Cesium fluoride and tetra-n-butylammonium fluoride mediated 1,4-N-->O shift of disubstituted phenyl ring of a bicalutamide derivative

A novel 1,4-N→O migration of a disubstituted phenyl ring was observed during N-methylation of a bicalutamide derivative, (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2-methylpropionamide, in the presence of CsF-Celite/acetonitrile and desilylation of (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2,N-dimethylpropionamide in tetra-n-butylammonium fluoride/THF. Both NMR and X-ray analysis confirmed the structure of the 1,4-N→O disubstituted phenyl ring migrated product.     

Long-range and short-range Coulomb correlation effects as simulated by Hartree–Fock,local density approximation,and generalized gradient approximation exchange functionals

 Exchange functionals used in density functional theory (DFT) are generally considered to simulate long-range electron correlation effects. It is shown that these effects can be traced back to the self-interaction error (SIE) of approximate exchange functionals. An analysis of the SIE with the help of the exchange hole reveals that both short-range (dynamic) and long-range (nondynamic) electron correlation effects are simulated by DFT exchange where the local density approximation (LDA) accounts for stronger effects than the generalized gradient expansion (GGA). This is a result of the fact that the GGA exchange hole describes the exact exchange hole close to the reference electron more accurately than the LDA hole does. The LDA hole is more diffuse, thus leading to an underestimation of exchange and stronger SIE effects, where the magnitude of the SIE energy is primarily due to the contribution of the core orbitals. The GGA exchange hole is more compact, which leads to an exaggeration of exchange in the bond and the nonbonding region and negative SIE contributions. Partitioning of the SIE into intra-/interelectronic and individual orbital contributions makes it possible to test the performance of a given exchange functional in different regions of the molecule. It is shown that Hartree–Fock exchange always covers some long-range effects via interelectronic exchange while self-interaction-corrected DFT is lacking these effects. Received: 25 May 2002 / Accepted: 7 October 2002 / Published online: 21 January 2003 Correspondence to: E. Kraka e-mail: kraka@theoc.gn.se Acknowledgements. This work was supported financially by the Swedish Natural Science Research Council (NFR). Calculations were done on the supercomputers of Nationellt Superdatorcentrum (NSC), Link?ping, Sweden. The authors thank the NSC for a generous allotment of computer time.     

Design of a new warhead for the natural enediyne dynemicin A. An increase of biological activity

A concept for designing nontoxic enediyne-based antitumor drugs that was previously suggested (J. Am. Chem. Soc. 2000, 122, 8245) is converted into reality by merging amidines with the natural enediyne dynemicin A. The dynemicin-amidines (DADs) resulting from this combination are biologically not active because they form extremely labile singlet biradicals that can no longer abstract H from DNA. However, if protonated in the acidic environment of the tumor cell, they possess increased biological activity, as is reflected by a lowering of the activation enthalpy for the Bergman cyclization from 16.7 (dynemicin A) to 11-12 kcal/mol (DADs), kinetic stability of the singlet biradicals formed in the cyclization reaction, increased H abstraction ability of the singlet biradicals, and improved docking properties in the minor groove of the duplex 10-mer B-DNA sequence d(CTACTACTGG).d(CCAGTAGTAG) throughout the triggering and Bergman reactions. The implications and the consequences of using DADs to exploit the differences between normal and tumor cells and to design a nontoxic antitumor drugs are discussed.     

The para‐didehydropyridine,para‐didehydropyridinium,and related biradicals—a contribution to the chemistry of enediyne antitumor drugs

Structure and stability of seven singlet (S) biradicals formed by Bergman cyclization from enediynes are investigated with unrestricted DFT using B3LYP/6‐31G(d,p) and B3LYP/6‐311+G(3df,3pd). The corresponding triplets (T) are also calculated and compared with their S states utilizing the on‐top pair density and the S‐T difference on‐top pair density. A relationship between the geometry of a S biradical, its stability, and its biradical character is established using the on‐top pair density and calculated S‐T splittings. Through‐bond coupling between the single electrons of the S biradical can be enhanced by the incorporation of a N atom into para‐didehydrobenzene 1 due to lowering of antibonding orbitals, shortening of ring bonds by anomeric effect, and increased overlap between the interacting orbitals. Strong through‐bond interactions lead to a stabilization of the S state and an increase of the S‐T splitting. Because through‐bond interactions also determine the degree of coupling between the single electrons, stabilization of the S biradical, and an increase of the S‐T splitting always means a lowering of the biradical character and the H abstraction ability, which is relevant for the use of N‐containing enediynes and their biradicals in connection with the design of new antitumor drugs. The S para‐didehydropyridine biradical 2 is strongly stabilized and, therefore, has only reduced biradical character. However, the latter can be enhanced by protonation, because this always leads to a lengthening of ring bonds and a reduction of the overlap between interacting orbitals. In the weakly acidic medium of a tumor cell, S biradicals containing an amidine group can be protonated to yield S biradicals with high biradical character (low S‐T splittings, small changes in bond alternation relative to the T state), which will abstract H atoms from the DNA of a tumor cell. © 2000 John Wiley & Sons, Inc. J Comput Chem 22: 216–229, 2001     

Application of quadratic CI with singles,doubles, and triples (QCISDT): An attractive alternative to CCSDT

The size-extensive quadratic CI method with single(s), double(D ), and triple (T ) excitations, QCISDT , is compared with QCISD, QCISD (T ), CCSDT -n, and CCSDT . It is shown that QCISDT results are more accurate than are either QCISD or QCISD (T ) results. In particular, QCISDT turns out to be more stable than are QCISD and QCISD (T ) in cases with considerable multireference character. QCISDT and CCSDT results are of similar accuracy with slight advantages for the former method. Since QCISDT is much easier to implement on a computer than is CCSDT , it is an attractive alternative to CCSDT . © 1996 John Wiley & Sons, Inc.     

Structure, vibrational spectra, and unimolecular dissociation of gaseous 1-fluoro-1-phenethyl cations

The multiple CF bond character of PhCFMe (+) ions has been examined by means of theory, vibrational spectroscopy of the gaseous ions, and unimolecular decomposition chemistry. Atoms in Molecules analysis of DFT wave functions gives a CF bond order of n = 1.25 (as compared with n = 1.38 for Me 2CF (+), relative to n = 1 for fluoromethane and n = 2 for diatomic CF (+)), which is consistent with calculations of adiabatic CF stretching frequencies (nu CF). Experimental gas phase IR spectra, recorded by means of resonant multiphoton dissociation (IRMPD) using a free-electron laser connected to an FTICR mass spectrometer, show good agreement with predicted band positions for five deuterated isotopomers of PhCFMe (+). Metastable ion decompositions of deuterated analogues of PhCFMe (+) show the same HF/DF loss patterns as those produced by IRMPD. The evidence supports the conclusion that PhCFMe ions retain structural integrity until they become sufficiently excited to dissociate, whereupon they undergo intramolecular hydrogen scrambling that is competitive with HF/DF expulsion. Relative rates of hydrogen transposition and unimolecular dissociation are extracted from relative experimental fragment ion abundances. The predominant decomposition pathway is inferred to operate via a five-center transition state, as opposed to a four-center transition state for HF loss from gaseous Me 2CF (+).     

Evidence for the HOOO(-) anion in the ozonation of 1,3-dioxolanes: hemiortho esters as the primary products

Low-temperature ozonation (-78 degrees C) of 2-methyl-1,3-dioxolane (1a) in acetone-d6, methyl acetate, and tert-butyl methyl ether produced both the corresponding acetal hydrotrioxide (3a, ROOOH) and the hemiortho ester (2a, ROH) in molar ratio 1:5. Both intermediates were fully characterized by 1H, 13C, and 17O NMR spectroscopy, and they both decomposed to the corresponding hydroxy ester at higher temperatures. The mechanism involving the HOOO- anion formed by the abstraction of the hydride ion by ozone to form an ion pair, R+ -OOOH, with its subsequent collapse to either the corresponding hemiortho ester (ROH) or the acetal hydrotrioxide (ROOOH) was proposed. This mechanism is supported by the PISA/B3LYP/6-311++G(3df,3pd) calculations.