Algorithmic Analysis of Cahn–Ingold–Prelog Rules of Stereochemistry: Proposals for Revised Rules and a Guide for Machine Implementation

The most recent version of the Cahn–Ingold–Prelog
rules for the determination of stereodescriptors as described in Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred
Names 2013 (the “Blue Book”; Favre and Powell.
Royal Society of Chemistry, 2014; http://dx.doi.org/10.1039/9781849733069) were analyzed by an international team of cheminformatics software
developers. Algorithms for machine implementation were designed, tested,
and cross-validated. Deficiencies in Sequence Rules 1b and 2 were
found, and proposed language for their modification is presented.
A concise definition of an additional rule (“Rule 6”,
below) is proposed, which succinctly covers several cases only tangentially
mentioned in the 2013 recommendations. Each rule is discussed from
the perspective of machine implementation. The four resultant implementations
are supported by a 300-compound validation suite in both 2D and 3D
structure data file (SDF) format as well as SMILES (https://cipvalidationsuite.github.io/ValidationSuite). The validation suites include all significant examples in Chapter
9 of the Blue Book, as well as several additional structures that
highlight more complex aspects of the rules not addressed or not clearly
analyzed in that work. These additional structures support a case
for the need for modifications to the Sequence Rules.