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Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetra hydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.

Background Current modulator therapies for some cystic fibrosis-causing CFTR mutants, including N1303K, have limited efficacy. We provide evidence here to support combination potentiator (co-potentiator) therapy for mutant CFTRs that are poorly responsive to single potentiators. Methods Functional synergy screens done on N1303K and W1282X CFTR, in which small molecules were tested with VX-770, identified arylsulfonamide-pyrrolopyridine, phenoxy-benzimidazole and flavone co-potentiators. Results A previously identified arylsulfonamide-pyrrolopyridine co-potentiator (ASP-11) added with VX-770 increased N1303K-CFTR current 7-fold more than VX-770 alone. ASP-11 increased by ~65% of the current of G551D-CFTR compared to VX-770, was additive with VX-770 on F508del-CFTR, and activated wild-type CFTR in the absence of a cAMP agonist. ASP-11 efficacy with VX-770 was demonstrated in primary CF human airway cell cultures having N1303K, W1282X and G551D CFTR mutations. Structure-activity studies on 11 synthesized ASP-11 analogs produced compounds with EC 50 down to 0.5 μM. Conclusions These studies support combination potentiator therapy for CF caused by some CFTR mutations that are not effectively treated by single potentiators.

A Davis–Beirut reaction inspired nitroso Diels–Alder protocol is reported. The starting material for the procedure is a nitrophenyl moiety with the para position appropriately substituted with a 2°-amine (see 5) or 2°-alcohol (see 6). Deprotonation at the benzylic position followed by concomitant oxidation of the benzylic position and reduction of the nitro moiety delivers a nitrosophenyl intermediate, which subsequently undergoes a nitroso Diels–Alder reaction. This one-pot procedure delivers aryldihydro-1,2-oxazines in moderate yields.

A transition metal-free, one-pot protocol has been developed for the synthesis of 11H-indolo[3,2-c]isoquinolin-5-amines via the atom economical annulation of ethyl (2-cyanophenyl)carbamates and 2-cyanobenzyl bromides. This method proceeds via sequential N-alkylation and base-promoted cyclization. Optimization data, substrate scope, mechanistic insights, and photoluminescence properties are discussed.

Increased concentrations of secreted phospholipase A2 type IIA (sPLA2-IIA), have been found in the synovial fluid of patients with rheumatoid arthritis. It has been shown that sPLA2-IIA specifically binds to integrin αvβ3, and initiates a signaling pathway that leads to cell proliferation and inflammation. Therefore, the interaction between integrin and sPLA2-IIA could be a potential therapeutic target for the treatment of proliferation or inflammation-related diseases. Two one-bead-one-compound peptide libraries were co nstructed and screened, and seven target hits were identified. Herein we report the identification, synthesis, and biological testing of two pyrazolylthiazole-tethered peptide hits and their analogs. Biological assays showed that these compounds were able to suppress the sPLA2-IIA-integrin interaction and sPLA2-IIA-induced migration of monocytic cells and that the blockade of the sPLA2-IIA-integrin binding was specific to sPLA2-IIA and not to the integrin.

The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antimitochondrial autoantibodies (AMAs) directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Furthermore, approximately one-third of patients who have ingested excessive amounts of acetaminophen (paracetamol) develop AMA of the same specificity as patients with PBC. Quantitative structure-activity relationship (QSAR) data indicates that acetaminophen metabolites are particularly immunoreactive with AMA, and we submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate a loss of tolerance and lead to the development of PBC.

Copper catalyzed azide-alkyne cycloaddition (CuAAC) chemistry is reported for the construction of previously unknown 5-(1 H -1,2,3-triazol-1-yl)-4,5′-bithiazoles from 2-bromo-1-(thiazol-5-yl)ethanones. These novel triazolobithiazoles are shown to have cystic fibrosis (CF) corrector activity and, compared to the benchmark bithiazole CF corrector corr- 4a , improved log P values (4.5 vs 5.96).

Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.

The synthesis of glycosylated Fmoc amino acids by reaction of mono- and disaccharide peracetates with Fmoc amino acids having free carboxyl groups was rapidly promoted by Lewis acids (SnCl(4), BF(3)·Et(2)O) under microwave irradiation. The products are useful building blocks for the synthesis of glycopeptides.

A developing therapy of ΔF508-CFTR, the most common CFTR mutation causing cystic fibrosis, employs correction of defective CFTR chloride channel gating by a ‘potentiator’ and of defective CFTR protein folding by a ‘corrector’. Based on SAR data for phenylglycine-type potentiators and bithiazole correctors, we designed a hybrid molecule incorporating an enzymatic hydrolysable linker to deliver the potentiator (PG01) fragment 2 and the corrector (Corr-4a) fragment 13. The hybrid molecule 14 contained PG01-OH and Corr-4a—linker—CO2H moieties, linked with an ethylene glycol spacer through an ester bond. The potentiator 2 and corrector fragments 13 (after cleavage) had low micromolar potency for restoration of ΔF508-CFTR channel gating and cellular processing, respectively. Cleavage of hybrid molecule 14 by intestinal enzymes under physiological conditions produced the active potentiator (2) and corrector fragments (13), providing proof-of-concept for small-molecule potentiator-corrector hybrids as a single drug therapy for CF caused by the ΔF508 mutation.

SummaryMitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.

Two polymer-supported versions of the Corey, Bakshi, and Shibata (CBS) catalyst were prepared and examined. Polymeric beads, with the auxiliary bound in pendant and crosslinked fashion, were prepared utilizing an improved procedure based upon earlier work. Optimization of a procedure for ketone reduction gives results that match those in solution. Attempted reuse gave mixed results. For comparison purposes, CBS functionalized monoliths were formed and tested but performed poorly.

A solid phase strategy has been developed for the synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins. The key transformation is an intramolecular ipso substitution reaction which forms the coumarin heterocycle and culminates with cleavage of product from the polymer support. The pyridine moiety at C3 can be further modified with Suzuki coupling. A sample library with two diversity elements has been synthesized to demonstrate this ipso substation-based cyclo-elimination strategy.

3,4-Dihydro-2H-pyrrole derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of nitrile ylides with acrylamides. Acrylamide substitution patterns and benzimidoyl chloride equilibration were investigated.

A solid-phase synthetic route to quinoxaline, thiazine, and oxazine analogs is described. N-Alloc-3-amino-3-(2,4-difluoro-5-nitrophenyl)propanoic acid was tethered to Rink resin via its carboxylic acid group. The 4-arylfluorine was displaced with a primary amine, alcohol, or thiol to create, respectively, a resin bound aniline, phenol, or thiophenol derivative with one diversity element and one single atom (e.g., N, S, or O) diversity point. A fused heterocyclic system was subsequently created via a benzyne heterocyclization initiated by dehydrofluorination with strong base. Acid treatment released the desired products in high yield and moderate purity.

A traceless solid-phase route to 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinazolin-2-ones is described. N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was tethered to Rink resin via its carboxylic group. The protected amine was coupled with an organic acid after Alloc-deprotection and the arylfluorine was displaced with a primary amine to generate a resin-bound aniline with two diversity points. The aniline was released via cleavage to produce the desired products in high yield and purity.

A convenient solid phase synthesis of trisubstituted imidazolidinones and pyrimidinones via microwave assisted DIC-promoted intramolecular cyclization is described. Intramolecular cyclization of a resin-bound thiourea prepared by acylation of a dipeptide with an aryl isothiocyanate was rapidly promoted with DIC under microwave to afford imidazolidinones and tetrahydropyrimidinones in good yield and purity.

An enzyme labeling and screening strategy for the discovery of ligands selective in binding two structurally similar members of the aldo-keto reductase family of enzymes is reported. The resulting fluorescence microscope data obtained by screening a 74,088 member library led to the identification of selective ligands for aldose reductase (ALR2) and aldehyde reductase (ALR1). Resynthesis results validate the selectivity of these ligands.

Solid phase synthesis of 1, 2-disubstituted-6-nitro-1,4-dihydroquinazolines is described. The new tetrafunctional scaffold N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was prepared by nitration of 3-amino-3-(2-fluorophenyl)propionic acid. The scaffold was anchored to Rink resin via its carboxylic group and treated with primary amines to displace the arylfluorine followed by cyclization with aryl isothiocyanates in the presence of DIC upon Alloc deprotection to afford 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines in high yield.

Divinylbenzene (DVB) and diethylene glycol bis(4-vinylbenzyl) ether (DEG) were used as crosslinkers in the preparation of four resins of mixed micro- and macroporous character and differing polarity to examine the effects of crosslinker structure and macroporosity. The Suzuki coupling process was used as the probe reaction for this purpose. Results with 2% DVB, 2% DEG, 5% DEG and 15% DEG indicate that the DEG-crosslinked resins are somewhat better suited for this process, although the degree of crosslinking appears to have only minimal effect of degree of conversion to product.

A number of (1 H -1,2,3-triazol-1-yl)benzo[ d ]thiazoles were synthesized utilizing a versatile Cu-catalyzed azide–alkyne click reaction (CuAAC) on tautomeric benzo[4,5]thiazolo[3,2- d ]tetrazole ( 1 ) and 2-azidobenzo[ d ]thiazole ( 2 ) starting materials. Moreover, one of the resulting products of this investigation, triazolbenzo[ d ]thiazole 22 , was found to possess significant neuroprotective activity in human neuroblastoma (SH-SY5Y) cells.

A one-pot route to 3-benzo[b]thiophen-2-yl-acrylates ( 2 ) from the corresponding thiophenols ( 1 ) is reported. Ester reduction and subsequent hydroxyl esterification deliver psuedo trienoates ( II ) which undergo an intramolecular Diels–Alder (IMDA) reaction to give two 2-oxa-9-thiacyclopenta[b]fluoren-3-one products ( I )—the major Diels–Alder product rearomatizes to 7 .

Polymer-bound α-sulfonyl monocarbanions can be generated very effectively with dimsyl anion. The highly efficient and convenient protocols presented here report the preparation of α,β-unsaturated ketones and vinylaryl compounds using dimsyl anion to achieve the key solid-phase α-sulfonyl monocarbanion alkylation step.

Polymers of norbornene 4- O -(β- d -galactopyranosyl)-β-1′-((±)- exo -5-norbornene-2-carboxamido)-1′-deoxy glucitol were synthesized using PdCl 2 catalyst in water. Molecular weights were measured by MALDI and GPC with on-line MALLS and differential refractive index (DRI) detection. Polymer molecular weights were found to be dependent upon both the concentration of reagent monomer and catalyst (PdCl 2 ), while polydispersity was found to be independent of monomer and catalyst concentration. Molecular weights and polydispersity index derived from MALDI-MS were in good agreement with the MALLS-GPC method.

Novel heterocyclic compounds containing the 3-(4,5-dihydroisoxazol-5-yl)pyrrole ring system were synthesized in good yields (66–78%) by regioselective 1,3-dipolar cycloaddition of nitrile oxides to 1-phenylsulfonyl-1,3-dienes followed by Barton–Zard pyrrole annulation.

We have established that using an oxidation-Cope elimination cleavage protocol allows for the synthesis of N , N -disubstituted hydroxylamines from REM resin (polymer-bound benzyl acrylate). Michael addition of a secondary amine or addition of a primary amine followed by reductive alkylation provides polymer-bound tertiary amines. Oxidation of these resin-bound tertiary amines with MCPBA is followed by concomitant Cope elimination to regenerate the polymer-bound acrylate and provide the cleaved hydroxylamines.

Optically active derivatives of vesamicol are prepared using solid-phase chemistry. Zincke coupling of resin-bound amino ethers (trityl linker) with 2,4-dinitrophenyl pyridinium salts delivers Zincke products which can be (1) liberated from the resin (TFA) or (2) reduced (NaBH 4 ) to tetrahydropyridine derivatives and liberated. Subsequent reduction (H 2 /Pd) gives piperidines.

d -Glucal is converted to epoxy allylic alcohol 4 using an eight-step sequence that features a stereoselective methyl Grignard addition to an iodo-hexenulose. Epoxide formation via intramolecular iodide displacement occurs subsequent to an unusual hemiacetal reduction protocol involving LiBH4 in n-octanol. Alcohol 4 and the corresponding aldehyde (Z)-14 are potential C(4)–C(9) templates for eleutheside syntheses.

A simple method for the synthesis of pH-responding polymers containing barbituric acid moieties is described. The synthesis involves N-methyl-N′-(4-vinylbenzyl) urea (2) preparation and its polymerization in DMF using AIBN as the initiator to give poly(N-methyl-N′-(4-vinylbenzyl)urea) (4) with a number average molecular weight of 4.9×105 as determined by GPC. Cyclocondensation of urea with malonic acid in acetic acid/acetic anhydride affords the polymer (5) with pendant barbituric moieties. The pH-responding behavior of polymer 5 in water indicates that it has excellent pH-sensitivity at pH 6∼7. The potential and the versatility of this work are exciting and include the potential preparation of water-soluble polymers by modification of polyureas, metal chelating materials, and “smart” hydrogels upon crosslinking.

The flavonoid genistein and the benzo[c]quinolizinium MPB-07 have been shown to activate the cystic fibrosis transmembrane conductance regulator (CFTR), the protein that is defective in cystic fibrosis. Lead-based combinatorial and parallel synthesis yielded 223 flavonoid, quinolizinium, and related heterocyclic compounds. The compounds were screened for their ability to activate CFTR at 50 microm concentration by measurement of the kinetics of iodide influx in Fisher rat thyroid cells expressing wild-type or G551D CFTR together with the green fluorescent protein-based halide indicator YFP-H148Q. Duplicate screenings revealed that 204 compounds did not significantly affect CFTR function. Compounds of the 7,8-benzoflavone class, which are structurally intermediate between flavones and benzo[c]quinoliziniums, were effective CFTR activators with the most potent being 2-(4-pyridinium)benzo[h]4H-chromen-4-one bisulfate (UCcf-029). Compounds of the novel structural class of fused pyrazolo heterocycles were also strong CFTR activators with the most potent being 3-(3-butynyl)-5-methoxy-1-phenylpyrazole-4-carbaldehyde (UCcf-180). A CFTR inhibitor was also identified. The active compounds did not induce iodide influx in null cells deficient in CFTR. Short-circuit current measurements showed that the CFTR activators identified by screening induced strong anion currents in the transfected cell monolayers grown on porous supports. Compared with genistein, the most active compounds had up to 10 times greater potency in activating wild-type and/or G551D-CFTR. The activators had low cellular toxicity and did not elevate cellular cAMP concentration or inhibit phosphatase activity, suggesting that CFTR activation may involve a direct interaction. These results establish an efficient screening procedure to identify CFTR activators and inhibitors and have identified 7,8-benzoflavones and pyrazolo derivatives as novel classes of CFTR activators.

Synthesis of the strained 2 H -thieto[3,2- b ]quinoline ring system is reported for the first time. Treatment of ( Z )-2-benzyliden-2 H -thieto[3,2- b ]quinoline derivatives of this heterocycle with base, at reflux in ethanol, causes a novel rearrangement to 2-phenylthieno[3,2- b ]quinolines. Indeed, the one-pot reaction of 2-aminobenzaldehydes and ( Z )-2-benzylidenethietan-3-one in refluxing basic ethanol leads directly to 2-phenylthieno[3,2- b ]quinolines in good yields.

A series of thermo-sensitive hydrogels has been prepared from reactions of acylated poly(ethylene glycol) bis(carboxymethyl) ether (PEGBCOCl) (M n =600 dalton ) with lactitol-based polyether polyols (LPEPs). These LPEP hydrogels swelled extensively in water at neutral pH and their swelling behaviors depended strongly on the PEGBCOCl:LPEP molar ratios or extent of PEGBCOCl crosslinking. A maximum swelling of 81 fold was observed on hydrogels formed with LPEP (M n =4055 dalton ) at a PEGBCOCl:LPEP molar ratio of 4.25. At temperatures above 25°C, the hydrogels exhibited a phase transition and collapsed, expelling water. These super-absorbent hydrogels were stable under acidic conditions, but were sensitive to base hydrolysis. Enzyme proteins, i.e. lipase, were incorporated in the hydrogels (0.4–1.2 mg/g) by immersing the collapsed hydrogels in the protein solutions at 25°C. Protein desorption at 40°C occurred rapidly with over 90% of protein released during the first hour. The extent of protein desorption was similar among hydrogels with varying levels of absorbed proteins. The release of the lipase protein molecules is due to the structural collapse of the hydrogels and is not diffusion controlled.

cyclo-Elimination reactivity differences in I→II are reported. These reactivity differences dictate the selection of Wang resin for N1-substituted hydantoin formation and Merrifield resin for N1-unsubstituted hydantoin formation.

Preparation of a β-dimethylphenylsilylethyl (BMPSE) ester linker from 2% divinylbenzene–styrene copolymer by lithiation, chlorodimethylvinylsilane silylation, hydroboration/oxidation (giving 9 ), and O -acylation is reported. The resulting polymer-bound BMPSE esters were employed in a reaction sequence consisting of RCHO→RCHNOH→isoxazoline/isoxazole (giving 12 ).

A wider scope of the one-step reaction of amino-substituted heterocycles with diiodomethane is demonstrated by the synthesis of a variety of novel pyridino, isoquinolino, benzimidazolo, and benzthiazoloazacyanines.

The intermolecular Knoevenagel condensation of β-hemiacetyl ester proceeds by an in situ unmasking of a reactive ω-hydroxy-β-keto ester giving unsaturated ω-hydroxy-β-keto esters 6–12 which accommodate acetal formation.

Acid hydrazides were coupled with acrylic acid derivatives and cyclodehydration gave 1,3,4-oxadiazoles. Lastly, in-situ nitrile oxide formation from aryl oximes treated with sodium hypochlorite, and subsequent 1,3-dipolar cycloaddition to the exomethylene moiety delivered 2-(4,5-dihydroisoxazol-5-yl)-1,3,4-oxadiazoles. This library was evaluated in a high-throughput screen at Dow AgroSciences. Several compounds were active against fungal pathogens and pest insects.

An unexpected selectivity trend in the nitrile oxide cycloaddition and epoxidation reactions of 4,4-disubstituted cyclopentenes is reported. A variety of facially distinct, ‘X-’ and ‘Y-substituted’ cyclopentenes were investigated.

The preparation of polyamine lipids via Michael addition of diamines to tetraester bisacrylates is described. A new pentaerythritol protection strategy enabled the synthesis of a bis( p -methoxybenzyl)diether diol which was used to prepare the saturated and unsaturated diester cores.

Solid-phase regioselective nitrile oxide 1,3-dipolar cycloaddition to an ω-alkynyl ester followed by reductive α- N -alkylation and isocyanate α- N -acylation delivers I and sets the stage for the uncatalyzed carbanilide cyclo-elimination of isoxazoloimidazolidinedione heterocycles ( I → II ). This traceless release step is induced by simply warming the urea ester intermediate, but requires that the N 3 of the nascent hydantoin be fully substituted ( I → II ; R c ≠H).

A general method is described to prepare pyrazolo [3,4-g] - [2,1] dihydrobenzoisoxazol (in) es utilizing intramolecular nitrile oxide cycloaddition (INOC) as the key step.

Copolymerization of d -lactose-O-(p-vinylbenzyl)-hydroxime (LVH), a new vinyl monomer, with acrylonitrile (AN) was performed in DMSO with AIBN as the initiator. The conversion of LVH is much faster than that of AN and reaches 100% in 2 h. The reactivity ratios of LVH and AN, as determined by the extended Kelen-Tudos method, are 1.0975 and 0.0554, respectively. Increasing the proportion of LVH in the monomer mixture significantly increases the LVH content in the copolymer. The conversion of monomers and the AN content in the copolymer rise gradually with increasing reaction time and initiator concentration. The number average molecular weights of the copolymers are independent of the monomer feed ratios. The LVH-co-AN copolymers exhibit lower glass transition temperatures than PLVH homopolymer. The presence of small amounts of LVH in the copolymer chain reduce the cyclization of nitrile groups in AN segments of the copolymer. Complete disappearance of nitrile cyclization is observed when the contents of LVH reaches and exceeds 16.9%.

Cu(II)-catalyzed coupling of polymer-bound ω-haloalkyn-l-ols to terminal alkynes proceeds in moderate yield to give unsymmetrical diynes upon hydrolytic removal from the polymer. Formation of the symmetrical homocoupled byproduct is suppressed relative to conventional Cadiot-Chodkiewicz conditions in homogeneous solution.

Hydantoin ring formation via carbanilide cyclization is achieved in high yield with short reaction time by employing catalytic amounts of Ba(OH) 2 (anhydrous or octahydrate) in DMF under microwave irradiation. Evidence is provided that kinetic product 4 (trans, anti, cis stereochemistry) epimerizes to thermodynamic product 3 (trans, anti, trans stereochemistry).

Radical-mediated ring expansion methodology is presented wherein 7-membered carbocycles can be prepared from the corresponding xanthate derivatives of bicyclo[4.1.0]heptan-1-methanol. In certain systems, an intermediate cycloheptyl radical appears to be kinetically favored over the cyclohexyl radical, but the direction of cyclopropylcarbinyl radical fragmentation is subject to substitution about the bicyclo[4.1.0]heptan-1-methyl ring.

An efficient, diastereoselective route to 2, 5, 6, 7-tetra-substituted 1H-purrolo[1,2-c]imidazoles has been developed using azomethine ylide cycloaddition and urea cyclization reactions. Relative stereochemical assignments at the four contiguous pyrrolidine stereogenic centers were established by single-crystal X-ray analysis.

By tethering allyl sulfone to polystyrene (3-steps from polystyrene beads consisting of lithiation, sulfination, and allylation), trisubstituted olefins can be generated by Cα-sulfone alkylation and subsequent resin cleavage by S N 2′ nucleophilic displacement of sulfinate.

A solid-phase split-mix organic synthesis method was developed which, by two synthetic steps, converts polymer-bound aldehyde I into resins III. Step one consists of dividing I into three equal portions in separate flasks, condensing each with a different ylide, and subsequently recombining to give II. This mixture of beads was again equally divided into three flasks, and each flask treated with a thiolate Michael donor. Prior to recombining the contents of each flask (i.e., sub-library), samples of each resin were removed and incubated with a THF/HCO2H mixture to liberate the small molecule products. GC-MS established that each sub-library (A, B, and C) contained the three anticipated formate esters. In addition, GC analysis illustrates that, while there were no purification steps involved in this solid-phase analogous organic synthesis save bead washings between steps, the desired products are obtained in excellent purity. Single bead (200–400 mesh) selection from library D (combined sub-libraries A-C), solvolysis, and GC-MS analysis shows that compound identities can be established on a per bead basis.

Intermolecular Pauson-Khand (PK) reactions of norbornene-derived substrates have been carried out with several α,ω-alkynols under both normal homogeneous conditions and with the alkynol bound to functionalized Merrifield's polymer beads. With 2% crosslinked resin chemoselectivity favoring PK product formation over alkyne trimerization and other related side reactions is enhanced over that found either in solution or on 1% crosslinked polymer. Alkynol chain length and nature of the linker also significantly affect the outcome of the polymer-supported process.