The last installment in this series discussed the limitations in today's molecular languages and how FlexMol is designed to overcome them. Although these limitations are clearly present theoretically, what's the practical effect likely to be?
For the last two years, a series of articles highlighting specific examples from the current chemical literature have appeared here. Variously titled "How would your cheminformatics tool do this?", "Can your cheminformatics tool to this?", and "Cheminformatics Puzzler", each entry featured an article from a mainstream chemistry journal in which SMILES, Molfile, CML, and/or InChI would be incapable of faithfully representing a centerpiece structure. The examples are taken from well-read journals in synthetic organic, natural products, and medicinal chemistry.
The purpose was not to bash these languages, but rather point to an important common set of limitations among them - a kind of groupthink if you will. As mentioned before, this may not be a problem at all for the work you're currently doing. But given the rapid exploration by chemists of areas in which cheminformatics' standard simplifying assumptions don't apply, it's possible you'll need a solution sooner than you might think.
The remainder of this article groups these examples by topic.
The literature is replete with examples of axial chirality. None of the molecular languages in common use today can represent this form of chirality. The examples below are but a small selection.
Stereoselective Synthesis of Both Enantiomers of N-Aryl Indoles with Axially Chiral N−C Bonds from J. Org. Chem.
This example does double-duty as an example of planar chirality.
Atropisomeric 3-(β-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K Potassium Channel Openers from J. Med. Chem.
Note: both structures are actually identical - a typographical error
Preparation and Use of Enantioenriched Allenylsilanes for the Stereoselective Synthesis of Homopropargylic Ethers from Org. Lett.
3,3‘-Dipyridyl BINOL Ligands. Synthesis and Application in Enantioselective Addition of Et2Zn to Aldehydes from Org. Lett.
Cytotoxic Metabolites from an Indonesian Sponge Lendenfeldia sp. from J. Nat. Prod.
Chiral Bifunctional Organocatalysts in Asymmetric Aza-Morita−Baylis−Hillman Reactions of Ethyl (Arylimino)acetates with Methyl Vinyl Ketone and Ethyl Vinyl Ketone from J. Org. Chem.
Kadsuralignans H−K from Kadsura coccinea and Their Nitric Oxide Production Inhibitory Effects from J. Nat. Prod.
Carboranylphosphites—new effective ligands for rhodium-catalyzed asymmetric hydrogenation of dimethyl itaconate from Tetrahedron Lett.
Enantiopure Anthrylene−Ethynylene Cyclic Tetramer and Racemization via Rotation of Anthracene Unit about Acetylenic Axes from Org. Lett.
The Marinopyrroles, Antibiotics of an Unprecedented Structure Class from a Marine Streptomyces sp. from Org. Lett.
Arylbiphenylene Atropisomers: Structure, Conformation, Stereodynamics, and Absolute Configuration from J. Org. Chem.
Other Forms of Atropisomerism
Enantioselective Synthesis of an Atropisomeric Diaryl Ether from Angew. Chem. Int. Ed. Engl.
Design and Synthesis of Planar Chiral Heterocyclic Carbene Precursors Derived from [2.2]Paracyclophane from J. Org. Chem.
Reduction of cis,trans,cis-[PtCl2(OCOCH3)2(NH3)2] by Aqueous Extracts of Cancer Cells from J. Med. Chem.
Large-Scale Synthesis and Resolution of TRISPHAT [Tris(tetrachlorobenzenediolato) Phosphate(V)] Anion from J. Org. Chem.
Once the domain of organometallics chemists, these molecules are making their way into a variety of other applications.
Dual Mechanisms of DNA Damage by MoCH3(η3-allyl)(CO)2(phen) Complexes from J. Org. Chem.
Multisignaling Optical-Electrochemical Sensor for Hg2+ Based on a Rhodamine Derivative with a Ferrocene Unit from Org. Lett.
A Re-Evaluation of the Electrophilic Substitution Reactions of the Ramirez Ylide from J. Org. Chem.
α-Arylation of Ketones Using Highly Active, Air-Stable (DtBPF)PdX2 (X = Cl, Br) Catalysts from Org. Lett.
ClickFerrophos: New Chiral Ferrocenyl Phosphine Ligands Synthesized by Click Chemistry and the Use of Their Metal Complexes as Catalysts for Asymmetric Hydrogenation and Allylic Substitution from Org. Lett.
Triple Channel Sensing of Pb(II) Ions by a Simple Multiresponsive Ferrocene Receptor Having a 1-Deazapurine Backbone from Org. Lett.
Catalytic applications of 1,2,4-diazaphospholide-based ruthenium complexes in the Heck reaction from Tetrahedron Lett.
Discreteness of π-conjugation of 1,6-methanoannulene by troponoid fusion at the 3,4-positions from Tetrahedron Lett.