å. Such dimers are related to their neighbors in the same plane parallel to bc and having identical orientation by inversion centers at a/2 and midpoints ac and ab, forming a sheet. There are no comparable bonds between these dimers; the N2−H2··· Cl2 distance to the neighboring dimer in the crystal is significantly longer than within the dimers (N2−H2 0.87(3) Å, H2···Cl2 2.82(3), N2···Cl2 3.428(2) Å, N2−H2···Cl2 129(3)°). The dimers of the next sheet stacked along a axis are related to the former by two glide planes, four 2-fold screw axes, and a further four inversion centers. The dimers of such adjacent sheets intermesh giving rise to a herringbone pattern when viewed as a projection on the ab plane. Association appears predominantly due to interdimer N2−H2···Cl2** (2.82(3) Å) H-bond contacts, but there are also short CH···F2 (2.54(3), 2.57(3) Å) contacts.

Figure 2. Crystal and molecular structure of {C7H10F2(NH)2)}PtCl2 (D1): (a) structure of the molecules; (b) unit cell of D1, showing the centrosymmetric dimers by held together by a pair of N1−H1···Cl1 bonds. Selected bond distances (Å), nonbonding distances (Å), and bond angles (deg): Pt1−N1 = 2.040(1), Pt1−N2 = 2.035(1), Pt−Cl1 = 2.3051(4), Pt−Cl2 = 2.3044(4), N1···N2 = 2.768(2), N1···Cl1* (intermolecular) = 3.217(2), C7−F1 = 1.373(2), C7−F2 = 1.375(2); N1−Pt1−N2 = 85.56(6), Cl1−Pt1−Cl2 = 91.68(1), C2−C7−C5 = 109.3(1), F1−C7−F2 = 105.0(1).

A relatively tight packing of the molecules in D1 is also reflected by the molecular volume Vm = 259.9 Å3, which is only slightly larger than that of parent A1 (252.2 Å3).21 The increase of ΔVm = 7.7 Å3 is about half of the value expected on the basis of the Hofmann atom volume increments42 (ΔVinc = 12.2 Å3; see D). The tight packing of the intermeshing dimers, combined with reduced hydrophilicity because of fluorine substitution, is seen as the reason for the poor interaction with potential solvent molecules and therefore for the relatively low solubility. The structure of the 9,9-difluorobispidine-modified carboplatin analogue (C7H12F2N2)Pt{C4H6(CO2)2}·5H2O (D2) (space group P1̅ (No. 2)) is isomorphous to the structures of (C7H14N2)Pt{C4H6(CO2)2}·5H2O (A2)21 and (OC6H12N2)Pt{C4H6(CO2)2}·5H2O (C2),8 whereas the 9,9-diol derivative crystallizes with a lower defined water content, {(HO)2C7H12N2}Pt{C4H6(CO2)2}·2H2O (B2; space group P4/n (No. 85)).22 There are 2 independent Pt complexes and 10 water molecules in the asymmetric unit of D2. The unit cell comprises two such entities (Z = 2), which are related to one another by inversion at the center of the unit cell, so the unit cell contains a total of 4 Pt complexes and 20 water molecules (Figure 3b). A detailed description of the structure and the packing is given in ref 21. Worthy of note is the molecular volume of the difluorinated D2. At Vm = 480.5 Å3 it is only slightly larger (ΔVm = 9.5 Å3) than that of the nonfluorinated A2 (Vm = 471.0 Å3), similar to H


Article

Inorganic Chemistry

Cell Studies. Cytotoxic potency of D1−D3 toward the ovarian cancer line A2780 was tested, but found much lower than for the parental bispidine complexes A1−A3. Testing was made by the MTT assay47 and was performed as already described.21 The findings coincide with the fact that the 9,9diol- (B1−B3) and 9-oxabispidine complexes (C1−C3) also show lower potency than A1−A3. There appears to be a sequence of declining potency. A1‐A3 > B1‐B3 > C1‐C3 ≈ D1‐D3

Tentatively we explain the low potency of the oxygen or fluorine modified bispidines by an unwanted polarization of virtually all bonds in the bispidine skeleton due to the high electronegativity of the O and F substituents. This is thought to lower lipophilicity and increase acidity of the NH protons with strengthening of the intermolecular H-bonds, which among other effects is expected to lead to reduced solubility. This seems consistent with the suggestion by others that introduction of fluorine may impart membrane permeability owing to reduction of amine basicity.27,48

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CONCLUSIONS The present results complement our previous studies on a series of Pt(II)-bispidine analogues of cisplatin, carboplatin, and oxaliplatin, using N-unsubstituted bispidines as carrier ligands: Figure 3. Crystal and molecular structure of (C7H12F2N2)Pt{C4H6(CO2)2}·5H2O (D2): (a) drawing of the structure of molecule 1; (b) unit cell (two water O atoms are hidden). Selected bond distances (Å), nonbonding distances (Å), and bond angles (deg): Molecule 1: Pt1−N1 = 2.026(2), Pt1−N2 = 2.025(2), N1···N2 = 2.772(3), Pt1−O1 = 2.032(2), Pt1−O2 = 2.0105(19), C7−F1 = 1.372(3), C7−F2 = 1.366(3), N1−Pt1−N2 = 86.34(9), O1−Pt1−O2 = 89.94(8), F1−C7−F2 = 105.3(2), C2−C7−C5 = 109.5(2); molecule 2: Pt2−N3 = 2.018(2), Pt2−N4 = 2.020(2), N3···N4 = 2.777(3), Pt2−O5 = 2.014(2), Pt2−O6 = 2.015(2), C20−F3 = 1.373(4), C20−F4 = 1.371(4), N3−Pt2−N4 = 86.90(11), O5−Pt2− O6 = 88.94(8), F3−C20−F4 = 105.3(2), C15−C20−C18 = 109.3(2).

Here, a viable route for the synthesis of N-unsubstituted 9,9difluorobispidine (D) is reported. Difluorinated D (mp 227 °C) crystallizes from solution below 0 °C in the ordered-crystalline phase D-II and undergoes a transition to a plastically crystalline mesophase D-I at ambient temperature. There are interesting crosswise relations in the series in that regarding plasticity D resembles the parent A (mp 198 °C), but contrasts to (nonplastic) 9-oxabispidine C (mp 76 °C), whereas the ordered crystals of C and D-II are isomorphous, but different from A-II. Using D the Pt(II)-9,9-difluorobispidine complexes D1−D3 have been synthesized. The solubility of the dichloride D1 and the oxalate D3 in water is very low, whereas the pentahydrate D2 dissolves well. Complexes D1 and D2, which have been characterized by structure analyses, are isomorphous to the homologues A1 (solvent-free) and A2 and C2 (forming pentahydrates). As the crystal structures of D1 and D2 show, the bulk of the bispidine ligand is only marginally increased by the introduction of the two fluorine substituents on C9, ruling out steric effects as a possible explanation for the difference in the cytotoxic potency toward the ovarian cancer line A2780 compared with parental bispidine complexes A1 and A2. Water encapsulation of the Pt(II) complex molecules in D2 in the solid is virtually unchanged as compared to the situation in A2 and C2, appearing to rule out a distinct hydrophobic effect of the fluorine atoms on the molecules D2. The low solubility of D1 and D3 in water and other polar solvents is attributed to the presence of relatively strong intermolecular N−H···X hydrogen bonds in the solids, resulting from enhanced N−H acidity. As for C1−C3 containing oxygen, the low cytotoxic potency of D1−D3 to the ovarian cancer line A2780 is attributed to relatively high bond polarity in the bispidine skeleton caused by

the situation observed for D1. A larger increase would have been expected on the basis of the Hofmann atom volume increments. These data and the isomorphism of A2, C2, and D2, which includes all details of the water solvation of the Pt complex molecules, rule out any significant (attractive or repulsive) interaction between the water coating and the CF2 entity in D2 or the 9-O atom in C2. Coordination of D at the Pt(II) center leads to a shortening of the N1···N2 distance from 2.830(3) Å in D to 2.768(2) Å in D1 and 2.775(3) Å in D2 (mean of molecules 1 and 2). The C−N bonds (all mean values) are lengthened from 1.452(5) Å in D to 1.494(4) Å in D1 and 1.496(5) Å in D2, and, less so, the C2/C5−C7 bonds are elongated from 1.490(3) Å in D to 1.515(6) Å in D1 and D2 (all are mean values). The C7−F bonds shrink slightly from 1.379(3) Å (D) to 1.374(3) Å (D1) and 1.371(4) Å (D2) (mean values). As a result, the geometrical changes experienced by the bispidine skeleton when A becomes fluorinated to form D are partially reversed upon coordination to Pt(II), and the skeleton partially retains the more bulbous shape, as evidenced by the increase of the nonbonding distances C2···C5 (from 2.435(2) Å in D to 2.468(2) Å in D1 and 2.475(4) Å in D2) and C1/C3···C6/C4 (from 2.407(7) Å in D to 2.460(6) Å in D1 and D2; mean values). I


Article

Inorganic Chemistry

3,7-Di(ethylcarboxylate)-9,9-difluorobispidine (3). Compound 2a (5.69 g, 20.0 mmol) was dissolved in 50 mL of dry dichloromethane (DCM) and was cooled to −30 °C. To the solution diethylaminosulfurtrifluoride (DAST; 5.5 g, 34.0 mmol) was added with stirring. The reaction mixture turned light yellow and was allowed to warm to room temperature where it was stirred for 12 h. While cooling in an ice-bath dilute potassium carbonate solution (50 mL) was added, and the mixture was stirred vigorously for 30 min to quench the reaction. The DCM layer was separated and washed with dilute potassium carbonate solution (3 × 50 mL). The aqueous layers were combined and extracted with DCM (2 × 50 mL). Finally, all organic layers were combined, dried over anhydrous MgSO4, and evaporated to dryness to give a light yellow viscous oil. Vacuum distillation (10−2 mbar) at 110 °C afforded a light yellow highly viscous oil (4.59 g, 75%). The oil was dissolved in 30 mL of warm pentane and recrystallized at 4 °C to afford white rectangular crystals (3.12 g, 51%) which were collected by filtration. The filtrate was concentrated and kept at 4 °C for a further crop of crystals (0.61 g, 10%); total yield of recrystallized 3 was 3.73 g (61%). Colorless crystals; mp 58−60 °C. C13H20F2N2O4 (306.3). EI MS (50 °C): m/e (%) 306 ([M]+, 45), 233 ([M − CO2Et]+, 100), 112 ([C6H7FN]+, 72), 98 ([C5H5FN]+, 32), 42 ([C2H4N]+, 40). ESI-pos (MeOH/DCM): m/e = 329 [M + Na]+. For IR data, see SI. 1H NMR (600 MHz, CDCl3): δ 4.40/4.29 (each d, 2J = 12 Hz, 4H, Heq), 4.08/4.03 (each m, 4H, OCH2), 3.30/3.23 (each d, 2J = 12 Hz, 4H, Hax), 2.05 (br s, 2H, CH), 1.22 (t, 3J = 7.1 Hz, 6H, CH3). 13 C NMR (CDCl3): δ 155.5 (CO2), 121.8 (t, 1J(FC) = 248 Hz, CF2), 61.8 (OCH2), 45.7 (NCH2), 36.4 (t, 2J(FC) = 19 Hz, CH), 14.6 (CH3). 19F NMR (CDCl3): δ −108.6, −108.8. 9,9-Difluorobispidine (D). Compound 3 (3.06 g, 10.0 mmol) was dissolved in 15 mL of ethanol and 40 mL of 10 N aqueous KOH was added. The mixture was refluxed for 6 h. After ethanol was removed under a vacuum, the aqueous solution was further refluxed for 24 h. Water was azeotropically removed from the reaction mixture by toluene distillation. The solid was filtered through a Celite pad, and toluene was removed under a vacuum to afford 1.34 g of a yellowish white solid (83%). Vacuum sublimation (10−1 mbar) at 40 °C into a trap at −78 °C afforded a pure white crystalline solid; yield 0.92 g (57%). Compound D is highly hygroscopic and best stored under argon. Plate-like crystals of D have been obtained by cooling a pentane solution from 20 to 0 °C. C7H12F2N2 (162.2). Mp 227 °C. EI MS (20 °C): m/e (%) 162 (63), 112 (80), 98 (100), 43 (50) (see text). ESIpos MS (MeOH): m/e = 163 ([M + H]+); (DMSO/MeOH): m/e = 241 ([M + DMSO + H]+, 30), 163 ([M + H]+, 100). For IR data, see SI. 1H NMR (THF-d8, 600 MHz): δ 3.15 (d, J = 14.4 Hz, 4H, NCH2), 3.11 (d, J = 14.4 Hz, 4H, NCH2), 2.32 (br s, 2H, NH), 1.76 (pseudo t, 2H, CH). 13C NMR (THF-d8, 600 MHz): δ 124.4 (t, 1J(FC) = 247 Hz, CF2), 50.8 (t, 3J(FC) = 3.6 Hz, NCH2), 39.6 (t, 2J(FC) = 17.1 Hz, CH). 19F NMR (THF-d8): δ −102.9. (C7H12F2N2)PtCl2 (D1). A light yellow DMF solution (5 mL) of (1,5-hexadiene)PtCl2 (348 mg, 1.00 mmol) was mixed with a colorless DMF solution (5 mL) of D (162 mg, 1.00 mmol). The solution was stirred at 40 °C for 24 h to obtain a colorless precipitate in an intense yellow reaction solution. The mixture was diluted with about 50 mL of diethyl ether to obtain more precipitate. The colorless microcrystalline solid was collected by filtration, washed with diethyl ether, and dried under a vacuum; yield 305 mg (70%). Anal. Calcd for C7H12F2N2PtCl2 (428.2): C, 19.64; H, 2.82; Cl, 16.56; F, 8.87; N, 6.54; Pt, 45.56. Found: C, 21.04; H, 3.22; Cl, 14.44; F, 7.80; N, 6.61; Pt, 45.05. ESIpos MS (DMSO): m/e (%) 470 ([(C7H12F2N2)PtCl(DMSO)]+, 100), 179 ([C5H8FN·C2H6SO]+, 20). For IR data, see SI. 1H NMR (DMFd7/DMSO-d6): δ 6.92/7.03 (s br, 2H, NH), 3.68/3.44 (d, 2J(HH) = 12.4 Hz, 4H, NCHeqHax), 3.36/3.02 (d, 2J(HH) = 12.4 Hz, 3J(PtH) = 70 Hz, 4H, NCHeqHax), 2.80/2.61 (br “s”, 2H, CH). 13C NMR (DMFd7/DMSO-d6): δ 121.6/121.1 (t, 1J(FC) = 248 Hz, CF2), 51.2/50.3 (t, 3 J(FC) ≈ 4 Hz, NCH2), 35.7/34.5 (t, 2J(FC) ≈ 21 Hz, CH). 19F NMR (DMF-d7): δ −107.4. [(C7H12F2N2)PtCl(DMSO]Cl (D1-DMSO). Dissolving D1 (86 mg, 0.2 mmol) in 5 mL of DMSO affords a colorless microcrystalline precipitate of D1-DMSO over the course of a day: yield 35 mg (35%). C7H12F2N2PtCl2·C2H6OS (506.3). ESI-pos MS (DMSO): m/e (%)

the high electronegativity of F. Substituents of high electronegativity at C9 of the bispidine ligand appear to decrease lipophilicity of the compounds, thus hampering cell membrane permeability. To maintain cytotoxic potency with bispidines as possible carrier ligands, it appears that variations in the bulk of the ligand are less relevant than ensuring low bond polarity in the skeleton. The strongly electronegative O and F substituents should therefore be avoided. Moreover, O or OH groups do not necessarily increase water solubility, since they provide additional base sites for association. Partial F substitution does not appear to necessarily enhance hydrophobicity. We conclude that for enhancement of lipophilicity of the bispidine carrier ligand (di)alkylation or (di)silylation at C9 might be a worthwhile objective for future studies. Promising starting materials for such an endeavor are the 9-ketones {(O)C7H10(NH)2}PtX2, which are accessible from the 9,9-diols B1−B322 by dehydration.

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EXPERIMENTAL SECTION

The reactions were performed with Schlenk-type glassware under argon. 3,7-Diallyl-bispidin-9-one (1; FW 220.3)20 and (1,5-hexadiene)PtCl243 were prepared according to the literature. DAST and XtalFluor-E were used as obtained from Aldrich.

3,7-Di(ethylcarboxylate)-bispidin-9,9-diol (2b). To a suspension of sodium iodide (37.5 g, 250 mmol) in 200 mL of dry acetonitrile was added ethyl chloroformate (27.1 g, 250 mmol), and the mixture was stirred for 1 h, giving a white precipitate of NaCl. The reaction mixture was cooled to 4 °C (ice bath) and 3,7-diallyl-3,7diazabicyclo[3.3.1]nonan-9-one (1, 11.0 g, 50.0 mmol) was added. After addition, the reaction mixture was refluxed under argon for 20 h. Insolubles were removed by filtration through a small Celite pad and then acetonitrile was removed under a vacuum to afford a brown viscous oil. The oil was dissolved in 300 mL of ethyl acetate, and the solution was washed twice with 50 mL of a saturated aqueous solution of K2CO3. The organic layer was washed with saturated NaCl brine (50 mL), dried over anhydrous MgSO4, and evaporated to dryness to leave a yellowish powder (13.2 g, 87%). The solid decolorized upon washing with cold acetone (0 °C); remaining yield 10.3 g (68%). Mp 110−112 °C. C13H22N2O6 (302.3). EI and ESI-pos MS as for 2a. For IR data, see SI. The 1H and 13C NMR spectra of 2b in nonaqueous solvents (DMSO, DMF, acetone, and THF) indicated partial elimination of water. 1H NMR (D2O): 4.70 (HOD), 4.11 (dd, 4H, Hax), 4.03 (q, 4H, OCH2), 3.38 (“t”, 4H, Heq), 1.90 (br, 2H, CH), 1.23 (t, J = 7.1 Hz, 6H, CH3). 13C NMR (D2O): 157.0 (CO2), 92.1 (C(OH)2), 62.6 (OCH2), 45.9 (NCH2), 38.2 (CH), 13.9 (CH3). 3,7-Di(ethylcarboxylate)-bispidin-9-one (2a). A solution of 2b (302 mg, 1.00 mmol) in 20 mL of toluene was concentrated by distillation at normal pressure. The remaining solution was decanted from some brownish oily material and evaporated to dryness to leave an off-white residue. The solid was dissolved in pentane by gentle warming, again decanted from minor impurities, and left for crystallization; yield 215 mg (76%). Mp 61 °C. Anal. Calcd for C13H20N2O5 (284.3): C, 54.92; H, 7.09; N, 9.85. Found: C, 53.37; H, 7.19; N, 9.54. EI MS (50 °C): m/e = 284 ([M]+, 100). ESI-pos (MeOH/CH2Cl2): m/e = 307 ([M + Na]+). For IR data, see SI. 1H NMR (CDCl3, 400 MHz): δ 4.70/4.60 (each d, 2J = 12 Hz, total 4H, Heq), 4.11 (br m, 4H, OCH2), 3.34/3.29 (overlapping d, 2J = 12 Hz, total 4H, Hax), 2.41 (br s, 2H, CH), 1.27 (t, 3J = 7.1 Hz, 6H, CH3). 13C NMR (CDCl3): δ 211.4 (C = O), 155.4 (CO2), 62.0 (OCH2), 50.1 (NCH2), 47.0 (CH), 14.5 (CH3). J


Article

Inorganic Chemistry 470 ([(C7H12F2N2)PtCl(DMSO)]+, 100). 1H NMR (DMSO-d6; 600 MHz): δ 7.45 (s, 1H, NH), 6.30 (s, 1H, N′H), 3.68 (d, 2H, NCHeq), 3.36 (d, 2H, NCHax), 3.34 (d, 2H, N′CHeq), 3.03 (d, 2H, N′CHax), 2.77 (“s”, 2H, CH). 13C NMR (DMSO-d6; 150.9 MHz): δ 120.5 (t, 1C, 1J(FC) = 249 Hz), 50.9 (d, 2C, 3J(FC) ≈ 5 Hz, NC), 49.0 (d, 2C, 3 J(FC) ≈ 5 Hz, N′C), 34.3 (t, 2C, 2J(FC) = 21 Hz, CH). (C7H12F2N2)Pt{C4H6(CO2)2}·5H2O (D2). A suspension of D1 (86 mg, 0.20 mmol) and Ag2(cbdca) (72 mg, 0.20 mmol) was stirred in 40 mL of water at room temperature for 48 h. AgCl was removed by filtration, and the clear solution was concentrated under a vacuum at 50 °C. The concentrated solution was kept at 4 °C for 3 days to afford rectangular white crystals (48 mg). The mother liquor was concentrated further and after cooling at 4 °C a second crop of crystals (14 mg) was obtained. The crystals were collected by filtration and dried under air; total yield 62 mg (53%). While the X-ray structure analysis of crystals picked directly from water revealed a content of five water molecules, drying of the compound under vacuum resulted in a major loss of the solvate water. C13H18F2N2O4Pt·5H2O (589.5). Anal. Calcd for C13H18F2N2O4Pt·1H2O (517.4): C, 30.18; H, 3.90; F, 7.34; N, 5.41; Pt, 37.71. Found: C, 30.17; H, 3.38; F, 5.24; N, 4.81; Pt, 34.28. ESI-pos (MeOH): m/e (%) 522 ([(C7H12F2N2)Pt(C6H6O4) + Na]+, 10), 179 ([C7H11F2N2·H2O]+, 100). HR-ESI-pos (MeOH): m/e = 522.07750 (calcd 522.07749 for [M + Na]+). ESI-neg (MeOH): m/e (%) 498 ([M − H]−, 85), 420 (20), 280 (100). For IR data, see SI. 1H NMR (DMSO-d6): δ 7.63 (s br, 2J(PtH) = 77 Hz, 2H, NH), 3.45 (d, 2 J(HH) = 13.2 Hz, 4H, NCHeqHax), 3.03 (d, 2J(HH) = 13.2 Hz, 4H, NCHeqHax), 2.67 (t, 3J(HH) = 7.9 Hz, 4H, CCH2CH2), 2.63 (br, 2H, CH), 1.67 (quint, 3J(HH) = 7.9 Hz, 2H, CCH2CH2). 13C NMR (DMSO-d6): δ 177.2 (CO2), 121.0 (t, 1J(FC) = 248 Hz, CF2), 55.4 (s, CCH2), 51.3 (t, 2J(FC) = 3.8 Hz, 4C, NCH2), 34.7 (t, 2J(FC) = 20.6 Hz, CH), 30.3 (2C, CCH2CH2), 14.9 (1C, CCH2CH2). 19F NMR (DMSO-d6): δ −106.4. (C7H12F2N2)Pt(C2O4) (D3). A hot (70 °C) light yellow solution of D1 (128.5 mg, 0.30 mmol) in 40 mL of water was mixed with a hot aqueous solution (5 mL) of Na2C2O4 (44 mg, 0.33 mmol). After 1 h the heat was turned off and a white microcrystalline solid precipitated within 2 h. The reaction mixture was kept at 4 °C for 3 days to complete precipitation. The microcrystals were collected by filtration, washed with water, and dried under a vacuum; yield 88 mg (66%). Anal. Calcd for C9H12Cl2F2N2O4Pt (445.2): C, 24.28; H, 2.72; F, 8.53; N, 6.29; Pt, 43.81. Found: C, 24.30; H, 2.68; F, 8.47; N, 6.31; Pt, 43.76. For IR data, see SI. No 1H and 13C NMR spectra of D3 have been recorded due to low solubility. 19F NMR (DMSO-d6): δ −106.4.

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Angelika Dreier and Waltraud Gamrad from the MaxPlanck-Institute for technical assistance and Dr. Alexandra Hamacher and Professor Matthias U. Kassack from the University of Düsseldorf for the cell studies. General funding by the Max Planck Society is gratefully acknowledged.

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(1) Siegel, R. L.; Miller, K. D.; Jemal, A. Cancer Statistics, 2015. CaCancer J. Clin. 2015, 65, 5. (2) See website of the NIH National Cancer Institute (www.cancer. gov). (3) (a) Rosenberg, B.; Van Camp, L.; Krigas, T. Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode. Nature 1965, 205, 698−699. (b) Rosenberg, B.; Van Camp, L.; Trosko, J. E.; Mansour, V. H. Platinum Compounds: a New Class of Potent Antitumour Agents. Nature 1969, 222, 385−386. (c) Rosenberg, B.; Van Camp, L. The Successful Regression of Large Solid Sarcoma 180 Tumors by Platinum Compounds. Cancer Res. 1970, 30, 1799−1802. (d) Rosenberg, B. Some Biological Effects of Platinum Compounds. Platinum Met. Rev. 1971, 15, 42−51. (e) Rosenberg, B. Platinum Complexes for Treatment of Cancer. Interdiscip. Sci. Rev. 1978, 3, 134−147. (f) Rosenberg, B. In Nucleic Acid−Metal Ion Interactions; Spiro, T. G., Ed.; Wiley: New York, 1980; pp 1−29. (g) Hoeschele, J. D. In Remembrance of Barnett Rosenberg. Dalton Trans. 2009, 10648−10650. (h) Muggia, F. M.; Bonetti, A.; Hoeschele, J. D.; Rozencweig, M.; Howell, S. B. Platinum Antitumor Complexes: 50 Years Since Barnett Rosenberg’s Discovery. J. Clin. Oncol. 2015, 33, 4219−4226. (4) (a) Wheate, N. J.; Walker, S.; Craig, G. E.; Oun, R. The status of platinum anticancer drugs in the clinic and in clinical trials. Dalton Trans. 2010, 39, 8113. (b) Dasari, S.; Tchounwou, P. B. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol. 2014, 740, 364. (5) As of January 2015, the U.S. Federal Drug Administration (FDA) had approved cisplatin to be used to treat bladder cancer, cervical cancer, malignant mesothelioma, nonsmall cell lung cancer, ovarian cancer, squamous cell carcinoma of the head and neck, and testicular cancer, carboplatin to treat nonsmall cell lung cancer and ovarian cancer, and oxaliplatin to treat colorectal and state III colon cancer (always after surgery or radiation therapy or when such therapy cannot be applied, and for advanced, metastasized, and recurred tumors). (6) (a) Cleare, M. J.; Hoeschele, J. D. Studies on the Antitumor Activity of Group VIII Transition Metal Complexes. Part I. Platinum(II) Complexes. Bioinorg. Chem. 1973, 2, 187−210. (b) Cleare, M. J.; Hoeschele, J. D. Anti-tumour Platinum Compounds. Relationship Between Structure and Activity. Platinum Met. Rev. 1973, 17, 2−13. (c) Cleare, M. J. Transition Metal Complexes in Cancer Chemotherapy. Coord. Chem. Rev. 1974, 12, 349−405. (d) Cleare, M. J.; Hydes, P. C.; Malerbi, B. W.; Watkins, D. M. Anti-tumour Platinum Complexes: Relationships Between Chemical Properties and Activity. Biochimie 1978, 60, 835−850. (e) Connors, T. A.; Cleare, M. J.; Harrap, K. R. Structure-Activity Relationships of the Antitumor Platinum Coordination Complexes. Cancer Treat. Rep. 1979, 63, 1499−1502. (f) van der Veer, J. L.; Reedijk, J. Investigating Antitumour Drug Mechanisms. Chem. Br. 1988, 24, 775−780. (g) de Mier-Vinué, J.; Montaña, A. M.; Moreno, V. Platinum Complexes with Cytotoxic Activity: Models for Structure−Activity Relationship Studies. In Metal Compounds in Cancer Chemotherapy; Pérez, J. M., Fuertes, M. A., Alonso, C., Eds.; Research Signpost: Trivandrum, India, 2005; pp 47−154. (h) Montaña, A. M.; Batalla, C. The Rational Design of Anticancer Platinum Complexes: The Importance of the Structure-Activity Relationship. Curr. Med. Chem. 2009, 16, 2235−2260.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b00836. IR spectra of all new compounds and some reference bispidines (PDF) Accession Codes

CCDC 1515983−1515985 (for D, D1, and D2, respectively) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc. cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Raja Mitra: 0000-0002-3317-3800 Klaus-Richard Pörschke: 0000-0003-4138-0831 K


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