Assignment of the liposidomycin diazepanone stereochemistry

The liposidomycins comprise a family of complex nucleoside antibiotics that inhibit bacterial peptidoglycan synthesis. Their structures (1, 2) feature nucleoside, ribofuranoside, diazepanone, and lipid regions. Several stereogenic centers remain unassigned, including three within the diazepanone region: C-6', C-2'", and C-3'". An intramolecular reductive amination reaction has been used to prepare model diazepanones. Analysis of 40 and two of its diastereomers by NMR spectroscopy, X-ray crystallography, and molecular modeling indicates a close relative configurational and conformational match between 40 and the liposidomycin diazepanone degradation product 43 and allows the assignment of stereochemistry of the natural products as either [C-6'(R), C-2'"(R), C-3'"(R)] or [C-6'(S), C-2'"(S), C-3'"(S)].     

New cytotoxic bufadienolides from the biotransformation of resibufogenin by Mucor polymorphosporus

Resibufogenin is a cytotoxic steroid isolated from the Chinese drug ChanSu. The biotransformation of resibufogenin by Mucor polymorphosporus afforded 22 products, and 15 of them were new. The transformation reactions involved hydroxylations at C-1β, C-5, C-7α, C-7β, C-12α, C-12β and C-16α, as well as epimerization or dehydrogenation of 3-OH. Hydroxylations at C-12α, C-12β and C-16α were the major reactions, each giving products in >5% yields, whereas the other products were obtained in fairly low yields. Some of the products showed decreased but still potent cytotoxicities. This investigation provided a useful approach to prepare new bufadienolides and most of them were difficult to obtain by chemical means.     

Inactivation of the carbamoyltransferase gene refines post-polyketide synthase modification steps in the biosynthesis of the antitumor agent geldanamycin

The post-polyketide synthase modification of geldanamycin (1) biosynthesis is of interest as a means of introducing structural diversity into the compound. From the inactivation of a gene encoding carbamoyltransferase, we demonstrated that the C-17 hydroxylation and the C-21 oxidation precede O-carbamoylation and that the hypothetical progeldanamycin does not possess a double bond at C-4 and C-5. More importantly, our result revealed new intermediates 4,5-dihydro-7-O-descarbamoyl-7-hydroxygeldanamycin (3) and 4,5-dihydrogeldanamycin (5), indicating that O-carbamoylation occurs prior to the C-4,5 cis double bond formation in geldanamycin biosynthesis.     

Remote functionalization on the steroid β-face: Attack on an angular methyl group,and into the sidechain

Benzophenonealkanoate esters of 6-β-cholestanes insert photolytically into C-15, C-16, and the C-18 methyl, or into C-23 and C-25 of the sidechain, depending on the length of the attaching chain.     

Amphidinolides T2, T3, and T4, new 19-membered macrolides from the dinoflagellate Amphidinium sp. and the biosynthesis of amphidinolide T1.

Three new 19-membered macrolides, amphidinolides T2 (2), T3 (3), and T4 (4), structurally related to amphidinolide T1 (1) have been isolated from two strains of marine dinoflagellates of the genus Amphidinium. The structures of 2-4 were elucidated on the basis of spectroscopic data. The absolute configurations at C-7, C-8, and C-10 of 1-4 were determined by comparison of NMR data of their C-1-C-12 segments with those of synthetic model compounds for the tetrahydrofuran portion. The biosynthetic origins of amphidinolide T1 (1) were investigated on the basis of 13C NMR data of a 13C enriched sample obtained by feeding experiments with [1-(13)C], [2-(13)C], and [1,2-(13)C2] sodium acetates and 13C-labeled sodium bicarbonate in the cultures of the dinoflagellate. These incorporation patterns suggested that amphidinolide T1 (1) was generated from four successive polyketide chains, an isolated C1 unit formed from C-2 of acetates, and three unusual C2 units derived only from C-2 of acetates. Furthermore, it is noted that five oxygenated carbons of C-1, C-7, C-12, C-13, and C-18 were not derived from the C-1 carbonyl, but from the C-2 methyl of acetates.     

Characteristics of the mass spectra of ecdysteroids with different numbers of -OR groups

The mass spectra of 15 phytoecdysteroids and acetyl derivatives have been compared. With a decrease in the number of -OR groups, the contribution of cleavages of the bonds of the steroid skeleton increases. 20,22-Diols are characterized by the greatest significance of fragmentation at the C-20–C-22 bond. In all the spectra, clear indications of fragmentation of the side chain at the C-22–C-23, C-23–C-24, and C-24–C-25 bonds are observed.     

Establishing the absolute configuration of the asbestinins: enantioselective total synthesis of 11-acetoxy-4-deoxyasbestinin D

A highly stereoselective synthesis of 11-acetoxy-4-deoxyasbestinin D (1) has been completed in 26 linear steps. The synthesis hinges on a selective glycolate aldol addition to establish the C-2 stereocenter, a ring-closing metathesis reaction to complete the oxonene, and an intramolecular Diels-Alder cycloaddition to establish the relative configuration at C-1, C-10, and C-14. This initial total synthesis of an asbestinin also serves to confirm the absolute configuration of this subclass of the C-2-C-11-cyclized cembranoid natural products.     

Synthetic modifications of ascomycin - I. A chemoselective removal of the cyclohexyl residue of ascomycin

An efficient semisynthetic preparation of des-28-(cyclohexyl)methylene-28-oxo-ascomycin derivatives starting from 24,33-O-bis(tert-butyldimethylsilyl)-ascomycin (1) is described. The strategy for preparing 28-oxo-ascomycin derivatives involves the reduction of C-22 carbonyl group, followed by 5-endo-cyclization of the resulting C-22 alcohol with the C-19/C-20 double bond using an oxymercuration reaction; ozonolysis of the C-28/C-29 double bond and regeneration of the C-19/C-20 double bond. Further, the 20-mercury-substituted ascomycin derivatives could be reduced to the corresponding metal free cyclic ethers using n-Bu₃SnH.     

Mobile Phase Selectivity in the Separation of Epimeric and Positionally Isomeric Triterpenoids by Reversed Phase High Performance Liquid Chromatography

The chromatographic behavior of 8 lanostanoid triterpenes including 4 pairs of C-3 epimers and 2 pairs of C-3/C-15 positional isomers was studied by reversed phase HPLC. A consistent elution sequence of these paired isomers in all combination of three distinct solvent systems was observed. The mobile phase selectivity to separate specific, paired isomers was mainly dependent on the polarity difference contributed by C-3/C-15 hydroxyl and acetoxyl groups. The stereochemistry at C-3 played more profound role in guiding the hydrophobic interaction with C₁₈ stationary phase in the separation of C-3/C-15 positional isomers.     

Two New Bis-tetrahydrofuran Ring Annonaceous Acetogenins from the Roots of Uvaria calamistrata

Althoughourresearchrevealedthatnarumicin-IIanddesacetyluvaricinwerethetwomajorbioactivebis-THFringacetogeninsintherootsofUvariacalamistralaHance,twonewbis-THFringannonaceousacetogeninswithmild-activitiesnamedcalamistrinsF(l)andG(2)hadalsobeenisolated.TheacetogeninsweretraceconstituentsintheplantandstructurallyhadthecharacteristicsofOH-flankedTHFringfromC-l8toC-25andathirdOHgroupatC-5.lwasisolatedaswaxysolid.TheFABMSoflgave[MH1 peakatm/:623,which,combiningwithelementalanaIysis,sugge…     

A Pauson-Khand approach to the synthesis of ingenol

[reaction: see text] Pauson-Khand cyclization of dioxanone photoadduct 21 leads to the formation of a single product in good yield. However, retro-aldol fragmentation of the pentacyclic cyclopentenone 22 leads to the formation of 23, with cis C-8/C-10 intrabridgehead stereochemistry, unlike the target compound ingenol 1, which possesses C-8/C-10 trans intrabridgehead stereochemistry.     

On the stereochemistry of palmerolide A

Degradative studies of the anticancer macrolide palmerolide A have resulted in re-assignment of the C-7, C-10, and C-11 stereocenters.     

Relative stereochemical assignment of C-33 and C-35 in the antibiotic gladiolin

Gladiolin is a macrolide antibiotic isolated from Burkholderia gladioli BCC0238 with promising activity against Mycobacterium tuberculosis, including several multidrug resistant strains. The configuration of all but one of the stereogenic centers of gladiolin has previously been elucidated using a combination of NOESY NMR experiments and predictive sequence analysis of the polyketide synthase responsible for its assembly. However, it was not possible to assign the configuration of the C-35 methyl group using such methods. Here we report the synthesis of C-33/C-35-syn and C-33/C-35-anti mimics of the C-30 to C-38 fragment of gladiolin from (R) and (S)-citronellol, respectively. Comparison of HSQC NMR data for the mimics and the natural product showed that the C-35 methyl is anti to the C-33 hydroxyl group, indicating that gladiolin has the 35S configuration.     

Ruthenium-catalyzed alkene-alkyne coupling: synthesis of the proposed structure of amphidinolide A

The ruthenium-catalyzed alkene-alkyne coupling provides a powerful method for the synthesis of 1,4 dienes and a way to simplify synthetic strategy. The latter potential is explored in the context of a synthesis of the assigned structure of amphidinolide A, which also raises the question of the applicability of this reaction for macrocyclizations. Employing this reaction allows simplification of the target to three subunits corresponding to C-1 to C-6, C-7 to C-15, and C-16 to C-25. The C-7 to C-15 subunit involves introduction of chirality by an asymmetric dihydroxylation. The route to the C-16 to C-25 subunit introduces chirality by a Pd-catalyzed asymmetric allylic alkylation and an asymmetric epoxidation. Assembly of the three subunits employs the Ru-catalyzed addition inter- and intramolecularly. The synthesis culminated in the formation of the assigned structure and is identical to the synthetic samples prepared independently by two completely different routes. As noted by the other two groups, this structure appears to be a diastereomer of the natural product. Because this synthesis introduces all of the stereochemistry of the subunits by catalytic asymmetric processes, either enantiomer as well as diastereomers can be readily accessed to define the correct structure. Notably, the Ru-catalyzed macrocyclization to this macrolide proceeded in better yields than either a Pd-catalyzed cross-coupling or a Ru-catalyzed metathesis, macrocylization methods for the other two total synthesis.     

Molecular conformations at the cellulose–water interface

¹³C-NMR chemical shifts were measured for C-4 and C-6 in a collection of eight crystalline glucoses and glucosides. The influence of the hydroxymethyl conformation was greater at C-4 than at C-6, with mean chemical shifts for gauche–trans molecules displaced 3.1 ppm (C-4) and 2.5 ppm (C-6) relative to gauche–gauche molecules. This information was used to interpret ¹³C-NMR spectra of crystalline celluloses. Chemical shifts for C-4 in the crystallite cores of celluloses I and II differed by just 0.2 ppm, but the corresponding chemical shifts for well-ordered crystallite surfaces differed by 3.0 ppm. The separation between crystallite-surface signals was attributed to different hydroxymethyl conformations at the cellulose–water interface, i.e., gauche–gauche and gauche–trans on crystallites of cellulose I and cellulose II, respectively. A broad C-4 signal in the spectrum of cellulose II indicated gauche–gauche conformations in disordered cellulose. Chemical shifts for C-6 were consistent with these conformations.     

Stereoselective C-glycosylation reactions of pyranoses: the conformational preference and reactions of the mannosyl cation

A systematic study of C-glycosylations of acetals related to mannose and other pyranoses was conducted. The C-5 alkoxyalkyl group provides only a modest influence on stereoselectivity. On the other hand, studies of pentopyranoses bearing alkoxy groups at C-2, C-3, and C-4 showed that the alkoxy groups exerted powerful influences on selectivity. In the case of mannose, the high alpha selectivity observed with C-mannosylation was reversed to high beta selectivity if the C-5 alkoxyalkyl group were removed. An analysis of the conformational preferences of the intermediate oxocarbenium ions, including the mannosyl cation, as well as consideration of steric effects that develop in the transition states for nucleophilic attack provide explanations for these phenomena.     

Mass spectroscopy of natural products. VI—Localization of functional groups in the hopane skeleton

The mass spectral fragmentation of hopane derivatives with oxygenated substituents at C-3, C-6, C-7, C-15, C-16 and C-22 is discussed. It is shown, that the positions of functional groups in rings A and B or D and E respectively can be distinguished using several derivatives and deuterated analogues.     

Quantitation of Long Chain Fatty Acids as the Methoxyphenacyl Esters

Abstract

In recent years High Performance Liquid Chromatography has been used for the separation of long chain fatty acids. This study establishes a procedure for the quantitation of the major fatty acids found in oral bacteria. The acids studied were C-10, C-12, C-14, C-16, C-18, C-18:1, C-20, and C-22. The samples were esterified with α-Bromo-m-methoxyacetophenone, separated by reversed phase chromatography and monitored at both 254nm and 280nm. The fatty acids have approximately the same linear absorbance range at 254nm from 100 picomoles to 50 nanomoles. While the linear absorbance range was similar, the response factors varied by more than 40% when using peak heights, compared to less than a 15% variation when using peak areas. Several A-NHI fatty acid reference mixtures were used to assure the reliability (average relative error = 3.72%) of the method. Subsequent analysis of a bacteria sample was made by both High Performance Liquid Chromatography (HPLC) and Gas Liquid Chromatography (GLC) in order to further substantiate the validity of the technique.     

Derivatives and reactions of glutacondialdehyde V : The crystal and molecular structure of 5-hydroxy-trans-2, trans-4-pentadienal acetate. The charge distribution in the glutacondialdehyde anion

The structure of 5-hydroxy-trans-2, trans-4-pentadienal acetate has been determined, using three-dimensional diffractometercollected X-ray data. The compound has the all-trans configuration with the atoms C-1 to C-5 in a plane. The charge distribution in the acetate and in the glutacondialdehyde anion have been calculated using the CNDO/2 approximation. In both compounds higher negative charges were found on carbon atoms C-2 and C-4 than on C-1, C-3 and C-5.