Asymmetric synthesis and applications of beta-amino Weinreb amides: asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.     

An activation mechanism for ATP cleavage in muscle.

Evidence for a proposed activation mechanism is summarized. The low rate of ATP cleavage in the resting state of muscle is considered to result from the formation of a stable ring structure involving the two essential sulfhydryl groups on each myosin head and MgATP. Activation is thought to occur by interaction of actin in the vicinity of one of the essential sulfhydryl groups. Thus opening the stable ring leading to rapid dissociation of split products. This idea is consistent with the kinetic scheme of ATP cleavage developed recently by other workers and allows a prediction of the shift in population of intermediate states with changes in solvent conditions. It is also supported by our recent studies on the spatial geometry of the ring. The possibility that other nucleophilic groups may replace the sulfhydryl groups in other contractile systems is considered. The relevance of the ring structure to the tension generating event is discussed on the basis of recent measurements of the rate of contraction of modified (SH1-blocked) actomyosin threads. Results indicate the ability to form the ring structure is an essential requirement of the contractile process in these systems, and, moreover, that single, modified heads of myosin can act independently to produce the same rate of contraction as native myosin. This latter finding suggests that the myosin duplex exhibits some type of negative cooperativity in the contractile process.     

Time-dependent density functional theory: past, present, and future

Time-dependent density functional theory (TDDFT) is presently enjoying enormous popularity in quantum chemistry, as a useful tool for extracting electronic excited state energies. This article discusses how TDDFT is much broader in scope, and yields predictions for many more properties. We discuss some of the challenges involved in making accurate predictions for these properties.     

DEPTH RESOLUTION IN PHOTOELECTRON MICROSCOPY OF ORGANIC SURFACES. THE PHOTOELECTRIC EFFECT OF PHTHALOCYANINE THIN FILMS

Abstract— The application of photoelectron microscopy as a general method of imaging organic and biological surfaces requires a knowledge of the photoelectric effect of very thin organic films. In this study, low magnification images of a 7 Å thick pattern of copper phthalocyanine were obtained, demonstrating that it is possible to visualize a monolayer of organic compound in photoelectron microscopy. Relative photoelectron currents were measured for a series of copper phthalocyanine films ranging in thickness up to 1900 Å. The relative photoelectron currents were independent of temperature (90–298°K), suggesting that electron-electron and not electron-phonon scattering is the dominant mechanism. The photoelectric properties measured are determined primarily by the large organic ring structure and not the central metal atom, as evidenced by the fact that substitution of metal-free phthalocyanine for copper phthalocyanine did not substantially alter the values of observed photoelectron currents. An analysis of the data indicates the depth resolution is 15 ű 5 Å, and equals the electron mean free path. This very good depth resolution is a result of the low kinetic energy associated with electrons released by irradiation near the photoemission threshold.     

A versatile microfabricated platform for electrophoresis of double- and single-stranded DNA

We demonstrate a versatile microfabricated electrophoresis platform, incorporating arrays of integrated on-chip electrodes, heaters, and temperature sensors. This design allows a range of different sieving gels to be used within the same device to perform separations involving both single- and double-stranded DNA over distances on the order of 1 cm. We use this device to compare linear and cross-linked polyacrylamide, agarose, and thermo-reversible Pluronic-F127 gels on the basis of gel casting ease, reusability, and overall separation performance using a 100 base pair double-stranded DNA ladder as a standard sample. While cross-linked polyacrylamide matrices provide consistently high-quality separations in our system over a wide range of DNA fragment sizes, Pluronic gels also offer compelling advantages in terms of the ability to remove and reload the gel. Agarose gels offer good separation performance, however, additional care must be exercised to ensure consistent gel properties as a consequence of the need for elevated gel loading temperatures. We also demonstrate the use of denaturing cross-linked polyacrylamide gels at concentrations up to 19% to separate single-stranded DNA fragments ranging in size from 18 to 400 bases in length. Primers differing by 4 bases at a read length of 30 bases can be separated with a resolution of 0.9-1.0 in under 20 min. This level of performance is sufficient to conduct a variety of genotyping assays including the rapid detection of single nucleotide polymorphisms (SNPs) in a microfabricated platform. The ability to use a single microelectrophoresis system to satisfy a wide range of separation applications offers molecular biologists an unprecedented level of flexibility in a portable and inexpensive format.     

Stabilization of excess charge in isolated adenosine 5'-triphosphate and adenosine 5'-diphosphate multiply and singly charged anions

Multiply charged anions (MCAs) represent highly energetic species in the gas phase but can be stabilized through formation of molecular clusters with solvent molecules or counterions. We explore the intramolecular stabilization of excess negative charge in gas-phase MCAs by probing the intrinsic stability of the [adenosine 5'-triphosphate-2H](2-) ([ATP-2H](2-)), [adenosine 5'-diphosphate-2H](2-) ([ADP-2H](2-)), and H(3)P(3)O(10)(2-) dianions and their protonated monoanionic analogues. The relative activation barriers for decay of the dianions via electron detachment or ionic fragmentation are investigated using resonance excitation of ions isolated within a quadrupole trap. All of the dianions decayed via ionic fragmentation demonstrating that the repulsive Coulomb barriers (RCB) for ionic fragmentation lie below the RCBs for electron detachment. Both the electrospray ionization mass spectra (ESI-MS) and total fragmentation energies for [ATP-2H](2-), [ADP-2H](2-), and H(3)P(3)O(10)(2-) indicate that the multiply charged H(3)P(3)O(10)(2-) phosphate moiety is stabilized by the presence of the adenosine group and the stability of the dianions increases in the order H(3)P(3)O(10)(2-) < [ADP-2H](2-) < [ATP-2H](2-). Fully optimized, B3LYP/6-31+G* minimum energy structures illustrate that the excess charges in all of the phosphate anions are stabilized by intramolecular hydrogen bonding either within the phosphate chain or between the phosphate and the adenosine. We develop a model to illustrate that the relative magnitudes of the RCBs and hence the stability of these ions is dominated by the extent of intramolecular hydrogen bonding.     

A planning strategy for diversity-oriented synthesis

In contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chemistry, which aim to access precise or dense regions of chemistry space, diversity-oriented synthesis (DOS) populates chemical space broadly with small-molecules having diverse structures. The goals of DOS include the development of pathways leading to the efficient (three- to five-step) synthesis of collections of small molecules having skeletal and stereochemical diversity with defined coordinates in chemical space. Ideally, these pathways also yield compounds having the potential to attach appendages site- and stereoselectively to a variety of attachment sites during a post-screening, maturation stage. The diverse skeletons and stereochemistries ensure that the appendages can be positioned in multiple orientations about the surface of the molecules. TOS as well as medicinal and combinatorial chemistries have been advanced by the development of retrosynthetic analysis. Although the distinct goals of DOS do not permit the application of retrosynthetic concepts and thinking, these foundations are being built on, by using parallel logic, to develop a complementary procedure known as forward-synthetic analysis. This analysis facilitates synthetic planning, communication, and teaching in this evolving discipline.     

The effect of thermal pretreatment on the electrochemical response for palladium in aqueous media

Previous work on the electrochemistry of palladium in aqueous acid solution demonstrated the existence of two multilayer hydrous oxide reduction peaks, one at ca. 0.24 V and another at ca. 0.55 V vs. RHE, plus the presence of a reversible active surface state transition at ca. 0.24 V. In the present work with thermally activated palladium it was observed that, in agreement with the hydrous oxide reduction behaviour of the system, there is a second active state transition at E≥ca. 0.45 V. In most of its reactions in aqueous acid solution, apart from its unusual capacity to absorb hydrogen, palladium exhibits properties very similar to those of platinum; however, palladium seems to be more prone to dissolution and subsurface oxygen formation. Also the premonolayer oxidation responses of these two metals are often different as the more active state of the palladium surface is not as readily generated as that of platinum. The electrocatalytic properties of palladium, as reported earlier, correlate quite well with the hydrous oxide and premonolayer oxidation behaviour of this electrode system. Electronic Publication     

Comparison of photosensitizer (AIPcS2) quantification techniques: in situ fluorescence microsampling versus tissue chemical extraction

A noninvasive in situ fluorescence-based method for the quantification of the photosensitizer chloroaluminum disulfonated phthalocyanine was compared to the highly accurate but nonreal time ex vivo spectrofluorometry method. Our in vivo fluorescence technique is designed to allow real-time assessment of photosensitizer in tumor and normal tissues and therefore temporally optimal light delivery. Laser-induced fluorescence was used to measure photosensitizer concentration from multiple microscopic regions of tissue. Ex vivo chemical extraction was used to quantify photosensitizer concentration in the same volume of tissue. The amount of photosensitizer in the vascular and/or parenchymal compartments of skeletal muscle and liver was determined by quantifying fluorescent signal in vivo, ex vivo and after blood removal. Confocal microscopy was used to spatially document photosensitizer localization 30 min and 24 h after delivery. While a linear correlation can exist between the fluorescence intensity measured by our fiber-optic bundle system and actual tissue concentration, temporal changes to this calibration line exist as the photosensitizer changes its partitioning fraction between the blood (vasculature) and the tissue parenchyma. In situ photosensitizer fluorescence microsampling (dosimetry) systems can be performed in real time and linearly correlated to actual tissue concentration with minimal intertissue variance. Tissue-specific differences may require temporal alterations in the calibration.     

Real-space analysis of the exchange-correlation energy

The exchange-correlation energy of a many-electron system may be written as the electrostatic interaction between the electron density at position r and the density of the exchange-correlation hole at position r + u. If we average the hole over the entire system, we find that the energy is uniquely decomposed into contributions from various electronic separations u. We may also decompose the hole into contributions from parallel and antiparallel spins. We give several exact conditions which this system-averaged, spindecomposed exchange-correlation hole satisfies. Local spin density (LSD ) and generalized gradient approximations (GGAS ), are more appropriate for u → 0 than for large u and more trustworthy for antiparallel spins than for parallel spins. We illustrate how good LSD is as u = 0 with explicit examples, but also note that, contrary to expectation, LSD is not exact for u=0, except in certain limiting cases. We show that the dramatic failure of the second-order gradient expansion for large u can be cured by a real-space cutoff procedure which generates a nonempirical GGA, the Pw91 functional. We conclude with some thoughts about the search for greater accuracy in the next 30 years of density functional theory. © 1995 John Wiley & Sons, Inc.