How to assign E/Z configuration according to the Cahn-Ingold-Prelog rules when subsituents differ only by stereochemistry

Question

I stumbled-upon this compound:

I'm wondering how to determine the configuration of the double bond. Is it E or Z? How do I decide on the priorities when the substituents can only differ in the configurations on the chiral centers?

Answer 1

In your example, the stereodescriptors R and S are already given. The remaining question is about the double bond which gives rise to cis-trans isomerism.

In the hierarchical Sequence Rules, we finally find

P-92.1.3.5 Sequence Rule 5

An atom or group with descriptor ‘R’, ‘M’, and ‘seqCis’ has priority over its enantiomorph ‘S’, ‘P’ or ‘seq Trans’.

Source: Nomenclature of Organic Chemistry – IUPAC Recommendations and Preferred Names 2013 (Blue Book)

Therefore, the configuration would be ‘E’ since ‘R’ precedes ‘S’.

However, the ‘E’ and ‘Z’ stereodescriptors do not distinguish between double bonds whose descriptors are reflection invariant from the geometrically enantiomorphic double bonds whose stereodescriptors are reflection variant.

Following the recommendations for enantiomorphic double bonds, the configuration is ‘seqTrans’.

Answer 2

I remember that when all the basic rules end up in a tie (including the ghost atoms), the following priority is used:

• $R > S$
• $cis > trans$
• $Z > E $

So R is given higher priority and the above mentioned molecule will be considered as $E$ and not $Z$.

Answer 3

The authoritative article for CIP rules is Spezifikation der molekularen Chiralität. According to the article, the double bond has the E configuration. The reason for this is that R has priority over S.