Unnatural Enantiomer Research Articles

Lipid Chirality Revisited: A Change in Lipid Configuration Transforms Membrane-Bound Protein Domains

Since its discovery by Louis Pasteur in 1848 (1), chirality has been—and still is to this day—one major topic for chemists and biochemists alike. Many chirality-related phenomena, from alteration of polarized light to enantioselectivity of enzymes for their substrate, form an integral part of today's university courses in chemical and biological sciences. Similar to the enzymes in charge of their synthesis, phospholipids, glycolipids, and sterols found in biological membranes are chiral. However, even though the effect of chirality on the organization of lipid membranes has been studied (see for example, Weis and McConnell (2)), little is known about the impact of lipid configuration on biological function. In this issue of the Biophysical Journal, Schutte et al. (7) resort to cutting-edge chemical synthesis to generate the unnatural enantiomer of Globotriaosylceramide 3 (Gb3, a glycolipid of established biological importance), and investigate the consequences of changing Gb3 configuration on membrane binding and deformation by Shiga toxin, for which Gb3 is the biological receptor. The Shiga toxin of the bacteria Shigella dysenteriae is a protein that binds Gb3 on the plasma membrane via its B subunit (STxB), and forms membrane-bound protein domains. Importantly, by doing so Shiga toxin induces its own internalization in cells by causing inward curvatures of membranes. This phenomenon is reproduced in vitro by adding STxB to giant unilamellar vesicles (GUVs) containing a small fraction of Gb3, in conditions favoring low membrane tension (3). Like in cells, Gb3 used in in vitro assays is the Gb3-R enantiomer. By replacing Gb3-R with its unnatural enantiomer Gb3-S, Schutte et al. (7) observe that STxB-induced tubulation of GUVs is significantly enhanced, based on experiments with a total of 1253 GUVs. Although the affinity of STxB was the same for Gb3-S as for its natural counterpart, reflectometric interference spectroscopy suggested that the domain height and protein distribution in Gb3-S membranes significantly differed from that in Gb3-R membranes. Those observations were confirmed by atomic force microscopy (AFM) imaging of STxB domains formed in mica-supported planar bila-yers composed of DOPC, DPPC, and Gb3. Taken together, those observation show that, in the words of the authors, .Gb3-R favorably induces large

ChemInform Abstract: Total Synthesis of Racemic, Natural (+) and Unnatural (‐) Scorzocreticin.

Abstract The first total synthesis of racemic scorzocreticin and its pure enantiomers is described from readily available 3,5-dihydroxybenzoic acid. The key steps include Wittig olefination, asymmetric Me-CBS (Corey–Bakshi–Shibata) oxazaborolidine reduction, and improved Pd-catalyzed intramolecular lactonization reactions. Both the (S)-natural and (R)-unnatural enantiomers of scorzocreticin have been synthesized in excellent enantioselectivities (>99% and 99% ee, respectively). In addition, 1,10-phenanthroline, a bidentate N-ligand was employed in palladium-catalyzed intramolecular carbonylation/lactonization reaction for the construction of 3,4-dihydroisocoumarin ring.

Enantioselective synthesis of dictyoceratin-A (smenospondiol) and -C, hypoxia-selective growth inhibitors from marine sponge

Total syntheses of (+)-dictyoceratin-C (1) and (+)-dictyoceratin-A (smenospondiol) (2), hypoxia-selective growth inhibitors isolated from marine sponge, were executed. The absolute stereochemistry of the each compound was determined through the enantioselective total syntheses of them. It revealed that the unnatural enantiomers of them also exhibited the hypoxia-selective growth inhibitory activity against human prostate cancer DU-145 cells.

Total synthesis and biological evaluation of the antibiotic lysocin E and its enantiomeric, epimeric, and N-demethylated analogues.

Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid-phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N-demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.

ChemInform Abstract: Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)‐ and (‐)‐Frondosin B and (+)‐Frondosin A.

AbstractA synthesis of both the natural and unnatural enantiomers of frondosin B (I) and the natural enantiomer of frondosin A (II) is developed.

Total synthesis of racemic, natural (+) and unnatural (−) scorzocreticin

The first total synthesis of racemic scorzocreticin and its pure enantiomers is described from readily available 3,5-dihydroxybenzoic acid. The key steps include Wittig olefination, asymmetric Me-CBS (Corey–Bakshi–Shibata) oxazaborolidine reduction, and improved Pd-catalyzed intramolecular lactonization reactions. Both the (S)-natural and (R)-unnatural enantiomers of scorzocreticin have been synthesized in excellent enantioselectivities (>99% and 99% ee, respectively). In addition, 1,10-phenanthroline, a bidentate N-ligand was employed in palladium-catalyzed intramolecular carbonylation/lactonization reaction for the construction of 3,4-dihydroisocoumarin ring.

Total synthesis of (−)-kopsinine and ent-(+)-kopsinine

The total synthesis of (−)-kopsinine and its unnatural enantiomer is detailed, enlisting a late-stage SmI2-mediated transannular free radical conjugate addition reaction for construction of the core bicyclo[2.2.2]octane ring system with strategic C21–C2 bond formation. Key to the approach is assemblage of the underlying skeleton by an intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the precursor C21 functionalized pentacyclic ring system 1 in a single step in which the C3 methyl ester found in the natural product served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels–Alder reaction and stabilizing the intermediate 1,3-dipole.

Stereocontrolled Synthesis of a C1–C10 Building Block (“Southwestern Moiety”) for the Unnatural Enantiomers of the Polyene Polyol Antibiotics Filipin III and Pentamycin: A Sultone‐Forming Ring‐Closing Metathesis for Protection of Homoallylic Alcohols

AbstractIn C2‐symmetric diol 10 one OH group was substituted by crotonic acid and the other was incorporated in an ethenesulfonate. A twofold ring‐closing metathesis under forcing conditions provided unsaturated lactone/unsaturated sultone 24. Conjugate addition of Li2(PhMe2Si)2Cu(CN) to both C=C bonds was followed by opening of the sultone moiety with Bu4N+F–. Resultant homoallylic alcohol 28 was carried on to acetonide‐containing lactone 31. Its CpTiCl2 enolate underwent a completely diastereoselective aldol addition to hexanal. Functional group interconversions rendered “southwestern” C1–C10 building block 37. The steps (1) ethenesulfonylation of a homoallylic alcohol, (2) sultone formation, (3) Li2(PhMe2Si)2Cu(CN) addition, and (4) alcohol release by fluoride‐induced fragmentation, from our main sequence represent a new protection/deprotection stragegy for a secondary homoallylic alcohol, as demonstrated with a model compound, too.

Anticonvulsant potencies of the enantiomers of the neurosteroids androsterone and etiocholanolone exceed those of the natural forms

Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms. The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models. Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ). In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α-A and 5α,3α-A, respectively. Similar relationships were obtained for the 5β-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5β,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5β,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5β,3α-A also persisted longer (~3 h) than for 5β,3α-A (~2 h). The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics.

Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ25–35 peptide-induced toxicity in vitro and in vivo in mice

Pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are pro-amnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient's brains, their low concentrations are correlated with high levels of Aβ and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models. The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Aβ25-35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice. B104 cells pretreated with the steroids before Aβ25-35 were analysed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Aβ25-35 and the steroids were analysed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured. ent-PREGS and PREGS significantly attenuated the Aβ25-35-induced decrease in cell viability. Both steroids prevented the Aβ25-35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Aβ25-35-induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Aβ25-35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Aβ25-35-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before Aβ25-35 in contrast to the natural steroids. The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD.

ChemInform Abstract: A Short, Protecting Group‐Free Total Synthesis of Bruceollines D, E, and J.

A short, protecting group-free total synthesis of bruceollines D, E, and J has been achieved. The enantioselective reduction of bruceolline E with β-chlorodiisopinocampheylborane delivers both the natural and unnatural enantiomers of bruceolline J in excellent yields and enantioselectivities. Reduction with baker’s yeast and sucrose was shown to provide the unnatural enantiomer of bruceolline J in 98% ee.

Stereocontrolled Synthesis of a Cn–Cn+6Building Block for the Unnatural Enantiomers of Important Polyol,Polyene Antibiotics from an Epoxy Alcohol by a Reduction/Conjugate Addition/Hydroxylation Sequence

AbstractEpoxy alcoholanti‐10, derived from a desymmetrizing Sharpless epoxidation (up to 97 %ee) of divinylcarbinol9, provided the unsaturated 1,3‐diolsyn‐11upon treatment with RedAl®;syn‐11was converted into the α,β‐unsaturated esters (E)‐ or (Z)‐7bin three steps. Cu‐promoted 1,4‐addition of vinylmagnesium halides to the (E)‐ester proceeded with diastereoselectivities of up to 91 % and Cu‐catalyzed 1,4‐additions with diastereoselectivities of up to 82 %. The potassium enolate of the major vinylation productsyn‐22bwas hydroxylated by the Davis oxaziridine with perfect but unprecedented diastereoselectivity. The resulting hydroxy ester,α,βsyn,β,γsyn‐32, furnished the “eastern moiety” building block6of the title compounds in three steps.

ChemInform Abstract: A Short and Elegant Synthesis of (.+‐.)‐Streptopyrrolidine.

AbstractA short synthesis of the natural (4R,5R)‐streptopyrrolidine (I) and its unnatural (4S,5S) enantiomer is described.

A Short, Protecting Group-Free Total Synthesis of Bruceollines D, E, and J

A short, protecting group-free total synthesis of bruceollines D, E, and J has been achieved. The enantioselective reduction of bruceolline E with β-chlorodiisopinocampheylborane delivers both the natural and unnatural enantiomers of bruceolline J in excellent yields and enantioselectivities. Reduction with baker's yeast and sucrose was shown to provide the unnatural enantiomer of bruceolline J in 98% ee.

A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence

(-)-Deguelin is a rotenoid natural product that possesses significant potential as a chemopreventive and chemotherapeutic agent. While several racemic syntheses of deguelin have been reported, a formal evaluation of the anticancer activity of both the natural and unnatural enantiomers remains lacking. We describe herein the successful application of a flexible and selective thiourea-catalyzed cyclization strategy toward the enantioselective total synthesis of deguelin, which allows access to either stereoisomer for biological studies. The synthesis was completed in six steps (longest linear) with no protecting groups. The evaluation of both enantiomers of the natural product demonstrated potent inhibition of several cancer cell lines by these compounds, but interestingly showed that the unnatural (+)-deguelin preferentially inhibited the growth of MCF-7 breast cancer and HepG2 liver carcinoma cells when compared to the natural product.

Absolute Configuration of Beer′s Bitter Compounds

Absolute Configuration of Beer′s Bitter Compounds

(R)-Desmolactone, A Female-produced Sex Pheromone Component of the Cerambycid Beetle Desmocerus californicus californicus (subfamily Lepturinae)

We report the identification, synthesis, and field bioassays of a female-produced sex attractant pheromone for the cerambycid beetle Desmocerus californicus californicus Horn. Headspace volatiles from females contained a sex-specific compound, (R)-desmolactone [(4R,9Z)-hexadec-9-en-4-olide], which elicited strong responses from the antennae of adult males in coupled gas chromatography-electroantennogram analyses. Short syntheses of both enantiomers were developed from commercial chiral synthons. In field bioassays, significant numbers of males were collected in traps baited with (R)-desmolactone, whereas the (S)-enantiomer attracted no males. The racemate was less attractive than the pure (R)-enantiomer, indicating some degree of antagonism by the unnatural enantiomer. This compound is the first example of a new structural class of cerambycid pheromones, and is the second pheromone identified for a species in the subfamily Lepturinae.

One-pot reductive coupling of N-acylcarbamates with activated alkenes: application to the asymmetric synthesis of pyrrolo[1,2-a]azepin-5-one ring system and (−)-xenovenine

The one-pot reductive coupling of N-acylcarbamates with activated alkenes is described. The method is based on partial reduction of N-acylcarbamates with DIBAL-H, followed by N-acyliminium ion formation and SmI(2)-mediated radical coupling with activated alkenes. Both acyclic and cyclic N-acylcarbamates can be used as stable substrates, and a range of activated alkenes serve as effective radical receptors. The reductive coupling of l-N-acylcarbamates 12/13 gave 2,5-disubstituted pyrrolidine derivatives in high trans-diastereoselectivities. The reductive coupling with penta-2,4-dienoate proceeded exclusively in a 1,6-addition fashion, producing a single non-conjugated E-isomer. On the basis of this method, a three-step construction of pyrrolo[1,2-a]azepin-5-one 16, the skeleton of many stemona alkaloids and lehmizidine alkaloids, and a seven-step synthesis of (-)-xenovenine (pyrrolizidine cis-223H, ent-6), the unnatural enantiomer of the frog/ant venom alkaloid possessing potent inhibitory activity towards nAChR channel, were achieved starting from L-12.

Stereoselective synthesis of a tetrahydropyranyl diarylheptanoid, ent-diospongin A

The stereoselective synthesis of the unnatural enantiomer of a cyclic diarylheptanoid, diospongin A is described. The salient feature of this synthesis is the formation of a tetrahydropyran ring via the AgOTf-catalysed intramolecular oxa-Michael addition of a β-hydroxy ynone followed by hydrogenation

The Absolute Configuration of the Pyrrolosesquiterpenoid Glaciapyrrol A

The total syntheses of the structurally unique and moderately cytotoxic pyrrolosesquiterpenoid glaciapyrrol A that has been isolated from a marine streptomycete by Macherla et al. and of seven of its stereoisomers have been performed from geraniol or nerol, respectively, using a known diastereoselective Ru-catalysed approach for the synthesis of tetrahydrofurans previously reported by Stark and co-workers. Comparison of (1)H and (13)C NMR data unambiguously clarified the relative configuration of natural glaciapyrrol A that was previously only partly solved from the available NMR data. An enantioselective synthesis was carried out resulting in the unnatural enantiomer (11S,12R,15R)-(-)-glaciapyrrol A. These data establish the absolute configuration of the natural product as (11R,12S,15S)-(+)-glaciapyrrol A.