Intermediate Alcohol Research Articles

Synthesis of Dihydropyran Subunit of (+)-Sorangicin A Using RCM Reaction

The macrolide (+)-sorangicin A (1), isolated by Hofle and co-workers from the gliding myxobacterium Sorangium cellulosum, has highly effective biological activity against a broad panel of both Gram-positive and Gram-negative bacteria, displaying average MIC values of 10 ng/mL and 10 μg/mL, respectively. The mechanism of action has been shown to be the inhibition of RNA polymerase in both Escherichia coli and Staphylococcus aureus. In addition, sorangicin A is active in vitro against several cancer cell lines. This fact motivated us to be interested in the synthesis toward sorangicin A. One of key steps in our synthetic plan is the successful preparation of dihydropyran. There have been numerous synthetic efforts reported in the literature. In general, dihydropyran units has been elegantly constructed by reactions such as Claisen rearrangement, Ferriertype reaction, radical, hetero Diels-Alder cyclizations and a few other reactions. We sought new and concise synthetic methods for this ring. Herein, we describe two new and simple preparations of the dihydropyran moiety based on olefinic ring-closing metathesis (RCM) reaction employing Grubbs catalyst. We planned two pathways according to retrosynthetic concept included formation of the C11-C12 double bond by RCM reaction (Scheme 1). First route A is employing oxazolidinone to yield the syn-aldol product. This methodology was implemented by Crimmins and She. The second route B is utilizing enantiospecific rhodium-catalyzed allylic etherification with the copper(I) alkoxide as a nucleophile. In the first reaction pathway A according to our synthetic plan (Scheme 2), the alcohol 5 was reacted with sodium salt of bromoacetic acid in refluxing THF to give glycolic acid, which was converted to its mixed pivalic anhydride and treated with (R)-3-lithio-4-benzyl-2-oxazolidinone to generate the N-glycolyloxazolidinone 7 in 81% yield over two steps. The addition reaction of 7 with acrolein furnished hydroxy compound 8 in good yield and high diastereoselectivity (73%, 93:7 dr by H NMR analysis). Protection of the resulting alcohol 8 as its TBS ether 3 and reductive removal of the chiral auxiliary group afforded primary alcohol 9 in 83% yield. The olefinic RCM reaction in the presence of Grubbs’ catalyst in CH2Cl2 transformed 9 to the desired dihydropyran compound 2. In the more convenient second synthetic approach B to dihydropyran 2 (Scheme 3), the stereospecificity in the reaction of rhodium-catalyzed allylic etherification could be maintained by suppressing the rate of isomerization. The copper(I) alkoxide as a nucleophile served to promote the etherification. Thus, this reaction allows for net retention of the absolute configuration through the alkylation of a rhodium-enyl complex. We began the second pathway with an aldol addition of chiral oxazolidinone 10 to acrolein to give syn-aldol adduct (84%, 92:8 dr by H NMR analysis). Protection of the resulting secondary hydroxy group as its TBS ether 11 and reductive removal of the chiral auxiliary group afforded an intermediate primary alcohol in 92% yield. Then, silylation of the hydroxy group as the TBS ether and removal of the MPM group yielded the alcohol 12 in 93% yield. Treatment of the allylic carbonate 13 with the trimethylphosphitemodified Wilkinson catalyst and the copper(I) alkoxide derived from the alkenyl alcohol 12, afforded the diene 4 in 67% yield with excellent diastereoselectivity (98:2 dr by H NMR analysis). The high selectivity observed can be explained using the reported proposed mechanism. Desilylation of the primary hydroxyl group with CSA gave alcohol 14 in 76% isolated yield. Finally, The RCM reaction was

Corrosion and passivity of metals in methanol solutions of electrolytes

Electrochemical and corrosion behaviour of metals in alcohols are the subject of numerous investigations because of the application of mentioned solvents in chemical engineering, production of oxide nanoparticles (sol-gel techniques) and application of alcohols as fuels. Despite relatively rich bibliography related to electro-catalytic oxidation of alcohols on metal surface in mixed aqueous–alcohol solutions, the knowledge of the mechanism of reactions on metal/anhydrous alcohol interface is still not sufficient. Anodic oxidation of metal surface in alcohol leads to several electro-catalytic reactions with formation of surface compounds being the product of metal and alcohol oxidation. Identification of these products is very difficult. Therefore, our knowledge of the composition and structure of passive films or corrosion products on metal surface in anhydrous alcohol solvents is poor. Our paper presents the investigations of anodic behaviour of metals (Cu, Zn, Fe, Ni, Al and Ti) and semiconductors (p-Si) in methanol solutions of electrolytes, performed in our laboratory within the last 10 years. On the base of electrochemical measurements (linear sweep voltammetry, electrochemical impedance spectroscopy), spectroscopic investigations (X-ray photoelectron spectroscopy, ultraviolet photoelectron spectroscopy and low-energy electron diffraction) and scanning electron microscopy techniques, the role of metal–alcohol intermediates in the formation of surface and soluble compounds is discussed. The practical application of electrochemical etching of metals as a method of production of micro- and nanoparticles of metals and oxides is also shown.

Synthetic Studies on Tedanolide: Stereoselective Synthesis of the C1-C7 Fragment

Tedanolide (1), an 18-membered macrolide, was isolated by Schmitz et al. in 1984 from the Caribbean sponge Tedania ignis and structurally related 13-deoxytedanolide (2) was isolated from a Japanese sea sponge, Mycale adhaerens, by Fusetani et al. in 1991. Both tedanolide (1) and 13-deoxytedanolide (2) exhibit very potent biological activities against certain tumor cell lines. Their complex structures and distinctive biological properties make them extremely attractive targets for synthetic chemists. Recently Kalesse and Smith have reported successful total syntheses of tedanolide (1). As shown in Scheme 1, our retrosynthetic strategy for tedanolide (1) was the disconnection to two subunits 4 and 5 via cleavage at ester C-O bond and the aldol condensation transformation. The subunit 5 was envisioned to be obtained from the coupling between precursors 6 and 7. Herein we disclose our efforts in the construction of the C1-C7 fragment 6 of tedanolide (1). At first stage, we have utilized the Roush protocol as a key methodology toward fragment 6. The synthesis began with the known aldehyde 9. The Roush asymmetric crotylation upon 9 with 10 gave the desired product in 80% yield as a 92:8 mixture of two diastereomers, which was methylated to the methyl ether 11 in good yield. Ozonolysis of 11 furnished aldehyde 12. The second Roush crotylation on 12 did not yield the desired product. Instead we obtained a mixture of diastereomers (Scheme 2). Because of the observed lability of aldehyde 12 during the second crotylation, we considered the modification of the synthetic pathway. As a replacing measurement for the second Roush crotylation, we devised the combined application of Sharpless asymmetric epoxidation and Gilman cuprate reaction. As shown in Scheme 3, we established a highly stereoselective synthesis of precursor 6 via epoxide ring-opening and Mitsunobu reaction. The oxidative cleavage of the terminal vinyl group of 11 followed by immediate HornerWadsworth-Emmons reaction provided α,β-unsaturated ester 15 in 75% yield over two steps (trans:cis = 96:4). Subsequent reduction of ester 15 using DIBAL-H gave the intermediate allylic alcohol and Sharpless epoxidation upon this alcohol with Ti(OPr)4, L-DET and TBHP afforded stereoselectively epoxide 8 in nearly quantitative yield (β/α ≥ 30). Epoxide ring opening of 8 by the treatment with MeLi and CuI furnished the intermediate 1,3-diol (1,3-diol:1,2diol = 88:12) and the exposure of the resulting 1,3-diol to 16 with PPTS yielded p-methoxyphenyl acetal 17 in 70% yield. To introduce the requisite stereochemistry at C2, the

CRH Haplotype as a Factor Influencing Cerebrospinal Fluid Levels of Corticotropin-Releasing Hormone, Hypothalamic-Pituitary-Adrenal Axis Activity, Temperament, and Alcohol Consumption in Rhesus Macaques

Both highly stress-reactive and novelty-seeking individuals are susceptible to alcohol use disorders. Variation in stress reactivity, exploration, and response to novelty have been attributed to differences in corticotropin-releasing hormone (CRH) system function. As such, CRH gene variation may influence risk for alcohol use and dependence. To determine whether CRH variation influences relevant intermediate phenotypes, behavior, and alcohol consumption in rhesus macaques. We sequenced the rhesus macaque CRH locus (rhCRH) and performed cladistic clustering of haplotypes. In silico analysis, gel shift, and in vitro reporter assays were performed to identify functional variants. Cerebrospinal fluid (CSF) and blood samples were obtained, and levels of CRH and corticotropin (ACTH) were measured by radioimmunoassay. Behavioral data were collected from macaques during infancy. Among adolescent/adult animals, we recorded responses to an unfamiliar conspecific and measured levels of ethanol consumption. National Institutes of Health Animal Center. Rhesus macaques. Animals were genotyped for a single-nucleotide polymorphism disrupting a glucocorticoid response element, rhCRH -2232 C>G, and the effects of this allele on CSF levels of CRH, plasma levels of ACTH, behavior, and ethanol consumption were assessed by analysis of variance. We show that -2232C>G alters DNA x protein interactions and confers decreased sensitivity of the CRH promoter to glucocorticoids in vitro. Consistent with the known effects of glucocorticoids on CRH expression in the brain, carriers of the G allele had lower CSF levels of CRH but higher levels of ACTH. Infants carrying the G allele were more exploratory and bold, and among adolescent and adult male macaques, the G allele was associated with exploratory/bold responding to an unfamiliar male. Adults with the C/G genotype also exhibited increased alcohol consumption in the social group, a model for high-risk alcohol-seeking behavior. Haplotypes that differ in terms of corticosteroid sensitivity have been identified in humans. Our data may suggest that functionally similar CRH variants could influence risk for externalizing disorders in human subjects.

Synthesis of 2′-β- C-methyl-neplanocin derivatives as anti-HCV agents

The synthesis of 2′-β- C-methyl-neplanocin derivatives is described. The key intermediate cyclopentenyl alcohol 12 is prepared from sugar 5 in 12 steps. Coupling of 12 with appropriately protected purine, 7-deaza pyrimidine, uracil and pyrimidine bases via the Mitsunobu reaction followed by deprotection afforded the target cyclopentenyl nucleosides ( 18– 23, 27). The synthesized compounds were evaluated as potential inhibitors of the hepatitis C virus (HCV) in vitro. Unfortunately, none of them show anti-HCV activity below EC 50 100 μM.

Biosynthesis of the Sesquiterpene Antibiotic Albaflavenone in Streptomyces coelicolor A3(2)

Cytochrome P450 170A1 (CYP170A1) is encoded by the sco5223 gene of the Gram-positive, soil-dwelling bacterium Streptomyces coelicolor A3(2) as part of a two-gene cluster with the sco5222 gene. The SCO5222 protein is a sesquiterpene synthase that catalyzes the cyclization of farnesyl diphosphate to the novel tricyclic hydrocarbon, epi-isozizaene (Lin, X., Hopson, R., and Cane, D. E. (2006) J. Am. Chem. Soc. 128, 6022-6023). The presence of CYP170A1 (sco5223) suggested that epiisozizaene might be further oxidized by the transcriptionally coupled P450. We have now established that purified CYP170A1 carries out two sequential allylic oxidations to convert epi-isozizaene to an epimeric mixture of albaflavenols and thence to the sesquiterpene antibiotic albaflavenone. Gas chromatography/mass spectrometry analysis of S. coelicolor culture extracts established the presence of albaflavenone in the wild-type strain, along with its precursors epi-isozizaene and the albaflavenols. Disruption of the CYP170A1 gene abolished biosynthesis of both albaflavenone and the albaflavenols, but not epi-isozizaene. The combined results establish for the first time the presence of albaflavenone in S. coelicolor and clearly demonstrate that the biosynthesis of this antibiotic involves the coupled action of epi-isozizaene synthase and CYP170A1.

Cascade approach for synthesis of R-1-phenyl ethyl acetate from acetophenone: Effect of support

One-pot synthesis of R-1-phenylethyl acetate starting from acetophenone hydrogenation was studied over supported palladium catalysts in combination with an immobilized lipase. Ethyl acetate was used as an acyl donor and the experiments were carried out under 1 bar hydrogen at 70 °C. In this work, the effect of support acidity was systematically investigated by using two mesoporous Pd–H–MCM-41 and Pd–Si–MCM-41 catalysts as hydrogenation catalysts. Furthermore their performance was compared with the performances of Pd–SiO 2 and Pd–Al 2O 3. The catalysts acidity was determined by pyridine adsorption while the metal crystallite sizes were measured by XRD technique. The initial hydrogenation rates of acetophonene decreased with increasing Pd crystallite sizes. Initially both R- and S-1-phenylethanol were formed with the same rates. After prolonged reaction times activities of both hydrogenation catalyst and lipase declined. The former catalyst deactivated due to formation of acetic acid via deacylation reaction, whereas ethanol formed as a stoichiometric product in acylation decreased the lipase activity. The formation of ethylbenzene via dehydration of an intermediate alcohol, ( R,S)-1-phenylethanol was enhanced by acidic catalysts. The most selective catalyst for one-pot synthesis of R-1-phenylethylacetate was a slightly acidic Pd–Al 2O 3 in combination with lipase. A reaction network was proposed based on the kinetic data.

Synthesis and application of monoterpene-based chiral aminodiols

Primary, secondary and tertiary aminodiols were synthetized regio- and stereoselectively from (−)-α-pinene 1 via α-pinene oxide 2, (−)- trans-pinocarveol 3 and key intermediate epoxy alcohol 4. N-Benzyl derivative 5 was transformed to spiro-fused oxazolidine 13 in a highly regioselective ring closure. Aminodiols and their derivatives 5– 13 were applied as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde, resulting in chiral 1-phenyl-1-propanol. The substituent effect on the nitrogen was studied in detail and the best enantioselectivity was observed in the case of N-methyl- N-benzyl-substituted derivative 8. The phenomenon was interpreted by using molecular modelling at an ab initio level.

The application of water-soluble ruthenium catalysts for the hydrogenation of the dichloromethane soluble fraction of fast pyrolysis oil and related model compounds in a two phase aqueous–organic system

The hydrogenation of a dichloromethane soluble fraction of flash pyrolysis oil (bio-oil, BO), obtained by treatment of BO with a water–dichloromethane solvent mixture, was investigated using a water-soluble homogeneous ruthenium catalyst (RuCl 3·3H 2O/tris( m-sulfonatophenyl)phosphine, TPPTS). The catalyst is active at mild conditions (<70 °C, 45 bar hydrogen) and particularly the levels of aldehydes in the BO fraction are reduced considerably. Model studies using vanillin ( 1), acetoguaiacone ( 2) and iso-eugenol ( 3) (45 bar hydrogen and 45–70 °C) showed that vanillin is the most reactive and unexpectedly forms creosol ( 6) instead of the vanillylalcohol ( 5). An optimisation study was performed on the latter reaction and the highest TOF (36.4 mol/(mol h)) was obtained at 60 °C, 45 bar hydrogen and a NaI concentration of 0.08 M. Kinetic studies imply that the formation of 6 proceeds via the intermediate alcohol 5 in a series type of mechanism. TEM-EDX measurements suggest that the reactions are most likely catalyzed by single metal homogeneous Ru complexes and not by Ru nanoparticles/colloids.

A phase I pharmacokinetic study of PR-104, a hypoxia-targeting agent, in patients with solid tumors

3516 Background: PR-104 is a novel pre-prodrug (precursor of a prodrug) designed to form a cytotoxic nitrogen mustard (alkylating agent) in hypoxic regions of tumors. Following IV administration, PR-104 is converted by systemic phosphatases to the alcohol intermediate PR-104A, which, under hypoxic conditions, is reduced to form the active DNA-crosslinking mustard species PR-104H. This phase I trial defines a Maximally Tolerated Dose (MTD) and pharmacokinetics (PK) for this schedule. Methods: Patients (pts) with relapsed/recurrent solid tumors received PR-104 as a 1-hour IV infusion every 3 weeks with PK sampling on days 1–2 of cycle 1. Cohorts of ≥3 pts were treated starting at 135 mg/m2. Results: 23 pts have been enrolled: median age 51 years (range 29–72); 13 (57%) male. Most pts had received prior radiation or chemotherapy and had metastatic disease. Six dose levels (135, 216, 354, 550, 770, and 1,100 mg/m2) have been evaluated. Dose-limiting toxicity (DLT) was observed in one patient at 1,100 mg/m2 (grade 3 fatigue) and this dose level was expanded to 6 pts. In the first 4 cohorts, 54 adverse events (AEs) were considered drug-related by the investigator including nausea (26% of all AEs), fatigue (19%), vomiting (11%) and anorexia (6%); remaining AEs each constituted &lt; 3% of the total. Of 16 grade 3 AEs, 3 were considered drug-related by the investigator (anemia, dehydration and vomiting). Prophylactic anti-emetics largely prevented nausea and vomiting at higher doses, at which dose-related decreases in neutrophils and platelets were seen. Conclusions: PR-104 has shown manageable toxicities similar to other cytotoxic agents, with no serious mucositis, diarrhea or alopecia. DLT is likely to be myelosuppression based on preclinical and current clinical data, with the MTD close to 1,100 mg/m2. The preclinical PK target for the alcohol intermediate has been exceeded at higher doses and, while no objective responses have been documented, reductions in tumor volume have been seen at these doses. [Table: see text] No significant financial relationships to disclose.

Sorption of Methyl tert -Butyl Ether (MTBE) and tert -Butyl Alcohol (TBA) to Hyporheic Zone Soils

Soil water distribution coefficients (K d ) for methyl tert-butyl ether (MTBE) and its primary biodegradation intermediate tert-butyl alcohol (TBA) were determined for seven hyporheic zone soils ranging from 1 to 7% in organic carbon. Samples were collected in the area of the Spring Creek hyporheic zone in Ronan, Montana. Values for K d ranged from 1.5 to 8.7 L kg−1 for MTBE and from 0.15 to 0.41 L kg−1 for TBA, and were highly correlated to the organic carbon content of the solids. However, for TBA the use of non-linear K F values is more appropriate based on the results obtained, and the value of K OC is calculated based on linear K d transformation of the data. Distribution coefficients normalized to the fraction of organic carbon (log K OC ) for MTBE and TBA were determined to be 2.13 ± 0.060 and 0.762 ± 0.088, respectively.

Synthesis of aromatic spiroacetals related to γ-rubromycin based on a 3 H-spiro[1-benzofuran-2,2′-chromane] skeleton

The synthesis of a series of aromatic 5,6-benzannelated and naphthyl-benzannelated spiroacetals related to the spiroacetal unit present in the quinonoid antibiotic γ-rubromycin is reported. The key steps include the use of Sonogashira coupling to construct an aryl acetylene that is coupled to an aryl aldehyde forming a propargyl alcohol intermediate. Hydrogenation of the resultant alkynol followed by oxidation produces a masked dihydroxyketone that upon treatment with silica-supported sodium hydrogen sulfate undergoes concomitant deprotection and cyclisation to afford the desired fused aromatic spiroacetal.

1,1-Dioxonaphtho[1,2-b]thiophene-2-methyloxycarbonyl (α-Nsmoc) and 3,3-Dioxonaphtho[2,1-b]thiophene-2-methyloxycarbonyl (β-Nsmoc) Amino-Protecting Groups

Of the three theoretically possible, Bsmoc-related, naphthothiophene sulfone-based amino-protecting groups, the two most readily available derivatives, the alpha- and beta-Nsmoc analogues, have been examined as substitutes for the Bsmoc residue in cases where the latter lead to oily protected amino acids or amino acid fluorides. All of the naphtho systems gave easily handled solid amino acid derivatives. The intermediate sulfone alcohol 11 used as the key reagent for introduction of the alpha-Nsmoc protecting group was readily made from alpha-tetralone (Scheme 1). The corresponding beta-analogue 17 was made similarly on a small scale, but due to the high cost of beta-tetralone, an alternate route involving reaction of rhodanine with alpha-naphthaldehyde was used for large-scale work (Scheme 2). All proteinogenic amino acids were converted to their alpha- and beta-Nsmoc derivatives. Deblocking studies showed that the reactivity toward deblocking by piperidine followed the order alpha-Nsmoc > Bsmoc > beta-Nsmoc. 1H NMR experiments showed that deblocking of the two new systems was mechanistically similar to that previously established for the Bsmoc derivative in that the reaction is initiated by Michael addition to the beta-carbon atom of the alpha,beta-unsaturated sulfone system. Application of alpha- and beta-Nsmoc amino acids to the solid-phase synthesis of two model peptides was examined. An advantage of the alpha-Nsmoc system over the long-known Bsmoc system proved to be the milder conditions needed for the deblocking step relative to the Bsmoc case, which is itself more readily deblocked than the classic Fmoc analogue.

Palladium‐Catalyzed α‐Arylation of Methyl Isobutyrate and Isobutyronitrile: An Efficient Synthesis of 2,5‐Disubstituted Benzyl Alcohol and Amine Intermediates.

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Directed Reductive Amination of β-Hydroxy-ketones: Convergent Assembly of the Ritonavir/Lopinavir Core

An efficient procedure for the directed reductive amination of beta-hydroxy-ketones (3) for the stereoselective preparation of 1,3-syn-amino alcohols (6) is reported. The operationally simple protocol uses Ti(iOPr)4 for coordination of the intermediate imino alcohol (5) and PMHS as the reducing agent. The method was expanded to an asymmetric aldol reductive amination sequence to allow a highly convergent synthesis of the hydroxy-amine core of the HIV-protease inhibitors ritonavir and lopinavir. [reaction: see text].

Apomorphine‐Induced Growth Hormone Response Is Attenuated by Ethanol but Not Dextromethorphan

Misuse of alcohol drinking is a major health problem. Alcohol decreases spontaneous growth hormone (GH) secretion, but the mechanism is unclear. The aim of this study was to test whether administration of alcohol (study 1) or a N-methyl d-aspartate (NMDA) receptor antagonist (study 2) attenuates the GH response to pharmacological dopaminergic stimulation. The 2-session repeated measures design was conducted at the endocrine laboratory at the Department of Psychiatry at the Free University Berlin. Twenty healthy Caucasian males aged 35+/-10 years without a history of alcohol use disorders were tested using the Apomorphine (APO) challenge test. In study 1, we injected APO (0.01 mg/kg s.c.) 1 hour after oral administration of 1 g/kg ethanol and placebo, respectively. In study 2, the APO challenge was conducted after 0.3 mg/kg dextromethorphan (DXM) and placebo. The main outcome measures were the peak serum GH concentration and area under the time/concentration curve up to 120 minutes after APO. The effects of ethanol and DXM were tested using the Wilcoxon signed-rank tests. Compared with placebo, alcohol significantly decreased the APO-induced GH release (mean and SEM peak GH concentration 19.9+/-3.2 vs 6.2+/-1.9 ng/mL, p=0.002). Dextromethorphan did not change APO-induced GH response (22.5+/-5.4 vs 21.0+/-5.8 ng/mL, p=0.105). A single intermediate alcohol dose markedly reduces GH response to dopaminergic stimulation. Although alcohol is thought to stimulate dopaminergic function in certain pathways, but not necessarily in the hypothalamus, our results are in line with the alcohol effect on baseline GH secretion. Growth hormone suppression appears not to be mediated by ethanol's NMDA-antagonistic properties.

Polyol synthesis through hydrocarbon oxidation: de novo synthesis of L-galactose.

Polyol synthesis through hydrocarbon oxidation: de novo synthesis of L-galactose.

Synthesis of C-Protected 2,2-Dideutero β3-Amino Acids

A simple three-step procedure for the preparation of C-protected 2,2-2H-β3-amino acids has been developed starting from the natural α-amino acids. Our synthetic path is based on the homologation reaction of α-amino acids through the formation of dideuterated alcohol intermediates obtained by heavy isotope reduction (NaBD4) of the carboxylic function.

Palladium catalyzed α-arylation of methyl isobutyrate and isobutyronitrile: an efficient synthesis of 2,5-disubstituted benzyl alcohol and amine intermediates

Several 2,5-disubstituted benzyl alcohols containing a functionalized t-butyl moiety were synthesized via palladium catalyzed α-arylation of methyl isobutyrate and butyronitrile on synthetically useful scales. The resulting benzyl alcohols could then be further elaborated to benzyl amines or other desirable intermediates.

Total Synthesis and Biological Assessment of Cyclopropane-Based Epothilone Analogues - Modulation of Drug Efflux through Polarity Adjustments

Benzimidazole-based analogues of epothilones containing a cyclopropane ring in place of the natural epoxide moiety have been prepared based on the selective cyclopropanation of homoallylic alcohol intermediates as one of the key steps. In contrast to the epoxide-containing parent compounds the cyclopropane analogues are not or only minimally susceptible to P-gp170-mediated drug efflux.