Marino Cavazza

On the Chiroptical Behavior of Conjugated Multichromophoric Compounds of a New Pseudoaromatic Class: Bicolchicides and Biisocolchicides

Background It is well known that, stemming from the mutual interplay between chromophores, circular dichroism (CD) is a powerful technique to deal with structural problems for both the small organic molecule and the biopolymer. However, quantitative interpretations of the spectroscopic and structural terms that give rise to the exciton couplet are usually presented for ideal cases, or a few CD bands only are taken into account, overlooking the role of the solvent medium. Methodology/Principal Findings Circular dichroism and UV absorption spectra were carried out for colchicide (3) and isocolchicide (6), as well as their coupling products, 10,10′-bicolchicide (2) and 9,9′-biisocolchicide (5), in both hydrogen bonding and non hydrogen bonding solvents, as well as MeCN/H2O mixtures. A dramatic control by the solvent emerged, as even tiny changes in the composition of solvent mixtures, at ca 1 water molar fraction, induced a dramatic modification of their CD bands. A mutarotation phenomenon - long known for isocolchicine (8) - was also observed for 5, and can be attributed to the interconversion between atropisomers (R a,7S),(R a,7′S)-5a and (R a,7S),(S a,7′S)-5b. Conclusions/Significance Our data show that with molecules built on two structurally identical moieties which embody both hydrophilic and hydrophobic groups, even tiny changes in the composition of solvent mixtures cause a dramatic modification of the CD bands. Their analysis arrives at a qualitative rationalization of the observed CD couplets from the coupling of high energy transitions, while attempts at a quantitative interpretation of these phenomena through time-dependent density functional theory allowed to reproduce satisfactorily the CD spectrum in the 300–450 nm region only. Failure with higher energies probably reflects currently inadequate specific theoretical treatments of the solvent medium.

Isolation of atropisomers in both the isocolchicide and colchicide series of alkaloids and determination of their chiroptical properties

Abstract The isolation and dichroic behavior of atropisomeric colchicinoids is described here for the first time. The cases range from stable to rapidly interconverting atropisomeric couples.

SYNTHESIS OF 1,3-DIAZAAZULENE DERIVATIVES OF COLCHICINOIDS AND ISOCOLCHICINOIDS VIA IPSO- OR TELE-SUBSTITUTION-CONDENSATION WITH AMIDINES

Abstract Condensation of colchicinoids and isocolchicinoids with amidines in dry benzene affords regioselectively 1,3-diazaazulene derivatives: ipso -substitution-condensation products (e.g. 7 ) are best obtained from cycloheptatrienone-ring deactivated substrates (e.g. 4 ), whereas isomeric tele -substitution-condensation products (e.g. 13 ), are best accessible from cycloheptatrienone-ring activated substrates (e.g. 10 ). Hydroxylic solvents inhibit tele -substitution-condensation, arguably by undergoing protonation in preference of the intermediate σ adduct.

A General Entry to 10-Halocolchicides and 9-Haloisocolchicides

Abstract Readily accessible 10-tosyloxycolchicide (1) and LiX (X=Cl or Br or I) in MeOH/BF3Et2O at reflux give 10-chloro- (2), 10-bromo- (4), or 10-iodocolchicide (5), in good yields. 9-Chloro- (7) and 9-bromoisocolchidide (8) can be similarly obtained from 9-tosyloxyisocolchidide (6) and the method applies also to troponoids.

Hemithio-analogues of meisenheimer complexes and sulphide group activation of aromatic substitution by alkoxides

Abstract EtO− in DMSO adds to ethylthiopicrate at C-3 to generate an ephemeral -adduct which ends into 1-ethylthio-4-ethoxy-2,5-dinitrobenzene, whilst ethyl picrate gives two adducts of attack of EtS− at C-3 or C-1.

Synthesis of 1-Oxaazulan-2-ones and Furanotropones from Troponoids: a Reexamination and Extension to Colchicinoids

Abstract Reactions of [3,5,7-2H3]-2-tosyloxytropone (1b) in DMSO with enolates that, like sodium ethyl acetoacetate or sodium diethyl malonate, bear a leaving group, occur at C-7, followed by either sequential protonation at C-2, 1,6-elimination, and intramolecular heterocyclization (to give 1-oxaazulan-2-ones), or sequential sulfinate loss and intramolecular heterocyclization (to give furanotropones). The latter is the exclusive route with enolates that, like sodium acetylacetonate, do not bear a leaving group. 9-Tosyloxyisocolchicide (15) behaves like 2-tosyloxytropone, giving the product 16 of C-11 attack, whereas 10-tosyloxycolchicide (17) resists attack at C-8 and only a very slow nucleophilic attack at C-10 by the enolate to give 18 is observed. Hydroxylic solvents do not allow any of these processes.

Laser photochemistry: The intramolecular cyclization of carvone to carvonecamphor

Abstract Kr-ion laser irradiation of carvone ( 1 ) at 350.7 and 356.4 nm gave carvonecamphor ( 2 ) in a much higher yield (88%) than in conventional photochemistry, while ( 3 ) was a primary photo-by-product.

Halogenatedp-quinols of marine sponges. Synthesis via anodic oxidation of phenols and NHI-like rearrangement

Abstract Oxidation of either 2,6-dibromo- ( 1 ), 2-bromo- ( 3 ), or 2-bromo-chloro- p -acetamidophenol ( 5 ) at a Pt anode in aq. HClO 4 affords the corresponding common, 2 , or rare, 4 and 6 , marine halo- p -quinols in practicable yields, whereas literature recipes as to either chemical or electrochemical proved to be ineffective; these halo- p -quinols proved to be extremely alkali-labile, in part due to a rearrangement

Colchicine red-ox chemistry revisited: Cathodic behavior and EPR observation of an intermediate radical anion

Abstract Colchicine ( 1 ), a potently antimitotic alkaloid and useful laboratory tool in cancer research, undergoes cathodic reduction in DMF forming and ESR-observable radical anion ( 1r ) which is characterized by the isotropic hyperfine coupling constants 8.9, 4.3, 0.75, 0.49 and 0.48 G for H-8, H-12, OCH 3 , H-11 and H-4, respectively, and a much flattened troponoid ring. Assignments are aided by selective deuteriation of colchicine at C-8, C-11 and COCH 3 , as well as by spectral simulation and ab initio calculations of electron spin densities. Whether the colchicine radical anion may exist in nature is also discussed.

ipso-vs. tele-Nucleophilic substitution by piperidine on isocolchicides and colchicides bearing an α-leaving group

Product studies of the reactions of piperidine with colchicides carrying a C-10 nucleofugic group show that only ipso substitution occurs. For isocolchicides carrying an X nucleofugic group at C-9, similar behaviour was observed for X = F, OTs or OMe, while for X = SMe, SOMe or Cl tele substitution (at C-11) competes with ipso substitution. These results together with the observation that the reaction rates for the two series are similar, may be useful in guiding the refunctionalization of similar compounds.