Search

Protein cages are hollow protein nanoparticles, such as viral capsids, virus-like particles, ferritin, heat-shock proteins and chaperonins. They have well-defined capsule-like structures with a monodisperse size. Their protein subunits can be modified by genetic engineering at predetermined positions, allowing for example site-selective introduction of attachment points for functional groups, catalysts or targeting ligands on their outer surface, in their interior and between subunits. Therefore, protein cages have been extensively explored as functional entities in bionanotechnology, as drug-delivery or gene-delivery vehicles, as nanoreactors or as templates for the synthesis of organic and inorganic nanomaterials. The scope of functionalities and applications of protein cages can be significantly broadened if they are combined with synthetic polymers on their surface or within their interior. For example, PEGylation reduces the immunogenicity of protein cage-based delivery systems and active targeting ligands can be attached via polymer chains to favour their accumulation in diseased tissue. Polymers within protein cages offer the possibility of increasing the loading density of drug molecules, nucleic acids, magnetic resonance imaging contrast agents or catalysts. Moreover, the interaction of protein cages and polymers can be used to modulate the size and shape of some viral capsids to generate structures that do not occur with native viruses. Another possibility is to use the interior of polymer cages as a confined reaction space for polymerization reactions such as atom transfer radical polymerization or rhodium-catalysed polymerization of phenylacetylene. The protein nanoreactors facilitate a higher degree of control over polymer synthesis. This review will summarize the hybrid structures that have been synthesized by polymerizing from protein cage-bound initiators, by conjugating polymers to protein cages, by embedding protein cages into bulk polymeric materials, by forming two- and three-dimensional crystals of protein cages and dendrimers, by adsorbing proteins to the surface of materials, by layer-by-layer deposition of proteins and polyelectrolytes and by encapsulating polymers into protein cages. The application of these hybrid materials in the biomedical context or as tools and building blocks for bionanotechnology, biosensing, memory devices and the synthesis of materials will be highlighted. The review aims to showcase recent developments in this field and to suggest possible future directions and opportunities for the symbiosis of protein cages and polymers.

A total synthesis of the potent antibacterial agent platencin is described. The reaction sequence used involves, as starting material, an enantiomerically pure cis-1,2-dihydrocatechol derived from the whole-cell biotransformation of iodobenzene. Simple chemical manipulations of this metabolite provide a triene that engages in a thermally promoted intramolecular Diels–Alder reaction to establish the octa­hydro-2H-2,4a-ethanonaphthalene core of platencin.

RANEY® cobalt, which was first prepared in the 1930s, is known to function effectively as a catalyst for certain chemoselective reductions. However, its utility in chemical synthesis does not seem to have been fully appreciated. This first comprehensive survey of the literature on chemical transformations involving RANEY® cobalt attempts to redress matters by, among other things, highlighting the differences between the performance of this system and its much more well-known but usually less selective congener RANEY® nickel. A reliable method for preparing consistently effective RANEY® cobalt is presented together with a protocol that avoids the need to use it with high pressures of dihydrogen. As such, it is hoped more attention will now be accorded to the title reagent that offers considerable promise as a powerful tool for chemical synthesis, particularly in the assembly of polycyclic frameworks through tandem reductive cyclisation processes.

The total syntheses of the title compounds (I)-(III) from the microbially derived enantiomerically pure catechol (IV) are presented along with the confirmation of the structures of ribisins A, B and D.

Reaction sequences are reported to synthesize eight-membered carbocycles such as (IV), starting from the enzymatically-derived enantiopure cis-diol (I).

A series of enantiomerically pure 1,2-dihydrocatechol derivatives (I), (VI), (XI), and (XIV) bearing diazoketone, nitrile oxide, or azide residues is prepared and their regio- and stereoselective intramolecular cycloaddition reactions are described.

Treatment of readily available o-(buta-1,3-diyn-1-yl)-substituted N-aryl ureas with Echavarren′s gold(I) catalyst under microwave irradiation affords, via a twofold cyclization process, pyrimido[1,6-a]indol-1(2H)-ones.

A series of 2-hydroxyaryl ketoximes were converted to the corresponding 1,2-benzisoxazole 2-oxides by treatment with iodobenzene diacetate (in acetic acid or methanol) or N-chlorosuccinimide in water. Both methods gave moderate to excellent yields for a variety of substituted oximes under mild conditions within short reaction times. The latter method has the advantages of an aqueous solvent and lack of halogenated organic by-products.

We thank the Australian Research Council and the Institute of Advanced Studies for generous financial support.

Lamellarin K, and three closely related analogues are prepared in a concise and fully regiocontrolled fashion via the addition of an azomethine ylide to an ester-linked tolan, cf.

The use of ring-fused gem-dihalocyclopropanes, Au(I)-catalyzed cyclization reac- tions, and chemoenzymatic techniques in the synthesis of natural products is described.

Compounds (I) and (IV) are synthesized by Goldberg—Buchwald cross-coupling and compounds (VII) by intramolecular Mitsunobu cyclization.

A series of N-protected and propargylated 1-amino-2-arylcyclohex-2-enes is prepared on routes similar to that described for (V).

The resorcylic acid lactone L-783,277 (V), a potent and irreversible inhibitor of nitrogen-activated protein kinase, is prepared via macrocyclization of alkyne (II) followed by a Lindlar-type hydrogenation and a subsequent deprotection of compound (IV) with BCl3 as key steps.

The Pd[0]-catalyzed Ullmann cross-coupling of o-nitrohaloarenes 1a–e with the brominated heterocycles 2a–f delivers the expected products 3a–j in good to excellent yields. The reductive cyclization of such products, as well as N-acyl derivatives 3k, l, and m, has been investigated and provided the C-3 mono-substituted oxindoles 5a–d, f, g, k, and m, the direct reduction products 4i and j or indole 5l.

CpRh(PMe 3 )(C 2 H 4 ) (1), CpIr(PMe 3 )(C 2 H 4 ) (6), and CpIr(C 2 H 4 ) 2 (8) (Cp=η 5 -C 5 H 5 ) are isomerized on photolysis in argon matrices at 12-20 K to metal vinyl hydride complexes CpM(L)(C 2 H 3 )H (L=PMe 3 , C 2 H 4 ). The products are identified by their characteristic metal hydride and vinyl group vibrations in the IR spectra and by the effect of 2 H-labeling experiments. The same products may be generated by photolysis of a frozen toluene solution at 77 K (1 and 8) or a cold toluene solution (6) and characterized by 1 H, 13 C, and 31 P NMR

Regio- and stereo-controlled syntheses of the title compounds (1) and (2), starting from cyclohexane-1,3-dione (10) and cyclohexa-1,3-diene (17) respectively, are reported.

Under biomimetic conditions, both phloroglucinol and resorcinol cause significant inhibition of the oxidative conversion of dopa to dopachrome, a key step in the biosynthesis of melanin pigments. The major product (λmax = 377 nm) from oxidation of dopa in the presence of phloroglucinol was characterized as 2, containing the unusual tetrahydromethanobenzofuroazocine ring system. Another product, formed in somewhat smaller amount, was formulated as 3, arising from coupling of phloroglucinol with 2 dopaquinone derived units. Analogous cross coupling adducts 4 and 5 were obtained by reaction of dopa or dopa methylester with resorcinol, respectively. These results suggest the trapping of labile dopaquinone, generated in situ from oxidation of dopa, by the reactive phenolic compounds, leading to the novel adducts 2, 4 and 5.

4-Phenylphenoxazinones 4 were isolated after biomimetic oxidation, using diphenoloxidases of insect cuticle, mushroom tyrosinase, or after autoxidation of N-acetyldopamine (1) in the presence of β-alanine, β-alanine methyl ester or N-acetyl-L-lysine. They are formed presumably by addition of 2-aminoalkyl-5-alkylphenols 2 to the o-quinone of biphenyltetrol 3 which, in turn, arises from oxidative coupling of 1. The structures of 4 present the first examples for the assembly of reasonably stable intermediates in the rather complex process of chemical modifications of aliphatic amino acid residues by o-quinones.

The reactions of halogenated [n.m.1]propellenes with potassium t-butoxide have been investigated. Propelladiene 9,9-dichloro-1,4,5,8-tetrahydro-4a,8a-methanonaphthalene affords 1,6-methano[10]-annulene, 4-methylazulene, and 5H-benzocycloheptene, while the related tetracyclic compound-1,1,8,8-tritrachloro-1a,2,3,6,7,7a-hexahydro-2a,6a-methano-1H-cyclopropa[b]naphthalene reacts to give 12-chlorotricyclo[5.4.1.03,5]dodeca-1,3(5),6,8,10-pentaene. Treatment of 8,8-dichloro-2,3,4,7-tetrahydro-3a,7a-methano-1H-indene with the same base produced a mixture of the chlorodiene 8-chloro-2,3-dihydro-3a,7a-methano-1H-indene, azulene, and 4-methylazulene. The structure of the chlorodiene was established by an X-ray crystallographic study of its Diels–Alder adduct with 4-phenyl-4H-1,2,4-triazole-3,5-dione. While reaction of tetracycle 1,1,syn-8-trichloro-1 a,2,3,6,7,7a-hexahydro-2a,6a-methano-1H-cyclopropa[b]naphthalene with base failed to produce any characterisable products, under the same conditions epimer 1,1,anti-8-trichloro-1a,2,3,6,7,7a-hexahydro-2a,6a-methano-1H-cyclopropa [b] naphthalene was converted into the cycloproparene tricyclo-[5.4.1.03,5]dodecs-1,3(5),6,8,10-pentaene. Mechanistic proposals which account for the observed conversions have been advanced and are supported by 13C-labelling studies. The initial steps in most of the reaction pathways of the substrates are probably 1,4-elimination processes involving abstraction of an allylic hydrogen, fragmentation of the strained propellene σ-bond, and ejection of the halogen in an endo-relationship to the abstracted proton. The primary product of these processes, bridgehead dienes such as bicyclo[4.4.1]undeca-1,3,6(11),8-tetraene, 4,4,12-trichloro-tricyclo[5.4.1.03.5]dodeca-1 (11), 7(12),9-triene. and 10-chlorobicyclo[4.3.1]deca-1,3,6(10)-triene, then undergo further reaction involving, amongst other things, 1,3-prototropic shifts. Attempts to probe the mode of formation of the C11-4-methylazulene from the C10-precursor 8,8-dichloro-2,3,4,7-tetrahydro-3a,7a-methano-1H-indene have uncovered a novel methylation reaction of azulene by the dimsyl anion.

A 19-step synthesis of deacetamidoisocolchicine 4 has been developed starting from commercially available benzaldehyde 10. Key elements of the strategy used include Robinson annulation of the benzosuberone 15 to produce the tricyclic enone 18 and elaboration of this latter compound to the tetracyclic α-methoxy enone 7a. Base-promoted ring-expansion of 7a then provided the title compound 4, the acquisition of which constitutes a formal total synthesis of the alkaloid colchicine 1. In connection with efforts to optimise the yield of 4, the novel acid-catalysed conversion of 32 into dibenzocyclooctene 35 has been observed. The X-ray crystal structures of compound 35 and the novel dichlorocarbene insertion product 24 are reported.

The highly oxygenated α-tropolone antibiotic 3,4-dimethoxy-α-tropolone 3 has been synthesized in a fully regiocontrolled manner from commercially available cis-1,2-dihydrocatechol 5. Demethylation of 3,4-dimethoxy-α-tropolone 3 produced the potent antitumour agent 3,4-dihydroxy-α-tropolone 4.

A series of triheterocycles; [graphic omitted] for X, Y, Z = OOO, SSS, SOS, SSO, OSO, SOO, O(N-Me)O, S(N-Me)O and S(N-Me)S have been synthesised; of these O(N-Me)O, SOO and S(N-Me)O are new. The triheterocycles were chemically polymerised and oxidised with NOPF6. Only the polymers derived from SSS, SOS and SSO show appreciable conductivities. EPR studies indicate the presence of polarons in SSS, SOS, SSO and, at lower concentrations, in OOO. All the samples appear to show an easily saturable EPR signal assigned to localised radicals. In OSO, SOO, O(N-Me)O, S(N-Me)O and S(N-Me)S this signal displays considerable asymmetry, and g-values significantly above the free electron value. S(N-Me)S shows a higher g-value consistent with a loss of planarity.

The title complex selectively oxidises the methylene unit adjacent to a cyclopropane ring producing synthetically useful yields of the corresponding cyclopropyl ketones and/or products resulting from cleavage of the three-membered ring.

The reaction of alkenyl glycosides 2a–2c with MCPBA gives diasteroisomeric mixtures of epoxides 3 and 4. The asymmetric induction decreases in the order 2a ≫ 2b > 2c. The absolute configuration of epoxyalkyl glycosides is determined by correlation with (R)-glycerinaldehyde in an independent synthesis of 3a and 3c.

Nezukone (1) has been synthesized in seven steps from the readily available Δ3-trinorcarene (4). Key features of the sequence used include formation of the bicyclic isomer (2) of compound (1). Base-promoted isomerization of compound (2) followed by acidic workup then produced the isolable but highly unstable heptafulvenol (3), an extended enolic tautomer of nezukone (1). Under mildly basic conditions compound (3) rearranged to give the natural product (1). The X-ray crystal structure of the ring-fused cyclobutanone (8) is reported.

Both enantiomeric forms, (S)-4 and (R)-4, of the tetracyclic skeleton associated with the title alkaloids 1 and 2 have been prepared; the key step involved silver isocyanate-promoted ring-opening of gem-dibromocyclopropane 5 and trapping of the resulting allylic isocyanate (±)-6 with (–)-menthol.

The known dihydroazafluoranthene 6 is elaborated to the σ-homo-o-benzoquinone monoacetal 9 which reacts with trifluoroacetic acid to give the title alkaloid 1.

The synthesis of N-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-L-histidine amide (10) and N-(2-acetamido-4-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-2-deoxy-β-D-glucopyranosyl)-L-histidine amide (11) is achieved via coupling of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosylamine (2) and 2-acetamido-4-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)-3,6-di-O-acetyl-2-deoxy-β-D-glucopyranosylamine (4), respectively, with N α ,N τ -di-Boc-L-histidine (5) in the presence of 2-ethoxy-1-N-ethoxycarbonyl-1,2-dihydroquinoline and subsequent deproteotion. Compound 11 is an inhibitor of chitinase from the brine shrimp Artemia salina

Reaction of the tricyclic compound (1a) with potassium t-butoxide has been shown to give the diene (5) and not the isomeric homotropilidene (2a) as previously reported. The structure of compound (5) was established by single-crystal X-ray analysis at 130 K.

Fragmentation of methyl 3-O-benzyl-6-bromo-2-O-(tert-butyldimethylsilyl)-6-deoxy-4-O-(4-methoxybenzyl)-α-D-mannopyranoside (2) and in situ reductive amination give (3R,4S,5R)-6-benzylamino-4-benzyloxy-5-(tert-butyldimethylsilyloxy)-3-(4-methoxybenzyloxy)hexene (3) which is converted by intramolecular aminomercuration into an epimeric mixture of the bromomercuriopiperidine derivatives 4 and 5. The minor D-manno epimer 4 is transformed into mesylate 10 which, upon reaction with LiN3 in DMF, suffers a piperidine-pyrrolidine ring contraction to give azidomethylpyrrolidine 11. Reductive acetylation by means of thioacetic acid affords the fully protected pyrrolidine aza sugar derivative 12. The major L-gulo epimer 5 is transformed into the mesylate 15 which, again, upon reaction with LiN3 in DMF undergoes piperidine-pyrrolidine ring contraction to give the 1-azido-3-O-benzyl-2,5-benzylimino-6-bromomercurio-1,2,5,6-tetradeoxy-4-O-(4-methoxybenzyl)-L-iditol (16). Eliminative dehalomercuration by means of Zn powder is accompanied by in situ reduction of the azido group to give amino alkene 17. Intramolecular aminomercuration of 17 followed by N-acetylation yields the protected 1,2,5,6-tetradeoxy-2,5-imino-D-glucitol derivative 20 as the major epimer. Reductive oxygenation of 20 leads to pyrrolidine 22 which is deprotected to give title compound 1. Selective cleavage of the PMB group of 22 leads to 24. Benzylation of 22 affords again 12 from which the OH group at C-4 is liberated by selective cleavage of the PMB ether to give pyrrolidine 13. Compound 1 inhibits NAGase from bovine kidney.