ABSTRACT
The influence of an F-atom in the side chain of benzo[7]annulen-7-amines on the affinity towards GluN2B subunit containing NMDA receptors and the selectivity over related receptors was investigated. The synthesis of 5a and 5b was performed by reductive amination of the ketone 6 with primary alkanamines 14a and 14b bearing an F-atom in ß-position. The GluN2B affinities of non-fluorinated and fluorinated ligands 4 and 5 are almost identical. The low impact of the F-atom on GluN2B affinity was unexpected, as it influences several chemical and physicochemical properties of the ligands. However, introduction of the F-atom led to reduced selectivity over σ receptors. Whereas 5a and 5b display still a 2-3-fold preference for GluN2B over σ1 receptors, they show almost the same affinity to GluN2B and σ2 receptors.
ABSTRACT
The combination of a Goodwin-Lions-type chiral N4 ligand, (R)-Ph-BINAN-H-Py ((R)-3,3'-diphenyl-N(2),N(2')-bis((pyridin-2-yl)methyl)-1,1'-binaphthyl-2,2'-diamine; L), with Ru(π-CH2C(CH3)CH2)2(cod) (A) (cod = 1,5-cyclooctadiene) catalyzes the hydrogenation of acetophenone (AP) to (R)-1-phenylethanol (PE) with a high enantiomer ratio (er). Almost no Ru complex forms, with A and L remaining intact throughout the reaction while generating PE quantitatively according to [PE] = k(obs)t(2). An infinitesimal amount of reactive and unstable RuH2L (B) with C2-Λ-cis-α stereochemistry is very slowly and irreversibly generated from A by the action of H2 and L, which rapidly catalyzes the hydrogenation of AP via Noyori's donor-acceptor bifunctional mechanism. A CH-π-stabilized Si-face selective transition state, CSi, gives (R)-PE together with an intermediary Ru amide, D, which is inhibited predominantly by formation of the Ru enolate of AP. The rate-determining hydrogenolysis of D completes the cycle. The time-squared term relates both to the preliminary step before the cycle and to the cycle itself, with a highly unusual eight-order difference in the generation and turnover frequency of B. This mechanism is fully supported by a series of experiments including a detailed kinetic study, rate law analysis, simulation of t/[PE] curves with fitting to the experimental observations at the initial reaction stage, X-ray crystallographic analyses of B-related octahedral metal complexes, and Hammett plot analyses of electronically different substrates and ligands in their enantioselectivities.
Subject(s)
Acetophenones/chemistry , Hydrocarbons, Aromatic/chemistry , Ketones/chemistry , Ruthenium/chemistry , Alkadienes/chemistry , Benzyl Alcohols/chemistry , Catalysis , Crystallography, X-Ray , Diamines/chemistry , Hydrogenation , Ligands , Models, Molecular , Naphthalenes/chemistry , StereoisomerismABSTRACT
The plant growth regulatory activity of furofuran lignan (7,9':7',9-diepoxylignan) was evaluated by employing optically pure synthesized (+)- and (-)-enantiomers. (+)-Sesamin possessing a 3,4-methylenedioxy group on the aromatic rings and 7-aryl structure showed growth promotion activity against lettuce roots (EC50 = 0.50 mM); on the other hand, growth inhibitory activity was observed against lettuce shoots (EC50 = 0.38 mM). Against ryegrass shoots, (-)-sesamolin, which has 3,4-methylenedioxy groups on the aromatic rings and a 7-acetal structure, was effective in showing growth inhibitory activity (EC50 = 0.23 mM). Different activity levels were observed between (+)- and (-)-enantiomers. It was assumed that the 3,4-methylenedioxy group on the aromatic ring was more potent for the plant growth regulatory activity.
Subject(s)
Dioxoles/chemistry , Dioxoles/pharmacology , Lactuca/drug effects , Lignans/chemistry , Lignans/pharmacology , Plant Growth Regulators/chemistry , Plant Growth Regulators/pharmacology , Plant Roots/drug effects , Lactuca/growth & development , Lolium/drug effects , Lolium/growth & development , Molecular Structure , Plant Roots/growth & development , Plant Shoots/drug effects , Plant Shoots/growth & development , StereoisomerismABSTRACT
(-)-Dihydroguaiaretic acid (DGA) and its derivatives having 3-hydroxyphenyl (3-OH-DGA) and variously substituted phenyl groups instead of 3-hydroxy-4-methoxyphenyl groups were synthesized to measure their larvicidal activity against the mosquito Culex pipiens Linnaeus, 1758 (Diptera: Culicidae). Compared with DGA and 3-OH-DGA (LC50 (M), 3.52 × 10(-5) and 4.57 × 10(-5), respectively), (8R,8'R)-lignan-3-ol (3) and its 3-Me (10), 2-OH (12), 3-OH (13), and 2-OMe (15) derivatives showed low potency (ca. 6-8 × 10(-5) M). The 4-Me derivative (11) showed the lowest potency (12.1 × 10(-5) M), and the 2-F derivative (4) showed the highest (2.01 × 10(-5) M). All of the synthesized compounds induced an acute toxic symptom against mosquito larvae, with potency varying with the type and position of the substituents. The 4-F derivative (6), which killed larvae almost completely within 45 min, suppressed the O2 consumption of the mitochondrial fraction, demonstrating that this compound inhibited mitochondrial O2 consumption contributing to a respiratory inhibitory activity.
Subject(s)
Culex/drug effects , Guaiacol/analogs & derivatives , Insecticides/toxicity , Larva/metabolism , Lignans/toxicity , Oxygen/metabolism , Animals , Culex/growth & development , Culex/metabolism , Guaiacol/chemistry , Guaiacol/toxicity , Insecticides/chemistry , Larva/drug effects , Larva/growth & development , Lignans/chemistry , Molecular StructureABSTRACT
In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure-activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n-butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR-ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering logP and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds.
Subject(s)
Houseflies/drug effects , Insecticides/chemistry , Insecticides/metabolism , Nitro Compounds/chemistry , Nitro Compounds/metabolism , Receptors, Nicotinic/metabolism , Amino Acid Sequence , Animals , Aplysia , Female , Houseflies/physiology , Methylation , Molecular Docking Simulation , Molecular Sequence Data , Quantitative Structure-Activity Relationship , Receptors, Nicotinic/chemistryABSTRACT
Ficifolidione (1), a moderately active insecticidal compound from two species of Myrtaceae, and its derivatives were synthesized to evaluate their insecticidal activity. X-ray crystallographic analyses and specific rotation values of ficifolidione and its C-4 (2) demonstrated that the structure of ficifolidione differs from the reported absolute structure; that is, the C-4 configuration of ficifolidione should have an S configuration. The reported insecticidal activity of ficifolidione (1) and its C-4 epimer (2) against adult houseflies (Musca domestica), mosquito larvae (Culex pipiens), and cutworms (Spodoptera litura) was not observed. The cytotoxicities of ficifolidione and its derivatives (1-4) against four cell lines, Sf9, Colon26, HL60, and Vero, were also measured because ficifolidione has a phloroglucinol-derived moiety, a motif that is often present in the structure of cytotoxic chemicals. Compound 1 exhibited IC50 values of ca. 32, 9, 3, and 12 µM for Sf9, Colon26, HL60, and Vero cells, respectively, indicating that ficifolidione possesses selective cytotoxicity against the four cell lines. In HL60 cells treated with 1, DNA fragmentation and the activation of procaspase 3 were observed, suggesting that the cytotoxicity is induced by apoptosis.
Subject(s)
Insecticides/chemistry , Insecticides/pharmacology , Phloroglucinol/analogs & derivatives , Animals , Chlorocebus aethiops , Culex/drug effects , HL-60 Cells , Houseflies/drug effects , Humans , Insecta/drug effects , Larva/drug effects , Molecular Structure , Phloroglucinol/chemistry , Phloroglucinol/pharmacology , Spodoptera/drug effects , Vero CellsABSTRACT
The synthesized 7-aryl derivatives of (7R,7'S,8S,8'S)-(+)-verrucosin were applied to growth inhibitory activity test against ryegrass at 1mM. 7-(3-Ethoxy-4-hydroxyphenyl) derivative 12 and 7-(2-hydroxyphenyl) derivative 4 showed comparable activity to those of (+)-verrucosin against the root (-95%) and the shoot (-60%), respectively. The growth inhibitory activity test against lettuce using synthesized 7-aryl derivatives of (7S,7'R,8R,8'R)-(-)-verrucosin at 1mM showed that the activities of 7-(3-hydroxyphenyl) derivative 20 and 7-(3-ethoxy-4-hydroxyphenyl) derivative 28 are similar to that of (-)-verrucosin against the root (-95%). Against the shoot, 7-(3-hydroxyphenyl) derivative 20 showed higher activity (-80%) than that of (-)-verrucosin (-60%). As the next step, (7S,7'R,8R,8'R)-7-(3-hydroxyphenyl)-7'-aryl-(-)-verrucosin derivatives, in which the most effective 3-hydroxyphenyl group is employed as 7-aromatic ring, were synthesized for the assay against lettuce. In this experiment, 7'-(2-hydroxyphenyl) derivative 37 and 7'-(3-hydroxyphenyl) derivative 38 showed similar activity to that of derivative 20. The effect of 7- and 7'-aryl structures of 7,7'-epoxylignanes on the plant growth inhibitory activity was clarified. The 7- and 7'-aryl structures were simplified to show comparable activity to or higher activity than that of (-)-verrucosin. The plant growth inhibitory activity of a nutmeg component, (+)-fragransin C3b, was estimated as -80% inhibition at 1mM against ryegrass roots.
Subject(s)
Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Furans/chemistry , Furans/pharmacology , Lactuca/drug effects , Lignans/chemistry , Lignans/pharmacology , Dose-Response Relationship, Drug , Epoxy Compounds/chemical synthesis , Furans/chemical synthesis , Lactuca/growth & development , Lignans/chemical synthesis , Molecular Structure , Plant Roots/drug effects , Plant Roots/growth & development , Plant Shoots/drug effects , Plant Shoots/growth & development , Stereoisomerism , Structure-Activity RelationshipABSTRACT
All stereoisomers of 3,3'-dimethoxy-7,7'-epoxylignane-4,4'-diol were synthesized to examine the effect of stereochemistry on their plant growth inhibitory activity using lettuce and Italian ryegrass. The effect of structural modifications such as dehydroxylation, methoxylation and hydroxylation at the 9- and 9'-positions of the lignans on the activity was also studied. Most of the epoxylignanes showed higher plant growth inhibitory potency against ryegrass than against lettuce, and the inhibitory activity varied depending on the configurations of each position of the tetrahydrofuran ring (7-, 7'-, 8-, and 8'-positions of the epoxylignanes). Among the 9,9'-position-modified derivatives, the dehydroxy derivatives showed the highest potency. These results suggested that the plant growth inhibitory activity should be influenced by the structure of the epoxylignanes.
Subject(s)
Lignans/chemical synthesis , Lignans/pharmacology , Plant Growth Regulators/chemical synthesis , Plant Growth Regulators/pharmacology , Lactuca/drug effects , Lactuca/growth & development , Lignans/chemistry , Lolium/drug effects , Lolium/growth & development , Molecular Structure , Plant Growth Regulators/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The syntheses of 55 lariciresinol derivatives containing derivatives on the 9-position and an aryl group at both 7- and 7'-positions were successful to examine the effect of structure of (-)-lariciresinol (1) on plant growth regulatory activity. (-)-(7R,8R,8'S)-9-Dehydroxylariciresinol 9 showed activity 2-fold more potent than that of natural (-)-lariciresinol (1) and -95% growth inhibitory activity to negative control against rye grass root at 1 mM. The derivatives bearing hydrophobic and smaller groups at the 9-position showed higher activity. The importance of 4- and 4'-hydroxy groups and 3- and 3'-small hydrophobic groups on 7- and 7'-phenyl groups for higher activity was also suggested.
Subject(s)
Furans/chemistry , Furans/pharmacology , Herbicides/chemistry , Herbicides/pharmacology , Lignans/chemistry , Lignans/pharmacology , Lolium/drug effects , Lolium/growth & development , Structure-Activity RelationshipABSTRACT
The insecticidal activity of (-)-(8R,8'R)-3,3'-dimethoxy-9,9'-epoxylignane-4,4'-diol (1) against houseflies was clarified for the first time. The activities of other stereoisomers were weaker than that of the (8R,8'R)-stereoisomer. In the course of research into structure-activity relationships involving 30 newly synthesized (8R,8'R)-derivatives, 5-fold higher activity (ED50 = 0.91 nmol/fly) was observed for (-)-(8R,8'R)-3,3',4-trimethoxy-9,9'-epoxylignan-4'-ol (21) than for the naturally occurring compound (1). The activity of 1 was weaker than that of (-)-(8R,8'R)-dihydroguaiaretic acid ((-)-DGA) (4); however, compound 21 showed almost the same level of activity as 4.
Subject(s)
Epoxy Compounds/pharmacology , Guaiacol/analogs & derivatives , Houseflies , Insecticides/pharmacology , Lignans/pharmacology , Animals , Guaiacol/pharmacology , Plant Extracts/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of imidacloprid (IMI) derivatives with an alkylated imidazolidine ring were asymmetrically synthesized to evaluate their insecticidal activity against adult female housefly, Musca domestica, and affinity to the nicotinic acetylcholine receptor of the flies. The bulkier the alkyl group, the lower was the receptor affinity, but the derivatives methylated and ethylated at the R-5-position of the imidazolidine ring were equipotent to the unsubstituted compound. Quantitative structure-activity relationship (QSAR) analysis of the receptor affinity demonstrated that the introduction of a substituent into the imidazolidine ring was fundamentally disadvantageous, but the introduction of a substituent at the R-5-position was permissible in the case of its small size. The binding model of the synthesized derivatives with the receptor supported the QSAR analysis, indicating the existence of space for a short alkyl group around the R-5-position in the ligand-binding site. In addition, positive correlation was observed between the insecticidal activity and receptor affinity, suggesting that the receptor affinity was the primary factor in influencing the insecticidal activity even if the imidazolidine ring was modified.
Subject(s)
Houseflies/drug effects , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazolidines/chemistry , Insecticides/chemical synthesis , Insecticides/pharmacology , Nitro Compounds/chemistry , Nitro Compounds/pharmacology , Receptors, Nicotinic/metabolism , Alkylation , Animals , Dose-Response Relationship, Drug , Female , Houseflies/metabolism , Imidazoles/chemical synthesis , Insecticides/chemistry , Models, Molecular , Molecular Sequence Data , Molecular Structure , Neonicotinoids , Nitro Compounds/chemical synthesis , Quantitative Structure-Activity Relationship , Receptors, Nicotinic/genetics , Sequence AlignmentABSTRACT
Optically pure (+)- and (-)-boronolides were stereoselectively synthesized from yeast reductive products which had been obtained by yeast reduction of one common racemic substrate. The lactone structure of boronolide was constructed by Baeyer-Villiger oxidation. The stereochemistry of the yeast reduction products was studied to obtain the stereocenters at 5 positions of the dodecanolides of (+)- and (-)-boronolides. The stereochemistry of the 6 and 7 positions was obtained by AD-mix-α or ß oxidation. The chiral center at the 8 position was constructed by employing (R)-(+)- or (S)-(-)-2-methyl-CBS-oxazaborolidine reduction or the Mitsunobu reaction. The plant growth-inhibitory activity against Echinochloa crusgalli L. of naturally occurring (+)-boronolide was higher than that of the (-)-boronolide.
Subject(s)
Echinochloa/drug effects , Lactones/chemistry , Aza Compounds/chemistry , Biocatalysis , Echinochloa/growth & development , Lactones/metabolism , Lactones/pharmacology , Molecular Structure , Oxidation-Reduction , Plant Growth Regulators , Pyrones/pharmacology , Stereoisomerism , Yeasts/metabolismABSTRACT
All stereoisomers of lariciresinol were synthesized to examine the effect of stereochemistry on plant growth. Configuration of benzylic 7-positions was constructed through S(N)1 or S(N)2 intramolecular etherification. 8- and 8'-position configurations were established from the starting material except for all cis stereoisomers, the 8-position configurations of which were achieved by employing stereoselective hydroboration. (-)-Lariciresinol and its 7S,8S,8'R stereoisomer inhibited the root growth of Italian ryegrass to 51-55% relative to the negative control, whereas other stereoisomers had less effect. These results demonstrate that the stereochemistry of lignans is one of the important factors influencing their inhibitory activity.
Subject(s)
Furans/chemistry , Furans/pharmacology , Lignans/chemistry , Lignans/pharmacology , Plant Development , Plants/drug effects , Furans/chemical synthesis , Germination/drug effects , Lactuca/drug effects , Lactuca/growth & development , Lignans/chemical synthesis , Lolium/drug effects , Lolium/growth & development , Plant Roots/drug effects , Plant Roots/growth & development , Seeds/drug effects , Seeds/growth & development , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The larvicidal activity against Culex pipiens of all stereoisomers of dihydroguaiaretic acid (DGA) and secoisolariciresinol was measured, and these DGAs were found to be potent. Sixteen (-)-DGA derivatives were then newly synthesized to analyze their structure-activity relationship. Two derivatives monohydroxylated at the 3- or 4-position of the 7-phenyl group of DGA induced acute paralytic activity in the mosquitoes. Derivatives with several hydroxyl groups had lower activity than the natural compound, suggesting that hydrophobicity was probably an important factor for their insecticidal activity.
Subject(s)
Butylene Glycols , Culex/drug effects , Guaiacol/analogs & derivatives , Insect Control/methods , Insecticides , Larva/drug effects , Lignans , Animals , Butylene Glycols/chemical synthesis , Butylene Glycols/pharmacology , Culex/growth & development , Disease Vectors , Guaiacol/chemical synthesis , Guaiacol/pharmacology , Hydrophobic and Hydrophilic Interactions , Hydroxylation , Insecticides/chemical synthesis , Insecticides/pharmacology , Larva/growth & development , Lethal Dose 50 , Lignans/chemical synthesis , Lignans/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Four imidacloprid derivatives with an asymmetrically methylated imidazolidine ring were synthesized. Their affinity to the nicotinic acetylcholine receptor of housefly Musca domestica and insecticidal activity against the housefly were measured. The compound with a 5R-methylated imidazolidine ring demonstrated intrinsic activity comparable to that of the unsubstituted compound. Most of the compounds were synergized by oxygenase inhibitors.
Subject(s)
Imidazoles/chemistry , Imidazoles/metabolism , Imidazolines/chemistry , Insecticides/chemistry , Insecticides/metabolism , Nitro Compounds/chemistry , Nitro Compounds/metabolism , Receptors, Nicotinic/metabolism , Animals , Houseflies , Imidazoles/chemical synthesis , Insecticides/chemical synthesis , Methylation , Neonicotinoids , Nitro Compounds/chemical synthesis , Protein Binding , StereoisomerismABSTRACT
BACKGROUND: To compare the frequency of Y-chromosome microdeletions in Japanese and African azoospermic and oligozoospermic men and describe embryo characteristics and reproductive outcome following in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). METHODS: Our study was performed prospectively at two centers, a private IVF clinic and a university hospital. Japanese and African (Tanzanian) men with nonobstructive azoospermia (NOA) and oligozoospermia (concentration < 5 x 10(6) /ml) were evaluated for Y-chromosome microdeletions (n = 162). Of the 47 men with NOA, 26 were Japanese and 21 were Africans. Of the 115 men with oligozoospermia, 87 were Japanese and 28 were Africans. Reproductive outcomes of patients with Y-chromosome microdeletions were then compared with those of 19 IVF+ICSI cycles performed on couples with Y-chromosome intact males/tubal factor infertility which served as a control group. RESULTS: Seven azoospermic and oligozoospermic patients had Y-chromosome deletions; the total number of deletions in the AZFc region was five. There was only one deletion in the AZFa region and one complete deletion involving all three regions (AZFa, b, and c) within AZF. In our study population, microdeletion frequency among Japanese men was 6.2% (95% CI, 4.25%-14.45%), whereas no deletions were identified in the African group (95% CI, 0.0%-7.27%). The difference between the two groups was not statistically significant, however. Embryos derived from ICSI utilizing sperm with Y-chromosome microdeletion showed reduced rates of fertilization, blastocyst development, implantation, and pregnancy compared to the Y-chromosome intact group, although these observed differences were not statistically significant. CONCLUSION: The observed frequency of Y-chromosome microdeletion was 6.2% among Japanese azoospermic and oligozoospermic males; no microdeletions were identified among our African study patients. In this population of couples undergoing IVF+ICSI, there was no statistically significant difference in embryo characteristics or pregnancy outcome between patients with Y-chromosome microdeletion and those with an intact Y-chromosome.
ABSTRACT
The mechanism of the liver damage and lethality in Propionibacterium acnes (P. acnes)-LPS system remains obscure. To examine the role of CD14 in the system, M14M mice, in which CD14 was expressed heterotopically under the control of the metallothionein promoter were used. The production of soluble CD14 (sCD14) was increased by both P. acnes - priming and LPS challenge (1 microg per mouse) in both nontransgenic and M14M mice, although the plasma level was much higher in M14M nontransgenic than mice. The size of granulomas induced by an intraperitoneal administration of P. acnes in M14M mice 7 days after priming was smaller than that in nontransgenic mice. An LPS challenge induced apoptotic and necrotic changes in hepatocytes in nontransgenic mice but not in M14M mice. The challenge dose resulted in almost 90% lethality in nontransgenic mice but not in M14M mice 24h after challenge. TNF-alpha, IFN-gamma, IL-12, IL-18 and inducible nitric oxide synthase (iNOS) mRNA expressions produced by LPS challenge in M14M mice were low compared with those in nontransgenic mice. IL-18 mRNA expression was upregulated in P. acnes-primed nontransgenic mice but not in M14M mice. These results suggest that the high sCD14 concentration may account for less marked liver damage in M14M mice. Increase in the challenge dose of LPS (2 microg per mouse) resulted in increased lethality of M14M mice without liver damage. The levels of endothelial cell leukocyte adhesion molecule (ELAM)-1 mRNA expression in several organs in M14M mice 1-3h after LPS challenge were, however, lower than those in nontransgenic mice. The high sCD14 concentration may stimulate endothelial cell activation, which may account for lethality without liver damage in M14M mice. Thus, CD14 is involved in both the priming and induction phases as well as lethality in P. acnes-LPS system.
Subject(s)
E-Selectin/metabolism , Lipopolysaccharide Receptors/physiology , Lipopolysaccharides/toxicity , Liver Diseases/immunology , Propionibacterium acnes/physiology , Animals , Apoptosis , Chemical and Drug Induced Liver Injury , Cytokines/genetics , Cytokines/metabolism , E-Selectin/genetics , Lipopolysaccharide Receptors/blood , Lipopolysaccharide Receptors/genetics , Liver/drug effects , Liver/pathology , Liver Diseases/microbiology , Mice , Mice, Knockout , Mice, Transgenic , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , RNA, Messenger/analysis , RNA, Messenger/metabolism , Survival Analysis , Tissue Distribution/geneticsABSTRACT
The stereocontrolled total synthesis of the non-chlorinated analog of cyanobacterin, a potent photosynthesis inhibitor, was achieved by 12 steps in a 10.0% overall yield. Its enantiomer was also synthesized from the same starting material. This synthetic strategy is expected to be applicable to prepare cyanobacterin and all its stereoisomers, together with other similar bioactive compounds.
Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
Stereocontrolled total syntheses of the (2S,3R)- and (2R,3S)-isomers of the non-chlorinated analog of cyanobacterin, a potent photosynthesis inhibitor, were achieved. Since both the (2R,3R)- and (2S,3S)-isomers of this compound had been previously synthesized from the same starting material, a systematic strategy for the synthesis of all stereoisomers could be established.
Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/chemical synthesis , Alkynes/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
The segments C(1)-C(13) and C(15)-C(21) containing the 13 stereogenic centers required for the frame of (+)-discodermolide were synthesized in good to excellent enantio- and diastereoselectivities from a common racemic aldehyde, derived from 2-methyl-1,3-propanediol. The enantioselective aldol reactions of the racemic aldehyde with a silylketene acetal, derived from ethyl 2-bromopropionate, in the presence of chiral oxazaborolidinones, prepared in situ with N-p-toluenesulfonyl-(R)- and -(S)-valine and BH(3).THF, proceeded under kinetic control to give the stereotriads with a high degree of enantioselectivity. Enantioselective (chiral borane) and diastereoselective (BF(3).OEt(2) and TiCl(4)) aldol reactions with the silylketene acetal, coupled with diastereoselective radical debrominations (Bu(3)SnH, Et(3)B, with or without MgBr(2)), were used iteratively. This aldol reaction strategy for the construction of the polypropionate frame dramatically shortened the steps needed for the construction of the final segments.