Azabicycloalkenes as synthetic intermediates: application to the preparation of diazabicycloalkane scaffolds

[reaction: see text] A general method to synthesize bicyclic dipeptide mimetics is reported. Key intermediates are azabicycloalkenes 9 and 17, which are prepared via Diels-Alder reactions and subsequent mild deprotection. These unsaturated bicyclic heterocycles are versatile intermediates for different dipeptide mimetics of the aza- and diazabicycloalkane type, which is demonstrated by the synthesis of diazabicycloalkanes 11 and 19 in only 3-6 steps and good overall yield.     

Asymmetric control in Diels–Alder cycloadditions of chiral 9-aminoanthracenes by relay of stereochemical information

Two approaches to the synthesis of chiral 9-amino anthracenes are described. The first, by nucleophilic addition of organolithium reagents to imines promoted by BF₃·OEt₂, unexpectedly provided stable aminoboranes as products. The second approach, using palladium catalysed cross coupling, was more successful for primary amines, and the key 9-(α-methylbenzylamino)anthracene subjected to cycloadditions with N-methyl maleimide and maleic anhydride. Excellent reactivity was achieved with good levels of diastereoselectivity, through a favourable combination of electrostatic and hydrogen bonding effects. Trial studies of the retro Diels–Alder reaction of these cycloadducts were also performed.     

Nickel-catalyzed electrochemical couplings of vinyl halides: synthetic and stereochemical aspects

Homo- and cross-coupling involving alkenyl halides have been performed efficiently using an electroassisted nickel-complex catalysis. Valuable product such as conjugated dienes, beta,gamma- or gamma,delta-unsaturated esters, ketones, or nitriles, as well as alkenylated aryl compounds are thus prepared with high yields and high stereoselectivity. Partial isomerization is only observed in a few cases, when the alkenyl halide is involved in a late step of the catalytic cycle. This is the case in the preparation of (Z,Z)-1,3-diene.     

Synthetic approaches to phomactins: Late stage stereochemical and reactivity issues

Oxidation of a 15-methylenebicyclo[9.3.1]pentadeca-3,7-dien-14-ol with a 10-phenylsulfonyl substituent provided a 14-oxobicyclo[9.3.1]pentadeca-1(15),3,7-triene-15-carbaldehyde that on reduction with DIBAL-H was converted into a 15-hydroxymethylbicyclo[9.3.1]pentadeca-1(15),3,7-triene-14-ol with the relative configuration at C14 required for incorporation into a synthesis of phomactin A. The oxidation and reduction of an analogous 3,4-epoxide that lacked the 10-phenylsulfonyl group gave a diol with the opposite relative configuration at C14. However, the TPAP oxidation and DIBAL-H reduction of a 14-hydroxy-15-methylene-3,4-epoxide that still had the 10-phenylsulfonyl group gave a diol with the required configuration at C14 although the expected spontaneous participation of the 14-hydroxyl group in an intramolecular epoxide ring-opening was only observed under Lewis acidic conditions.     

Iodomethyl phenyl sulfoxide: reactivity and synthetic applications

Lithio iodomethyl phenyl sulfoxides reacted with alkyl halides and carbonyl compounds to give adducts in good to moderate yields. Solvolysis of the carbonyl adducts led to sulfones or the ring expanded product.     

Organocatalytic enantioselective pyrazol-3-one addition to maleimides: reactivity and stereochemical course

The enantioselective synthesis of pyrazol-3-ones has not been extensively studied in organic synthesis. Here in we report the first asymmetric addition of pyrazolones to maleimides catalyzed by bifunctional thiourea catalysts.     

A synthetic approach to 2,3,4-substituted pyridines useful as scaffolds for tripeptidomimetics

The synthesis of 2,3,4-substituted pyridine derivatives useful as scaffolds in the development of peptidomimetics is described. The use of a variety of electrophiles in a halogen-dance reaction to produce 3-alkyl-2-fluoro-4-iodo-pyridine derivatives as ‘functionalized scaffolds’ and the possibility to differentiate between the reactivities of the two halogen handles have been explored. Coupling of amino acid derivatives in the 4-position of the pyridine was found to proceed efficiently by conversion of iodo-pyridine to a Grignard derivative, which was allowed to react with a protected amino aldehyde. Substitution of fluorine in the 2-position of the pyridine was found to be facile with alkoxide nucleophiles, whereas amines were much less reactive.     

Establishing a flow process to coumarin-8-carbaldehydes as important synthetic scaffolds

Despite their usefulness as fluorophores and synthetic precursors, efficient and reliable routes to coumarin-8-carbaldehydes are lacking. We describe here a high-yielding continuous flow synthesis that requires no manual intermediate purification or work-up, giving access to multigram quantities of the aldehyde product.     

Azabicycloalkenes as synthetic intermediates--synthesis of azabicyclo[X.3.0]alkane scaffolds

A general method to synthesize functionalized azabicyclo[X.3.0]alkane scaffolds 5 is reported. Key intermediates are azabicycloalkenes such as 1 and 2, which are acylated with unsaturated carboxylic acids and subsequently submitted to tandem olefin metathesis. The resulting bicyclic heterocycles are versatile intermediates for different dipeptide mimetics and can be used as intermediates for natural products with indolizidine scaffolds or analogues thereof. [reaction: see text].     

Enantioselective synthesis of erythro-4-deoxyglycals as scaffolds for target- and diversity-oriented synthesis: new insights into glycal reactivity

An efficient, enantioselective synthesis of erythro-4-deoxyglycals has been developed using asymmetric aldehyde allylation and tungsten-catalyzed alkynol endo-cycloisomerization as the key steps. These versatile synthetic scaffolds have been elaborated to a variety of products using stereoselective transformations that are complementary to those available using the corresponding threo glycals. This work has provided valuable insights into the relationships between glycal structure and reactivity. In addition, a new diene-forming side reaction during tungsten-catalyzed alkynol cycloisomerization has been discovered.     

Active-site stereochemical control of oxygen atom transfer reactivity in sulfite oxidase

A number of both experimental and computational studies have recently been reported for symmetric, six-coordinate dioxomolybdenum(VI) complexes as models of the fully oxidized form of the molybdopterin enzyme sulfite oxidase (SO). Such studies have suggested that the two terminal oxo donors in SO are electronically equivalent. However, the consensus structure of the catalytically competent Mo(VI) active site in SO is five-coordinate square pyramidal, possessing two terminal oxo donors, an ene-1,2-dithiolate chelate and a cysteine sulfur donor ligand. Computational studies at the density functional level of theory have been performed on a minimal model of the SO active site, [Mo(VI)O2(S2C2Me2)(SCH3)]-, in C1 symmetry to evaluate the composition of the LUMO, which is the putative electron acceptor orbital in the oxygen atom transfer (OAT) reaction with the sulfite substrate. The LUMO in this model is principally composed of a Mo dxy - ppi* interaction between the Mo and the equatorial oxygen (Oeq), while the axial oxygen (Oax) possesses no contribution to this orbital. In fact, the LUMO+1 orbital which possesses a substantial amount of Oax character lies nearly 1 eV higher in energy than the LUMO. It has also been suggested that changes in the Oax-Mo-Sthiolate-C torsion angle during the course of enzyme catalysis may aid in selection of Oeq for OAT. Calculations were performed in which this torsion angle was varied by 20 degrees through 360 degrees . These calculations demonstrate that the Mo dxy -Oeq ppi* interaction, and therefore the Oeq atom character, always dominates the LUMO. The results presented here suggest that oxygen atom selection and activation are a direct function of the low-symmetry structure of the oxidized SO active site and provide a role for the ene-1,2-dithiolate in promoting OAT reactivity through its kinetic trans effect on the equatorial oxo donor.     

Alpha-helix-inducing dimerization of synthetic polypeptide scaffolds on gold

Designed, synthetic polypeptides that assemble into four-helix bundles upon dimerization in solution were studied with respect to folding on planar gold surfaces. A model system with controllable dimerization properties was employed, consisting of negatively and positively charged peptides. Circular dichroism spectroscopy and surface plasmon resonance based measurements showed that at neutral pH, the peptides were able to form heterodimers in solution, but unfavorable electrostatic interactions prevented the formation of homodimers. The dimerization propensity was found to be both pH- and buffer-dependent. A series of infrared absorption-reflection spectroscopy experiments of the polypeptides attached to planar gold surfaces revealed that if the negatively charged peptide was immobilized from a loading solution where it was folded, its structure was retained on the surface provided it had a cysteine residue available for anchoring to gold. If it was immobilized as random coil, it remained unstructured on the surface but was able to fold through heterodimerization if subsequently exposed to a positively charged polypeptide. When the positively charged peptide was immobilized as random coil, heterodimerization could not be induced, probably because of high-affinity interactions between the charged primary amine groups and the gold surface. These observations are intended to pave the way for future engineering of functional surfaces based on polypeptide scaffolds where folding is known to be crucial for function.     

Transfer of stereochemical information in a minimal self-replicating system

[structure: see text]. The rational design, synthesis, and characterization of a minimal self-replicating system based on a 1,3-dipolar cycloaddition between a nitrone and a maleimide is presented. The importance of molecular recognition in this system is demonstrated using a competitive inhibitor. Doping experiments demonstrate that only one of the two diastereoisomeric products of the cycloaddition reaction is capable of acting as an efficient template for its own formation, accelerating the reaction between the nitrone and maleimide and controlling the stereochemical outcome of the reaction.     

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.     

Configurational stability and transfer of stereochemical information in the reactions of enantioenriched organolithium reagents

The conversion of a prochiral methylene group into a stereogenic center by means of a lithiation/substitution sequence has emerged as a powerful synthetic transformation over the past 15 years. This reaction proceeds via a chiral organolithium intermediate, and the stereochemical fidelity of the overall reaction sequence is intimately dependent on the stereochemical behavior of the chiral organolithium as well as on the rate and stereochemical sense of the electrophilic substitution step. Chiral organolithium reagents were first reported by Letsinger, Curtin, and Applequist half a century ago. The lithiated intermediates in these early studies were not highly configurationally stable, and applications in stereoselective synthesis were not immediately forthcoming. The two decades that followed the 1980 report by Still and Sreekumar of a configurationally stable alpha-oxyorganolithium were marked by an increased interest in these reagents. As the synthetic applications of chiral organolithium reagents have grown, so have accompanying mechanistic studies of these intermediates which serve as the basis for this review.     

Mineralization of synthetic polymer scaffolds: a bottom-up approach for the development of artificial bone

The controlled integration of organic and inorganic components confers natural bone with superior mechanical properties. Bone biogenesis is thought to occur by templated mineralization of hard apatite crystals by an elastic protein scaffold, a process we sought to emulate with synthetic biomimetic hydrogel polymers. Cross-linked polymethacrylamide and polymethacrylate hydrogels were functionalized with mineral-binding ligands and used to template the formation of hydroxyapatite. Strong adhesion between the organic and inorganic materials was achieved for hydrogels functionalized with either carboxylate or hydroxy ligands. The mineral-nucleating potential of hydroxyl groups identified here broadens the design parameters for synthetic bonelike composites and suggests a potential role for hydroxylated collagen proteins in bone mineralization.