An oligomer-based approach to skeletal diversity in small-molecule synthesis

Access to small molecules of widely varying molecular shapes has been identified as an enabling step in the discovery of biologically active materials. In this communication we introduce an approach to the systematic development of architecturally distinct chemical compounds based upon the assembly of reactive monomers into linear oligomers, each of which encodes a unique molecular framework under a common set of reaction conditions. Certain products of the initial chemical transformation (Ru-catalyzed metathesis reaction) encode additional skeletons upon treatment with a second common set of reagents (Diels-Alder dienophiles). Application of this oligomerization approach has led to the discovery of a previously unreported tandem ene-yne-yne metathesis-6pi-electrocyclization-1,5-hydride migration that converts a linear substrate into a complex tricyclic 1,3-diene in a single step. Thus, the reported strategy might serve not only as a generator of skeletally diverse small molecules but also as a discovery platform for the identification of novel chemical transformations.     

Stereochemical and skeletal diversity employing pipecolate ester scaffolds

[structure: see text] The stereocontrolled synthesis of pyridooxazinones by Mg(OTf)2-promoted epoxide ring-opening with use of chiral pipecolates as nucleophiles is described. Pyridooxazinone products derived from azido-epoxides can be further rearranged to seven-membered pyridodiazepinones by azide reduction. The sequence of functional group interconversions generates diversity through topological and stereochemical variation.     

Exploring skeletal diversity via ring contraction of glycal-derived scaffolds

Aryl ether C-glycoside scaffolds have been prepared from tri-O-acetyl-D-glucal by C-glycosylation followed by allylic substitution with phenols mediated by Pd(0). The aryl ethers were subjected to either [3,3]-sigmatropic rearrangement to produce 3-pyranyl-phenols or Au(III)-mediated ring contraction to create highly substituted tetrahydrofurans. [structure: see text]     

An orthogonal approach to multifunctional molecularly imprinted polymers

[structure: see text] An "orthogonal" approach to molecularly imprinted polymers has been demonstrated using a crown ether derived monomer that does not exhibit cross-reactivity with other functional monomers. This strategy provides multiple functional groups in the binding site of molecularly imprinted polymers (MIPs) without unproductive interactions between functional monomers. The orthogonal functional group system was shown to act cooperatively in MIPs to bind a template with higher selectivity than any of the individual functional monomers alone.     

A general approach to N-heterocyclic scaffolds using domino Heck-aza-Michael reactions

Palladium-catalyzed domino Heck-aza-Michael reactions for the synthesis of a series of C1-substituted tetrahydro-β-carbolines, tetrahydroisoquinolines and isoindolines are described. The domino process involves the initial intermolecular Heck reaction of an aryl bromide with an electron deficient alkene, followed by an intramolecular aza-Michael reaction to form the new N-heterocycle in high yield.     

A unified synthetic approach to polyketides having both skeletal and stereochemical diversity

An efficient systematic approach to the diversity-oriented synthesis of polyketides has been developed to provide both skeletal and stereochemical diversity. Each synthetic intermediate is also a desired polyketide fragment and no protecting group manipulations are required. A first-generation synthesis provides a 74-membered polyketide library comprising six different skeletal classes, each in one to five steps from propargylic alcohol precursors. A study of epoxyol opening reactions revealed unusual reactivity trends based on epoxide configuration.     

Small-molecule diversity using a skeletal transformation strategy

[reaction: see text] We describe a short synthetic sequence resulting in >4000 skeletally diverse small molecules that have three distinct skeletal frameworks among other unique structural features. The sequence entails skeletal transformations pioneered by Winterfeldt and co-workers. We use epoxide ring openings and subsequent functionalizations that provide, e.g., spirocyclic oxazolidines, Lewis acid catalyzed Diels-Alder reactions of a steroid-derived diene that afford stable and isolable ring B adducts, and subsequent retro-Diels-Alder fragmentations that yield 14-membered paracyclophanes.     

Synthesis of multifunctional nanogels using a protected macromonomer approach

Nanoparticles possessing multiple functionalities provide synthetic handles for varied surface chemistries, making them useful for a range of applications such as biotargeting and drug delivery. However, the combination of interfering functionalities on the same particle is often challenging. We have employed a synthetic scheme involving chemical protection/deprotection to combine interfering functional groups on the same hydrogel nanoparticle. The synthesis of amine-containing poly(N-isopropylacrylamide) nanogels was carried out via free radical precipitation polymerization by incorporating a Fmoc-protected amine poly(ethylene glycol) (PEG) macromonomer. The Fmoc group was then removed to obtain free amines, which were shown to be available for conjugation. We further explored pNIPAm-co-acrylic acid nanogels with a protected amine-PEG, yielding zwitterionic particles. With careful attention to the order of the chemoligation and deprotection steps, these interfering functional groups can be forced to behave in a pseudo-orthogonal fashion, allowing for multiple chemoligation steps that employ both the amine and carboxylic acid groups.     

Enzymatic approach to unnatural glycosides with diverse aglycon scaffolds using glycosyltransferase VinC

Glycosyltransferase VinC was explored for a construction of glycoside libraries using dTDP-vicenisamine and structurally unrelated unnatural aglycons, and new unnatural vicenisaminides were successfully constructed. Structural elements of aglycon recognition by VinC were proposed by modeling studies and were confirmed by the success of transglycosylation upon a designed aglycon.     

Synthesis of new phenylpyridyl scaffolds using the Garlanding approach

One-pot reaction for the synthesis of novel phenylpyridyl derivatives and mixed quater phenylpyridyl compounds is described by using the Garlanding approach. The reactions proceed with moderate to good yields in mild conditions and good reaction times. This work represents a second application of the simplicity and versatility of Garlanding concept for the construction of new phenylpyridyl scaffolds, which can be considered as non-peptidic foldamer α-helix mimetics.     

Microbial pathway prediction: a functional group approach

We have developed a system to predict microbial catabolism, using the University of Minnesota Biocatalysis/Biodegradation Database (UM-BBD, http://umbbd.ahc.umn.edu/) as a knowledge base. The present system, available on the Web (http://umbbd.ahc.umn.edu/predict/), can predict biodegradation of most of the major aliphatic and aromatic organic functional groups containing C, H, N, O, and halogens. It can duplicate at least one known biodegradation pathway for 60% of the compounds in a 84-member validation set; most pathways that did not completely duplicate known metabolism could plausibly occur in nature. Users are encouraged, and have begun, to submit additional biotransformation rules and comment on existing rules; the system will further develop under the direction of the scientific community.     

An investigation of the di-Grignard approach to metallabenzocyclobutenes of group 14

The reactions of 1,2-dihydro-1-magnesabenzocyclobutene (5) with dichlorodimethylsilane (12a), dichlorodimethylgermane (12b) and dichlorodimethylstannane (12c) are reported; 1,2-dihydro-1,1,dimethyl-1-silabenzocyclobutene (14a) and 1,2-dihydro-1,1-dimethyl-1-germabenzocyclobutene (14b) were formed in high yields, but the tin analogue 14c was not obtained. Eight-membered ring species, the dimers 17 and 18, were isolated for all three metals. Other products gave useful indications of the probable course of these interesting and complex reactions.     

Skeletal diversity by sequential one-pot and stepwise routes using morpholine ester scaffolds

A skeletal diversity approach starting from morpholine acetals has been achieved by tuning a three-step process from stepwise to sequential one-pot to provide diverse scaffolds containing either a 2-oxopiperazine or a diketopiperazine skeleton.     

Explorations of stemona alkaloid-inspired analogues: skeletal modification and functional group diversification

A tandem Diels-Alder/Schmidt reaction provided an efficient route for the exploration of unnatural Stemona alkaloid analogues. Thus, a series of tricyclic scaffolds were efficiently prepared and then elaborated into seven sets of functionalized analogues. These derivatives incorporated appended heterocycles, such as indoles and quinolines, or other diversity-incorporating moieties such as carbamates and amines. Both the scaffold-generation sequence and the diversification steps could be manipulated to provide regio- and diastereochemically pure products.     

Gel template leaching: An approach to functional nanoporous membranes

A novel preparation method for nanoporous structures, denoted “Gel Template Leaching”, is described. The approach is based on the gelation of solutions containing two low molecular weight compounds of which one is crystallizable and the other curable. Gelation of the solute upon cooling followed by curing of the solvent below the gelation temperature lead to the formation of a semi-IPN consisting of a reversibly and a covalently crosslinked network. After leaching of the solute (the template) a well-defined nanoporous architecture was formed. Functional pores could be obtained after charging the pore walls with ionic sites.     

An efficient approach to chiral nonracemic trans- and cis-decalin scaffolds for drimane and labdane synthesis

Optically active trans- and cis-ring junction decalinic intermediates, which represent useful precursors for the synthesis of more complex natural targets, have been conveniently prepared starting from the β-ketoester 2 obtained by standard chemistry from β-ionone and dimethyl carbonate. The chiral auxiliary (−)-menthol, easily attached to 2 through DMAP-catalyzed transesterification, allowed a clean separation of the diastereomers obtained in the key electrocyclization step, which were further elaborated to chiral intermediates already taken to drimane and labdane sesquiterpenes.     

Biomimetic mineralisation of polymeric scaffolds using a combined soaking and Kitano approach

Chitosan hydrogels are of considerable interest in synthetic biomimetic mineralisation strategies due to their favourable characteristics such as the presentation of a large surface area for crystal nucleation within a structured yet responsive scaffold. Chitosan hydrogels were prepared and subsequently calcium carbonate mineralisation was initiated using a method which combines alternate soaking of the films with precursor solutions followed by treatment with Kitano solution. This combined approach allows for increased extent of mineralisation, inducement of mineralisation uniformly throughout the hydrogel rather than only at the peripheral surface and ready scalability and shape manipulation. The base synthetic system is readily modified through the introduction of additives that manipulate the nucleation and growth of the calcium carbonate. Addition of poly(acrylic acid) inhibits nucleation and induces tangential crystal growth along the internal and external interfaces of the hydrogel. The resulting composite is comprised of stacked overlapping plates of calcium carbonate intercalated with carbohydrate. The method is applicable in combination with a variety of hydrogels including macroporous chitosan, chitosan-alginate bilayers and pure alginate hydrogels. The composite materials were analysed by SEM, XRD, microRaman spectroscopy and mechanical strength testing.     

Organocatalyzed domino reactions: diversity oriented synthesis of pyran-annulated scaffolds using in situ-developed benzylidenemalononitriles

Research on Chemical Intermediates - Molecular diversity for the synthesis of pyran annulated heterocyclic scaffolds has been achieved from the multicomponent reaction of aldehyde, malonitrile and...     

Modular approach to functional hyaluronic acid hydrogels using orthogonal chemical reactions

A modular approach for the synthesis of hyaluronic acid hydrogels using orthogonal chemoselective reactions for subsequent enzymatic decomposition to nanoparticles is described.     

The immune diversity in a test tube--non-immunised antibody libraries and functional variability in defined protein scaffolds

Technologies to develop and evolve the function of proteins and, in particular, antibodies have developed rapidly since the introduction of phage display. Importantly, it has become possible to identify molecules with binding properties that cannot be found by other means. A range of different approaches to create general libraries that are useful for the selection of such molecules specific for essentially any kind of target have emerged. We herein review some of the most prominent approaches in the field and in particular discuss specific features related to the development of antibody libraries based on single antibody framework scaffolds. This approach not only permits identification of a range of specific binders, but also facilitates further evolution of initially derived molecules into molecules with optimised functions.