A Study of Stereoselective Hydrolysis of Symmetrical Diesters with Pig Liver Esterase

Pig liver esterase-(PLE) catalyzed hydrolysis of dimethyl esters of symmetrical dicarboxylic acids, including meso-diacids, cis-1,2-cycloalkanedicarboxylic acids, and diacids with a prochiral center, was studied with 14 substrates. The products of these stereoselective hydrolyses are chiral monoesters of dicarboxylic acids, with an enantiomeric excess (e.e.) from 10% to 100%. Some of these optically active monoesters are valuable synthons in natural products synthesis. An additivity pattern of α- and β-substituents with the glutaric esters on the stereoselectivity of enzymatic hydrolysis was observed. Analysis of the experimental results leads to a model of enzyme stereoselectivity of diester hydrolysis in which the substitution pattern at α- and β-C-atoms is found to determine the absolute configuration of the resulting monoester.     

Les β-cétonitriles groupes protecteurs de la fonction amine. Préparation d'amino-alcools

β-Ketonitrile-Derived Protecting Groups of the Amino Function. Synthesis of Amino Alcohols The amino group of natural L -amino acid esters is protected by condensation with 2-oxocyclopentanenitrile ( 1 ) or 2-formyl-2-phenylacetonitrile ( 10 ). Only the ester group of the formed cyanoenamino esters 2 and 11 reacts with nucleophilic reagents such as organometallics (RMgX, RLi), borohydrides, or metal amides, whereas the cyanoenamino group is unchanged (Schemes 1 and 2). Cyanoenamino alcohols obtained by reduction of cyanoenamino esters 2 are hydrolyzed under acidic conditions to amino alcohols with retention of the configuration of the starting amino acid. This sequence of reactions allows to prepare derivatives of L -tyrosinol from (?)-L -tyrosine (see, e.g., Scheme 4). Cyanoenamino esters 11 are readily methylated at the N-atom to give N-methylated cyanoenamino esters (Scheme 3). This property is exploited on the way of a multistep procedure to obtain N-methylated amino alcohols homologous to natural (?)-(1R,2S)-ephedrine.     

An alternative approach for predicting peak width in gas chromatography

Summary The linear relationship between natural logarithm of width factor (lnp′)and natural logarithm of retention factor (lnk) is demonstrated. This relationship is then used to establish the relationship between (lnp′), absolute temperature (T), and carbon number (z), as follows: Inp′=A+bz+c/T+dz/T where A, b, c and d are thermodynamically related constants. The above equation is used to predict the unadjusted widths (w _R ) ofn-alkanes, fatty alcohols and fatty acid methyl esters (FAMEs) at various temperatures, predicted values are in good agreement with experimental values. The above equation can be used to predict the width of FAMEs from rice bran oil. The largest difference between the experimental and predicted values is 0.66 s or 6.32%.     

Total Synthesis of a Mycolic Acid from Mycobacterium tuberculosis

In Mycobacterium tuberculosis, mycolic acids and their glycerol, glucose, and trehalose esters (“cord factor”) form the main part of the mycomembrane. Despite their first isolation almost a century ago, full stereochemical evaluation is lacking, as is a scalable synthesis required for accurate immunological, including vaccination, studies. Herein, we report an efficient, convergent, gram‐scale synthesis of four stereo‐isomers of a mycolic acid and its glucose ester. Binding to the antigen presenting protein CD1b and T cell activation studies are used to confirm the antigenicity of the synthetic material. The absolute stereochemistry of the syn‐methoxy methyl moiety in natural material is evaluated by comparing its optical rotation with that of synthetic material.     

Desymmetrization of C2-Symmetric Bis(Boronic Esters) by Zweifel Olefinations

anti-Configured 1,3-dimethyl deoxypropionate motifs are important sub structures in natural products. Herein, we describe a bidirectional approach for the rapid construction of natural products featuring such motifs by using C₂-symmetrical 1,3-bis(boronic esters). As for its application in convergent syntheses it was important to establish a selective mono-Zweifel olefination we describe the scope and limitations by using different 1,3-bis(boronic esters) and nucleophiles. This protocol takes advantage of the combination of the Hoppe–Matteson–Zweifel chemistry, which was elegantly put into practice by Aggarwal et al. In order to show its applicability the total syntheses of two natural products, serricornin and (+)-invictolide, were performed.     

Leucascandrolide A,a New Type of Macrolide: The first powerfully bioactive metabolite of calcareous sponges (Leucascandra caveolata,a new genus from the coral sea)

Leucascandrolide A ((+)- 1 ), a doubly O-bridged 18-membered macrolide of a new type, i.e., showing little C₁-branching vs. extensive 1,3-dioxygenation and a peculiar side chain, was isolated from a calcareous sponge of a new genus, Leucascandra caveolata BOROJEVIC and KLAUTAU from the Coral Sea. Transesterification of (+)- 1 gave the methyl ester 3 , derived from the side chain, and the 5-hydroxy derivative (+)- 2 , derived from the macrolide portion and with the natural configuration at C(5) (axial). Mosher's MTPA esters 4 and 5 obtained from (+)- 2 showed scattered Δδ = (δ(S) ? δ(R)) data. However, inversion of the configuration at C(5) led, via ketone (+)- 6 , to the less encumbered 5-equatorial hydroxy derivative (+)- 7 , whose MTPA esters 8 and 9 gave consistent Δδ data, allowing the assignment of the absolute configuration of (+)- 7 , and hence of (+)- 1 . The structural novelty of (+)- 1 and its powerful antifungal and cytotoxic activities are likely to renew interest in calcareous sponges, previously limited to scarcely biologically active 2-aminoimidazoles.     

A general method for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations. Part 2, via catalytic reduction of acetylene alcohol MαNP esters

A general method for synthesizing enantiopure (100% ee) aliphatic alcohols with established absolute configurations has been developed and applied to alcohols CH₃(CH₂)_n–CH(OH)–(CH₂)_mCH₃, the enantiomeric discrimination of which is the most difficult, if m = n + 1 and n is large. Racemic saturated alcohols with short chains could be directly enantioresolved as (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) esters by HPLC on silica gel, and their absolute configurations were simultaneously determined by ¹H NMR diamagnetic anisotropy. However, the application of this powerful MαNP ester method to alcohols with long chains was difficult, because of smaller values of the separation factor α. In such cases, the use of the corresponding acetylene alcohol MαNP esters was crucial. Acetylene alcohol MαNP esters were largely separated by HPLC on silica gel, and their absolute configurations were unambiguously determined by ¹H NMR as reported in the Part 1 paper. The MαNP esters obtained with established absolute configurations were catalytically hydrogenated to yield saturated alcohol MαNP esters. It was evidenced that no racemization occurred at the stereogenic center of the alcohol moiety during catalytic hydrogenation, by the coinjection of MαNP esters in HPLC. From the MαNP esters obtained, enantiopure (100% ee) aliphatic chain alcohols with established absolute configurations were recovered. Although the [α]_D values of these alcohols were too small for the identification of the enantiomers, it was clarified that the analytical HPLC of MαNP esters is useful for identification in most cases.     

Nonreductive Enantioselective Ring Opening of N-(Methylsulfonyl)dicarboximides with Diisopropoxytitanium α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5-dimethanolate

The bicyclic and tricyclic meso-N-(methylsulfonyl)dicarboximides 1a–f are converted enantioselectively to isopropyl [(sulfonamido)carbonyl]-carboxylates 2a–f by diisopropoxytitanium TADDOLate (75–92% yield; see Scheme 3). The enantiomer ratios of the products are between 86:14 and 97:3, and recrystallization from CH₂Cl₂/hexane leads to enantiomerically pure sulfonamido esters 2 (Scheme 3). The enantioselectivity shows a linear relationship with the enantiomer excess of the TADDOL employed (Fig.3). Reduction of the ester and carboxamide groups (LiAlH₄) and additional reductive cleavage of the sulfonamido group (Red-Al) in the products 2 of imide-ring opening gives hydroxy-sulfonamides 3 and amino alcohols 4 , respectively (Scheme 4). The absolute configuration of the sulfonamido esters 2 is determined by chemical correlation (with 2a,b ; Scheme 6), by the X-ray analysis of the camphanate of 3e (Fig. 1), and by comparative ¹⁹F-NMR analysis of the Mosher esters of the hydroxy-sulfonamides 3 (Table 1). A general proposal for the assignment of the absolute configuration of primary alcohols and amines of Formula HXCH₂CHR¹R², X = O, NH, is suggested (see 11 in Table 1). It follows from the assignment of configuration of 2 that the Re carbonyl group of the original imide 1 is converted to an isopropyl ester group. This result is compatible with a rule previously put forward for the stereochemical course of reactions involving titanium TADDOLate activated chelating electrophiles ( 12 in Scheme 7). A tentative mechanistic model is proposed ( 13 and 14 in Scheme 7).     

Chemoenzymatic and yeast-catalysed synthesis of diastereomeric ethyl γ-phenyl and γ-(n-pyridyl)paraconates

The synthesis of γ-phenyl and γ-(n-pyridyl)paraconates was accomplished by chemical reduction of their respective ketodiester precursors followed by cyclisation of the resulting hydroxy diester intermediates. The cis- and trans-lactones thus obtained were separated and separately subjected to enzymatic hydrolysis with HLAP. The cis-lactonic esters had enantiomeric excesses ranging from 94% to 99%, while for the trans-isomers the ee’s ranged from 80% to 93%. The same ketodiester precursors were subjected to reduction with a series of yeasts. The absolute configuration of trans-(−)-2-pyridyl paraconic acid was assigned by means of X-ray analysis of its hydrobromide salt, while the absolute configurations of the other lactones were determined via analysis of their respective CD curves.     

Phthalimide as a chromophoric tag in the circular dichroism determination of absolute configuration of α-aminoacid amides and dipeptides. A case of a dipeptide isostructurality

Both N-phthaloyl aminoacid amides and methyl amides as well as N-phthaloyl dipeptide methyl esters give Cotton effects of opposite signs at around 220 and 240 nm. The signs of these Cotton effects are directly correlated with the absolute configuration of the N-phthaloyl substituted stereogenic center: for -configuration the Cotton effect at 240 nm is positive and the Cotton effect at 220 is negative. The X-ray analysis shows that the diastereomeric , and , N-phthaloyl alanylvaline methyl esters form isostructural orthorombic crystals due to the conformational flexibility of the molecules and a similar space requirements of the methoxycarbonyl and isopropyl groups.     

Absolute configuration of diterpenoid diacylglycerols from the Antarctic nudibranch Austrodoris kerguelenensis

The R absolute configuration at C-2′ of the glyceryl moiety of the natural diterpenoid 1,3-glyceryl esters 1 and 2 has been established by applying the modified Mosher method. These esters have been isolated, together with the corresponding 1,2-derivatives (3 and 4), from different collections of the Antarctic dorid nudibranch Austrodoris kerguelenensis. Surprisingly, such a configuration is opposite to that of all marine terpenoid diacylglycerols so far reported. Compounds 1 and 3 are new natural products closely related to austrodorin 5, already described from the same species.     

Evaluation of a PTV injector for quantitative analysis of volatile compounds at low concentrations

The performance of a PTV injector operated in the solvent venting mode with Tenax in the glass insert was evaluated with synthetic mixtures containing 5 to 50 ng of n-alkanes, ethyl esters, n-alcohols, and carboxylic acids. The influence of the sampled amount, the injected volume, and the nature of the solvent on accuracy and precision were studied. Coefficients of variation of relative (normalized) peak areas and absolute peak area ratios of each compound to the standard are of the order of 5 %.     

One‐dimensional TOCSY 1H NMR experiments on adducts of amino acid esters with cobalt(III) tetramethylchiroporphyrin. Prospects for the analysis of amino acid mixtures

Cobalt(III) tetramethylchiroporphyrin, CoCl(TMCP), is a useful chiral shift reagent for structure attribution, absolute configuration assignment and enantiomeric excess determination of amino acid methyl esters by ¹H NMR spectroscopy. However, it has two axial sites available for amine coordination, a structural feature which generates n(n + 1)/2 diastereomeric species and n² distinct spin systems from a mixture of n amino ester enantiomers, making the analysis of complex amino acid samples exceedingly difficult by classical 1‐D or 2‐D NMR methods when n > 3. The 1‐D TOCSY experiment is shown to be a powerful tool for the selective excitation and detection of every single component of a mixture of four amino acid methyl esters bound to CoCl(TMCP): those of(S)‐Leu, (S)‐Asp, (R)‐Asp and (S)‐Glu, for example. The potential utility of this methodology for the determination of amino acid enantiomers in carbonaceous meteorites or other extraterrestrial samples is suggested. Copyright © 2002 John Wiley & Sons, Ltd.     

Total Synthesis of Plakortone B

Plakortone B is a naturally occurring bicyclic[3.3.0]furanolactone compound with attractive bioactivities. Although the relative configuration of plakortone B’s central core had been established by NMR spectroscopic methods, the absolute configuration of its four stereocenters remained unknown. In the present paper, all four possible isomers of plakortone B were synthesized and one of these molecules was found to be identical with the natural plakortone B on the basis of ¹H, ¹³C NMR spectra and specific rotation comparisons. Thus, the absolute configuration of the natural plakortone B was determined to be (3S,4S,6R,10R).     

Trichodermates A–F,New Cytotoxic Trichothecenes from the Plant Pathogenic Fungus Trichoderma sp.

Trichodermates A – F ( 1 – 6 , resp.), six new trichothecene polyunsaturated octadioic acid esters, and (?)‐harzianum B ( 7 ) were isolated from the fermentation extract of Trichoderma sp., a plant pathogenic fungus isolated from stem rot of an unidentified tree in Thailand. The structures of 1 – 7 were elucidated by NMR experiments. The absolute configuration at C(12) in 3 was assigned by in situ dimolybdenum circular dichroism method, whereas that in 7 was deduced after hydrolysis of 7 to 8 via modified Mosher's method. Compounds 1 and 2 showed modest cytotoxic activities against the K562 (human myelogenous leukemia) cell line with IC₅₀ values of 12.12 and 13.08 μM , respectively.     

Elucidation of the absolute configuration of rhizopine by chiral supercritical fluid chromatography and vibrational circular dichroism

The absolute configuration of rhizopine, an opine‐like natural product present in nitrogen‐fixing nodules of alfalfa infected by rhizobia, is elucidated using a combination of state‐of‐the‐art analytical and semi‐preparative supercritical fluid chromatography and vibrational circular dichroism spectroscopy. A synthetic peracetylated racemate was fractionated into its enantiomers and subjected to absolute configuration analysis revealing that natural rhizopine exists as a single enantiomer. The stereochemistry of non‐derivatized natural rhizopine corresponds to (1R,2S,3R,4R,5S,6R)‐4‐amino‐6‐methoxycyclohexane‐1,2,3,5‐tetraol.     

Total Synthesis,Proof of Absolute Configuration,and Biosynthetic Origin of Stylopsal,the First Isolated Sex Pheromone of Strepsiptera

The asymmetric total synthesis of the diastereomers of stylopsal establishes the absolute configuration of the first reported sex pheromone of the twisted‐wing parasite Stylops muelleri as (3R,5R,9R)‐trimethyldodecanal. The key steps for the diastereo‐ and enantiodivergent introduction of the methyl groups are two different types of asymmetric conjugate addition reactions of organocopper reagents to α,β‐unsaturated esters, whereas the dodecanal skeleton is assembled by Wittig reactions. The structure of the natural product was confirmed by chiral gas chromatography (GC) techniques, GC/MS and GC/electroantennography (EAD) as well as field tests. An investigation into the biosynthesis of the pheromone revealed that it is likely to be produced by decarboxylation of a 4,6,10‐trimethyltridecanoic acid derivative, which was found in substantial amounts in the fat body of the female, but not in the host bee Andrena vaga. This triple‐branched fatty acid precursor thus seems to be biosynthesized de novo through a polyketide pathway with two consecutive propionate‐propionate‐acetate assemblies to form the complete skeleton. The simplified, motionless and fully host‐dependent female exploits a remarkable strategy to maximize its reproductive success by employing a relatively complex and potent sex pheromone.     

Use of shift reagent with diastereomeric MTPA esters for determination of configuration and enantiomeric purity of secondary carbinols in 1H NMR spectroscopy

The relative magnitude of the lanthanide induced shift(LIS)_by Eu(fod)₃ for ¹H NMR spectra of the OMe group of diastereomeric (R)-(+)-α-trifluoromethylphenylacetate esters [(R)-(+)-α-methoxy-α-trifluoromethylphenylacetate esters [(R)-(+)-MTPA esters (3)] of thirty-two secondary carbinols have been measured. There is a regularity in the relative magnitudes of the LIS values of the OMe signals of the alternate diastereomers which can be correlated with their absolute configurations. This constitutes a versatile method for assigning absolute configurations to secondary carbinols. Furthermore, the relative intensity of the OMe signals can be used for determination of the composition of these diastereomeric MTPA esters and thus the enantiomeric carbinols from which they are quantitatively prepared. These studies extend the usefulness of MTPA derivatives in stereochemical studies.     

Chemoenzymatic synthesis of diastereomeric ethyl γ-benzyl paraconates and determination of the absolute configurations of their acids

Enantiopure (99% ee) cis- and trans-γ-benzylparaconic acids and their ethyl esters were synthesized by a procedure involving kinetic enzymatic resolution of the corresponding lactonic esters with α-chymotrypsin (α-CT) with acetone added as a cosolvent. Their absolute configurations were determined by ¹H NMR analysis of their 1-(9-anthryl)-2,2,2-trifluoroethyl esters.     

Sampling of volatile components using a PTV in the solvent split mode

Several packing materials were evaluated for their sampling performance with a cold programmed temperature vaporizing injector operated in the solvent split (solvent elimination) mode. Evaluations were made by comparing accuracy and precision of the data for mixtures of n-alkanes, ethyl esters, n-alcohols, and carboxylic acids covering polarity and volatility ranges typical of compounds present in food samples. Tenax exhibits the most desirable retention characteristics. Careful selection of the experimental conditions lowers losses of volatile compounds by co-evaporation with the solvent and allows a reliably quantitative analysis. Coefficients of variation of relative (normalized) peak areas and absolute peak area ratios of each compound to the standard are generally less than 2%.