-Vivekananda Vrudhula, Bireshwar Dasgupta, Jingfang Qian-Cutrone, Edward Kozlowski, Christopher Boissard, Steven Dworetzky, Dedong Wu, Qi Gao, Roy Kimura, Valentin Gribkoff, and John Starrett, Jr., J. Med. Chem.

Yet another case of axial chirality in the recent literature comes in the form of ion channel openers described by Vrudhula et al. A previous Depth-First article illustrated how most popular cheminformatics tools are incapable of distinguishing axially chiral enantiomers such as those shown above. If your application suddenly needed to do so, could it cope?

FlexMol is an XML language designed to solve the molecular representation problems of today and, hopefully, those of tomorrow. Some of its capabilities have already been introduced:

• planar chirality
• square-planar isomerism
• axially chiral amides
• axially chiral biaryls
• tetrahedral chirality
• alkene geometrical isomerism
• multiatom bonding in metallocenes

Given the two previous articles on axial chirality, it should be clear how to represent the two enantiomers enantiomers of the structure shown above using FlexMol. What is far from clear at this point is how to bring this capability to chemists. For example, no 2-D structure editor I'm aware of can systematically encode axial chirality. Likewise, no 2-D rendering toolkit can draw it. FlexMol and languages like it are important first steps to solving these problems, but they are by no means the last.

Postscript: the two structures depicted above are actually identical! You can prove this to yourself by verifying that the phenol oxygen points into the plane of your screen and the chlorine atom points out of the plane in both structures. Clearly the authors intended for the phenyl ring to be flipped by 180 degrees, but they hand-placed the wedges on the wrong side of the benzene ring. The fact that this error appears in none other than J. Med. Chem. further underscores the need for tools that understand axial chirality.

-Andre Lapierre, Steven Geib, and Dennis Curran, J. Am. Chem. Soc. ASAP

Recently, Heck cyclizations of axially chiral N-arylacrylanilids were reported by Lapierre, Geib, and Curran. Faithfully communicating this kind of chirality in machine-readable form is virtually impossible using today's most popular technologies. A previous article showed how a new XML-based molecular language, FlexMol, could fully represent the axial chirality of BINOL. This article will apply the same principles to an N-arylacrylanilide.

The Complete FlexMol Representation

Given the atom numbering of the above molecule, we can construct a complete FlexMol representation. Rather than reproduce the entire XML document here, I'll just include stereochemically-relevant excerpts.

Stereochemistry: Chiral Axis

The chiral axis is directed from Atom 11 to Atom 7. Half planes are arranged in clockwise fashion about this axis. To better visualize the placement of atoms into half planes, consider the following diagram:

This leads to the following FlexMol representation:

<!-- snip -->
<conformationWheel>
  <gammaSequence source="11" target="7">
    <connections>
      <atomPair source="11" target="7"></atomPair>
    </connections>
  </gammaSequence>
  <halfPlane>
    <lower atom="10"></lower>
  </halfPlane>
  <halfPlane>
    <upper atom="5"></upper>
  </halfPlane>
  <halfPlane>
    <lower atom="12"></lower>
  </halfPlane>
  <halfPlane>
    <upper atom="8"></upper>
  </halfPlane>
</conformationWheel>
<!-- snip -->

Stereochemistry: Olefin Geometry

Assignment of olefin geometry in FlexMol was introduced in a previous article. A simple disubstituted olefin was used as an example. Exactly the same principles apply in encoding the trisubstituted olefin geometry of our molecule of interest:

<!-- snip -->
<conformationWheel>
  <gammaSequence source="3" target="2">
    <connections>
      <atomPair source="3" target="2"></atomPair>
    </connections>
  </gammaSequence>
  <halfPlane>
    <lower atom="4"></lower>
    <upper atom="1"></upper>
  </halfPlane>
  <halfPlane>
    <lower atom="5"></lower>
  </halfPlane>
</conformationWheel>
<!-- snip -->

Conclusions

Axial chirality can be fully represented using FlexMol's simple system of axes and half planes. This system can be applied in novel situations, increasing FlexMol's potential as a self-describing molecular language.

... To discover high-performance asymmetric catalysts, developing an excellent chiral ligand is crucial. Attracted by its molecular beauty[Chemica Scripta 1985, 25, 83], we initiated the synthesis of BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)[J. Am. Chem. Soc. 1980, 102, 1932] in 1974 at Nagoya with the help of H. Takaya, my respected long-term collaborator. BINAP was a new fully aromatic, axially dissymmetric C₂ chiral diphosphine that would exert strong steric and electronic influences on transition metal complexes. Its properties could be fine-tuned by substitutions on the aromatic rings. ...

-Ryoji Noyori, Nobel Lecture, December 8, 2001

Axial chirality results, not from a tetrahedral chiral center, but from a chiral axis. This form of chirality most frequently occurs in biaryls and allenes. The importance of axial chirality to organic chemistry was recognized in 2001, when Ryoji Noyori was co-awarded the Nobel Prize in Chemistry, in part for his work with highly selective catalysts derived from the axially-chiral BINAP ligand.

Since the early 1980s, axial chirality has played an increasingly significant role in organic chemistry. Much of this research has focused on catalysis; consider two recent reviews, one on modified BINOLs, and one on modified BINAPs. But axial chirality isn't just restricted to catalysts; it's also a feature of numerous natural products.

Once merely a curiosity, axial chirality now plays a role in virtually every subdiscipline of organic chemistry. At the same time, this important concept is alien to most molecular languages and toolkits. Consider, for example, that the specifications of all four of the most popular molecular languages (SMILES, InChI, Molfile, and CML) are silent on the representation of axial chirality. In other words, axial chirality is undefined in these languages. Although support for axial chirality could be "hacked" into these languages, this would require nonstandard conventions that would be unintelligible to any third party.

This situation poses a significant problem for those needing to discriminate axially chiral stereoisomers in molecular databases or other applications. For example, PubChem's entry on the axially-chiral drug gossypol is devoid of stereochemical information. If PubChem used an internal representation of molecular structure capable of encoding axial chirality, coupled with a suitable molecular language to be used by depositors, separate entries for each gossypol enantiomer would be feasible. After all, PubChem users have come to expect the same of other chiral drugs containing stereogenic atoms.

To address this problem, a new XML-based molecular language called FlexMol has been developed. Recent articles have highlighted FlexMol's use with the multi-atom bonding found in metallocenes, and E/Z alkene geometrical isomerism. Based on a specification by Andreas Dietz, Flexmol can represent all forms of axial chirality using a single flexible formalism..

Chemical informatics is beginning to embrace the concepts of Open Source and Open Data already in widespread use elsewhere. This shift will bring into sharp focus the need for robust and open methods for accurately encoding molecular structure. Existing technologies have not kept up with the chemists themselves, as the axial chirality problem demonstrates. Future articles in this series will show how FlexMol can offer a solution to this and other important molecular representation problems.

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