[Show abstract][Hide abstract] ABSTRACT: Invited for this month's cover picture is the group of Professor Mark Peczuh at the University of Connecticut. The cover picture compares the rearrangement of a small molecule to the process of turning a stuffed animal inside out. The recycled, inside-out stuffed animals are both artistic and philosophically provocative. They capture the essence of the rearrangement reaction because the compounds themselves turn inside out over the course of the reaction, extending the diversity of products that can arise from simple starting materials. Small molecules often have functional groups with latent reactivity; under the appropriate conditions, those groups can react with other compounds (e.g., reagents) and also with other groups in the same molecule in an intramolecular reaction. The research team found that the epoxidation of some highly functionalized spiroketal compounds promoted rearrangements of their structures that turned them inside out. Some of the features of the products led them to use X-ray crystallography or a combination of computer-assisted structure elucidation, computation, and a new version of the 1,1-ADEQUATE NMR experiment to determine their structures. For more details, see the Communication on p. 577 ff.
[Show abstract][Hide abstract] ABSTRACT: Spiroketals organize small molecule structures into well-defined , three-dimensional configurations that make them good ligands of proteins. We recently discovered a tandem cyclo-isomerization–dimerization reaction of alkynyl hemiketals that delivered polycyclic, enol-ether-containing spiroketals. Here we describe rearrangements of those compounds, triggered by epoxidation of their enol ethers that completely remodel their structures, essentially turning them " inside out ". Due to the high level of substitution on the carbon skeletons of the sub-strates and products, characterization resorted to X-ray crystallography and advanced computation and NMR techniques to solve the structures of representative compounds. In particular, a new proton-detected ADEQUATE NMR experiment (1,1-HD-ADEQUATE) enabled the unequivocal assignment of the carbon skeleton of one of the new compounds. Solution of the structures of the representative compounds allowed for the assignment of product structures for the other compounds in two separate series. Both the rearrangement and the methods used for structural determination of the products are valuable tools for the preparation of characterization of new small molecule compounds.
[Show abstract][Hide abstract] ABSTRACT: The impact of LR-HSQMBC very long-range nJCH heteronuclear shift correlation data as a supplement to HMBC data as input for the computer-assisted structure elucidation (CASE) program, Structure Elucidator®, is assessed for the first time. The severely proton-deficient xanthone antibiotic cervinomycin A2 and the alkaloid staurosporine were employed as a model compounds.
[Show abstract][Hide abstract] ABSTRACT: Other topics: 1,n-ADEQUATE, inverted 1Jcc 1,n-ADEQUATE
2D NMR methods have become the cornerstone of modern structure elucidation protocols. In many instances, structures can be determined using the ensemble of experiments that includes one-dimensional proton and carbon spectra (the latter assuming that there is sufficient sample), homonuclear correlation spectroscopy (COSY), multiplicity-edited heteronuclear single quantum correlation (HSQC), and 1H-13C heteronuclear multiple bond correlation (HMBC). For nitrogenous compounds, adding 1H-15N HMBC to the standard suite of experiments can be extremely beneficial. As molecules become progressively more proton deficient, the challenge of assembling a structure increases significantly. Application of the 1,n-ADEQUATE experiment and modified variants thereof for proton-deficient structure elucidation problems is discussed in addition to hyphenated variants calculated using covariance methods.
[Show abstract][Hide abstract] ABSTRACT: Long-range heteronuclear shift correlation methods have served as the cornerstone of modern structure elucidation protocols for several decades. The (1)H-(13)C HMBC experiment provides a versatile and relatively sensitive means of establishing predominantly (3)JCH connectivity with the occasional (2)JCH or (4)JCH correlation being observed. The two-bond and four-bond outliers must be identified specifically to avoid spectral and/or structural misassignment. Despite the versatility and extensive applications of the HMBC experiment, it can still fail to elucidate structures of molecules that are highly proton-deficient, e.g., those that fall under the so-called "Crews rule". In such cases, recourse to the ADEQUATE experiments should be considered. Thus, a study was undertaken to facilitate better investigator understanding of situations where it might be beneficial to apply 1,1- or 1,n-ADEQUATE to proton-rich or proton-deficient molecules. Equipped with a better understanding of when a given experiment might be more likely to provide the necessary correlation data, investigators can make better decisions on when it might be advisible to employ one experiment over the other. Strychnine (1) and cervinomycin A2 (2) were employed as model compounds to represent proton-rich and proton-deficient classes of molecules, respectively. DFT methods were employed to calculate the relevant (n)JCH heteronuclear proton-carbon and (n)JCC homonuclear carbon-carbon coupling constants for this study.
[Show abstract][Hide abstract] ABSTRACT: The recently reported LR-HSQMBC experiment has been optimized for H-1-N-15 long-range heteronuclear couplings. Several previously unreported four-bond correlations, consistent with the predicted by DFT calculations (0.2-0.3 Hz (4)J(NH)] couplings), have been observed for strychnine using 2 Hz optimization of the LR-HSQMBC experiment. This experiment offers an advantage over accordion-optimized experiments such as IMPEACH and CIGAR for the observation of long-range H-1-N-15 correlations in that the experiment is refocused and employs a CLIP pulse sequence element to bring the long-range correlations into phase, allowing broadband X-decoupling to be employed during acquisition.
[Show abstract][Hide abstract] ABSTRACT: HMBC is one of the most often used and vital NMR experiments for the structure elucidation of organic and inorganic molecules. We have developed a new, high sensitivity NMR pulse sequence that overcomes the typical 2,3JCH limitation of HMBC by extending the visualization of long-range correlation data to 4-, 5-, and even 6-bond long-range nJCH heteronuclear couplings. This technique should prove to be an effective experiment to complement HMBC for probing the structure of proton-deficient molecules. The LR-HSQMBC NMR experiment can, in effect, extend the range of HMBC to provide data similar to that afforded by 1,n-ADEQUATE even in sample limited situations. This is accomplished by optimizing responses for very small nJCH coupings as opposed to relying on the markedly less sensitive detection of long-range coupled 13C-13C homonuclear pairs at natural abundance. DFT calculations were employed to determine whether the very long-range correlations observed for cervinomycin A2 were reasonable based on the calculated long-range couplings.
The Journal of Organic Chemistry 04/2014; 79(9). DOI:10.1021/jo500333u · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bacteria continue to evade existing antibiotics by acquiring resistance by various mechanisms, leading to loss of antibiotic effectiveness. To avoid an epidemic from infections of incurable drug-resistant bacteria, new antibiotics with new modes of action are desperately needed. Using a genome-wide mechanism of action-guided whole cell screening approach based on antisense Staphylococcus aureus fitness test technology, we report herein the discovery of altersolanol P (1), a new tetrahydroanthraquinone from an unknown fungus from the Hypocreales isolated from forest litter collected in Puerto Rico. The structure was elucidated by high-resolution mass spectrometry and 2D NMR spectroscopy. Relative stereochemistry was established by NOESY correlations, and absolute configuration was deduced by the application of MPA ester-based methodology. Observed (1)H and (13)C NMR shifts were well aligned with the corresponding chemical shifts predicted by DFT calculations. Altersolanol P exhibited Gram-positive antibacterial activity (MIC range 1-8 μg/mL) and inhibited the growth of Gram-negative Haemophilus influenzae (MIC 2 μg/mL). The isolation, structure elucidation, and antibacterial activity of altersolanol P are described.
[Show abstract][Hide abstract] ABSTRACT: Piperidines are ubiquitous in pharmaceuticals and bioactive natural products. Understanding the structural and functional properties of piperidines plays a key role in drug design and development. This Letter reported studies of conformation of a set of gem-disubstituted methylphenylpiperidines in the context of discovery of NK1 antagonists. The findings led to re-design and an efficient synthesis of a potent NK1 antagonist with excellent in vivo activity and rodent and monkey pharmacokinetic profiles.
[Show abstract][Hide abstract] ABSTRACT: Quantum chemical calculations of one-bond carbon-carbon coupling constants are demonstrated as potential probes for the configurational assignment of organic molecules. The stereochemical analysis of strychnine and its possible stereoisomers is presented as proof of concept.
[Show abstract][Hide abstract] ABSTRACT: This paper describes a novel synthetic route for the preparation of ortho–ortho disubstituted biphenyls and compounds possessing highly condensed ring system represented by structures X and Y, respectively. Several approaches, such as intermolecular Grubb's olefin metathesis, Heck and, Suzuki reactions were incorporated to functionalize the core structures of X and Y making it suitable for the preparation of a library of compounds.