Assignment Of Relative Configuration Research Articles

Absolute configuration reassignment of nectamazin A: Implications to related neolignans

The ability of nature to produce structurally complex molecules makes the determination of the absolute configuration of natural products a challenging task. Although extensive NMR analysis generally allows for the reliable assignment of relative configurations, the assignments of absolute stereochemistry are commonly performed by empirical comparisons of optical rotation (OR) and/or electronic circular dichroism (ECD) data obtained for related molecules. Such an approach, however, may lead to misassignments and consequent error propagations. Herein, we present the case of the bicyclo(3.2.1)octane neolignan named (+)-nectamazin A. This compound was first reported in 2009 from Nectandra amazonum Nees. (Lauraceae) and had its absolute configuration determined as 7R,8S,3′S,4′R,5′S by means of experimental ECD spectroscopy. Our chemical studies on Ocotea aciphylla (Lauraceae) led to the isolation of (+)-nectamazin A. The extensive analysis of OR, ECD, and vibrational CD data aided by quantum chemical calculations, however, indicated (+)-nectamazin A to have the 7S,8R,3′R,4′S,5′R absolute configuration, in conflict with the configuration reported in the literature. The cause of the original incorrect assignment of (+)-nectamazin A derives from the direct comparison of experimental OR and ECD data obtained for structurally related molecules with different chromophoric systems. As an alternative, VCD spectroscopy is presented as a more reliable and sensitive technique to stereochemical investigations of bicyclo(3.2.1)octane neolignans.

Microcosamine A, Microgrewiapine A and Microgrewiapine B: three homochiral alkaloids?

An asymmetric synthesis of microcosamine A, microgrewiapine A and microgrewiapine B ( Microcos paniculata alkaloids) is reported. Conjugate addition of lithium ( S )- N -benzyl- N -(α-methylbenzyl)amide to tert -butyl crotonate followed by enolate oxidation generates the C(2) and C(3) stereogenic centres of the targets, with subsequent diastereoselective intramolecular reductive amination being used to form the piperidine ring, simultaneously producing the C(6) stereogenic centre. 1 H NMR 3 J coupling constant and nOe analyses allow unambiguous assignment of relative configuration of the alkaloids. Comparison of specific rotation data for microcosamine A and microgrewiapine B is consistent with both possessing the absolute (2 S ,3 R ,6 S )-configuration. For microgrewiapine A, conflicting data regarding the absolute configuration are revealed: in the isolation study a Mosher’s analysis concludes a (2 S ,3 R ,6 S )-configuration, but comparison of specific rotation data suggests a (2 R ,3 S ,6 R )-configuration. Thus it is promulgated it is imprudent to suggest the absolute configuration of this natural product; its re-isolation is required for resolution of this problem.

Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 – 31.11 µM compared to the positive controls: bicalutamide (IC50 = 45.20 –51.61 µM) and enzalutamide (IC50 = 11.47 – 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15–30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH2) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.

Natural Products among Brown Algae: The Case of Cystoseira schiffneri Hamel (Sargassaceae, Phaeophyceae).

A chemotaxonomic study on the marine brown alga Cystoseira schiffneri collected from the Tunisian marine coast allowed us to identify kjellmanianone (1) and a new isololiolide derivative named schiffnerilolide (2). The structure elucidation and the assignment of relative configurations of the isolated natural products were based on advanced mass spectrometric and nuclear magnetic resonance techniques. This outcome suggested a close phylogenetic relationship of C. schiffneri with brown algae belonging to genus Sargassum C. Agardh. Molecular characterization using the nuclear small subunit rRNA (SSU rRNA) gene (18S) sequence as genetic marker was made. Pigment analysis showed a significant seasonal change of carotenoids, in particular of fucoxanthin and fucoxanthinol. Also galactolipids, the main constituents of the thylakoid membranes, showed remarkable seasonal changes.

Yakushinamides, Polyoxygenated Fatty Acid Amides That Inhibit HDACs and SIRTs, from the Marine Sponge Theonella swinhoei.

Yakushinamides A (1) and B (2), prolyl amides of polyoxygenated fatty acids, have been isolated from the marine sponge Theonella swinhoei as inhibitors of HDACs and SIRTs. Their planar structures were determined by interpretation of the NMR data of the intact molecules and tandem FABMS data of the methanolysis products. For the assignment of the relative configurations of the three contiguous oxymethine carbons in 1 and 2, Kishi's universal NMR database was applied to the methanolysis products. During the assignments of relative configurations of the isolated 1-hydroxy-3-methyl moiety in 1 and the isolated 1-hydroxy-2-methyl moiety in 2, we found diagnostic NMR features to distinguish each pair of diastereomers. The absolute configurations of 1 and 2 were determined by a combination of the modified Mosher's method and Marfey's method. Although the modified Mosher's method was successfully applied to the methanolysis product of 1, this method gave an ambiguous result at C-20 when applied to the methanolysis product of 2, even after oxidative cleavage of the C-14 and C-15 bond.

Synthesis of Phenostereum A and Related Diol and Attempted Assignment of Relative Configurations of Remote Stereocenters by13C NMR

Synthesis of Phenostereum A and Related Diol and Attempted Assignment of Relative Configurations of Remote Stereocenters by¹³C NMR

ChemInform Abstract: A Stereocontrolled Synthesis of Hagen′s Gland Lactones via Iterative Proline Catalyzed α‐Aminoxylation and Oxa‐Michael Addition Reactions.

A simple and efficient synthesis of Hagen's gland lactones was achieved using a sequential α-aminoxylation/oxa-Michael approach in a highly diastereoselective manner with assignment of relative configurations. This method was found to be applicable to the synthesis of various other isomers of Hagen's gland lactones.

A stereocontrolled synthesis of Hagen's gland lactones via iterative proline catalyzed α-aminoxylation and oxa-Michael addition reactions

A simple and efficient synthesis of Hagen's gland lactones was achieved using a sequential α-aminoxylation/oxa-Michael approach in a highly diastereoselective manner with assignment of relative configurations.

Corrigendum: Assignment of Relative Configuration of Desoxypropionates by1H NMR Spectroscopy: Method Development, Proof of Principle by Asymmetric Total Synthesis of Xylarinic Acid A and Applications

The authors have noticed an error in the assignment of the structure given in Figure 15. The structure of the natural product xylarinic acid A is correctly drawn in the (R,R) configuration, but the caption and the descriptive text state that the configuration is (S,S). The correct caption for Figure 15 is presented below. The attendant text should state: “Thus, we assigned the absolute configuration of the natural product to be (R,R)-33, as depicted in Figure 15.” The authors apologize for this error and thank Pamela Stephenson from the Chemical Abstracts Service for pointing it out. Figure 15: Assigned absolute configuration of xylarinic acid (R,R-33).

Mandelalides A–D, Cytotoxic Macrolides from a New Lissoclinum Species of South African Tunicate

Mandelalides A-D are variously glycosylated, unusual polyketide macrolides isolated from a new species of Lissoclinum ascidian collected from South Africa, Algoa Bay near Port Elizabeth and the surrounding Nelson Mandela Metropole. Their planar structures were elucidated on submilligram samples by comprehensive analysis of 1D and 2D NMR data, supported by mass spectrometry. The assignment of relative configuration was accomplished by consideration of homonuclear and heteronuclear coupling constants in tandem with ROESY data. The absolute configuration was assigned for mandelalide A after chiral GC-MS analysis of the hydrolyzed monosaccharide (2-O-methyl-α-L-rhamnose) and consideration of ROESY correlations between the monosaccharide and aglycone in the intact natural product. The resultant absolute configuration of the mandelalide A macrolide was extrapolated to propose the absolute configurations of mandelalides B-D. Remarkably, mandelalide B contained the C-4' epimeric 2-O-methyl-6-dehydro-α-L-talose. Mandelalides A and B showed potent cytotoxicity to human NCI-H460 lung cancer cells (IC(50), 12 and 44 nM, respectively) and mouse Neuro-2A neuroblastoma cells (IC(50), 29 and 84 nM, respectively).

Stereoselective Synthesis and Relative Configuration Assignment of Gabosine J

The first total synthesis of (+)-gabosine J and that of the epimer at C4 of its enantiomer have been accomplished through an enantioselective approach from a common intermediate 1. These syntheses have allowed us to establish the correct relative configuration of the natural metabolite, which was originally misassigned. This work, together with our former syntheses of other gabosines and related compounds, validates enone 1 as a general synthetic precursor for this kind of carbasugars.

Assignment of Relative Configuration of Desoxypropionates by 1H NMR Spectroscopy: Method Development, Proof of Principle by Asymmetric Total Synthesis of Xylarinic Acid A and Applications

The determination of the relative configuration of 1,3-dimethyl-substituted alkyl chains is possible by interpretation of (1)H NMR shift differences. Additionally, assignments are feasible in a variety of deuterated solvents, because the corresponding shift differences are not significantly influenced by the solvent. The trends for Δδ values depending on functional groups adjacent to the stereogenic centers are shown. Based on a thorough comparison with literature data, the relative configuration of natural products can be predicted. For this purpose, we derived an empirical rule for the ranges in which Δδ values usually occur. Furthermore, we were able to proof the validity of our method by the successful prediction of the relative configuration for the polyketide natural product xylarinic acid A, which was confirmed by the asymmetric total synthesis of its enantiomer. Based on the proposed simple analysis of published (1)H NMR data and the determination of the relevant chemical-shift differences, we predicted the relative configurations of several previously unassigned natural products.

Quantitative NMR-Derived Interproton Distances Combined with Quantum Mechanical Calculations of 13C Chemical Shifts in the Stereochemical Determination of Conicasterol F, a Nuclear Receptor Ligand from Theonella swinhoei

Here we report the first application of combined accurate ROE-distance analysis with DFT calculations of NMR chemical shifts to achieve the relative configuration assignment of a marine natural product, conicasterol F, a new polyhydroxylated steroid isolated from the marine sponge Theonella swinhoei. We demonstrate the substantial advantages of this combined approach as a tool for structural studies of natural products, providing a powerful alternative to, or information to underpin, total synthesis when more classical NMR data analysis fails to provide unequivocal results. In this paper, we also describe the isolation and structure elucidation of conicasterol F and its 24-ethyl derivative, theonellasterol I, and their pharmacological evaluation as human nuclear receptor modulators.

Structure and Anti-TB Activity of Trachylobanes from the Liverwort Jungermannia exsertifolia ssp. cordifolia

In the critical search for new antituberculosis lead compounds, bryophytes represent a largely untapped resource of chemically diverse structures. From the liverwort Jungermannia exsertifolia subsp. cordifolia, 11 new trachylobane diterpene derivatives, as well as three known compounds, were isolated. Their structures were elucidated by spectroscopic means, and full (1)H NMR spin analysis of one model compound confirmed the relative configurational assignments of the congeners. Four of the isolates exhibited noticeable activity against virulent Mycobacterium tuberculosis H(37)Rv with minimal inhibitory concentrations of 61-24 microg/mL. This finding suggests that bryophytes in general and trachylobanes in particular deserve further attention in the search for new antimycobacterial leads.

Aplysqualenols A and B: Squalene‐Derived Polyethers with Antitumoral and Antiviral Activity from the Caribbean Sea Slug Aplysia dactylomela

The novel bromotriterpene polyethers aplysqualenol A (1) and aplysqualenol B (2) have been isolated from the Caribbean sea slug Aplysia dactylomela collected in Puerto Rico, and their structures and relative configurational assignments established from spectroscopic data aided by quantum mechanical calculations of NMR chemical shifts. Although both these compounds may be conceived as polyoxycyclic derivatives of the C30 squalene skeleton, remarkably 1 and 2 possess an unprecedented C15 to C24 flexible chain of 14S* spatial disposition that contains a unique ether bridge between C16 and C19. Biological activity screening tests revealed that, although aplysqualenol A (1) does not have significant anti-infective properties, it possesses potent antitumoral and antiviral activities.

A Convenient Method for the Assignment of Relative Configuration of Acyclic α-Alkyl-β-hydroxy Carbonyl Compounds by 1H NMR

The relative configuration of acyclic alpha-alkyl-beta-hydroxy carbonyl compounds can be determined by using (1)H NMR spectroscopy. The assignment can be achieved by recording the (1)H NMR spectrum of the syn-anti mixture. The upfield carbinol hydrogen signal belongs to the anti whereas the downfield to the syn stereoisomer.

Determination of absolute configuration—An overview related to this Special Issue

Rapid progress in asymmetric synthesis stimulated a further development of methods and techniques for the determination of absolute configuration of chiral molecules. In recent years the direct methods, i.e. X-ray diffraction analysis, circular dichroism (vibrational and electronic), Raman optical activity, optical rotation measurements, as well as indirect methods for relative configuration assignment with the use of NMR spectroscopy or enzymatic transformations, are receiving increasing attention not only by specialists in the field but also by synthetic and structural chemists alike. This paper provides a short overview of the methods currently used, as well as references to contributions collected in this Thematic Issue of Chirality.

Toward computing relative configurations: 16-epi-latrunculin B, a new stereoisomer of the actin polymerization inhibitor latrunculin B.

The title compound, 16-epi-latrunculin B (3), has been isolated from the sponge Negombata magnifica collected from the Red Sea near Hurghada, Egypt. This new natural product was determined to be an epimer of latrunculin B (1), which was found in the same sponge collection. The structure of 3 was initially deduced from proton and carbon NMR chemical shift trends and proton-proton nuclear Overhauser effect experiments. The cytotoxicity (murine tumor and normal cell lines) and antiviral (HSV-1) properties of 3 and 1 were determined. A computational study applicable to this class of stereochemical problems was then investigated. Specifically, the complete set of vicinal and allylic coupling constants was calculated for each of the four diastereomers whose configurations differed at C(8) and C(16). These computed J's were then compared with the experimental J values (28 in number) determined for 1 and 3. This analysis resulted in the same assignment of relative configuration for compound 3 reached using the more classical methods. The validity of the method is established by the fact that the 28 computed coupling constants for (known) 1 and (newly determined) 3 varied from the experimental J values with an average of just 0.57 and 0.53 Hz, respectively. This strategy represents a general, powerful, and readily adoptable tool for determining the relative configuration of complex molecules.

Baker's yeast reduction of cyclic δ-ketoesters: synthesis and chiroptical properties of condensed δ-lactones

Enantiomerically pure condensed δ-lactones have been prepared from the corresponding δ-ketoesters by the use of Saccharomyces cerevisiae. The reactions were not only highly enantioselective but also highly diastereoselective, provided the baker's yeast was preincubated at 50°C for 30 min. Interestingly, and contrary to what is usually found, the use of nutrients inhibited the bioreductions. The relative configurational assignments have been made by means of NMR, while the absolute configurations and conformations of the lactone rings were attributed by means of CD studies.

Assignment of all Diastereomers of Perhydrofluorene in a mixture using13C NMR spectroscopy

By hydrogenation of fluorene 1 using different catalysts, mixtures containing variable amounts of the six possible diastereomers of perhydrofluorene 2 were obtained. The 13C NMR spectra of all diastereomers have been determined in these mixtures whithout previous separation procedures. By molecular mechanics calculations the structures of the preferred conformations were simulated for all diastereomers. The substituent induced 13C NMR chemical shifts in conformers were calculated by using increments for the non-bonding 1,3-synaxial interactions. Three stereochemical increments, combined with the shift values found earlier by Beierbeck and Saunders, were sufficient to calculate the chemical shift differences of conformers empirically. The assignment of relative configurations of the diastereomers was possible by comparison of the empirically calculated and experimental 13C chemical shifts of the clearly distinguishable bridgehead carbons. The difference between calculated and experimentally determined shift values was only 1.3 ppm, averaged over all bridgehead carbons.