A theoretical and experimental study of the racemization process of hexaaza[5]helicenes

A dynamic ¹H NMR study, together with DFT calculations, of bis-([1,2,3]triazolo)[1,5-a:5′,1′-k][1,10]phenanthroline 2 has allowed to identify the ring and open forms of a new example of ring/chain tautomerism, as well as their interconversion barriers (ring/ring and ring/open). The barrier of the exchange process between the chain forms and the ring form was found higher than the ‘racemization’ process in the closed form, so the ring opening does not contribute to the ‘racemization’. The di-1,10-methyl and di-1,10-iodo derivatives have been prepared and their properties calculated.     

Water-promoted unprecedented chemoselective nucleophilic substitution reactions of 1,4-quinones with oxygen nucleophiles in aqueous micelles

Unique nucleophilic substitution and addition reactions of nitrogen and sulfur nucleophiles with 1,4-quinones in aqueous suspension with amines and thiols have recently been demonstrated by us.² However, the reactivity of oxygen nucleophiles toward nucleophilic substitution compared to nitrogen and sulfur nucleophiles ‘on water’ is not facile. An unprecedented economical, green methodology approach using ordinary laundry detergent (LD; washing powder, 0.5 mol %, reusable)/SDS as surfactant ‘in water’ for nucleophilic substitution by oxygen nucleophiles in 1,4-quinones in excellent yields has been demonstrated.     

Unprecedented ‘ring transformation-rearrangement’ of pyran-2-ones into 5,6-dihydropyran-2-ones through insertion of acetol

One-pot efficient synthesis of functionalized 5,6-dihydropyran-2-ones has been delineated by reacting 2H-pyran-2-ones and acetol in the presence of a base at room temperature. The formation of 5,6-dihydropyran-2-ones revealed that the reaction proceeded in a unique ‘ring transformation-rearrangement’ sequence.     

Synthesis of a functionalized furan via ozonolysis—further confirmation of the Criegee mechanism

A new method for the synthesis of a tetrahydrofuran ring is described which involves ozonolysis of a diene possessing a free hydroxy group in the γ-position. The reaction proceeds via ozone attack on the terminal double bond, cleavage, and intramolecular cyclization through the free hydroxy group. The cyclization event can be rationalized through formation of Criegee’s carbonyl oxide, but not through the ‘unified’ mechanism, thereby lending support to the Criegee mechanism as a method of producing oxygen-containing heterocycles.     

Isolation and structural analysis of novel conformational isomers of the m-xylylene-bridged calix[6]arenes: the ‘partial cone’ and ‘inverted cone’ isomers

In the benzylation of a m-xylylene-bridged calix[6]arene tetrol, the first example of the ‘partial cone’ isomer of a calix[6]arene was obtained in addition to the corresponding cone and 1,2,3-alternate isomers, and its structure was established by X-ray crystallographic analysis. The synthesis and crystal structure of the ‘inverted cone’ isomer as well as its thermal conversion to the ‘normal cone’ isomer are also described.     

A practical synthesis of carbamates using an ‘in-situ’ generated polymer-supported chloroformate

A versatile method for the synthesis of carbamates from an ‘in-situ’ generated polymer-supported chloroformate resin is presented. BTC (bis-trichloromethyl carbonate) is used as phosgene equivalent to afford a supported chloroformate, which, by sequential ‘one-pot’ reaction with a variety of alcohols and amines, furnishes the corresponding carbamates in high yields and purities.     

Synthesis of seco-psymberin/irciniastatin A: the discovery of a novel PhI(OAc)2 mediated cascade cyclization reaction

The psymberin unsaturated ‘psymberate’ side chain 7 was synthesized in 7 steps (36% yield) with good diastereoselectivity using commercially available starting material to control the stereochemistry at C₄ and C₅. The synthesis of seco-psymberin was completed in an efficient manner based on a CuI mediated coupling reaction between vinyl iodide 8 and ‘psymberamide’ 7. In an attempt to synthesize natural psymberin from the seco-intermediate, a novel PhI(OAc)₂ mediated cascade ring closing reaction was discovered. A possible mechanistic pathway for the formation of the ring closing product was presented.     

Synthesis of 9-oxa-noradamantane derivative, an aesthetically pleasing ‘oxa-basket’

A simple protocol for the synthesis of an aesthetically pleasing ‘oxa-basket’ (5-methoxy-2,8,13-trioxapentacyclo[7.2.1.1.^5,120.^4,110^6,10]tridecane-3,7-dione), possessing 9-oxa-noradamantane core, is described. The readily available diquinane based dichloro bis-γ-lactone precursor upon treatment with MeSO₃H furnished dichloro ‘oxa-basket’ which was dechlorinated using TBTH/AIBN to obtain the title compound. The key role of the chlorines was demonstrated by replacement with hydrogen or allyl substituents which redirects the cascade to simple hydrolysis products.     

A ‘push-pull’ tropylium-fused aminoporphyrazine

Crossover Linstead macrocyclization of cycloheptatrienylmaleonitrile and (dimethylamino)-maleonitrile gave access to an unsymmetrical (A₃B) porphyrazine bearing six peripheral amino substituents and a fused cycloheptatrienyl ring. Subsequent hydride abstraction gave a tropylium-fused aminoporphyrazine, which contains both strongly electron-donating and withdrawing groups and thus can be labelled as a ‘push-pull’ macrocycle. Detailed structural studies of this novel porphyrazine are described.     

‘O-Acyl isopeptide method’ for the efficient synthesis of difficult sequence-containing peptides: use of ‘O-acyl isodipeptide unit’

A novel ‘O-acyl isodipeptide unit’, Boc-Thr(Fmoc-Val)-OH 5 has been successfully used for the efficient synthesis of a difficult sequence-containing pentapeptide based on the ‘O-acyl isopeptide method’, in which racemization-inducible esterification could be omitted, suggesting that the use of O-acyl isodipeptide units allows the application of this method to fully automated protocols for the synthesis of long peptides or proteins.     

Porphyrins with exocyclic rings. Part 23: Synthesis of porphyrins with large exocyclic rings—cyclohexadeca[b]pyrroles and porphyrins therefrom

Knorr-type condensation of cyclododecanone, cyclopentadecanone, and cyclohexadecanone with phenylhydrazones derived from acetoacetate esters in the presence of zinc dust at elevated temperatures gave the corresponding large ring cycloalka[b]pyrroles in excellent yields. A cyclohexadeca[b]pyrrole was reacted with lead tetraacetate to give an acetate derivative, and this condensed with α-unsubstituted pyrroles in the presence of p-toluenesulfonic acid in acetic acid to give a series of related dipyrrolic structures. Hydrogenolysis of the benzyl ester protective groups, followed by ‘2+2’ condensations with dipyrrylmethane dialdehydes, gave unusual cycloalkanoporphyrins with 16-membered exocyclic rings. When an alkyl group is situated next to the carbocyclic ring, proton NMR spectroscopy indicates that the conformational mobility of the carbocyclic unit is severely restricted.     

Omriolide A and B; two new rearranged spongian diterpenes from the marine sponge Dictyodendrilla aff. retiara

Two new rearranged spongian diterpenes designated omriolide A and B were isolated from the southern Kenyan sponge Dictyodendrilla aff. retiara collected at Wasini Is., Shimoni Channel. Omriolide A possesses an octalin linked to a unique trioxatricyclo[5.2.1.0^4,10]decane ring system, forming a tricyclic ‘cap’. Omriolide B comprised a tricyclo[5.4.0.0^2,4]undecane linked to a dioxabicyclo[3.3.0]octane. The structures of both diterpenes were elucidated by interpretation of MS results and, mainly, 1D and 2D NMR spectra.     

F-Induced ‘turn-on’ fluorescent chemosensor based on 1,3-alt thiacalix[4]arene

A new thiacalix[4]arene based fluorescent sensor 1 bearing two naphthyl groups has been synthesized in 1,3-alternate conformation. In the absence of fluoride ion, the receptor 1 is in ‘off-state’ showing no fluorescence emission. The presence of fluoride ion triggered the fluorescence emission to ‘on-state’. The receptor shows pronounced selectivity for fluoride ions. In THF, the presence of F⁻ ions induces the formation of a 1:1 (G:H) complex.     

‘Push-Pull’ and spirobicyclic structures by reacting N-methyl cyclic ketene-N,X (X=S, O)-acetals with isocyanates and isothiocyanates

Nucleophilic N-methyl cyclic ketene-N,X (X=S, O)-acetals can react with electrophilic aryl isocyanates and aryl isothiocyanates to form ‘push-pull’ mono-adducts, di-adducts and spirobicyclic 6/5 ring compounds.     

The absolute configuration of streptonigrin

A theoretical study of the molecular circular dichroism (CD) of the antitumor antibiotic natural product streptonigrin is described, aiming at the secure assignment of its absolute configuration by comparison of the CD spectra predicted for M and P, with the experimental one. The stereostructure of streptonigrin was previously investigated by two other groups, yet leading to two different attributions. Although streptonigrin possesses two biaryl axes, only the ‘southern’ one is configurationally stable and thus responsible for the chiroptical properties, since the ‘northern’ AB-ring system of the molecule is kept in plane with ring C by hydrogen bonding. All computational methods applied within this work to simulate the CD spectrum—semiempirical approaches and time-dependent density functional theory (TDDFT)—consistently attribute the M-configuration to streptonigrin.     

An unusual substitution reaction directed by an intramolecular re-arrangement

Secondary amines and thiols undertake a substitution reaction on the side chain of 2-bromoethyl-pyridinium derivatives ‘directed’ by an intramolecular re-arrangement. Experimental investigations strongly indicate that the reaction is initiated by an alpha addition of the nucleophile onto the iminium moiety of the N-heteroaromatic cation, followed by a cyclisation and an oxidative ring opening. This novel substitution process is able to occur with less reactive nucleophiles that would not undergo conventional substitution with ‘isolated’ bromoethyl moieties.     

‘Aromatic ring umpolung’, a rapid access to the main core of several natural products

Treatment of various substituted phenols in the presence of (diacetoxyiodo)benzene promotes the formation of a phenoxenium ion, a very electrophilic species able to react with various nucleophiles leading rapidly to a plethora of different cores present in natural products via several novel oxidative processes. This strategy fits within the concept of ‘aromatic ring umpolung’; in this paper a personal account by our laboratory on this thematic is described.     

Synthesis of (tetrahydrofuran-2-yl)acetates based on a ‘cyclization/hydrogenation/enzymatic kinetic resolution’ strategy

A variety of (tetrahydrofuran-2-yl)acetates and (pyrrolidin-2-yl)acetates have been prepared by hydrogenation of 2-alkylidenetetrahydrofurans and 2-alkylidenepyrrolidines, which are readily available by cyclization reactions of 1,3-dicarbonyl dianions (‘free dianions’) or 1,3-bis-silyl enol ethers (‘masked dianions’) with 1,2-dielectrophiles. The enzymatic kinetic resolution of (tetrahydrofuran-2-yl)acetates with recombinant esterase Est56 proceeded with excellent enantioselectivities (E>100).     

H-quadrupolar coupling-based analysis of stereochemical and regiochemical memory in the Pd-catalysed allylic alkylation of iso-cinnamyl type substrates employing the chiral monophosphine ligands ‘MOP’ and ‘MAP’

The reaction of iso-cinnamyl acetate with NaC(Me)(CO₂Me)₂, catalysed by Pd-‘MOP’ (MOP=2-methoxy-2′-diphenylphosphino-1,1′-binaphthalene) is known to proceed with a regiochemical memory effect that results in the predominant generation of the branched alkylation product. The analogous reaction employing ‘MAP’ as ligand (MAP=2-N,N-dimethylamino-2′-diphenylphosphino-1,1′-binaphthalene) proceeds with ‘normal’ regioselectivity to generate predominantly the linear isomer of product. A ²H-NMR based analysis, employing quadrupolar coupling in a chiral liquid crystal matrix, has been developed to facilitate the simultaneous study of the regiochemical and stereochemical outcome of the reaction of both enantiomers of iso-cinnamyl ester substrates in ²H-labelled but racemic samples. The analysis allows the comparison of relative rates of two competing isomerisation processes occurring in the π-allyl intermediates in the Pd-catalysed reaction, one of which facilitates asymmetric induction, the other resulting in loss of regiochemical memory. It is demonstrated that the two processes are partially coupled and that this then limits the attainment of high global enantiomeric excess in the branched product to reactions that proceed with low regiochemical retention. A key factor for the observation of high regiochemical memory is found to be the nucleophilicity of the malonate anion and the electrophilicity of the Pd-π-allyl intermediate with reduction in the reactivity of either partner resulting in the onset of substantial loss of memory.