Synthesis of selectively deuterated and tritiated lupane derivatives with cytotoxic activity

The aim of this work was to synthesize deuterated and tritiated analogues of highly oxidized lupane derivatives known from our group. We selected compounds that previously showed very high cytotoxic activity on multiple cancer cell lines in order to further investigate the mechanism of their action. From starting material (compounds 1–4), we obtained benzyl platanate (5) and its reaction with deuteromethyltriphenylphosphonium iodide gave deuterated compound 6. Following benzyl deprotection gave free acid 7 and oxidation with SeO₂ gave 30-oxo-[29-²H₂]lup-20(29)-en-28-oic acid (8), which is one of the most active compounds synthesized in our group to date (IC₅₀ 6 μmol/L on CEM cell line). The alkylation of benzyl 2-hydroxy-3-oxolupa-1,20(29)-dien-28-oate (9) with methyliodide or deuteromethyliodide followed by a series of deprotection and hydrogenation steps gave compounds 10–14, where 2β-[31-²H₃]methoxy-3-oxolupan-20(29)-en-28-oic acid (13) is especially interesting, it showed lower activity on CEM cell line (IC₅₀ 10 μmol/L) however, it was very active against Ph1—positive human leukemia BV-173 (IC₅₀ 0.91 μmol/L) and against human myelogenous leukemia K562 (IC₅₀ 0.52 μmol/L). Selectively labelled [3α-²H] and [3α-³H] methyl 3β-acetoxy-21,22-dioxolup-18-en-28-oates 24, 25 were prepared in three steps by reduction of corresponding 3-oxo derivatives and they showed moderate activity on CEM cell line (IC₅₀ 10 μmol/L). In total, 11 labelled compounds (6–8, 11, 14, 18, 19, 21, 22, 24 and 25) have not been reported before.     

Synthesis of indenes from phenylpropanones using alumina catalyst

1,3-Diphenylpronan-2-one undergoes dehydration over alumina at around 400° C to form 1,3-diphenylallene which cyclizes to 2-phenylindene. Since the parent ketone can be obtained under the reaction conditions from phenylacetic acid, the present reaction forms a one step syntheses of 2-phenylindene from phenylacetic acid. 3- and 4-methylphenylacetic acids also give the corresponding indenes. 1,3-Diphenylpropan-1-ones also give phenylindenes, presumably by a direct cyclodehydration reaction.     

Synthesis and reactivity of cyclam-based enediynes

Cyclam-based enediynes 1-3 have been synthesized for the first time either by direct bis- or tetra-alkylation of the cyclam or via double alkylation of the 1,8-bis-sulfonyl derivative. The enediyne 1 readily forms a complex with Ni(II), which also lowered the onset temperature for Bergman cyclization of the parent enediyne by 60 °C. In the presence of a co-oxidant, MMPP, the Ni-complex can cleave ds-DNA into the nicked relaxed form at micromolar concentrations.     

Solid phase synthesis of selectively deuterated arenes

A novel access to deuterated and D(3)CO-substituted arenes has been developed using immobilized triazenes as precursors. The linker system and the deuterating cleavage methodology could be shown to be compatible with various functional groups and are therefore suitable for the synthesis of derivatives only hardly available via comparable protocols.     

Synthesis of indenes from alkynes and phenyl amino chromium carbene complexes

Reactions of phenyl morpholino or pyrrolidino chromium carbene complexes with alkynes in DMF at 120–125°C resulted in exclusive formation of the indene derivatives.     

Solubility of polystyrene in selectively deuterated methyl acetate

Cloud point measurements were made for binary systems of polystyrene (PS) + methyl acetate (MA) and polystyrene (PS) + selectively deuterated MA: CD₃COOCH₃ and CH₃COOCD₃ with three PS samples of M_w = 4.0 × 10⁵, 2.0 × 10⁶, and 13.2 × 10⁶. All systems are characterized by the phase diagrams with upper and lower critical temperature. H/D isotope effects on miscibility for both selectively deuterated acetates are very large and appeared to be independent of the site of deuterium substitution. © 2009 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 47:2140–2143, 2009     

Synthesis of new fulvenes containing heterocyclic substituents

Four new fulvene derivatives bearing heterocyclic substituents have been prepared. Base-promoted condensation of cyclopentadiene with tetrahydropyran-4-one, tetrahydrothiopyran-4-one, and 1-methyl-4-piperidone afforded 4-(cyclopentadienylidene)tetrahydropyran 1 , 4-(cyclopentadienylidene)tetrahydrothiopyran 2 , and N-methyl-4-(cyclopentadienylidene)piperidine 3 in yields ranging from 28% to 75%. Methylation of 3 with methyl iodide gave the corresponding ammonium salt, 4 .     

Synthesis of the deuterated thymidine-d9 and deuterated oligonucleotides

The efficient synthesis of the highly-deuterated thymidine-d₉ by the glycosylation reaction between a deuterated nucleobase and deuterated sugar is described. It is also incorporated into the oligonucleotides using a DNA synthesizer. Using this approach, it is possible to make highly-deuterated oligonucleotides for biological studies and structural analyses.     

Synthesis and protein degradation capacity of photoactivated enediynes

[structure: see text] The viability of proteins as targets of thermally and photoactivated enediynes has been confirmed at the molecular level. Model studies using a labeled substrate confirmed the efficacy of atom transfer from diyl radicals produced from enediynes to form captodatively stabilized carbon centered aminoacyl radicals, which then undergo either fragmentation or dimerization. To exploit this finding, a family of enediynes was developed using an intramolecular coupling strategy. Derivatives were prepared and used to target specific proteins, showing good correlation between affinity and photoinduced protein degrading activity. The findings have potential applications in the design of artificial chemical proteases and add to our understanding of the mechanism of action of the clinically important enediyne antitumor antibiotics.     

A general,versatile and divergent synthesis of selectively deuterated amines

Deuterated organic molecules are of utmost importance in many areas of science and have been recently intensively investigated in medicinal chemistry due to their enhanced metabolic stability. The development of efficient and broadly applicable methods for the selective incorporation of deuterium atoms into organic molecules from readily available starting materials and reagents is therefore of extreme importance. Such methods however often lack generality and selectivity, notably in the nitrogen series. With nitrogen-containing molecules being indeed ubiquitous in medicinal chemistry, there is a strong need for efficient methods enabling the selective synthesis of deuterated amines. In this perspective, we report herein a general, versatile, divergent and metal-free synthesis of amines selectively deuterated at their α and/or β positions. Upon simple treatment of readily available ynamides with a mixture of triflic acid and triethylsilane, either deuterated or not, a range of amines can be smoothly obtained with high levels of deuterium incorporation by a unique sequence involving a domino keteniminium/iminium activation.

A general, versatile, divergent and metal-free synthesis of amines selectively deuterated at their α and/or β positions and relying on a simple treatment of ynamides with triflic acid and triethylsilane, either deuterated or not, is reported.     

Synthesis of Enantiomerically Pure Ferrocenes from Glycofuranosyl-cyclopentadienes,synthetic equivalents of (alkoxyalkyl)fulvenes

Cyclopentadienyl C-glycosides (= glycosyl-cyclopentadienes) have been prepared as latent fulvenes. Their reaction with nucleophiles leads to cyclopentadienes substituted with (protected) alditol moieties and, hence, to enantiomerically pure metallocenes. Treatment of 1 with cyclopentadienyl anion gave the epimeric glycosyl-cyclopentadienes 6 / 7 (Scheme 1). Each epimer consisted of a ca. 1:1 mixture of the 1, 3-and 1, 4-cyclopentadienes a and b , respectively, which were separated by prep. HPLC. Slow regioisomerisation occurred at room temperature. Diels-Alder addition of N-phenylmaleimide to 6a / b ca. 3:7 at room temperature yielded three ‘endo’-adducts, i.e., a disubstituted alkene ( 8 or 9 , 25%) and the trisubstituted alkenes 10 (45%) and 11 (13%). The structure of 10 was established by X-ray analysis. Reduction of 6 / 7 (after isolation or in situ) with LiAlH₄ gave the cyclopentadienylmannitols 12a / b (80%) which were converted to the silyl ethers 13a / b (Scheme 2). Lithiation of 13a / b and reaction with FeCl₂ or TiCl₄ led to the symmetric ferrocene 14 (76%) and the titanocene 15 (34%), respectively. The mixed ferrocene 16 (63%) was prepared from 13a / b and pentamethylcyclopentadiene. Treatment of 6 / 7 with PhLi at ?78° gave a 5:3 mixture of the 1-C-phenylated alcohols 17a / b and 18a / b (71%) which were silylated to 19a / b and 20a / b , respectively. Lithiation of 19 / 20 and reaction with FeCl₂ afforded the symmetric ferrocenes 21 and 22 and the mixed ferrocene 23 (54:15:31, 79%) which were partially separated by MPLC. The configuration at C(1) of 17–22 was assigned on the basis of a conformational analysis. The reaction of the ribofuranose 24 with cyclopentadienylsodium led to the epimeric C-glycosides 27a / b and 28a (57%, ca. 1:1, Scheme 3). The in-situ reduction of 27 / 28 with LiAlH₄ followed by isopropylidenation gave 25a / b (65%) which were transformed into the ferrocene 26 (79%) using the standard method. Phenylation of 27 / 28 , desilylation, and isopropylidenation gave a 20:1 mixture of 33a / b and 34a / b (86%) which was separated by prep. HPLC. The same mixture was obtained upon phenylation of the fulvene 32 which was obtained in 36% yield from the reaction of the aldehydo-ribose 30 with cyclopentadienylsodium at ?100°. Lithiation of 33 / 34 and reaction with FeCl₂ gave the symmetric ferrocene 35 (88%). Similarly, the aldehydo-arabinose 36 was transformed via the fulvene 37 (32%) into a 18:1 mixture of 38a / b and 39a / b (78%) and, hence, into the ferrocene 40 (83%). Conformational analysis allowed to assign the configuration of 33–35 , whereas an X-ray analysis of 40 established the (1S)-configuration of 38a / b and 40 . The opposite configuration at C(1) of 38a / b and 33a / b was established by chemical degradation (Scheme 4). Hydrogenation (→ 41 and 44 , resp.), deprotection (→ 42 and 45 , resp.), NaIO₄ oxidation, and NaBH₄ reduction yielded (+)-(S)- 43 and (?)-(R)- 43 , respectively.     

Synthesis of spiro-pyrazolines: reaction of 1,3-diphenylnitrilimine with fulvenes

A one-step synthesis of a new series of spiro-pyrazolines has been accomplished by the 1,3-dipolar cycloaddition of 1,3-diphenylnitrilimine with various fulvenes (2,3,4,5-tetraphenyl fulvene (1) and its analogues (2, 3), 9-benzalfluorene (7) and its analogues (8, 9) and 6,6-diphenylfluvene (13)). With the exception of 13 all other fulvenes undergo 1,3-dipolar cycloaddition across the exocyclic double bond to give the hitherto unreported spiro-pyrazoline derivatives (1-6, 10-12). In the case of 13, however, the addition of 1,3-dipole takes place at the site of endo-cyclic double bond, leading to the formation of a pyrazoline derivative (14).     

Synthesis of substituted fulvenes with inden-2-ylphosphonic acid fragments

We have developed preparative methods for the synthesis of substituted fulvenes including inden-2-ylphosphonic acid fragments, as well as aromatic and heterocyclic substituents, based on bis(trimethylsilyl)inden-2-ylphosphonate and substituted azomethines in the presence of sodium hydride as an efficient initiator of the reaction. Subsequent treatment of the phosphonates with methanolic solution of sodium methoxide furnished water-soluble disodium salts of the corresponding phosphonic acids.     

由富烯配体合成茂金属化合物的研究

报道了一系列富烯包括烷基取代富烯、6-氨基富烯和具有稠环结构的6-氨基苯并富烯经由去氢或加成反应合成取代二茂金属络合物;(1-二甲氨基)乙烯基环戊二烯基锂与过渡金属的络合反应在一定条件下可以发生分子内碳碳偶联及二甲基胺的消除反应,得到丙烯桥联茂金属化合物,从推导的反应历程提出该反应的反应机理;尚合成了两个新的外消旋手性化合物。     

6-羟基富烯及环戊二烯并[d]哒嗪的合成

本文以6, 6-二烷基富烯与烯丙基格氏试剂反应所得的取代环戊二烯基负离子与芳酰氯反应, 合成了5个新的6-羟基富烯化合物(1-5)。用此化合物与肼反应, 合成了5个新的环戊二烯并[d]哒嗪化合物(6-10)。通过^1H NMR、IR及元素分析确定了它们的结构。