A highly diastereoselective synthesis of (E)-B-2-(1-cyclopropyl-1-alkenyl)-1,3,2-dioxaborinanes. Isolation and oxidation to alkyl cyclopropyl ketones

A convenient, novel synthesis of alkyl cyclopropyl ketones based on Z-1-bromo-1-alkenylboronate esters is developed. α-Bromo-(Z)-1-alkenylboronate esters readily available from literature procedures smoothly undergo a reaction with cyclopropylmagnesium bromide in tetrahydrofuran to provide the corresponding ‘ate’ complexes. These ‘ate’ complexes undergo intramolecular nucleophilic substitution reactions to provide the corresponding (E)-1-alkenylboronate esters containing cylcopropyl moiety for the first time in good isolated yields (68-82%). The carbon skeleton present in these intermediates is confirmed by oxidation with hydrogen peroxide and sodium acetate to afford the corresponding alkyl cyclopropyl ketones in good yields (72-85%).     

Synthetic aspects of the oxidative amidation of phenols

The oxidative amidation of phenols effects the conversion of appropriately substituted phenols into 4-amidodienones (‘para-oxidative amidation’) or 2-amidodienones (‘ortho-oxidative amidation’) by the action of hypervalent iodine reagents. The reagent, (diacetoxyiodo)benzene (‘DIB’) is especially effective in these transformations. This paper focuses on techniques for the desymmetrization of the dienoes thus obtained, leading to the stereocontrolled creation of N-substituted spiro carbons. The methodology creates new opportunities in alkaloid synthesis, as apparent from a number of examples.     

A diastereoselective synthesis 1-trimethylsilyl-(E)-1,3-alkenynes and a simple synthesis of alkyl trimethylsilylethynyl ketones via organoboranes

A convenient, novel diastereoselective synthesis of 1-trimethylsilyl-(E)-1,3-alkenynes and a convenient synthesis of alkyl trimethylsilylethynyl ketones based on Z-1-bromo-1-alkenylboronate esters are developed. α-Bromo-(Z)-1-alkenylboronate esters readily available using literature procedures smoothly undergo a reaction with trimethylsilylethynyllithium (derived from the deprotonation of trimethylsilylethyne with n-butyllithium) in tetrahydrofuran to provide the corresponding ‘ate’ complexes. These ‘ate’ complexes undergo intramolecular nucleophilic substitution reactions to afford the corresponding (E)-1-alkenylboronate esters containing trimethylsilylethynyl moiety which upon protonolysis with acetic acid provide the corresponding 1-trimethylsilyl-(E)-1,3-alkenynes in good yields (70-82%) and in high stereochemical purities (>98%). These intermediates upon oxidation with hydrogen peroxide and sodium acetate afford the corresponding alkyl trimethylsilylethynyl ketones in good yields (66-78%).     

Porphyrins with exocyclic rings. Part 24. Synthesis and spectroscopic properties of pyrenoporphyrins, potential building blocks for porphyrin molecular wires

Porphyrins with fused pyrene units have been prepared by ‘2+2’ and ‘3+1’ methodologies. Nitration of 1,2,3,6,7,8-tetrahydropyrene, followed by oxidation with DDQ, gave 4-nitropyrene and this condensed with ethyl isocyanoacetate in the presence of DBU or a phosphazene base to generate a pyrenopyrrole ethyl ester. Ester saponification and decarboxylation with KOH in ethylene glycol at 190 °C gave the parent pyreno[4,5-c]pyrrole and this was further condensed with 2 equiv of acetoxymethylpyrroles to afford the corresponding tripyrranes protected at the terminal positions with tert-butyl esters. In a one pot procedure, the ester protective groups were cleaved with TFA and following dilution with dichloromethane, ‘3+1’ condensation with a pyrrole dialdehyde, and dehydrogenation with DDQ, the targeted pyrenoporphyrins were generated in good overall yields. A dialdehyde was also prepared from the pyrenopyrrole intermediate and this reacted to give an opp-dipyrenoporphyrin. The pyrenopyrrole ethyl ester reacted with dimethoxymethane in the presence of an acid catalyst to give a dipyrenopyrrolylmethane, and this was used to prepare an adj-dipyrenoporphyrin using the MacDonald ‘2+2’ approach. The pyrenopyrrole dialdehyde was also used to prepare a porphyrin with fused pyrene and phenanthroline moieties. Although the UV-vis spectra of these new porphyrin systems are unexceptional, pyrenoporphyrins show many of the features necessary for the construction of porphyrin molecular wires.     

An efficient synthesis of 1,5-benzodiazepine derivatives catalyzed by a solid superacid sulfated zirconia

2,3-Dihydro-1H-1,5-benzodiazepines are synthesized by the condensation of o-phenylendiamine and various ketones in the presence of a versatile solid superacid catalyst ‘sulfated zirconia’ under solvent free conditions.     

New synthesis of methyl 5-aryl or heteroaryl pyrrole-2-carboxylates by a tandem Sonogashira coupling/5-endo-dig-cyclization from β-iododehydroamino acid methyl esters and terminal alkynes

A new and versatile ‘Pd’/CuI catalyzed protocol was developed for the synthesis in good to high yields of substituted pyrroles from N-Boc-β-iododehydroamino acid methyl esters and several terminal alkynes. This one-pot, two-step procedure occurs by a Sonogashira coupling followed by a 5-endo-dig-cyclization, which involves the nitrogen atom of the dehydroamino acid. After several experiments using different Pd(0) and Pd(II) species it was possible to establish the more general reaction conditions, which are: the use of a Pd(II) catalyst, CuI and Cs₂CO₃ as base in dry DMF at 70 °C. The best yields were obtained with arylacetylenes bearing electron-donating groups and with electron-rich heteroarylacetylenes.     

Diastereoselective synthesis of 2-oxiranyl and 2-aziridinyl thiazoles

2-Chloroalkylthiazolyllithiums, prepared by deprotonating the 2-chloroalkylthiazoles with n-BuLi at −78°C in THF, add to ketones or imines affording in ‘one-pot’ oxiranes and aziridines in a Z stereoselective manner.     

Silenes as novel synthetic reagents: synthesis of diols and lactones from simple alkyldienes

Aryl substituted silenes can be generated by a modified Peterson olefination reaction and trapped in situ to afford silacycles with high diastereoselectivity. These silacycles can be elaborated by ‘Fleming-Tamao’ type oxidation to provide access to functionalized diols and lactones.     

Syntheses of β- and γ-fluorophenyl cis- and trans-α-methylene-γ-butyrolactones

Preparation of a series of cis-γ-fluorophenyl-β-phenyl-α-methylene-γ-butyrolactones is reported via ‘allylboration’ of fluorobenzaldehydes with (E)-methyl 3-phenyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)acrylate. The corresponding trans-γ-fluorophenyl lactones were prepared either (i) via ‘allylboration’ using the (Z)-reagents or (ii) via an indium triflate-mediated isomerization of the cis-products. The difficulty in isomerizing difluorinated cis-products confirms the probable intermediacy of carbocations. Finally, the synthesis of cis-β-fluorophenyl-γ-phenyl-α-methylene-γ-butyrolactones was achieved via an indium-catalyzed allylation–lactonization of aldehydes with (Z)-2-(bromomethyl)-3-(fluorophenyl)acrylates.     

First X-ray structural characterisation of host-guest interactions in tetra-tetrazole macrocycles

The syntheses of tetra-tetrazole macrocycles, containing two 1,3-bis(tetrazole)benzene units linked by a variety of n-alkyl (n=3, 5, 7 or 9 carbon atoms) chain lengths, are described. The crystal structures of two 1,3-bis(tetrazole)benzenes containing pendant bromoalkyl chains (n=3 or 5) are reported. A tetra-tetrazole macrocycle has also been structurally characterised and contains an unexpected ‘host-guest’ interaction through binding of a chloroform solvent molecule. The resulting deviation of the macrocycle from planarity results from a combination of the ‘host-guest’ interaction and strong intermolecular interactions between adjacent tetrazole and phenylene rings.     

Synthesis of C-11 linked active ester derivatives of vitamin D3 and their conjugations to 42-residue helix-loop-helix peptides

Derivatives of vitamin D₃ carrying an 8-carbon linker at C-11 terminating in an active ester were synthesized from commercial vitamin D₃ using a disassembly-reassembly strategy. Vitamin D₃ was cleaved at the C6-C7 double bond and the ‘upper’ fragment was converted, via a series of reactions, to derivatives substituted at C-11 with an 8-carbon linker terminating in an ethyl ester. Reassembly with modified ‘lower’ fragments using Horner-Wittig olefination followed by linker ester hydrolysis and re-esterification with p-nitrophenol gave C-11 substituted p-nitrophenyl esters. These vitamin D derivatives were conjugated to 42-amino acid helix-loop-helix peptides by reaction of their p-nitrophenyl esters with lysyl side-chain amino groups on the peptides. The vitamin D—peptide conjugates, being potential specific binder candidates for vitamin D-binding protein, were characterized by mass spectroscopy and CD measurements.     

Generation of ketone dilithio α,β-dianions and their reactions with electrophiles

Ketone dilithio α,β- and α,β′-dianions can be generated by a tin-lithium exchange reaction of the lithium enolate of β-tributyltin substituted ketones. A chelation-aided approach, which employs β-dichlorobutyltin substituted ketones and n-BuLi, is also useful for the generation of ketone α,β-dianions having the Z-geometry at the alkene. The generated dianions can be transformed into substituted ketones by reaction with various carbon electrophiles.     

Asymmetric aziridine synthesis by aza-Darzens reaction of N-diphenylphosphinylimines with chiral enolates. Part 2: Inversion of diastereoselectivity

The aza-Darzens (‘ADZ’) reactions of N-diphenylphosphinyl (‘N-Dpp’) imines with chiral enolates derived from N-bromoacetyl 2S-2,10-camphorsultam proceed in generally good yield to give N-diphenylphosphinyl aziridinoyl sultams. However, the stereoselectivity of the reaction is dependent upon the structure of the imine substituent: when the chiral enolate was reacted with arylimines substituted in the ortho-position, mixtures of cis- and trans-2′R,3′R-aziridines were obtained, often with a complete selectivity in favour of the trans-isomer.     

Highly efficient asymmetric transfer hydrogenation of ketones catalyzed by chiral ‘roofed’ cis-diamine-Ru(II) complex

A new type of chiral Ru(II) complex, prepared from a conformationally rigid, sterically bulky ‘roofed’ cis-diamine and [RuCl₂(benzene)]₂, functions as an efficient catalyst for the asymmetric transfer hydrogenation of a wide variety of aryl ketones, including sterically bulky ketones, when the reaction is conducted in the presence of 5HCO₂H·2NEt₃.     

Synthesis of cyclic peptides via O-N-acyl migration

We describe here a novel and convenient synthesis of head-to-tail cyclic peptide avoiding racemization. Linear depsipeptides including a serine residue as the key element for ester bond formation and acyl transfer were synthesized on 2-chlorotrityl chloride resin. After cleavage from the resin, intramolecular head-to-tail cyclization was performed in solution by C-terminal activation of urethane protected O-acyl serine residue. After removal of the N^α-serine protecting group, the final step consisted in O-N-acyl migration reaction on the ‘switch’ or ‘click’ element to restore native cyclic peptides.     

Environmentally benign electrophilic and radical bromination ‘on water’: H2O2-HBr system versus N-bromosuccinimide

A H₂O₂-HBr system and N-bromosuccinimide in an aqueous medium were used as a ‘green’ approach to electrophilic and radical bromination. Several activated and less activated aromatic molecules, phenylsubstituted ketones and styrene were efficiently brominated ‘on water’ using both systems at ambient temperature and without an added metal or acid catalyst, whereas various non-activated toluenes were functionalized at the benzyl position in the presence of visible light as a radical activator. A comparison of reactivity and selectivity of both brominating systems reveals the H₂O₂-HBr system to be more reactive than NBS for benzyl bromination and for the bromination of ketones, while for electrophilic aromatic substitution of methoxy-substituted tetralone it was higher for NBS. Also, higher yields of brominated aromatics were observed when using H₂O₂-HBr ‘on water’. Bromination of styrene reveals that not just the structure of the brominating reagent but the reaction conditions: amount of water, organic solvent, stirring rate and interface structure, play a key role in defining the outcome of bromination (dibromination vs bromohydroxylation). In addition, mild reaction conditions, a straightforward isolation procedure, inexpensive reagents and a lower environment impact make aqueous brominating methods a possible alternative to other reported brominating protocols.     

Synthesis of some novel spiro substituted pyrido[2,3-c]coumarins by exploring ‘tertiary amino effect’ reaction strategy

Some novel spiro substituted pyrido[2,3-c]coumarin derivatives were synthesized from 4-hydroxycoumarin by exploring ‘tertiary amino effect’ reaction strategy.     

Synthesis of porphyrin-quinolone conjugates

meso-Tetrakis(pentafluorophenyl)porphyrin reacts with propargyl alcohol to afford porphyrins substituted with one, two, three or four prop-2-yn-1-yloxy groups in the 4-position of the meso-aryl groups. These new porphyrin derivatives react with a 6-azidoquinolone under ‘click-chemistry’ conditions to give porphyrin-quinolone conjugates linked by 1,2,3-triazole units.     

Synthesis of o,m-cymene-cored biaryls through a carbanion-induced ring transformation strategy

Aromatic compounds derived from two or more ‘isoprene units’ are the core structures found in several natural products of biological importance. Among them, cymene derivatives are of particular interest due to the unique structural and biological properties associated with them. In this letter, we describe an expeditious synthesis of cymene-cored unsymmetrical biaryls functionalized with donor and acceptor substituents prepared in excellent yields by the carbanion-induced ring transformation of 2H-pyran-2-ones with ketones.     

The design and synthesis of a new potentially C3-symmetric ferrocenylphosphine

A new potentially C₃-symmetric phosphine ligand ‘manphos’ has been obtained and fully characterized. The ligand which is a tri-ferrocenyl-tetra-phosphine is obtained in a simple and effective two step synthesis starting from 1,1′-dibromoferrocene via the intermediate compound tris-(1′-bromoferrocenyl)phosphine or alternatively via 1'-bromo-1-diphenylphosphinoferrocene. The iso-propylphosphino-analogue of manphos, tris-(1'-diisopropylphosphinoferrocenenyl)phosphine, has also been obtained, in addition to several functionalised derivatives of triferrocenylphosphine where the ferrocene rings have been substituted in the 1′-position.