Search

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.

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.

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...

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.

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.

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.

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.

The preparation of functionalized 3,5-disubstituted cyclopent-2-enones via a solid-phase sulfone linker strategy is described. Polystyrene/divinylbenzene sulfinate 1 underwent S-alkylation followed by alpha,alpha-dialkylation with cis-1,4-dichloro-2-butene to form polymer-bound 3-phenylsulfonylcyclopentenes 8. Subsequent epoxidation of the cyclopentene moiety in 8 was accomplished by treatment of mCPBA, and the resulting oxirane ring in resin 9 was opened with various nucleophiles, i.e., Grignard and cuprate reagents, azide ion, and amines. To complete the sulfone-based linker strategy, Swern or TPAP oxidation of 10 gave a transient gamma-ketosulfone, which underwent sulfinate elimination, thus cleaving the sulfone linker. Eleven 3,5-disubstituted cyclopent-2-enones (11) were prepared with this five-step process in 18-40% overall yield from solid-phase benzene sulfinate 1.

An efficient and selective method for the synthesis of spiro-fused (C5)-isoxazolino-(C4)-pyrazolones (C) is reported. The process consists of utilizing the Baylis-Hillman reaction-or a quicker, stepwise MAC procedure-to give I followed by 1,3-dipolar cycloaddition and Swern oxidation to give beta-ketoesters H, which were condensed with hydrazine derivatives to provide hydrazones that underwent cycloelimination. These novel spiro-fused (C5)-isoxazolino-(C4)-pyrazolones were confirmed by spectroscopic analysis as well as single-crystal X-ray of 5. We also concluded that all condensations/cycloeliminations, except with hydrazine itself, were more effective with catalysts or higher reaction temperatures. For example, TiCl(4) was an efficient catalyst for hydrazone formation and cycloelimination with methylhydrazine, while phenyl-, benzyl-, and (4-methoxyphenyl)hydrazine reacted effectively without catalyst in refluxing xylene.

Indolizidines (-)-8-epi-swainsonine triacetate and (+)-1, 2-di-epi-swainsonine were synthesized from the O'Donnell Schiff base ester 1 derived from D-serine. Reductive-alkenylation of 1 with (i)()Bu(5)Al(2)H/H(2)C=CHMgBr followed by substrate-directed dihydroxylation of the pendant allylic group with OsO(4), reduction of imine, and cyclization with Ph(3)P/CCl(4) gave the polyhydroxylated pyrrolidines 8a and 8b as advanced intermediates. Efficient protecting group manipulations converted pyrrolidines 8a and 8b to their corresponding partially protected analogues 10a and 10b, which upon Swern oxidation and diastereoselective Keck-type allylation with BF(3).Et(2)O afforded the required three-carbon homologues (10a, >20:1 de; 10b, 3.5:1 de). Use of the chelating Lewis acid MgBr(2) instead of BF(3).Et(2)O with 10a led to a novel aza-pinacol rearrangement and allylation at the alpha-carbon to yield amino alcohol 17, which is similar to a hydride migration in the biosynthetic pathway of indolizidine alkaloids. Subsequent hydroboration, cyclization, and deprotection furnished (-)-8-epi-swainsonine triacetate 15a and (+)-1,2-di-epi-swainsonine 16b in good overall yields (6.3% for 1 --> 15a, 13 steps, and 4.0% for 1 --> 16b, 14 steps).

The proximity effect in the Swern oxidation of cis,cis-1,3,5-tris(hydroxymethyl)-1,3,5-trimethylcyclohexane (4) with TFAA was examined. The oxidation reaction of triol 4 with DMSO, TFAA, and relatively small amounts of triethylamine gave 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid hemiacetal (7a) as well as 1,7,9-trimethyl-3,5,12-trioxawurtzitane (6), 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone (5), and polymers of cis,cis-1,3,5-triformyl-1,3,5-trimethylcyclohexane (2). Hemiacetal 7a underwent novel solvent-dependent conversions to hemiacetal 7b, lactone 5, or 1,7,9-trimethyl-2-oxo-3,5-dioxatricyclo[5.3.1.04,9]undecane (8) via 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid. In the cases of relatively large amounts of triethylamine, trialdehyde 2 was given in moderate yield.

Opening of representative epoxides with 1,2-amino alcohols delivered the amino diols. The product amino diols were then oxidized under Swern conditions. The amino diketones so prepared were not isolated, but were condensed directly with hydroxylamine to give the substituted pyrazines.

Methods for the annulation of carbohydrates have found extensive applications in organic synthesis. We report here a new protocol for the stereoselective conversion of glucose into an enantiomerically pure cyclopentane aldehyde 22. The readily available epoxide 15 was reacted with allyl Grignard to produce alcohol 16 in 86% yield. Swern oxidation followed by epimerization using triethylamine in N,N-dimethylformamide furnished the ketone 17 also in 86% yield. Regioselective deprotonation with lithium hexamethyldisilazane in THF was followed by methylation with methyl iodide and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone as cosolvent to give 80% yield of ketone 18. Oxidation of ketone 18 by the Wacker procedure gave the 1,4-diketone 19 in 56% yield. Intramolecular aldol condensation occurred readily on treatment of diketone 19 with potassium tert-butoxide in toluene to furnish a 90% yield of enone 20. Treatment with N-bromosuccinimide produced the bromoester 21 in 72% yield, which was reduced to a mix...

An asymmetric total synthesis of (−)-epibatidine (1), isolated from the skin of the Ecuadorian poison frog, Epipedobates tricolor, of the family Dendrobatidae, has been achieved by virtue of the development of asymmetric hetero Diels−Alder (D−A) cycloaddition with an N-acylnitroso dienophile bearing the optically active 8-arylmenthol as a chiral source. Thus, in situ oxidation of the hydroxamic acid ent-12f incorporating the (1S,2R,5S)-8-(2-naphthyl)menthyl auxiliary was performed using the Swern conditions to produce the acylnitroso dienophile, which reacted at once with 2-chloro-5-(1,5-cyclohexadienyl)pyridine (7) to provide the (1S,4R)-meta-aza cycloadduct 24 as a major diastereoisomer. The observed facial diastereoselectivity is consistent with a transition-state model with the naphthyl group in “stacked” position and with the acylnitroso group in the s-cis conformation, wherein π attractive interaction between the naphthyl and nitrosocarbonyl groups may contribute to facial control. Compound 24 under...

Several intramolecular Prins double cyclizations are reported. The 2-alkyl 5-hepten-1,2-diols and their analogues, 9−11, were prepared and oxidized to the aldehydes 6−8 under Swern conditions. Treatment of these α-hydroxy aldehydes with TBSOTf and a hindered base gave the products of an intramolecular Prins double cyclization, namely the 7-(silyloxy)-2-oxabicyclo[2.2.1]heptanes, 17−19, in 84−92% yield. These compounds were formed as single diastereomers with only the anti silyl ethers being obtained. The cyclizations occur when five-membered rings are being formed and when the initially formed cation is highly stabilized. Other substrates do not cyclize, e.g., when the α-hydroxy aldehydes 20−22, prepared from 26−28, are treated under similar conditions, none of the corresponding cyclization products, 23−25, were obtained.

Methyl l-N,O-diacetyldaunosaminide was prepared from 3-nitro-4,5-dihydroisoxazole in 8.5% overall yield. A key step in the synthesis involved the AD reaction of (E)-3-(1-propenyl)-4,5-dihydroisoxazole (2b), affording the corresponding diol in 76% yield (92% ee). A second key step involved reductive cleavage of the dihydroisoxazole 4a and subsequent N-acetylation to afford separable diastereomeric γ-(acetylamino)alcohols 7a and 8a in 62% yield (72:28, 7a/8a). Swern oxidation of 7a and subsequent methanolysis followed by acetylation provided methyl l-N,O-diacetyldaunosaminide as an anomeric mixture. The AD reactions of chiral alkenyl dihydroisoxazole 16 with (DHQ)2−PHAL and (DHQD)2−PHAL afforded diastereomeric diol products, isolated as the acetates 18 and 19 (98:2 and 5:95 ratios, respectively, depending on the chiral auxiliary).

A total synthesis of the enantiomer 35 of kallolide B was achieved starting from (S)-(−)-perillyl alcohol (8). Oxidative cleavage to the ester aldehyde 11 was effected by treatment of the epoxide 9 with H5IO6 followed by CH2N2. The allenyl ketone 13, obtained by SnCl2-promoted addition of 1-bromo-2-butyne to aldehyde 11 and subsequent Swern oxidation, cyclized to the furan 14 in the presence of catalytic AgNO3. Homologation of the derived aldehyde 15 with CBr4−Ph3P followed by n-BuLi and CH2O led to the propargylic alcohol 17. Formylation of the furan 17 (s-BuLi, DMF) and then Still−Horner−Emmons homologation yielded the (Z)-conjugated ester 22. Conversion of the propargylic alcohol function to the chloride 23 and ester reduction (DIBAL-H) furnished the chloro alcohol 24, which formed the cyclic ether 25 upon treatment with NaH. Ether 25 underwent a highly diastereoselective [2,3]Wittig ring contraction to the propargylic alcohol 26. The derived mesylate 36 was converted to the allenic ester 37 with CO an...

The macrocyclic spermidine alkaloid (−)-oncinotine (1), isolated from Oncinotis nitida (Apocynaceae), was synthesized enantioselectively for the first time based on intramolecular iminium ion cyclization utilizing enantiomerically pure (2S)-N-[(benzyloxy)carbonyl]-2-piperidineacetaldehyde (8) as a chiral starting material. The required 8 was derived from the erythro adduct 16, which was obtained by diastereoselective 1,3-dipolar cycloaddition between 2,3,4,5-tetrahydropyridine 1-oxide (4) and (3S)-3-[(tert-butyldiphenylsilyl)oxy]-4-methyl-1-pentene (15). Wittig condensation of 8 with [8-(methoxycarbonyl)octyl]triphenylphosphonium iodide (21) followed by saponification provided the chiral piperidine moiety 23, which was coupled with the N-propyl-1,4-butanediamine segment 29 by using diethoxyphosphoryl cyanide in the presence of triethylamine to afford the tertiary amide 30. Conversion of 30 to the aldehyde 34 via desilylation and Swern oxidation, followed by hydrogenation over a palladium hydroxide catalys...

l-Serine methyl ester hydrochloride was converted to (S)-2-[N-(benzyloxycarbonyl)amino]-3-(tert-butyldimethylsiloxy)propanal (6). Homocoupling of 6 promoted by [V2Cl3(THF)6]2[Zn2Cl6] (1) gave C2-symmetric diol (7). After manipulation of protecting groups and Swern oxidation, 7 was converted to a 1,6-dialdehyde 10. Intramolecular pinacol coupling of 10 with 1 gave a selectively protected 1,4-diamino-2,3,5,6-tetrahydroxycyclohexane, which is the key skeleton of Fortimicin AM and AK.

Conversion of η 4 -cycloheptatriene-Fe(CO) 2 (OPh) 3 to ketocycloheptadiene-Fe(CO) 2 P(OPh) 3 complex 7 was accomplished by hydroboration followed by Swern oxidation. Methylation and hydroxylation of the enolate from 7 proceeds with complete stereoselectivity, anti to the metal moiety, and introduction of two methyl or hydroxyl groups at the α and α' positions was accomplished in high overall yield. Reduction of the ketone group on these complexes occurs with high stereoselectivity and is controlled by the boat conformation adopted by these complexes

The disulfide functionality is present in a number of organic compounds of interest in the fields of both chemistry and biology. Because the disulfide group is known to be highly susceptible to further oxidation by a wide range of agents, performing a chemoselective oxidation without further oxidizing the disulfide moiety poses a synthetic challenge. Reported herein are the first examples of such a chemoselective oxidation in which a series of novel secondary alcohol disulfides 2a-f have been converted to the corresponding symmetrical diketones 3a-f utilizing a modified Swern oxidation.

A biomimetic total synthesis of (±)-methyl homosecodaphniphyllate has been developed. The synthesis starts with a triply convergent, tandem Michael addition-enolate alkylation, wherein amide 9, enoate 7, and alkyl iodide 5 are assembled in essentially quantitative yield to obtain compounds 13, 14, and 15. The major isomer 13 is converted in three steps into a 1:1 mixture of diols 18a and 18b. These diols are subjected to a two-step process involving Swern oxidation and treatment of the resulting dialdehyde sequentially with ammonia and acetic acid

Tetraarylphosphonium (TAP)-supported DMSO, TEMPO, and DIB reagents were synthesized and used for the oxidation of alcohols, including Swern oxidation and for the alpha-acetoxylation of ketones. By taking advantage of the predictable solubility properties of the TAP unit, simple precipitation and filtration of the phosphonium moiety permit complete separation of the desired oxidation products. This paper describes the preparation of these three TAP-supported oxidative reagents and their activity in the aforementioned oxidative transformations. Furthermore, we have demonstrated that these reagents can be recycled directly when used in catalytic processes and following regeneration when used in stoichiometric processes.

Simple strategies for the synthesis of five series of cationic gemini surfactants and one series of zwitterionic gemini surfactants from pentaerythritol have been developed. Two lipophilic groups were introduced onto pentaerythritol by alkylation of the known compound, O-benzylidenepentaerythritol, with 1-bromooctane, 1-bromodecane, 1-bromododecane, and 1-bromotetradecane. Hydrogenolysis of the benzylidene acetals gave diols which were converted into three different series of trimethylammonium derivatives. The diiodides derived from the diols could be displaced by dimethylamine, even though they are adjacent to a quaternary carbon atom. Alkylation with methyl iodide gave the first series. The iodides were easily displaced by cyanide ion and the resulting dinitriles were hydrolyzed, converted to N,N-dimethylamides, and reduced to give a second series. Oxidation of the diols to dialdehydes under Swern conditions followed by Horner-Wadsworth-Emmons reactions with diethyl N,N-dimethylcarbamoylmethylphosphonate followed by two-stage reduction gave a third series. The dialkoxides derived from the four di-O-alkylpentaerthritol diols were reacted with 2-dimethylaminoethyl chloride and 3-dimethylaminopropyl chloride in neighboring-group assisted double Williamson ether syntheses to give precursors to two more series. As expected because the neighboring group participation occurs through a four-membered-ring intermediate, considerably more vigorous conditions were required for the reactions with 3-dimethylaminopropyl chloride. 2-Diethylaminoethyl bromide was found to be less reactive than 2-dimethylaminoethyl chloride. The products were alkylated with methyl iodide and, in some cases, other alkyl halides to give cationic gemini surfactants. Alkylation of one series with ethyl bromoacetate followed by anion exchange resin catalyzed ester hydrolysis gave zwitterionic gemini surfactants. The members of all series have superior surfactant properties.

In this paper we describe enantioselective syntheses of (+)-carbapentostatin (8) and its cyclopentyl analogue 12b. A new and efficient one-pot, two-step preparation of aldehyde 15 has been developed, based on the borane reduction of N-Pf-protected L-aspartic acid gamma-methyl ester (13) and Swern oxidation of the resulting alcohol. Homologation to diester 18 and ring formation by Dieckman cyclization, followed by reduction and dehydration steps, afford the 4-amino-1-cyclopentenemethanol derivative 22. Hydroboration and oxidation transform this compound stereospecifically into aminocyclopentanol 26, the key aminocyclitol component for an asymmetric synthesis of (+)-carbapentostatin.

Both antipodes of the Kishi lactam (3), the versatile intermediate for the synthesis of the perhydrohistrionicotoxin (pHTX) alkaloids, have been prepared. The synthetic route involved a "double Henry" condensation between glutaraldehyde and nitroacetal 5 giving meso dioxanyldiol 4 which was acetylated and reduced to afford meso dioxane amide 8. Ultrasound-promoted deacetalization of 8 followed by Wittig olefination and reduction provided meso amide ester 10. Hydrolysis of 10 with aqueous acid followed by dehydrative cyclization with dicyclohexylcarbodiimide gave lactamdiol 11. Acetylation of 11 gave meso diacetate 2 which was an excellent substrate for esterase-mediated hydrolysis to hydroxyacetate 12. Deoxygenation of 12 using a Barton protocol, followed by Zemplen deacylation and Swern oxidation, gave the (-)-antipode of the Kishi lactam (3). Moffatt oxidation of hydroxyacetate 12 followed by ketal protection and Zemplen deacylation gave ketalalcohol 19. Barton deoxygenation of 19 followed by ketal hydrolysis gave (+)-3.

16 páginas, 2 figuras, 18 esquemas, 1 tabla.-- Supporting Information Available: Experimental procedures and characterization data for compounds 7b-e, 23, 54, and 56, and tables of 1H NMR and 2D NOESY cross-peak intensities for the carbocyclic products 39, 43, 44a-c, 45, 50ad, 51a,b, 52a,b, 65a-c (8 pages)., The intramolecular reductive coupling of a series of simple or polyoxygenated oxime ethers δ- or ε-functionalized with bromide, α,β-unsaturated ester, aldehyde, or ketone groups is reported. The cyclization of a nitrile-tethered aldehyde is also studied. These reductive couplings are promoted by tributyltin hydride or samarium diiodide. The reactions proceed under mild conditions, in good chemical yield, and with high stereoselectivity. When applied to highly functionalized substrates derived from carbohydrates, this approach provides a selective entry to enantiomerically pure aminocyclitols of varying regio- and stereochemistry. In particular, the reductive coupling reaction of carbonyl-tethered oxime ethers promoted by samarium diiodide can be performed in a one-pot sequence, following a Swern oxidation step, allowing the direct transformation of hydroxyl-tethered oxime ethers into the corresponding aminocyclitols. Moreover, the resultant O-benzylhydroxylamine products of these cyclizations can be further reduced in situ with excess samarium diiodide, in the presence of water, to the corresponding amino alcohols in excellent yields. Some transformations of these compounds are discussed., Financial support from DGICYT (grants PB93-0127-C02-01, SAF97-0048-C02-02 and SAF94-0818-C02-02), CICYT (grant CE93-0023), Comunidad Autónoma de Madrid (grant AE-0094/94), and the European Union (Human Capital and Mobility Programme; contract ERBCHRXCT 92-0027) is greatefully acknowledged.

1-beta-(4-Imidazoyl)- and 1-beta-(5-uracilyl)-1,4-dideoxy-1,4-imino-L-lyxitols were synthesized stereoselectively via a sequential procedure by the addition of the corresponding metal salts of heterocycles, Swern oxidation, reductive aminocyclization, and deprotection. Their structures were determined based on X-ray crystallography. From the NMR measurements of their N-acyl derivatives, two rotational isomers were observed. Their bioassay is also described.

Readily available 6-(methylsulfinyl)hexanoic acid (1) is employed as a substitute for DMSO in Swern oxidation reactions using oxalyl chloride to smoothly convert primary or secondary alcohols to corresponding aldehydes or ketones in high yield. The resulting 6-(methylthio)hexanoic acid (2) is easily separable by aqueous extraction or by filtration through silica gel and can be reoxidized to 1 with sodium metaperiodate in 97% yield. Low temperature (-60 degrees C) (13)C NMR spectrometry is used to examine the intermediates of this Swern process. The results indicate that any residual unoxidized alcohol is generated during Pummerer elimination of the alkoxysulfonium intermediate and can be minimized by extended exposure to triethylamine at -40 degrees C. Reaction of the potassium salt of 1 with cross-linked chloromethyl polystyrene affords a polymer-bound reagent 12 that quantitatively oxidizes borneol to camphor when used in two-fold excess.

The zwitterionic Claisen rearrangement of optically-active N-allyl pyrrolidines and various acid chlorides proceeds with high simple diastereoselection (internal asymmetric induction) and high 1,2-asymmetric induction, generating a new C-C bond adjacent to a chiral C-O function. The resulting gamma,delta-unsaturated amides were cyclized to the corresponding optically active gamma-butyrolactones, which are useful intermediates in natural product synthesis. On one hand, a diastereoselective iodocyclization of several lactones led to tetrahydrofurans with a substitution pattern representing a key intermediate of an oxa-prostaglandin synthesis. On the other, a one-pot procedure of a Swern oxidation and consecutive Grignard reaction of one gamma-lactone allowed a diastereoselective chain elongation. The final oxidation/cyclization sequence completed a highly efficient synthesis of the (+)-dihydrocanadensolide or its C-3 epimer, respectively.

Addition of aqueous base to solutions of 2-halc-5-nitropyridines in dimethyl sulfoxide produces a stable substance which forms 2-hydroxy-5-nitropyridine if the molar ratio of hydroxide to pyridine is greater than 2:l. IR and 'H and 13C NMR spectra of the intermediate stable substance indicate that the pyridine ring is cleaved to form this material. An SN(ANRORC) mechanism is proposed for the reaction.