The direct insertion of Zn into olefin-halide bonds is a challenge. When ()-alkenyl iodides were treated with a very large excess of Zn nanoparticles, in the presence of Pd(PPh), the dimerization was observed but, unexpectedly, yielding mainly -1,3-dienes. This apparently contrathermodynamic -to- isomerization of organometallic intermediates is predicted to be general and is explained with the aid of DFT [principally M06/6-311+G(d,p)], MP2, and CCSD(T) calculations.
View Article and Find Full Text PDFThe tendency of carbonyl compounds to form iminium ions by reaction with pyrrolidine or chiral pyrrolidine derivatives (in other words, the relative stability to hydrolysis of these iminium ions) has been computationally examined, mainly using the M06-2X/6-311+G(d,p) method. We have thus obtained the equilibrium positions for R-CH=O + CH=CH-CH=NR* → R-CH=NR* + CH=CH-CH=O reactions and for related exchanges. In these exchanges, there is a transfer of a secondary amine between two carbonyl compounds.
View Article and Find Full Text PDFA long series of Michael acceptors are studied computationally as potential alternatives to the maleimides that are used in most antibody-drug conjugates to link Cys of mAbs with cytotoxic drugs. The products of the reaction of methanethiol (CHSH/MeSH, as a simple model of Cys) with N-methylated ethynesulfonamide, 2-ethynylpyridinium ion, propynamide, and methyl ethynephosphonamidate (that is, with HC≡C-EWG) are predicted by the M06-2X/6-311+G(d,p) method to be thermodynamically more stable, in relation to their precursors, than that of MeSH with -methylmaleimide and, in general, with HC═CH-EWG; calculations with AcCysOMe and BuSH are also included. However, for the addition of the anion (MeS), which is the reactive species, the order changes and N-methylated 2-vinylpyridinium ion, 2,3-butadienamide, and maleimide may give more easily the anionic adducts than several activated triple bonds; moreover, the calculated Δ values increase following the order HC≡C-SONHMe, -methylmaleimide, HC≡C-PO(OMe)NHMe, and HC≡C-CONHMe.
View Article and Find Full Text PDFAmides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.
View Article and Find Full Text PDFChiral nitroalkenes are used for the first time in Michael additions of aldehydes, catalyzed by pyrrolidine derivatives. They yield the same major stereoisomer with either ()-proline or ()-proline, but this asymmetric induction does not overcome the effect of sterically more congested catalysts. Nitrocyclobutane intermediates are often formed, which are more stable than those from ()-1-nitro-2-phenylethene.
View Article and Find Full Text PDFThe addition of aldehyde enamines to nitroalkenes affords cyclobutanes in all solvents, with all of the pyrrolidine and proline derivatives tested by us and with all of the substrates we have examined. Depending on the temperature, concentration of water, solvent polarity, and other factors, the opening and hydrolysis of such a four-membered ring may take place rapidly or last for several days, producing the final Michael-like adducts (4-nitrobutanals). Thirteen new cyclobutanes have now been characterized by NMR spectroscopy.
View Article and Find Full Text PDFWe have developed a conjugation reaction based on the thia-Michael addition to activated triple bonds, which can be an alternative to maleimides, the most commonly used reagents to link thiol groups (of Cys) to drugs and labels. An amino group is converted into its propynamide and, in aqueous media at 37 °C and pH 7.4, Cys derivatives are added.
View Article and Find Full Text PDFThe binding site of the macrolides laulimalide and peloruside A, which is different from that of the clinically useful drugs paclitaxel/taxol and ixabepilone (), is known to be between two adjacent β-tubulin units (). Here, we report our study of the binding of these molecules to an α1β1/α2β2-tubulin "tetramer" model. AutoDock 4.
View Article and Find Full Text PDFA formal total synthesis of the cytotoxic macrolide amphidinolide E is reported. The strategic steps are three Julia-Kocienski reactions (J-K), for the formation of the C5-C6, C9-C10, and C17-C18 double bonds, a Suzuki-Molander C21-C22 bond formation reaction, and a Kita-Trost macrolactonization. The "instability" of the two dienic systems and of the stereocenter at C2 (allylic methine, α to the carboxy group) and the protecting groups at C17-OH and C18-OH have posed difficult challenges.
View Article and Find Full Text PDFThe accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0) and confirmed the speed of AutoDock Vina.
View Article and Find Full Text PDFWhile B3LYP, M06-2X, and MP2 calculations predict the ΔG° values for exchange equilibria between enamines and ketones with similar acceptable accuracy, the M06-2X/6-311+G(d,p) and MP2/6-311+G(d,p) methods are required for enamine formation reactions (for example, for enamine 5a, arising from 3-methylbutanal and pyrrolidine). Stronger disagreement was observed when calculated energies of hemiaminals (N,O-acetals) and aminals (N,N-acetals) were compared with experimental equilibrium constants, which are reported here for the first time. Although it is known that the B3LYP method does not provide a good description of the London dispersion forces, while M06-2X and MP2 may overestimate them, it is shown here how large the gaps are and that at least single-point calculations at the CCSD(T)/6-31+G(d) level should be used for these reaction intermediates; CCSD(T)/6-31+G(d) and CCSD(T)/6-311+G(d,p) calculations afford ΔG° values in some cases quite close to MP2/6-311+G(d,p) while in others closer to M06-2X/6-311+G(d,p).
View Article and Find Full Text PDFThe total synthesis of (-)-amphidinolide K (1) based on asymmetric addition of allylsilane C1-C8 to enal C9-C22 is reported. The 1,9,18-tris-O-TBDPS ether was converted into the desired 9,18-dihydroxy acid. Its macrolactonization was accomplished by the Shiina method.
View Article and Find Full Text PDFThe use of the 2-(4-methylphenylsulfonyl)ethenyl (tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsv-protected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et3N or with catalytic amounts of NaH, the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP.
View Article and Find Full Text PDFEnamines from 3-methylbutanal and several Pro- and Phe-derived secondary amines were prepared in DMSO-d6, CD3CN, and CDCl3. For the first time, the relative thermodynamic stabilities of these and other enamines were compared, and rapid exchanges of 1-alkenyl groups were demonstrated. Competition experiments showed that the most favored enamines (without significant steric inhibition of resonance) react more rapidly with electrophiles.
View Article and Find Full Text PDFAdditions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-butyn-2-one, N-propynoylmorpholine, or N-methoxy-N-methylpropynamide in the presence of many potential catalysts were examined. DABCO and, second, DMAP appeared to be the best (highest reaction rates and E/Z ratios), while RuCl3, RuClCp*(PPh3)2, AuCl, AuCl(PPh3), CuI, and Cu2(OTf)2 were incapable of catalyzing such additions. The groups incorporated (for example, the 2-(methoxycarbonyl)ethenyl group that we name MocVinyl) serve as protecting groups for the above-mentioned heterocyclic CONH or CONHCO moieties.
View Article and Find Full Text PDFEquilibria between carbonyl compounds and their enamines (from O-TBDPS-derived prolinol) have been examined by NMR spectroscopy in DMSO-d(6). By comparing the exchange reactions between pairs (enamine A + carbonyl B → carbonyl A + enamine B), a quite general scale of the tendency of carbonyl groups to form enamines has been established. Aldehydes quickly give enamines that are relatively more stable than those of ketones, but there are exceptions to this expected rule; for example, 1,3-dihydroxyacetone acetals or 3,5-dioxacyclohexanones (2-phenyl-1,3-dioxan-5-one and 2,2-dimethyl-1,3-dioxan-5-one) show a greater tendency to afford enamines than many α-substituted aldehydes.
View Article and Find Full Text PDFThe C-Si bonds of triisopropylsilyl-substituted alkenes, 1,3-dienes, and related multifunctional substrates, as well as analogous C-TBDPS and C-TBS bonds, are readily and chemoselectively cleaved with NIS (or other sources of I(+), such as N-iodosaccharin, 1,3-diodohydantoin, and Ipy(2)BF(4)). The desired iodoalkenes are obtained stereospecifically without byproducts, provided that the reactions are carried out in CF(3)CHOHCF(3) and, in general, with 30 mol % of Ag(2)CO(3) (or AgOAc/2,6-lutidine) as an additive. Fragment C10-C18 of cytotoxic amphidinolides B1-B3 and D has been synthesized using this improved procedure.
View Article and Find Full Text PDF[N,1-(15)N(2)]-Guanosine, or [1,NH(2)-(15)N(2)]-guanosine, and derivatives were prepared from tri-O-acetylinosine, via N-nitration and reaction with (15)NH(2)OH, followed by conversion of the (15)N-labeled 1-hydroxyinosine to the corresponding 2,6-dichloropurine riboside. The sequential one-pot C-O and C-N key couplings of this dichloro derivative with PhCH(2)OH and PhCO(15)NH(2) or (i)PrCO(15)NH(2) was achieved in good overall yields, with Pd(0)-Xantphos as the best choice of five different catalytic systems examined.
View Article and Find Full Text PDFA new variant of the NO(2)-to-CO transformation (the Nef reaction) that occurs at room temperature under neutral conditions is uncovered. After the conversion of secondary nitroalkanes to phenylsulfenylketimines, these thiooximes are hydrolyzed quantitatively in situ, in THF-H(2)O at pH 7, by addition of AuBr(3) (but not with other MX(n)!). Adducts arising from asymmetric nitro-Michael and nitro-aldol reactions afford 1,4-diketones and alpha-alkoxy ketones, respectively, with full retention of the configuration of the stereocenters alpha to the CHNO(2)/C=N-SPh/C=O groups.
View Article and Find Full Text PDFA route to fluvirucinins B(2-5) (the common aglycon of fluvirucins B(2)-B(5), Sch 38518, and Sch 39185) is reported for the first time. A ring-closing metathesis (RCM) generated the C6-C7 double bond, which by catalytic hydrogenation (in toluene) gave the desired epimer with a 9:1 diastereoselection. Azide 8a and carboxylic acid 5 came from ethyl-branched fragments C9-C13 (CHO at C9) and C1-C5 via an asymmetric allylation of the former and a cross metathesis (CM) followed by a ketone methylenation (with 20 mol % of DMF as a sacrificial additive) of the latter.
View Article and Find Full Text PDFReplication of human immunodeficiency virus (HIV) requires base pairing of the reverse transcriptase primer, human tRNA(Lys3), to the viral RNA. Although the major complementary base pairing occurs between the HIV primer binding sequence (PBS) and the tRNA's 3'-terminus, an important discriminatory, secondary contact occurs between the viral A-rich Loop I, 5'-adjacent to the PBS, and the modified, U-rich anticodon domain of tRNA(Lys3). The importance of individual and combined anticodon modifications to the tRNA/HIV-1 Loop I RNA's interaction was determined.
View Article and Find Full Text PDF2,2'-Dipyridyl diselenide (PySeSePy) is the catalyst or activator of choice for the direct reaction of carboxylic acids with azides and trimethylphosphine at room temperature. The mechanism of the process, which is not an aza-Wittig reaction, has been elucidated.
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