Posts Tagged ‘natural product’

Impossible molecules.

Monday, April 1st, 2019

Members of the chemical FAIR data community have just met in Orlando (with help from the NSF, the American National Science Foundation) to discuss how such data is progressing in chemistry. There are a lot of themes converging at the moment. Thus this article[1] extolls the virtues of having raw NMR data available in natural product research, to which we added that such raw data should also be made FAIR (Findable, Accessible, Interoperable and Reusable) by virtue of adding rich metadata and then properly registering it so that it can be searched. These themes are combined in another article which made a recent appearance.[2]

One of the speakers made a very persuasive case based in part on e.g. the following three molecules which are discussed in the first article[1] (the compound numbers are taken from there). The question was posed at our meeting: why did the referees not query these structures? And the answer in part is to provide referees with access to the full/primary/raw NMR data (which almost invariably they currently do not have) to help them check on the peaks, the purity and indeed the assignments. I am sure tools that do this automatically from such supplied data by machines on a routine basis do exist in industry (and which is something FAIR is designed to enable). Perhaps there are open source versions available?

17 18 19

 
328[3] 348 713

Here I suggest a particularly simple and rapid “reality check” which I occasionally use myself. This is to compute the steric energy of the molecule using molecular mechanics. The mechanics method is basically a summation of simple terms such as the bond length, bond angle, torsion angle, a term which models non bonded repulsions, dispersion attractions and electrostatic contributions. The first three are close to zero for an unstrained molecule (by definition). The last three terms can be negative or positive, but unless the molecule is protein sized, they also do not depart far from zero. A suitable free tool that packages all this up is Avogadro.

The procedure is as follows

  1. Start from the Chemdraw representation of the molecule. If the publishing authors have been FAIR, you might be able to acquire that from their deposited data. Otherwise, redraw it yourself and save as e.g. a molfile or Chemdraw .cdxml file.
  2. Drop into Avogadro, which will build a 3D model for you using stereochemical information present in the Chemdraw or Molfile.
  3. In the  E tool (at the top on the left of the Avogadro menu) select e.g. the MMFF94 force field. This is a good one to use for “organic” molecules for which the total steric energy for “normal” molecules is likely to be < 200 kJ. Calculate that for your system; this normally takes less than one minute to complete. The values obtained for the three above are shown in the table. All three are well over 200 kJ/mol, which should set alarm bells ringing.
  4. A “more reasonable” structure for 17 is shown below. This has a steric energy of 152 kJ/mol, some 176 kJ/mol lower than the original structure. This does not of itself “prove” this alternative, but it is a starting point for showing it might be correct.Of course mis-assigned but otherwise reasonable structures are unlikely to be revealed by the steric energy test. But impossible ones will probably always be flagged as such using this procedure. 

Postscript: Hot on the heels of writing this, the molecule Populusone came to my attention.[4] On first sight, it seems to have some of the attributes of an “impossible molecule” (click on diagram below for 3D coordinates).

However, it has been fully characterised by x-ray analysis! The steric energy using the method above comes out at 384 kJ/mol, which in the region of impossibility! This can be decomposed into the following components: bond stretch 30, bend 51, torsion 32, van der Waals (including repulsions) 177, electrostatics 87 (+ some minor cross terms). These are fairly evenly distributed, with internal steric repulsions clearly the largest contributor. The C=C double bond is hardly distorted however, which is in its favour. Clearly a natural product can indeed load up the unfavourable interactions, and this one must be close to the record of the most intrinsically unstable natural product known!

References

  1. J.B. McAlpine, S. Chen, A. Kutateladze, J.B. MacMillan, G. Appendino, A. Barison, M.A. Beniddir, M.W. Biavatti, S. Bluml, A. Boufridi, M.S. Butler, R.J. Capon, Y.H. Choi, D. Coppage, P. Crews, M.T. Crimmins, M. Csete, P. Dewapriya, J.M. Egan, M.J. Garson, G. Genta-Jouve, W.H. Gerwick, H. Gross, M.K. Harper, P. Hermanto, J.M. Hook, L. Hunter, D. Jeannerat, N. Ji, T.A. Johnson, D.G.I. Kingston, H. Koshino, H. Lee, G. Lewin, J. Li, R.G. Linington, M. Liu, K.L. McPhail, T.F. Molinski, B.S. Moore, J. Nam, R.P. Neupane, M. Niemitz, J. Nuzillard, N.H. Oberlies, F.M.M. Ocampos, G. Pan, R.J. Quinn, D.S. Reddy, J. Renault, J. Rivera-Chávez, W. Robien, C.M. Saunders, T.J. Schmidt, C. Seger, B. Shen, C. Steinbeck, H. Stuppner, S. Sturm, O. Taglialatela-Scafati, D.J. Tantillo, R. Verpoorte, B. Wang, C.M. Williams, P.G. Williams, J. Wist, J. Yue, C. Zhang, Z. Xu, C. Simmler, D.C. Lankin, J. Bisson, and G.F. Pauli, "The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research", Natural Product Reports, vol. 36, pp. 35-107, 2019. https://doi.org/10.1039/c7np00064b
  2. A. Barba, S. Dominguez, C. Cobas, D.P. Martinsen, C. Romain, H.S. Rzepa, and F. Seoane, "Workflows Allowing Creation of Journal Article Supporting Information and Findable, Accessible, Interoperable, and Reusable (FAIR)-Enabled Publication of Spectroscopic Data", ACS Omega, vol. 4, pp. 3280-3286, 2019. https://doi.org/10.1021/acsomega.8b03005
  3. A.I. Savchenko, and C.M. Williams, "The Anti‐Bredt Red Flag! Reassignment of Neoveratrenone", European Journal of Organic Chemistry, vol. 2013, pp. 7263-7265, 2013. https://doi.org/10.1002/ejoc.201301308
  4. K. Liu, Y. Zhu, Y. Yan, Y. Zeng, Y. Jiao, F. Qin, J. Liu, Y. Zhang, and Y. Cheng, "Discovery of Populusone, a Skeletal Stimulator of Umbilical Cord Mesenchymal Stem Cells from <i>Populus euphratica</i> Exudates", Organic Letters, vol. 21, pp. 1837-1840, 2019. https://doi.org/10.1021/acs.orglett.9b00423

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Chiroptical spectroscopy of the natural product Steganone.

Tuesday, February 10th, 2015

Steganone is an unusual natural product, known for about 40 years now. The assignment of its absolute configurations makes for an interesting, on occasion rather confusing, and perhaps not entirely atypical story. I will start with the modern accepted stereochemical structure of this molecule, which comes in the form of two separately isolable atropisomers.
steganone
The first reported synthesis of this system in 1977 was racemic, and no stereochemistry is shown in the article (structure 2).[1] Three years later an “Asymmetric total synthesis of (-)steganone and revision of its absolute configuration” shows how the then accepted configuration (structure 1 in this article) needs to be revised to the enantiomer shown as structure 12 in the article[2] and matching the above representation. The system has continued to attract interest ever since[3],[4],[5],[6], not least because of the presence of axial chirality in the form of atropisomerism. Thus early on it was shown that the alternative atropisomer, the (aS,R,R) configuration initially emerges out of several syntheses, and has to be converted to the (aR,R,R) configuration by heating[3]. One could easily be fooled by such isomerism!

Absolute configurations can be established in several ways.

  1. From precursors of known absolute configuration. This was the most common method until relatively recently, but it is very expensive since asymmetric syntheses are often much more complex and longer than racemic ones. There is always a small residual doubt that any transformation in the synthesis might have altered the configuration in an unexpected manner.
  2. From an X-ray of the final configuration (Bijvoet). Very often the structure is determined on a derivative of the target compound (the original may not form suitable crystals). There is also the doubt that the selected crystals may in fact be a minor form and do not represent the bulk of the system in solution. This is especially true where atropisomerism is concerned, since the solid state structure may not represent the same atropisomer present in solution.
  3. In the last decade or so, it has become more common to make use of the computation of measured chiroptical spectroscopies to see if they match. It turns out that this method appears never to have been applied to Steganone, and here I attempt to rectify this.

First, let us compute the optical rotation. The (aR,R,R) stereoisomer is also known as (-)-Steganone, because the measured specific rotation is [α]589 -170° ± 30.[3] It is computed (MN12L/6-311++G(d,p)/SCRF=chloroform) as -240°, [α]365 -2251[7]. The other atropisomer (aS,R,R) is computed to be 4.5 kcal/mol higher in free energy with [α]589 +408°[8], and measured as +150.[3] There is some uncertainty in the computed values, since the rotations can be dependent on the conformation not only of the rings, but the substituents. You might imagine that the conformation of eg a -OMe group is unimportant, but this is not so. In this case, I have used a crystal structure of a related species to serve as the start point for optimising the MeO conformations. The greater mismatch between computation and experiment for the (aS,R,R) stereoisomer probably needs an exploration of more conformations of the -OMe groups. At least in both cases the signs match between computation and measurement.

Next, the electronic circular dichroism (ECD), which has also been measured[3] for the (aR,R,R) isomer as Δε 201nm (-ve Cotton effect), 218 (+ve), 244 (-ve), 276 (+ve) 304 (-ve) and 337 (-ve). Bearing in mind that the baselines in ECD spectra are notoriously difficult to define (moving it up or down can easily invert a Cotton effect), the agreement with the calculated spectrum MN12L/6-311++G(d,p)/SCRF=chloroform, nstates=200)[9] might seem reasonable, although the calculated version has more peaks in the region 225-265 than are reported (e.g. 235, +ve, 265, -ve).
(R,R)-steganone-9
The (aS,R,R) isomer seems a less good fit. The +ve peak at 218 is missing, the +ve 276 peak matches better than the other isomer, but the 337nm peak is again the wrong sign.
(aS,R,R)-steganone

Of course, in such a game it may be the DFT functional used for the simulation that itself might be misleading, MN12L in this case. Just to check, I also include the results using M062X[10] to see how variable these simulations might be. The measured peaks at 201, 218, 244 and 337nm match, but the ones at 276 and 304nm do not.

s-m062x

Although matching computed with measured ECD spectra is commonly used to assign absolute configurations of molecules, you can see from these results that the technique is not a cast iron one! Even scanning through myriad DFT procedures to find the one that fits best is probably not a complete solution either. Can anything be done to further increase confidence?

How about Vibrational Circular Dichroism (VCD) predictions?[11],[12]. Like ECD, VCD is also sensitive to conformation, which is why some modern instruments have low temperature probes operating at close to 0K which strive to capture only a single lowest energy conformation (although of course in any simulation, you have to identify that conformation reliably!). At some stage in the future, the VCD spectra of steganone might indeed be measured, and hence compared with the below. It might serve to increase confidence in the chiroptical methods as a means of assigning configuration.

(aR,R,R)-steganone (aS,R,R)-steganone

We might conclude from this short exploration of chiroptical spectroscopy that no one single measured or computed value can be absolutely definitive; rather it is the accumulation from various sources that builds up the case for a particular configuration. But at least the above simulations do serve to add some useful additional data for the record.

References

  1. D. Becker, L.R. Hughes, and R.A. Raphael, "Total synthesis of the antileukaemic lignan (±)-steganacin", J. Chem. Soc., Perkin Trans. 1, pp. 1674-1681, 1977. https://doi.org/10.1039/p19770001674
  2. J. Robin, O. Gringore, and E. Brown, "Asymmetric total synthesis of the antileukaemic lignan precursor (-)steganone and revision of its absolute configuration", Tetrahedron Letters, vol. 21, pp. 2709-2712, 1980. https://doi.org/10.1016/s0040-4039(00)78586-8
  3. E.R. Larson, and R.A. Raphael, "Synthesis of (–)-steganone", J. Chem. Soc., Perkin Trans. 1, pp. 521-525, 1982. https://doi.org/10.1039/p19820000521
  4. A. Bradley, W.B. Motherwell, and F. Ujjainwalla, "A concise approach towards the synthesis of steganone analogues", Chemical Communications, pp. 917-918, 1999. https://doi.org/10.1039/a900743a
  5. M. Uemura, A. Daimon, and Y. Hayashi, "An asymmetric synthesis of an axially chiral biaryl via an (arene)chromium complex: formal synthesis of (–)-steganone", J. Chem. Soc., Chem. Commun., vol. 0, pp. 1943-1944, 1995. https://doi.org/10.1039/c39950001943
  6. B. Yalcouye, S. Choppin, A. Panossian, F.R. Leroux, and F. Colobert, "A Concise Atroposelective Formal Synthesis of (–)‐Steganone", European Journal of Organic Chemistry, vol. 2014, pp. 6285-6294, 2014. https://doi.org/10.1002/ejoc.201402761
  7. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189647
  8. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189646
  9. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189649
  10. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189657
  11. https://doi.org/
  12. H.S. Rzepa, "C 22 H 20 O 8", 2015. https://doi.org/10.14469/ch/189651

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Anatomy of an asymmetric reaction. The Strecker synthesis, part 1.

Monday, May 24th, 2010

The assembly of a molecule for a purpose has developed into an art form, one arguably (chemists always argue) that is approaching its 100th birthday (DOI: 10.1002/cber.191104403216) celebrating Willstätter’s report of the synthesis of cyclo-octatetraene. Most would agree it reached its most famous achievement with Woodward’s synthesis of quinine (DOI: 10.1021/ja01221a051) in 1944. To start with, the art was in knowing how and in which order to join up all the bonds of a target. The first synthesis in which (relative) stereocontrol of those bonds was the primary objective was reported in 1951 (10.1021/ja01098a039). The art can be taken one step further. It involves control of the absolute stereochemistry, involving making one enantiomer specifically (rather than the mirror image, which of course has the same relative stereochemistry). Nowadays, a synthesis is considered flawed if the enantiomeric excess (of the desired vs the undesired isomer) of such a synthesis does not achieve at least ~98%. It is routine. But ask the people who design such syntheses if they know exactly the reasons why their reaction has succeeded, you may get a less precise answer (or just a lot of handwaving; chemists also like to wave their hands as well as argue).

Here I set out one such asymmetrically stereospecific scheme, which is the first part of a reaction used to make both natural and un-natural configurations of aminoacids; the Strecker synthesis.

The asymmetric synthesis of an S(S) sulfoxide. Click for 3D model

It makes use of a natural product based on the camphor ring system which nature provides as a single enantiomer. It is converted to an oxaziridine, and this reagent is now used to transfer one oxygen atom to an imino-thioether (DOI: 10.1021/ja00030a045). The result is the formation of a single S(S) enantiomer (the enantiomeric excess is > 98%) of a sulfoxide. In the second stage, cyanide is then delivered asymmetrically (i.e. to one face rather than the other) of the C=N group, the precursor to forming a pure enantiomer of an amino acid. Here we will probe why the first reaction, the asymmetric oxygen atom delivery, is so specific. It would be fair to say that this reaction was probably originally designed with no fundamental understanding of how it might achieve its magic asymmetric delivery. For example, those two chlorine atoms on the camphor ring look as if they were selected by trial-and-error. What indeed IS their role? Steric? Electronic? Other?

If you click on the diagram above, a rotatable 3D model should appear (a static version is shown below). This is an AIM (atoms-in-molecules) analysis of the curvature of the electron density in this transition state (see DOI: 10042/to-4929). To help you navigate, arrow 1 is pointing to the small purple sphere representing the BCP (bond critical point) for the forming S…O bond. Three more purple spheres are highlighted with a halo. One of these is pointed to by arrow 2 below (to see the other two, you really will need the 3D model). This represents a BCP which appears between the hydrogen of the N=CH group and one of the oxygen atoms of the sulphone group. The label indicates the electron density at that point (0.017 au). This is characteristic of a hydrogen bond, albeit an unusual C-H…O type (a type that is too rarely invoked when explanations of stereospecificity are sought), and the density indicates its a reasonably strong one!

AIM analysis of Transition state for oxygen transfer

In fact, two more BCPs can be located between this H and other groups, and they too are marked with halos. The first leads to the oxygen atom being transferred, and the second to specifically one of the two chlorine atoms (there are other interactions to the chlorines as well). Now, it turns out that these interactions are largely absent for the alternative transition state (which would form the enantiomeric R(S) sulfoxide). Since a C-H…O hydrogen bond can easily be worth ~2 kcal/mol, it is no surprise to find that the energy of the favoured transition state is overall 2.4 kcal/mol lower in free energy compared to the isomer not formed. This represents (@300K) a ratio of 60:1 in the predicted ratio of the two species, or indeed an ee ~98%.

Armed with this insight, one could design further experiments to test the hypothesis. For example, it appears only one of the two chlorines plays an active role. Replacing the passive chlorine with e.g. hydrogen might make little difference. Suppressing the hydrogen bonds by changing the N=CH to e.g. N=CF should have a big effect. The two oxygens of the sulfone also do not play equal roles. Perhaps this can be tested with a sulfoxide in place of the sulfone? All these hypotheses can of course first be tested with calculations. Of course, coming up with synthetic strategies for these new molecules might be tricky. But these experiments may give confidence (or demolish it) in the AIM technique used here to analyse the stereospecificity of this reaction.

So the next time you hear a synthetic chemist proudly announce a new enantioselective synthesis, ask them what their deeper understanding of why their reaction works is. And be prepared to run away fast if they growl at you!

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