Germanium Analogue of the Parent Phosphine-Borane FLP Compound.

Diimino-carbene-supported germylone dimNHCGe does not react with BPh3 and does not activate dihydrogen in the FLP mode in the combination with this borane. However, it reacts with B(C6 F5 )3 to give the zwitterionic borate dimNHCGe-(C6 F4 )BF(C6 F5 )2 . This compound can be converted into the hydroborate dimNHCGe-(C6 F4 )BH(C6 F5 )2 (8) and further into [dimNHCGe-(C6 F4 )B(C6 F5 )2 ]+ (4). Compound 4 is a Ge/B analogue of Stephan's FLP parent P/B compound (C6 H2 Me3 )2 P-C6 F4 -B(C6 F5 )2 but unlike the latter cannot split dihydrogen. Moreover, attempts to prepare a Ge/B analogue of the zwitterion (C6 H2 Me3 )2 HP-C6 F4 -BH(C6 F5 )2 by protonation of borate 8 resulted in immediate elimination of H2.

Conversion of Natural Narciclasine to Its C-1 and C-6 Derivatives and Their Antitumor Activity Evaluation: Some Unusual Chemistry of Narciclasine.

During the search for a general, efficient route toward the synthesis of C-1 analogues of narciclasine, natural narciclasine was protected and converted to its C-1 enol derivative using a novel semi-synthetic route. Attempted conversion of this material to its triflate in order to conduct cross-coupling at C-1 resulted in a triflate at C-6 that was successfully coupled with several functionalities. Four novel compounds were fully deprotected after seven steps and subjected to evaluation for cytotoxic activity against three cancer cell lines. Only one derivative showed moderate activity compared to that of narciclasine. Spectral and physical data are provided for all new compounds.

Reactivity of a Phosphinoamidinate-Stabilized Disilylene toward H-X Bonds.

An efficient method for the preparation of a phosphinoamidinate-supported disilylene was developed, and its reactivity toward H-E bonds (E = elements from Groups 13-15) was studied. With HBpin, transfer of the ligand from silicon to boron was observed to afford (NP)Bpin. Reaction with a silane (H3SiPh) took place only at elevated temperatures, at which point oxidative addition of the N-P bond of the NP-ligand to one of the silicon atoms of the disilylene occurred prior to Si-H addition involving the remaining silylene center. In contrast, reaction of the disilylene with phosphine, HPPh2 furnished the phosphidosilylene (NP)SiPPh2 (16) together with a highly transient species that, on the basis of a trapping experiment with H3SiPh, is proposed to be the hydridosilylene (NP)SiH, 17. Interestingly, 16 reacts with HPPh2 to give the diphosphine (PPh2)2, most likely via a direct σ-bond metathesis process. The aforementioned products have been characterized by multinuclear NMR and single-crystal X-ray diffraction studies.

Chemoenzymatic Total Synthesis of ent-Oxycodone: Second-, Third-, and Fourth-Generation Strategies.

Four distinct approaches to ent-oxycodone were designed and accomplished. All rely on the same starting material, the diene diol derived from phenethyl acetate by the whole-cell fermentation with E. coli JM109 (pDTG601A), a strain that overexpresses toluene dioxygenase. The key step in the first-generation approach involves the construction of the C-9/C-14 bond by a SmI2-mediated cyclization of a keto aldehyde. The second-generation design relies on the use of the Henry reaction to accomplish this task. In both of these syntheses, Parker's cyclization was employed to construct the D-ring. The third-generation synthesis provides an improvement over the second in that the nitrogen atom at C-9 is introduced by azidation of the C-9/C-10 olefin, followed by reduction and lactam formation between the C-9 amine and the Fukuyama-type lactone. Finally, the fourth generation takes advantage of the keto-nitrone reductive coupling to generate the C-9/C-14 linkage. The four generations of the total syntheses of ent-oxycodone were accomplished in 13, 18, 16, and 11 operations (19, 23, 24, and 18 steps), respectively. Experimental and spectral data are provided for all new compounds.

The assembly of (+)-vincadifformine- and (-)-tabersonine-derived monoterpenoid indole alkaloids in Catharanthus roseus involves separate branch pathways.

The biological activity of monoterpenoid indole alkaloids (MIAs) has led to their use in cancer treatment and other medical applications. Their biosynthesis has involved the formation of reactive intermediates by responsible enzymes to elaborate several different chemical scaffolds. Modification of scaffolds through different substitution reactions has produced chemically diverse MIAs and related biological activities. The present study characterizes the three-step pathway involved in the formation of (+)-echitovenine, the major O-acetylated MIA of Catharanthus roseus roots, and differentiates it from a parallel pathway involved in the formation of hörhammericine. Separate hydrolases convert a common reactive MIA intermediate to aspidosperma skeletons of opposite specific rotations, that is (+)-vincadifformine and (-)-tabersonine, respectively. The formation of (+) minovincinine from (+) vincadifformine 19-hydroxylase (V19H) is catalyzed by a root-specific cytochrome P450 with high amino acid sequence similarity to the leaf-specific tabersonine-3-hydroxylase involved in vindoline biosynthesis. Similarly, O-acetylation of (+)-minovincinine to form (+) echitovenine involves minovincinine-O-acetytransferase. The substrate specificity of V19H and MAT for their respective (+)-enantiomers defines the separate enantiomer-specific pathway involved in (+)-echitovenine biosynthesis and differentiates it from a parallel (-)-enantiomer-specific pathway involved in the formation of hörhammericine from (-)-tabersonine.

Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19E-geissoschizine.

Monoterpenoid indole alkaloids (MIAs) possess a diversity of alkaloid skeletons whose biosynthesis is poorly understood. A bioinformatic search of candidate genes, combined with their virus-induced gene silencing, targeted MIA profiling and in vitro/in vivo pathway reconstitution identified and functionally characterized six genes as well as a seventh enzyme reaction required for the conversion of 19E-geissoschizine to tabersonine and catharanthine. The involvement of pathway intermediates in the formation of four MIA skeletons is described, and the role of stemmadenine-O-acetylation in providing necessary reactive substrates for the formation of iboga and aspidosperma MIAs is described. The results enable the assembly of complex dimeric MIAs used in cancer chemotherapy and open the way to production of many other biologically active MIAs that are not easily available from nature.

Crystal structure and solvent-dependent behaviours of 3-amino-1,6-diethyl-2,5,7-trimethyl-4,4-di-phenyl-3a,4a-di-aza-4-bora-s-indacene.

In the title compound (3-amino-4,4-diphenyl-BODIPY), C28H32BN3, the central six-membered ring has a flattened sofa conformation, with one of the N atoms deviating by 0.142 (4) Šfrom the mean plane of the other five atoms, which have an r.m.s. deviation of 0.015 Å. The dihedral angle between the two essentially planar outer five-membered rings is 8.0 (2)°. In the crystal, mol-ecules are linked via weak N-H⋯π inter-actions, forming chains along [010]. The com-pound displays solvent-dependent behaviours in both NMR and fluorescence spectroscopy. In the 1H NMR spectra, the aliphatic resonance signals virtually coalesce in solvents such as chloro-form, di-chloro-methane and di-bromo-ethane; however, they are fully resolved in solvents such as dimethyl sulfoxide (DMSO), methanol and toluene. The excitation and fluorescence intensities in chloro-form decreased significantly over time, while in DMSO the decrease is not so profound. In toluene, the excitation and fluorescent intensities are not time-dependent. This behaviour is presumably attributed to the assembly of 3-amino-4,4-diphenyl-BODIPY in solution that leads to the formation of noncovalent structures, while in polar or aromatic solvents, the formation of these assemblies is disrupted, leading to resolution of signals in the NMR spectra.

A Formal Approach to Xylosmin and Flacourtosides E and F: Chemoenzymatic Total Synthesis of the Hydroxylated Cyclohexenone Carboxylic Acid Moiety of Xylosmin.

The hydroxylated cyclohexenone carboxylic acid moiety of xylosmin was synthesized in eight steps from benzoic acid. The key steps in the synthesis involved the enzymatic dihydroxylation of benzoic acid by the whole cell fermentation with Ralstonia eutrophus B9, and Henbest epoxidation. Early attempts led to the synthesis of a C6 epimer of the methyl ester of the hydroxylated cyclohexenone carboxylic acid moiety. The absolute stereochemistry of an advanced intermediate was confirmed by X-ray crystallography. Complete characterization of the previously reported but not fully characterized hydroxylated cyclohexenone carboxylic acid is provided.

Chemoenzymatic Total Synthesis of Hydromorphone by an Oxidative Dearomatization/Intramolecular [4 + 2] Cycloaddition Sequence: A Second-Generation Approach.

A second-generation approach to the synthesis of hydromorphone by oxidative dearomatization/Diels-Alder cycloaddition was investigated. Detailed analysis of the stereochemical outcome of the [4 + 2] cycloaddition was performed first on a truncated model system as well as on the material leading to ent-hydromorphone. The stereochemical assignments were made by NMR and X-ray methods. The second-generation synthesis of hydromorphone was completed in both enantiomeric series. Improvements in the dearomatization conditions were attained using hypervalent iodine reagents instead of Pb(OAc)4. Electrochemical methods of oxidative dearomatization were also investigated. New conditions enabling the rearomatization of ring A from the methoxyketal were developed, and a formal synthesis of the natural enantiomer of hydromorphone was completed. Experimental and spectral data are provided for all new compounds.

Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast.

Antitumor substances related to vinblastine and vincristine are exclusively found in the Catharanthus roseus (Madagascar periwinkle), a member of the Apocynaceae plant family, and continue to be extensively used in cancer chemotherapy. Although in high demand, these valuable compounds only accumulate in trace amounts in C. roseus leaves. Vinblastine and vincristine are condensed from the monoterpenoid indole alkaloid (MIA) precursors catharanthine and vindoline. Although catharanthine biosynthesis remains poorly characterized, the biosynthesis of vindoline from the MIA precursor tabersonine is well understood at the molecular and biochemical levels. This study uses virus-induced gene silencing (VIGS) to identify a cytochrome P450 [CYP71D1V2; tabersonine 3-oxygenase (T3O)] and an alcohol dehydrogenase [ADHL1; tabersonine 3-reductase (T3R)] as candidate genes involved in the conversion of tabersonine or 16-methoxytabersonine to 3-hydroxy-2,3-dihydrotabersonine or 3-hydroxy-16-methoxy-2,3-dihydrotabersonine, which are intermediates in the vindorosine and vindoline pathways, respectively. Biochemical assays with recombinant enzymes confirm that product formation is only possible by the coupled action of T3O and T3R, as the reaction product of T3O is an epoxide that is not used as a substrate by T3R. The T3O and T3R transcripts were identified in a C. roseus database representing genes preferentially expressed in leaf epidermis and suggest that the subsequent reaction products are transported from the leaf epidermis to specialized leaf mesophyll idioblast and laticifer cells to complete the biosynthesis of these MIAs. With these two genes, the complete seven-gene pathway was engineered in yeast to produce vindoline from tabersonine.

Unusual structure, fluxionality, and reaction mechanism of carbonyl hydrosilylation by silyl hydride complex [(ArN=)Mo(H)(SiH2Ph)(PMe3)3].

The reactions of bis(borohydride) complexes [(RN=)Mo(BH4)2(PMe3)2] (4: R = 2,6-Me2C6H3; 5: R = 2,6-iPr2C6H3) with hydrosilanes afford new silyl hydride derivatives [(RN=)Mo(H)(SiR'3)(PMe3)3] (3: R = Ar, R'3 = H2Ph; 8: R = Ar', R'3 = H2Ph; 9: R = Ar, R'3 = (OEt)3; 10: R = Ar, R'3 = HMePh). These compounds can also be conveniently prepared by reacting [(RN=)Mo(H)(Cl)(PMe3)3] with one equivalent of LiBH4 in the presence of a silane. Complex 3 undergoes intramolecular and intermolecular phosphine exchange, as well as exchange between the silyl ligand and the free silane. Kinetic and DFT studies show that the intermolecular phosphine exchange occurs through the predissociation of a PMe3 group, which, surprisingly, is facilitated by the silane. The intramolecular exchange proceeds through a new non-Bailar-twist pathway. The silyl/silane exchange proceeds through an unusual Mo(VI) intermediate, [(ArN=)Mo(H)2(SiH2Ph)2(PMe3)2] (19). Complex 3 was found to be the catalyst of a variety of hydrosilylation reactions of carbonyl compounds (aldehydes and ketones) and nitriles, as well as of silane alcoholysis. Stoichiometric mechanistic studies of the hydrosilylation of acetone, supported by DFT calculations, suggest the operation of an unexpected mechanism, in that the silyl ligand of compound 3 plays an unusual role as a spectator ligand. The addition of acetone to compound 3 leads to the formation of [trans-(ArN)Mo(OiPr)(SiH2Ph)(PMe3)2] (18). This latter species does not undergo the elimination of a Si-O group (which corresponds to the conventional Ojima's mechanism of hydrosilylation). Rather, complex 18 undergoes unusual reversible ß-CH activation of the isopropoxy ligand. In the hydrosilylation of benzaldehyde, the reaction proceeds through the formation of a new intermediate bis(benzaldehyde) adduct, [(ArN=)Mo(η(2)-PhC(O)H)2(PMe3)], which reacts further with hydrosilane through a η(1)-silane complex, as studied by DFT calculations.

A detailed NMR- and DFT-based study of the Sakurai-Hosomi-Yamamoto asymmetric allylation reaction.

A Lewis acid complex between benzaldehyde and the silver catalyst was detected by (31)P NMR and shown to be the direct precursor to allylation within the Sakurai-Hosomi-Yamamoto reaction. Structural and thermochemical hybrid-DFT calculations indicated that benzaldehyde predominantly formed an η(1)-σ-complex with the catalyst; however, two other competing conformers involving different coordination modes were found, including an activated µ(2)-bound complex. The differences in (31)P NMR shifts upon complexation were calculated by the gauge-independent atomic orbital (GIAO-DFT) method for each conformer. The minimum energy conformer was found to correlate well with chemical shift trends observed experimentally, and an analysis of Mullikan charge populations revealed that the carbonyl carbon of the highest-energy conformer was the most electron-deficient. Furthermore, one minor and three major silicon intermediates were detected by (29)Si NMR and, with the aid of (1)H-(29)Si HSQC, were assigned by comparison with parent compounds and GIAO-DFT calculations. Finally, a tentative mechanism was proposed based on these findings.

Observation of two N2-isobutyrylguanine tautomers by NMR spectroscopy.

N(2)-isobutyrylguanine was prepared by treatment of guanine with isobutyryl chloride. Two tautomers, 1,7-dihydro-2-(isobutyroyl)amino-6H-purin-6-one and 1,9-dihydro-2-(isobutyroyl)amino-6H-purin-6-one, were identified in almost 1:1 ratio in dichloromethane-dimethyl sulfoxide (1:1 v/v) by NMR spectroscopy. By using the selective-inversion experiments, enthalpy, entropy, and free energy for activation were determined. This work represents the first report of guanine tautomers observed directly by NMR spectroscopy.

Mechanistic aspects of hydrosilylation catalyzed by (ArN=)Mo(H)(Cl)(PMe3)3.

The reaction of (ArN=)MoCl(2)(PMe(3))(3) (Ar = 2,6-diisopropylphenyl) with L-Selectride gives the hydrido-chloride complex (ArN=)Mo(H)(Cl)(PMe(3))(3) (2). Complex 2 was found to catalyze the hydrosilylation of carbonyls and nitriles as well as the dehydrogenative silylation of alcohols and water. Compound 2 does not show any productive reaction with PhSiH(3); however, a slow H/D exchange and formation of (ArN=)Mo(D)(Cl)(PMe(3))(3) (2(D)) was observed upon addition of PhSiD(3). Reactivity of 2 toward organic substrates was studied. Stoichiometric reactions of 2 with benzaldehyde and cyclohexanone start with dissociation of the trans-to-hydride PMe(3) ligand followed by coordination and insertion of carbonyls into the Mo-H bond to form alkoxy derivatives (ArN=)Mo(Cl)(OR)(PMe(2))L(2) (3: R = OCH(2)Ph, L(2) = 2 PMe(3); 5: R = OCH(2)Ph, L(2) = η(2)-PhC(O)H; 6: R = OCy, L(2) = 2 PMe(3)). The latter species reacts with PhSiH(3) to furnish the corresponding silyl ethers and to recover the hydride 2. An analogous mechanism was suggested for the dehydrogenative ethanolysis with PhSiH(3), with the key intermediate being the ethoxy complex (ArN=)Mo(Cl)(OEt)(PMe(3))(3) (7). In the case of hydrosilylation of acetophenone, a D-labeling experiment, i.e., a reaction of 2 with acetophenone and PhSiD(3) in the 1:1:1 ratio, suggests an alternative mechanism that does not involve the intermediacy of an alkoxy complex. In this particular case, the reaction presumably proceeds via Lewis acid catalysis. Similar to the case of benzaldehyde, treatment of 2 with styrene gives trans-(ArN=)Mo(H)(η(2)-CH(2)═CHPh)(PMe(3))(2) (8). Complex 8 slowly decomposes via the release of ethylbenzene, indicating only a slow insertion of styrene ligand into the Mo-H bond of 8.

An unexpected mechanism of hydrosilylation by a silyl hydride complex of molybdenum.

Carbonyl hydrosilylation catalyzed by (ArN)Mo(H)(SiH(2)Ph)(PMe(3))(3) (3) is unusual in that it does not involve the expected Si-O elimination from intermediate (ArN)Mo(SiH(2)Ph)(O(i)Pr)(PMe(3))(2) (7). Instead, 7 reversibly transfers ß-CH hydrogen from the alkoxide ligand to metal.

Catalytic and stoichiometric reactivity of ß-silylamido agostic complex of Mo: intermediacy of a silanimine complex and applications to multicomponent coupling.

The reaction of complex (ArN═)(2)Mo(PMe(3))(3) (Ar = 2,6-diisopropylphenyl) with PhSiH(3) gives the ß-agostic NSi-H···M silyamido complex (ArN═)Mo(SiH(2)Ph)(PMe(3))(η(3)-ArN-SiHPh-H) (3) as the first product. 3 decomposes in the mother liquor to a mixture of hydride compounds, including complex {η(3)-SiH(Ph)-N(Ar)-SiHPh-H···}MoH(3)(PMe(3))(3) characterized by NMR. Compound 3 was obtained on preparative scale by reacting (ArN═)(2)Mo(PMe(3))(3) with 2 equiv of PhSiH(3) under N(2) purging and characterized by multinuclear NMR, IR, and X-ray diffraction. Analogous reaction of (Ar'N═)(2)Mo(PMe(3))(3) (Ar' = 2,6-dimethylphenyl) with PhSiH(3) affords the nonagostic silylamido derivative (Ar'N═)Mo(SiH(2)Ph)(PMe(3))(2)(NAr'{SiH(2)Ph}) (5) as the first product. 5 decomposes in the mother liquor to a mixture of {η(3)-PhHSi-N(Ar')-SiHPh-H···}MoH(3)(PMe(3))(3), (Ar'N═)Mo(H)(2)(PMe(3))(2)(η(2)-Ar'N═SiHPh), and other hydride species. Catalytic and stoichiometric reactivity of 3 was studied. Complex 3 undergoes exchange with its minor diastereomer 3' by an agostic bond-opening/closing mechanism. It also exchanges the classical silyl group with free silane by an associative mechanism which most likely includes dissociation of the Si-H agostic bond followed by the rate-determining silane σ-bond metathesis. However, labeling experiments suggest the possibility of an alternative (minor) pathway in this exchange including a silanimine intermediate. 3 was found to catalyze dehydrogenative coupling of silane, hydrosilylation of carbonyls and nitriles, and dehydrogenative silylation of alcohols and amines. Stoichiometric reactions of 3 with nitriles proceed via intermediate formation of η(2)-adducts (ArN═)Mo(PMe(3))(η(2)-ArN═SiHPh)(η(2)-N≡CR), followed by an unusual Si-N coupling to give (ArN═)Mo(PMe(3))(κ(2)-NAr-SiHPh-C(R)═N-). Reactions of 3 with carbonyls lead to η(2)-carbonyl adducts (ArN═)(2)Mo(O═CRR')(PMe(3)) which were independently prepared by reactions of (ArN═)(2)Mo(PMe(3))(3) with the corresponding carbonyl O═CRR'. In the case of reaction with benzaldehyde, the silanimine adduct (ArN═)Mo(PMe(3))(η(2)-ArN═SiHPh)(η(2)-O═CHPh) was observed by NMR. Reactions of complex 3 with olefins lead to products of Si(ag)-C coupling, (ArN═)Mo(Et)(PMe(3))(η(3)-NAr-SiHPh-CH═CH(2)) (17) and (ArN═)Mo(H)(PMe(3))(η(3)-NAr-SiHPh-CH═CHPh), for ethylene and styrene, respectively. The hydride complex (ArN═)Mo(H)(PMe(3))(η(3)-NAr-SiHPh-CH═CH(2)) was obtained from 17 by hydrogenation and reaction with PhSiH(3). Mechanistic studies of the latter process revealed an unusual dependence of the rate constant on phosphine concentration, which was explained by competition of two reaction pathways. Reaction of 17 with PhSiH(3) in the presence of BPh(3) leads to agostic complex (ArN═)Mo(SiH(2)Ph)(η(3)-NAr-Si(Et)Ph-H)(η(2)-CH(2)═CH(2)) (24) having the Et substituent at the agostic silicon. Mechanistic studies show that the Et group stems from hydrogenation of the vinyl substituent by silane. Reaction of 24 with PMe(3) gives the agostic complex (ArN═)Mo(SiH(2)Ph)(PMe(3))(η(3)-NAr-Si(Et)Ph-H), which slowly reacts with PhSiH(3) to furnish silylamide 3 and the hydrosilylation product PhEtSiH(2). A mechanism involving silane attack on the imido ligand was proposed to explain this transformation.

The unexpected mechanism of carbonyl hydrosilylation catalyzed by (Cp)(ArN[double bond, length as m-dash])Mo(H)(PMe(3)).

Complex (Cp)(ArN[double bond, length as m-dash])Mo(H)(PMe(3)) (2, Ar = 2,6-diisopropylphenyl) catalyzes the hydrosilylation of carbonyls by an unexpected associative mechanism. Complex 2 also reacts with PhSiH(3) by a σ-bond metathesis mechanism to give the silyl derivative (Cp)(ArN[double bond, length as m-dash])Mo(SiH(2)Ph)(PMe(3)).

Design of thermally stable versions of the burgess reagent: stability and reactivity study.

Three new versions of the Burgess reagent were synthesized and their thermal stability investigated by NMR. The new reagents exhibited improved reactivity toward epoxides, diols, and vinyl oxiranes as compared with the original version.

Diversity of catalysis by an imido-hydrido complex of molybdenum. Mechanism of carbonyl hydrosilylation and silane alcoholysis.

New Imido hydride complex 1 catalyzes a variety of silylation reactions that proceed via initial substrate activation but not silane addition.