The Mutarotation of Isocolchicine

Rapoport, Henry; Lavigne, Joe B.

doi:10.1021/ja01592a030

Cited by 21 publications

(17 citation statements)

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“…Deacetylation might decrease the size of this group sufficiently to lower the activation energy and make mutarotation unobservable at room temperature'. 11 In my alternative, thermodynamic rationalization, the acetamido chain may be seen to be more exposed to solvation in the pseudoequatorial than the pseudoaxial diastereomer. This would determine preferential solvation by ethanol of the pseudoequatorial acetamido group, thus favoring this conformer.…”

Section: Resultsmentioning

confidence: 96%

“…11 I disfavor this view. In the years elapsed since Rapoport and Lavigne work, 11 colchicine was subjected to so many thermal treatments, during synthetic work, with recrystallization from hot solvents. This offered any chance for the S a atropisomer to become sizably populated.…”

Section: Resultsmentioning

confidence: 99%

“…9,10 Axial chirality had already been proposed to rationalize the mutarotation of isocolchicine in non-polar solvents via equilibration of (R a ,7S)-2 and (S a ,7S)-2. 11 Thirty years later, this hypothesis proved correct on observing the coexisting species by high-field 1 H NMR in CDCl 3 solution at either room temperatures or slightly higher temperatures. 12 In striking contrast, mutarotation was never observed with colchicine (1), and the reasons remained obscure.…”

Section: Introductionmentioning

confidence: 96%

“…12 In striking contrast, mutarotation was never observed with colchicine (1), and the reasons remained obscure. To this regard, it should be noticed that simple functional group transformations like N-methylation or deacetylation are known to suppress mutarotation with isocolchicine, 11 while both atropisomers of 11-aminoisocolchicide proved stable enough to be isolated. 8 In addition, the (R a, 7S) and (S a ,7S) atropisomers of 8-aminocolchicide could be isolated, probably owing to the stabilizing role of intramolecular hydrogen bonds.…”

Section: Introductionmentioning

confidence: 99%

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Why colchicine does not show mutarotation. With M05‐2X density functional in the realm of tricky natural products

Pietra

2007

J of Physical Organic Chem

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It is shown here that density functional theory (DFT) calculations with the recent M05-2X hybrid functional correctly reproduced the conformation of, and energy difference between, (R a ,7S)-and (S a ,7S)-type atropisomers of isocolchicine. Interconversion of these 1 H NMR-observable atropisomers accounts for mutarotation with this compound. In contrast, the classical B3LYP hybrid functional failed to simulate satisfactorily both the geometries and the energies involved. This extends the use of M05-2X to natural products that embody aromatic and flexible pseudoaromatic and saturated rings, as well as cis/trans amide chains, which bring on subtle conformational problems. DFT calculations with M05-2X also shed new light on a long-date conundrum in organic chemistry and pharmacology, i.e., why mutarotation was never observed with colchicine. This is now best attributed to a larger energy gap between the (R a, 7S) atropisomer and the elusive (S a ,7S) atropisomer with this compound. These results solicit a rethinking of the interactions between colchicinoids and proteins.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Why colchicine does not show mutarotation. With M05‐2X density functional in the realm of tricky natural products

Pietra

2007

J of Physical Organic Chem

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“…Rapoport and Lavigne first rationalized the mutarotation of 8 in chloroform as due to atropisomeric inversion [16] . They also attributed lack of mutarotation of isocolchicine in ethanol to increased steric bulk of the ethanol-solvated pseudoaxial acetylamino group [16] .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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BackgroundIt 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 FindingsCircular 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/SignificanceOur 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.

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Total Synthesis of Indole‐Derived Allocolchicine Analogues Exhibiting Strong Apoptosis‐Inducing Activity

Sitnikov

Velder

Abodo³

et al. 2012

Chemistry A European J

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A series of novel pyrrolo-allocolchicine derivatives (containing a 1-methyl-1H-indol-5-yl moiety replacing ring C) was synthesized. The tetracyclic ring system was constructed by Suzuki-Miyaura cross-coupling of a 1-methylindole-5-boronate with an ortho-iodo-dihydrocinnamic acid derivative and subsequent intramolecular Friedel-Crafts acylation. After reduction of the resulting ketone, the nitrogen functionality was introduced in a Mitsunobu-type reaction by using zinc azide followed by LiAlH(4) reduction. Structural assignments were supported by X-ray crystallography. The compounds synthesized were then tested against BJAB tumor cells and found to exhibit pronounced cytotoxic activity (proliferation inhibition and apoptosis induction). The ketone 24 b was even active at sub-nanomolar concentration. In addition, the antitumor potential of the compounds was confirmed by using B lymphoid cell lines.

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The Mutarotation of Isocolchicine

Cited by 21 publications

References 0 publications

Why colchicine does not show mutarotation. With M05‐2X density functional in the realm of tricky natural products

Why colchicine does not show mutarotation. With M05‐2X density functional in the realm of tricky natural products

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

Total Synthesis of Indole‐Derived Allocolchicine Analogues Exhibiting Strong Apoptosis‐Inducing Activity

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