Solution phase synthesis of a diverse library of highly substituted isoxazoles

The iodocyclization of O-methyloximes of 2-alkyn-1-ones affords 4-iodoisoxazoles, which undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles. The palladium-catalyzed processes have been adapted to parallel synthesis utilizing commercially available boronic acid, acetylene, styrene, and amine sublibraries. Accordingly, a diverse 51-member library of 3,4,5-trisubstituted isoxazoles has been generated.     

Solution phase synthesis of libraries of variably substituted olefin scaffolds: a library of allylic amines

The synthesis of allylic amine libraries derived from olefin templates is described. The two-step, solution phase reaction sequence consists of amination of the template followed by Suzuki coupling and expedited purification via ion exchange chromatography. The methodology has been used to synthesize a 1344-member allylic amine library.     

Regiocontrolled synthesis of pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones from pyrrole Weinreb amides

A regiocontrolled synthesis of 3,4-disubstituted pyrrole-2-carboxaldehydes was completed in two steps from acyclic starting materials. A Barton-Zard pyrrole synthesis between N-methoxy-N-methyl-2-isocyanoacetamide and alpha-nitroalkenes or beta-nitroacetates provided N-methoxy-N-methyl pyrrole-2-carboxamides (pyrrole Weinreb amides), which were converted into the corresponding pyrrole-2-carboxaldehydes by treatment with lithium aluminum hydride. A regioselective oxidation of the pyrrole-2-carboxaldehydes gave the corresponding 3,4-disubstituted 3-pyrrolin-2-ones.     

Combinatorial library synthesis of two- and three-ring benzenoid amides on solid support

A liquid crystalline library of 100 molecules with three benzene rings and 18 molecules with two benzene rings was synthesized on solid support by means of benzoylation or acylation and palladium(0)-catalyzed carbonylation of a secondary amine obtained by a reductive amination of 4-iodoaniline and a backbone amide linker. The conversion and purity of the final products are high enough to investigate the mesomorphic properties.     

Solution phase synthesis of esters within a micro reactor

A range of techniques are demonstrated for the solution phase synthesis of esters within an EOF-based borosilicate glass micro reactor, including the use of mixed anhydrides and the in situ preparation of acyl halides.     

Solid phase synthesis of a spiro[5.5]ketal library

A spiro[5.5]ketal library embodying the core structure of numerous biologically active natural products was synthesized employing a double intramolecular hetero Michael reaction as a key transformation.     

Solution phase synthesis of alamethicin I

The total synthesis of alamethicin I by solution phase methods is reported.     

Enantiospecific synthesis of tetrasubstituted δ-lactones

For investigations concerning the selectivity of polyketide synthases (PKSs) which have been rationally engineered through genetic techniques the synthesis of substituted δ-lactones is of great importance. An enantiospecific route towards eight of the possible sixteen stereoisomers was developed which is also readily adaptable for the introduction of alkyl modifications and isotopic labels.     

A facile solution phase combinatorial synthesis of tetrasubstituted pyridines using the Bohlmann-Rahtz heteroannulation reaction

The solution phase combinatorial Bohlmann-Rahtz reaction gives highly functionalized pyridine libraries from enamino esters and alkynones in a single synthetic step. Good product ratios and library purities were obtained in reactions catalyzed by zinc(II) bromide, the acid-catalyzed heteroannulation procedure offering considerable improvements over traditional methodology.     

Diversity-oriented synthesis of tamoxifen-type tetrasubstituted olefins

A general synthetic scheme for tamoxifen-type tetrasubstituted olefins based on the novel Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane has been developed. A wide array of electronically and structurally diverse tetrasubstituted olefins can be prepared in a regiocontrolled, stereocontrolled, and diversity-oriented manner. Noteworthy features are that (i) the three aryl groups, which are believed to be important (essential) for anti-estrogenic activity, can be varied at will because they all stem from readily available aryl iodides, and (ii) any stereo- and regioisomers can, in principle, be prepared by simply changing the applying order of aryl iodides into the sequence.     

Solution phase synthesis of libraries of polycyclic natural product analogues by cascade radical annulation: synthesis of a 64-member library of mappicine analogues and a 48-member library of mappicine ketone analogues

An improved cascade radical annulation route to (+/-)-mappicine, (S)-mappicine, and mappicine ketone is reported. The route is used to prepare libraries of mappicine and mappicine ketone analogues in a semiautomated fashion. Key diversity generating steps include the addition of an aldehyde to a Grignard reagent derived from a D-ring iodopyridine, N-propargylation of a subsequently derived iodopyridone, and cascade radical annulation with an isonitrile to form a mappicine analogue. Parallel oxidation of mappicine analogues produced mappicine ketones. The route is general and flexible and could be used to make very large libraries. It is also illustrative of how late stage cascade reactions can be employed strategically to generate libraries of polycyclic natural product analogues.     

Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters

Multifunctionalized dihydropyrimidine-5-carboxylic amides and esters are generated in a multistep sequence integrating a variety of enabling and high throughput technologies such as automated or parallel microwave synthesis, the use of polymer-supported reagents, fluorous synthesis and purification strategies, and a continuous flow hydrogenation system. The key dihydropyrimidine-5-carboxylic acid intermediates are obtained in two steps by Biginelli multicomponent condensation of benzyl or allyl β-ketoesters with aldehydes and urea/thioureas, followed by suitable benzyl or allyl deprotection strategies. Further functionalization of the acid cores with amines using polymer-supported coupling reagents or with alcohols utilizing Mitsunobu chemistry provides the desired amides or esters, respectively.     

Fmoc solid phase synthesis of polyamides containing pyrrole and imidazole amino acids

[structure: see text]. Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids are synthetic ligands that have an affinity and specificity for DNA comparable to those of many naturally occurring DNA binding proteins. A machine-assisted Fmoc solid phase synthesis of polyamides has been optimized to afford high stepwise coupling yields (>99%). Two monomer building blocks, Fmoc-Py acid and Fmoc-Im acid, were prepared in multigram scale. Cleavage by aminolysis followed by HPLC purification affords up to 200 mg quantities of polyamide with purities and yields greater than or equal to those reported using Boc chemistry. A broader set of reaction conditions will increase the number and complexity of minor groove binding polyamides which may be prepared and help ensure compatibility with many commercially available peptide synthesizers.     

General synthesis of tetrasubstituted alkenyl-1,3,4-oxadiazoles

Tetrasubstituted alkenyl-1,3,4-oxadiazoles were synthesized in moderate to excellent yield, under mild conditions and in the presence of sensitive functional groups, via the cyclization of diacylhydrazides using PPh₃ and hexachloroethane in the presence of Hünig’s base. An efficient one-pot acylation/cyclization approach for the conversion of acylhydrazides to 1,3,4-oxadiazoles is also described. The complexity of our substrate as well as the wide range of functional groups incorporated substantially broadens the scope of this methodology.     

A new germanium-based linker for solid phase synthesis of aromatics: synthesis of a pyrazole library

An efficient synthesis of chlorogermane linker 12 is described. Economic introduction of germanium into this linker is accomplished by insertion of dichlorogermylene [from germanium(IV) chloride] into the homobenzylic C-Cl bond of 4-(2-chloroethyl)phenol 1. Using linker 12, transmetalation with lithiated 4-acetophenone, 3-acetophenone, and 4-(4'methoxy)biphenyl followed by Mitsunobu-type coupling to Argogel gives functionalized resins 14, 16, and 18, respectively. Treatment of resin 18 with TFA, ICl, Br2, or NCS effects clean ipso-degermylation releasing biphenyls 19-22, respectively. Resins 14 and 16 are employed for the parallel synthesis of a library of pyrazoles by enaminone formation (using Bredereck's reagent), condensative ring-closure (using a series of monosubstituted hydrazines), and cleavage (using TFA and Br2). Analysis of this library reveals the influence of the hydrazine substituent on both the regioselectivity of ring-closure and the propensity for electrophilic substitution at the 4-position of the pyrazoles during ipso-degermylative cleavage.     

The parallel synthesis of a disaccharide library using a solid phase, peptide-templated strategy

A novel strategy for the synthesis of oligosaccharides, involving the use of a solid phase peptide template, has been successfully applied to the construction of a twelve member disaccharide library.     

Solid phase synthesis of amides by the Beckmann rearrangement of ketoxime carbonates

In the presence of trifluoroacetic acid, ketoxime benzyl carbonates undergo a Beckmann rearrangement to the corresponding amides. This reaction was translated to a solid support by immobilizing oximes in the form of mixed carbonates derived from hydroxymethylpolystyrene in order to produce a diversity of amides with high efficiency.     

An improved aldehyde linker for the solid phase synthesis of hindered amides

A novel aldehyde dual-linker system has been developed for the solid phase synthesis of sterically hindered amides. The linker [5-(4-formyl-3-hydroxyphenoxy)pentanoic acid] exploits an intramolecular oxygen-nitrogen acyl transfer mechanism to prepare compounds that are unattainable with current commercially available linkers. A dual linker system, exploiting the hyper-acid labile Sieber amide linker as part of the construct, enabled the initial reductive alkylation reactions of hindered amines and their subsequent acylation with a range of carboxylic acids with varying stereoelectronic properties to be monitored. Simple acylation conditions (HBTU/HOBt/NMM) sufficed to provide near quantitative reaction of test acids with support-bound hindered amines, reaction conditions which failed when commercial linkers were used.     

A novel pyrrole synthesis

The silver(I)-promoted oxidative cyclization of homopropargylamines at room temperature provides a novel access to pyrroles. Homopropargylamines are readily available by the addition of a propargyl Grignard reagent to Schiff bases.