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Maresins are among the most potent antiinflammatory lipid metabolites. We report stereoselective syntheses of maresin 2 and maresin 2n-3 DPA. The anti-diol was constructed through epoxide ring opening of an optically active β,γ-epoxy aldehyde, synthesized in situ by Swern oxidation of the corresponding alcohol. Finally, the target compounds were synthesized through a Sonogashira coupling of a C9–C22 iodide and methyl (Z)-oct-4-en-7-ynoate or methyl oct-7-ynoate, respectively.

Ever since Hirata’s report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. Despite extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine-type Daphniphyllum alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol coupling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Our approach paves the way for the synthesis of other yuzurimine-type alkaloids and related natural products., Despite being known for more than 50 years, yuzurimine-type alkaloids have not been accessed by total synthesis. Here, the authors report the first enantioselective total synthesis of (+)-Caldaphnidine J, a highly complex yuzurimine-type Daphniphyllum alkaloid.

Oxalyl chloride, (COCl)2, as an inexpensive commercially available chemical is one of the most versatile applicable organic reagents in chemical transformations. It is also employed extensively in various chemical industries. It is employed in various chemical transformations such as chlorination, oxidation, reduction, dehydration, decarboxylation, and formylation reactions as well as ring cleavage of epoxides. During the past decades, numerous procedures using (COCl)2 as reagent have been developed and published. However, its importance has largely been overlooked by the absence of a comprehensive review in chemical literature dealing with its application in organic transformations and its utilization in the chemical industry. This Review aims to provide an overview for the applications of oxalyl chloride in organic synthesis, including its physical properties, synthesis, as well as its unique roles as the reagent in organic reactions, covering the literature over the past 103 years (from 1916 to date).

Preparation of benzaldehyde by Swern oxidation of benzyl alcohol was carried out in a continuous flow microreactor system. Dimethyl sulfoxide (Me2SO) was used as oxidizing agent and oxalyl chloride or p-toluenesulfonyl (p-TsCl) chloride was used as the activating agent. Benzyl alcohol was oxidized to benzaldehyde by the Me2SO-activating agent mixture in the continuous flow microreactor system. The optimized reaction conditions of the Swern oxidation were as follows: oxalyl chloride was used as the activating agent; the mole ratio of Me2SO, oxalyl chloride, and benzyl alcohol was 4:2:1; the ow rate of Me2SO was 1.5 mL/min; the reaction temperature was 15 ℃; length of delay loop was 1.5 m; a Caterpillar Split-Recombine Micro Mixer was used; and all of the experiments were completed at atmospheric pressure. The yield of benzaldehyde can reach 84.7% with selectivity of 98.5%. Due to the small reactor volume and short residence times, the Swern oxidation of benzyl alcohol in a continuous flow microreactor system can be operated at nearly room temperature (5–19 ℃) instead of –70 ℃ in a batch reaction, with residence time of reactants in microreactors in milliseconds instead of several hours in a batch reaction.

A conversion of trimethylsilylalkanes into the corresponding alcohols is established based on an iridium-catalyzed, chemoselective C(sp3)–H borylation of the methyl group on silicon. The (borylmethyl)silyl group formed by C(sp3)–H borylation is treated with H2O2/NaOH, and the resulting (hydroxymethyl)silyl group is converted into a hydroxyl group by Brook rearrangement, followed by oxidation of the resulting methoxysilyl group under Tamao conditions. An alternative route proceeding through the formylsilyl group formed from a (hydroxymethyl)silyl group by Swern oxidation is also established. The method is applicable to substituted trimethylsilylcycloalkanes and 1,1-dimethyl-1-silacyclopentane for conversion into the corresponding stereodefined cycloalkyl alcohols and 1,4-butanediol.

The Burgess reagent ([methoxycarbonylsulfamoyl]triethylammonium hydroxide) has historically found utility as a dehydrating agent. Herein we show that, in the presence of dimethyl sulfoxide, the Burgess reagent efficiently and rapidly facilitates the oxidation of a broad range of primary and secondary alcohols to their corresponding aldehydes and ketones in excellent yields and under mild conditions, and can be combined with other transformations (e.g., Wittig olefinations). A mechanism similar to those described for the Pfitzner-Moffatt and Swern oxidations is proposed.

In a one pot procedure , a series of novel Triazole linked thiazolidenone derivatives 8 a-g and 9 a-g was prepared by condensation of (3a R ,5 S ,6 R ,6a R )- 6-((1-(4-fluorophenyl)-1 H -1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydro[2,3- d ][1,3]dioxole-5- carbaldehyde 7 with mercapto acids and primary amines in presence of ZnCl 2 under both micro wave irradiation and conventional heating conditions. Compound 7 prepared from di Acetone D- Glucose with oxidation followed by reduction , click reaction, primary acetonide deprotection and with oxidative cleavage .Characterization of new compounds has been done by means of IR, NMR, MS and elemental analysis. The nematicidal and anti bacterial activity of the compounds has also been evaluated.

The synthesis and structure of the substituted trioxane compound 2,4,6,-tri­cyclo­butyl-1,3,5-trioxane is described. The three cyclo­butane rings attached to the 1,3,5-trioxane six-membered ring are all in a cis arrangement. The compound may find application as a stable trimeric form of the fragile cyclo­butane carbaldehyde., The synthesis and structure of 2,4,6,-tri­cyclo­butyl-1,3,5-trioxane, C15H24O3 1, is described. It was formed in 39% yield during the work-up of the Swern oxidation of cyclo­butyl­methanol and may serve as a stable precursor of the cyclo­butane carbaldehyde. The mol­ecule of 1 occupies a special position (3.m) located at the center of its 1,3,5-trioxane ring. The latter is in a chair conformation, with the symmetry-independent O and C atoms deviating by 0.651 (4) Å from the least-squares plane of the other atoms of the trioxane ring. All three cyclo­butane substituents, which have a butterfly conformation with an angle between the two planes of 25.7 (3)°, are in the cis conformation relative to the 1,3,5-trioxane ring. Inter­molecular C—H⋯O inter­actions between the 1,3,5-trioxane rings consolidate the crystal structure, forming stacks along the c-axis direction. The crystal studied was refined a as a racemic twin.

In order to improve the antitumor and/or antiviral activities of existing nucleoside analogs, eight new compounds (9a,b, 14a,b, 15a,b and 16a,b) were designed and synthesized. Halogen atom were incorporated at the 2-position of the purine base to render the amino group at the 6-position less susceptible to metabolism by adenosine deaminase. A methylene group was introduced at the 2′-position following the lead of nucleoside antibiotics angustmycin A and neplanocin A. The two key intermediates 9a and 9b were prepared from guanosine after protection of the 3′ and 5′ hydroxyl groups and oxidation of the 2′ hydroxyl group to the corresponding carbonyl group using swern method. The conversion of the carbonyl group to the methylene function was carried out by applying wittig reaction conditions. The final compounds 14a,b, 15a,b, 16a,b were prepared by means of nonaqueous diazotization of 9a and 9b. The prepared compounds were subjected to in vitro antileukemic and antiviral activity upon a new L1210 cell line that is doubly resistant to both hydroxyurea and deoxyadenosine which was grown and characterized. The new compounds showed potent antileukemic activity.

An efficient asymmetric synthetic route for the synthesis of anti-glaucoma agent, (15R)-latanoprost using Corey lactone diol as chiral substrate under Swern oxidation, allylic reduction and Wittig reaction conditions has been developed. In this method, reduction of keto and alkene functional groups has been achieved in a single step using low cost catalyst NiCl2/NaBH4 in methanol. This new synthetic protocol is a good alternative for the synthesis of latanoprost with high stereo selectivity and improved yield.

The preparation of nitriles from primary amides or aldoximes was achieved by using oxalyl chloride with a catalytic amount of dimethyl sulfoxide in the presence of Et3N. The reactions were complete within 1 h after addition at room temperature. A diverse range of cyano compounds were obtained in good to excellent yields, including aromatic, heteroaromatic, cyclic, and acyclic aliphatic species.

Lignin, the planet's most abundant renewable source of aromatic compounds, is difficult to degrade efficiently to welldefined aromatics. We developed a microwave-assisted catalytic Swern oxidation system using an easily prepared catalyst, MoO2 Cl2 (DMSO)2 , and DMSO as the solvent and oxidant. It demonstrated high efficiency in transforming lignin model compounds containing the units and functional groups found in native lignins. The aromatic ring substituents strongly influenced the selectivity of β-ether phenolic dimer cleavage to generate sinapaldehyde and coniferaldehyde, monomers not usually produced by oxidative methods. Time-course studies on two key intermediates provided insight into the reaction pathway. Owing to the broad scope of this oxidation system and the insight gleaned with regard to its mechanism, this strategy could be adapted and applied in a general sense to the production of useful aromatic chemicals from phenolics and lignin.

The stereoselective synthesis of resolvin D4 (RvD4) was achieved using the Wittig reaction of the C1–C10 dienal with the known C11–C22 phosphonium salt. The (S,E)-enantiomer (S)-10, corresponding to the C1–C8 part, was synthesized in 95% ee by the asymmetric transfer hydrogenation reaction of the corresponding acetylenic ketone followed by Red-Al reduction. Sharpless epoxidation of this alcohol using Ti(O-i-Pr)4/l-(+)-DIPT as a catalyst produced anti epoxy alcohol with >99% ee as the sole product in 82% yield. A subsequent functional group manipulation, including removal of the PMB group, produced the alcohol, which upon Swern oxidation afforded anti 4-hydroxy-5-TBS-oxy enal via epoxide ring opening of the resulting aldehyde. The Horner–Wadsworth–Emmons reaction was used to add the C9–C10 enal part to this aldehyde, and the resulting dienal was subjected to the Wittig reaction with C11–C22 phosphonium salt to furnish the entire structure of RvD4. Conversion of the primary alcohol to the methyl ester and d...

The total synthesis of pectinolide H and 4'- epi -pectinolide H was accomplished with 27% yield in nine steps from inexpensive and commercially available compound, (+)-diethyl tartrate ((+)DET)) by employing swern oxidation, Wittig olefination, Grignard and lactonization reactions.

Lignin oxidation reactions are increasingly being utilized in the field of lignin valorization. This is primarily due to the prospect of obtaining high-value aromatic products from cleavage of the Cα–Cβ bond in lignin's β-O-4 linkages. In this work activated dimethyl sulfoxide reactions, namely Swern and Parikh–Doering oxidations, were performed both on lignin and on compounds modeling the β-O-4 linkage. When phenolic moieties were present in the model compounds, enol ethers were formed rather than the ketone expected from oxidation of the β-O-4 alcohol moiety. Conversely, in the absence of phenolic moieties, the β-O-4 alcohol was oxidized to a ketone. These results are interpreted in terms of enol ether formation from a quinone methide intermediate formed via deprotonation of the phenolic –OH in the initial sulfur ylide species. When applied to Kraft lignin, alcohol oxidation was observed at both the α and γ positions in lignin under both Swern and Parikh–Doering conditions, although analytical data were unable to shed light on the relative importance of enol ether versus 1,3-diketone formation (or its tautomer). These results emphasize the importance of working with realistic lignin model compounds in order to understand and develop lignin chemistry.

A simple and efficient methylthiolation protocol was successfully established for the synthesis of ketone-substituted indoles bearing 3-methylthioether moiety. The new synthetic approach featured metal-free oxidation and methylthiolation of alcohol-containing indoles, in which new C–S bond and CO bond were formed simultaneously using dimethyl sulfoxide as the sulfur source under the Swern oxidation conditions. The methylthiolation reaction provides a simple and facile procedure to methylthiolated indoles from readily available starting materials in good yields.

A new dimethylsulfoxide activation method employing 1,1-dichlorocycloheptatriene has been developed for a mild Swern-type oxidation of a variety of alcohols. The carbonyl products can be obtained in good to excellent yields from this operationally simple and efficient method. This work is the first report of dimethylsulfoxide activation by a simple chlorinated hydrocarbon reagent, which has the unique ability of equilibrating to its reactive aromatic cationic form.

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium ( R )- N -benzyl- N -(α-methylbenzyl)amide to the requisite ( E )-α,β-unsaturated ester followed by in situ enolate oxidation with (−)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti -α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn -α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO 3 -mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn -α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti -α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.

A series of 4-hydroxyl-Δ 2 -isoxazol-6(6a H )-one derivatives was prepared by magnesium ion-mediated diastereoface-selective 1,3-dipolar cycloaddition of aromatic nitrile oxides with pyrrolidinone derivatives. The reaction of 4-hydroxyl-Δ 2 -isoxazol-6(6a H )-one derivatives with dimethylsulfoxide and oxalyl chloride under Swern conditions led to a Δ 2 -isoxazole-4,6(5 H ,6a H )-dione.

An efficient and Brønsted acid free one-pot protocol to directly generate structurally sophisticated α-formylpyrrole derivatives in moderate to good yields has been demonstrated, involving an iron-mediated domino oxidation/formylation reaction of readily available 2,3-dihydro-1H-pyrroles in dimethyl sulfoxide and air atmosphere, in which dimethyl sulfoxide acts as the formyl donor. A possible mechanism is presented.

A synthesis of carbocyclic sugars from carbohydrate-derived dialdehydes using organocatalysis has been developed. Sorbitol, mannitol, and galactitol were converted via 1,6-tritylation, perbenzylation or permethylation, detritylation, and Swern oxidation into 2,3,4,5-tetra-O-alkyl-dialdoses that were cyclized via the benzoin reaction promoted by a triazolium carbene. Manno- and galacto-configured dialdehydes gave predominantly single inosose stereoisomers in up to 75% yield if the mixture was acetylated prior to isolation while the gluco-dialdehyde afforded a mixture of three stereoisomers in 61% overall yield. The inososes were stereospecifically reduced using sodium borohydride and then deprotected to give allo- and epi-inositol in good yield that confirmed the structural and stereochemical assignments.

An efficient total synthesis of 18 membered macrolactone, (+)-Aspicilin (lichen macrolide) has been achieved in 12 linear steps with 10.2% overall yield from carbohydrate based building block D-glucal. Highlights of the strategy include preparation of 2-deoxysugar from protected glycal 14, two-carbon Wittig olefination of the Swern oxidised intermediate 7, union of ‘carbohydrate based’ fragment 5 and a long chain (C-11) chiral alcohol 6 by Yamaguchi esterification and finally ring closing metathesis of the resulting compound 4.

An effective synthesis of 4.5-spiro lactams 28/29, has been completed in nine steps with an overall yield of 5.8%. The 4.5-spiro lactams were made from 2-allyl-Cbz-Pro-OMe 21, which was converted into the corresponding alcohol 22 via a hindered borane reaction with (2-methylbutyl)2borane. Subsequent Swern oxidation of 22 gave novel aldehyde 23. Aldehyde 23 was treated under BucherereBergs reaction conditions to give hydantoin 26, which was opened to the corresponding amino acid 30 using di-tertbutyl dicarbonate and DMAP followed by hydrolysis. Treatment of amino acid 30 with acidic methanol gave 4.5-spiro lactams 28/29. Only 4.5-spiro lactam 29 displayed moderate activity against GPa with an IC50 of 241 mM. 2012 Published by Elsevier Ltd.

The total synthesis of the polyenoyltetramic acid polycephalin C is described. Key steps of the synthesis include a double Swern oxidation, double Takai reaction and a double Stille reaction. In addition, the absolute stereochemistry of the ring junction has been determined by synthesis of both isomers and comparison of their CD spectra with natural polycephalin C. © 2003 Elsevier Ltd. All rights reserved.

The oxidation of the biologically very important dimethyl sulfoxide system has been the subject of investigations. In present study Dimethyl sulfoxide (DMSO) can be oxidized to dimethyl sulfone by anodic electrolysis at a rotating platinum electrode. The polarographic method has been used to study qualitatively the effect of maxima suppressor gelatin, fuchsin, methyl red, thymol blue and supporting electrolyte HCl, CH3COOH on oxidation wave of DMSO. Polarographic oxidation of DMSO in 0.1 M HCl, 0.1 M CH3COOH solution using optimum concentration of fuchsin, methyl red, thymol blue as surface active substances is followed to determine the DMSO present in synthetic sample by calibration method. Wave analysis indicate the irreversible nature of the oxidation process which involves oxidation of dimethyl sulfoxide to dimethyl sulfone thereby increasing the oxidation state of sulphur from +2 to +4 state.

A new type of sulfoxide, 4-(2-(2-(methylsulfinyl) ethyl)-4-nitrophenyl)- morpholine (I) was designed and prepared in good yield. Upon the combination of I andbis (trichloromethyl)carbonate, the Swern oxidation of primary and secondary alcohols was significantly promoted under mild condition which afford the corresponding aldehydes or ketones in good yields. It's noteworthy that the re-oxidation of the isolated byproduct sulfide V could be further recycled in Swern oxidation.

1,3-Dipolar cycloaddition of 2-diazopropane to conjugated dienes 1 and α,β-unsaturated ketones 5 is taking place regiospecifically to give cycloadduit 4 and 6 . The reaction of 2-pyrazolines derivatives with dimethylsulfoxide and oxalyl chloride under Swern conditions led to a pyrazolenines 7 and 8 .

Deprotonation of the alkoxysulfonium intermediate has been shown to be rate-determining in the Swern oxidation of benzyl alcohol. Directly following this rate-determining step is the intramolecular syn-β-elimination of the ylide. In the present study, intramolecular (2)H kinetic isotope effects (KIEs) are used to gain insight into this syn-β-elimination step. As a result of the stereogenic sulfur center in the ylide intermediate, two diastereomeric transition states (endo-TS1 and exo-TS1) must be assumed to contribute to the intramolecular KIE. The intramolecular (2)H KIE determined at -78 °C is 2.82 ± 0.06. Attempts to reproduce this measurement computationally using transition state theory and a Bell tunneling correction yielded a value (1.58) far below that determined experimentally. Computational analysis is complicated by the existence of two distinct transition structures owing to the stereogenic center. Two extremes of Curtin-Hammett kinetics are explored using energies, vibrational frequencies, and moments of inertia from computed transition structures. Neither Curtin-Hammett scenario can reproduce the observed KIE to any acceptable degree of fidelity. Evidence based upon previous kinetics measurements and calculations upon a model system suggests that the stereogenic sulfur center is not likely to undergo inversion to a significant degree at the temperatures at which the Swern oxidation is performed here. Proceeding under the assumption of no stereoinversion at the sulfur center, calculations predict a nearly linear Arrhenius plot for the KIE--even with the inclusion of a one-dimensional tunneling correction. By contrast, the experimentally determined temperature dependence shows a significant concave upward curvature indicative of the influence of tunneling. Notably, KIEs measured in CCl(4), CHCl(3), CH(2)Cl(2), dichloroethane, and chlorobenzene at -23 °C showed little variance. This finding discounted the possible influence from dynamical effects due to incomplete vibrational relaxation. An ad hoc amplification of the imaginary frequencies corresponding to the first-order saddle points corresponding to endo-TS1 and exo-TS1 allowed us to reproduce the experimental temperature dependence of the KIE using only two adjustable parameters applied to a kinetic scenario that involves four isotopomeric transition states. The cumulative data and computational modeling strongly suggest that, even though the intramolecular (2)H KIE observed in these experiments is small, this reaction requires a multidimensional description of the tunneling phenomenon to accurately reproduce experimental trends.

FTY720 (2-amino-[2-(4-n-octylphenyl)ethyl]-1,3-propanediol, Fingolimod™, 1, Chart 1) is a synthetic analogue of the chiral sphingolipid myriocin (2).1 As an analogue of sphingosine, FTY720 is phosphorylated in vivo by sphingosine kinases, affording (S)-FTY720-phosphate (3), which activates four of the five known sphingosine 1-phosphate (S1P, 2a) G protein-coupled receptors.2 Chart 1 Structures of FTY720 (1); myriocin (2); S1P (2a); and FTY720 phosphate, phosphonate, and (E)-vinylphosphonate analogues 3–5. Internalization and subsequent polyubiquitination of the S1P receptors leads to their proteasomal degradation and renders the cells unresponsive to S1P; therefore, lymphocytes are not capable of recirculation to peripheral inflammatory tissues.3 Thus, FTY720 has therapeutic potential, and in fact is the first S1P receptor modulator that has entered the stage of a phase-III clinical study.4 Several syntheses of 15 and of phosphate 3 have been accomplished.6 In contrast to phosphates such as 3, phosphonate analogues are resistant to the action of lipid phosphate phosphatases and may offer improved cellular stability. A racemic mixture of the nonhydrolyzable phosphonate analogue of FTY720 (4) was reported in which the C-O-P bond is replaced with a C-C-P bond;2b rac-4 was found to be a high-affinity agonist of the S1P-type 1 receptor (S1P1), with a similar potency as (S)-3.7 We report here the first asymmetric syntheses of the chiral phosphonate analogues of FTY720, (R)-4 and (S)-4. Oxazoline intermediate (S)-14 (Scheme 1), prepared by a modification of our previous route,6c was further elaborated to give the corresponding (E)-vinylphosphonate analogue (S)-5. We have included a preliminary pharmacological characterization of the effects of these analogues on the non-transformed rat intestinal epithelial cell line IEC-6. This study revealed that (S)-5, but not its (R) enantiomer, exerts a potent anti-apoptotic effect in a camptothecin (CPT)-induced apoptosis model.8 Unlike phosphate (S)-3, (S)-5 did not activate the S1P1 receptor of the Endothelial Differentiation Gene (EDG) family of G protein-coupled receptors, making it a novel enantioselective probe activating a cytoprotective mechanism against apoptosis induced by DNA damage. Scheme 1 Synthesis of (S)-14 from 4-bromobenzaldehyde Wittig reaction of 4-bromobenzaldehyde with the ylide of n-heptyltriphenylphosphonium bromide gave arylalkene 6 as an E,Z (1:3) mixture (Scheme 1). Sonogashira coupling between 6 and 4-(phenylmethoxy)-1-butyne delivered enyne 7 as a 1:3 E:Z mixture in 92% yield. Alcohol 8 was obtained on reduction of the unsaturated bonds and hydrogenolysis of the O-benzyl group in the presence of Pearlman’s catalyst. After Swern oxidation of 8 provided aldehyde 9, use of a Mannich reagent, Eschenmoser's salt,9 afforded α-methylene aldehyde 10. Reduction of 10 with NaBH4 in the presence of CeCl3 (to suppress conjugate reduction) gave allyl alcohol 11.10 CeCl3, which is a mild Lewis acid, is not required, since CsCl also provided 11 as the only product. Asymmetric Sharpless epoxidation11 of 11 with cumene hydroperoxide (CHP) in the presence of L-(+)-DIPT, Ti(OPr-i)4, and molecular sieves gave epoxide (S)-12.12 The synthesis of (S)-12 was accomplished in 7 steps from p-bromobenzaldehyde and in 46% overall yield. Reaction of alcohol (S)-12 with trichloroacetonitrile in the presence of DBU gave 2,3-epoxy-1-trichloroacetimidate (R)-13. The tetrasubstituted carbon in oxazoline 14 was set up bearing the desired nitrogen substituent by opening of epoxide (R)-13 with catalytic Et2AlCl,13 affording (S)-14 in 74% yield for the two steps. Swern oxidation of oxazoline (S)-14 gave oxazoline aldehyde 15 (Scheme 2), which on Horner-Wadsworth-Emmons reaction with tetramethyl methylenediphosphonate afforded ester (S)-16 in 87% yield and with an E/Z ratio of ~10:1. Simultaneous demethylation and release of the hydroxy and amino groups by treatment with trimethylsilyl bromide (TMSBr) provided (S)-5, but the yield was low. Therefore, the hydroxy and amino groups were first released by treatment with 1 M HCl. After the amine hydrochloride was neutralized (saturated aq Na2CO3), amino alcohol 17 was converted to (S)-5 with TMSBr followed by 95% methanol; 84% yield for the two steps. Reduction of (S)-5 using Pearlman’s catalyst gave (S)-4. Scheme 2 Synthesis of (S)-4 from (S)-14 Asymmetric epoxidation of 11 with D-(−)-DIPT gave epoxide (R)-12, which was converted via (R)-14 to (R)-5 in six steps (Scheme 2). Catalytic hydrogenation of (R)-5 afforded (R)-4 (Scheme 3). Scheme 3 Outline of the synthesis of (R)-5 and (R)-4 S1P promotes the survival of many cell types.14 Both 2a and (S)-3 protect oligodendrocyte progenitor cells from apoptotic cell death in response to growth factor withdrawal, and (S)-3 was also shown to be cytoprotective in response to pro-apoptotic cytokines and microglial activation.15 The ability of 2a, (S)-3, and phosphonate analogues 4 and 5 to protect IEC-6 cells from apoptotic cell death in response to the topoisomerase inhibitor CPT was assessed by DNA fragmentation. Pretreatment with 2a, (S)-3, (R)-4, or (R)-5 did not result in a significant reduction in DNA fragmentation in response to a 4-h treatment with 20 µM CPT. However, we found that the cytoprotective effect was enantioselective, since pretreatment with 1 µM of (S)-4 or (S)-5 showed a significant reduction (21 and 50%, respectively) in DNA fragmentation in response to CPT. In a preliminary study of the activity of the FTY720-phosphonate analogues on S1P receptors, we performed Ca2+ mobilization assays with HTC4 cells that were stably transfected with S1P1. As shown in Figure 1, the S1P1 transfectants were activated by (S)-3 to 76% of the maximal S1P-induced activation, and displayed a similar potency as S1P (13 ± 2 nM for S1P vs 9 ± 1 nM for (S)-3). (R)-5 and (R)-4 both showed a modest activity against S1P1 with Emax values that ranged from 73 to 93% of the maximal S1P-induced responses, and EC50 values that were increased by ~2- to 3-fold. (S)-4 activated S1P1 to 36% of the maximal S1P-induced response, and the EC50 value was increased by ~5-fold to 75 ± 21 nM. Since (S)-5 did not elicit a Ca2+ response from cells transfected with the S1P1 receptor, we conclude that the potent cytoprotective effect of (S)-5 is not mediated by S1P1. Figure 1 Ca2+ mobilization dose-response relationships for S1P (2a), (S)-3, and FTY720 analogues 4 and 5 in HTC4 cells expressing the S1P1 receptor. In conclusion, we have described the synthesis of the enantiomers of FTY720 phosphonate analogues 4 and 5. (S)-4 and (S)-5, but not 2a or (S)-3, all at 1 µM, protected IEC-6 cells from apoptosis. The extent of CPT-induced DNA fragmentation was reduced by 50% and 21% in the presence of 1 µM of (S)-5 and (S)-4, respectively. The potent cytoprotective activity of (S)-5 is not mediated by S1P1. Experiments are underway to characterize the cellular effects of these analogues.

Ethylene glycol ethers (EGEs) are primary alcohols commonly used as solvents in numerous household and industrial products. Exposure to EGEs has been correlated with delayed encephalopathy, metabolic acidosis, sub-fertility and spermatotoxicity in humans. In addition, they also cause teratogenesis, carcinogenesis, hemolysis, etc., in various animal models. Metabolism EGEs parallels ethanol metabolism, i.e., EGEs are first converted to 2-alkoxy acetaldehydes (EGE aldehydes) by alcohol dehydrogenases, and then to alkoxyacetic acids by aldehyde dehydrogenases (ALDHs). The acid metabolite of EGEs is considered responsible for toxicities associated with EGEs. The role of human ALDHs in EGE metabolism is not clear; accordingly, we have investigated the ability of five different human ALDHs (ALDH1A1, ALDH2, ALDH3A1, ALDH5A1 and ALDH9A1) to catalyze the oxidation of various EGE aldehydes. The EGE aldehydes used in this study were synthesized via Swern oxidation. All of the human ALDHs were purified from human cDNA clones over-expressing these enzymes in E. coli. The ALDHs tested, so far, differentially catalyze the oxidation of EGE aldehydes to their corresponding acids (K(m) values range from approximately 10 microM to approximately 20.0mM). As judged by V(max)/K(m) ratios, short-chain alkyl-group containing EGE aldehydes are oxidized to their acids more efficiently by ALDH2, whereas aryl- and long-chain alkyl-group containing EGE aldehydes are oxidized to their acid more efficiently by ALDH3A1. Given the product of ALDH-catalyzed reaction is toxic, this process should be considered as a bio-activation (toxification) process.

Aryl allylic alcohols are converted to halogenated unsaturated ketones or allylic halides using excess Moffatt-Swern reagent. Electron-poor aromatic rings favor formation of the halogenated ketone, while electron-donating substituents in the ortho or para positions favor formation of the allylic halide. The oxidation/halogenation reaction performs well with both oxalyl chloride and oxalyl bromide, providing access to the corresponding chlorides or bromides, respectively.

The cyclization of gamma-chloroamine 11, derived from l-alanine, and acetylenic sulfone 12 afforded the dehydropiperidine 19 via conjugate addition followed by intramolecular alkylation of the corresponding sulfone-stabilized anion. An unexpected acid-catalyzed desulfonylation of 19 occurred in one step via desilylation and tautomerization of the enamine moiety to the corresponding aldehyde, followed by elimination of p-toluenesulfinic acid. The highly stereoselective reduction of the resulting unsaturated aldehyde 25 with sodium cyanoborohydride produced piperidine 23 with a diastereomeric ratio of >98:2. (-)-(ent)-Julifloridine (8) was obtained by Swern oxidation of 23, followed by Wittig olefination and hydrogenation/debenzylation.

We report the design and synthesis of novel prostaglandin–ethanolamide (PGE2–EA) analogs containing head and tail group modifications to aid in the characterization of a putative prostamide receptor(s). Our synthetic approach utilizes Horner–Wadsworth–Emmons and Wittig reactions to construct the head and the tail moieties of the key PGE2 precursor, which leads to the final products through a peptide coupling, Swern oxidation and HF/pyridine assisted desilylation. The synthesized analogs were shown not to interact significantly with endocannabinoid proteins and recombinant EP1, EP3 and EP4 receptors and suggest a yet to be identified prostamide receptor as their site(s) of action.

A five-step preparation of carbohydrate-based oxepines from hept-1-enitols is presented. The hept-1-enitols were subjected to silyl protection and hydroboration/oxidation to give the protected heptan-1-itols. Swern oxidation of the homologated alcohols followed by sequential acetal formation/cyclization provided methyl 2-deoxyseptanosides that underwent elimination reactions to give the carbohydrate-based oxepines. The new sequence is an alternative to the ring-closing metathesis for the synthesis of carbohydrate-based oxepines from protected pyranose sugars. The product oxepines can serve as glycosyl donors in the synthesis of novel septanose carbohydrates. In addition, C-methylenealdehydo arabinofuranoside 16 was formed from 2-deoxyseptanoside 10 as the only product during protic acid mediated elimination reactions. This novel ring contraction complements other reported preparations of C-methylenaldehydo furanosides and underscores the acid-mediated reactivity introduced by competing eliminations between the C-1/C-2 and C-2/C-3 bonds.

The levorotatory diol 7 has been sequentially monosilylated, dehydrated, and oxidized at the allylic methylene group to provide (+)-12. The enantiomeric dextrorotatory diol 7 has been directed down a different sequence of steps involving monosilylation, dehydration, hydroboration, Swern oxidation, and regioselective introduction of a conjugated double bond to generate (-)-33. The novel feature of these transformations is that two key deoxycarbospironucleoside intermediates of the proper absolute configuration have been made available from enantiomerically related precursors. Also reported is a highly practical and reliable means for the formation of novel 2'-deoxyribonucleosides of novel structural type from these spirocyclic cyclopentenones.

Organic reactions using microreactors have attracted significant research interest because of their inherent features such as fast mixing, precise temperature control, and precise residence time control. These features are especially advantages for fast and exothermic reactions, which are difficult to perform using conventional macro-scale batch reactors in a controlled manner.Some examples of such reactions including Friedel-Crafts alkylation, cationic polymerization, and Swern oxidation are described in this article. Other examples are also demonstrated with the special emphasis on multiphase reactions. These examples speak well for the potentiality of microreactors in the enhancement of the ability of organic synthesis to meet demanding expectations in future.

An efficient synthesis of cis-2,6-di-(2-quinolylpiperidine) has been developed. The key steps involve Wittig reaction of N-Cbz-protected cis-piperidine-2,6-dicarboxaldehyde (3) with 2-(triphenylphosphinyl- methyl)quinoline bromide (4) and sequential removal of the N-Cbz group and double bond reduction. This synthetic procedure provides an efficient preparation for this useful norlobelane analogue.