Re: QSAR - new question on chirality descriptors

Ovidiu Ivanciuc writes:

> The absolute configuration (R/S) describes a local chiral element,
> and not the optical properties of the molecule. Also, there is no
> relationship between R/S and the sign (+/-) of the specific rotation,
> even when a compound has only one chiral center.

This well-known textbook fact is strictly speaking wrong.

There is a strict relationship between the two for a given
species under given conditions, and it can be calculated,
though it's by no means trivial. The chiroptical properties
depend on the response of the electrons in the solution phase
ensemble to polarised light of a certain frequency, i.e. the
excited state wavefunctions, which in turn are a function of
the nuclear positions, which are a function of the structure,
to which (R/S) can be assigned.

It's now practical for some systems to solve absolute
configuration directly from chiroptical spectra and TDDFT,
and this is on the way to being a routine adjunct to
other methods of determination, alongside exciton coupling,
chiral HPLC, and xray crystallography.

> Changing a substituent
> might change the specific rotation sign, without changing the
> absolute configuration.

This is quite correct. When it does so (or more tellingly
when a substituent dramatically changes the ECD spectrum) it
may indicate that the preferred orientation of the pharmacophore
features in solution has changed due to the substituent, especially
if those features are attached to the chiral centre. Thus a
change in (R/S) vs. (+/-) may be reflected in the biological
activity (neglecting the case where the formal assignment
by Cahn-Ingold-Prelog rules doesn't follow the configuration
of the pharmacophore elements due to a change in priority of
the 4th substituent).

We recently described a case in which the optical properties
rather than the geometrical assignment followed the
biological activity, due to conformational restriction
causing the (+)(R) form to resemble the unrestricted (+)(S)
form at the receptor. In this series of a-amino acids near an
aromatic, the 3D orientation of the features giving rise to
biological activity is also largely responsible for the
chiroptical properties, so the sign of the peak in the ECD
spectrum is a better predictor of the eutomer than the absolute
configuration. It would be interesting to hear of other
examples.

"A stereochemical anomaly: the cyclised (R)-AMPA analogue
(R)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridine-5-carboxylic
acid [(R)-5-HPCA], resembles (S)-AMPA at glutamate receptors."
Stine B. Vogensen, Jeremy R. Greenwood, Annemarie R. Varming,
Lotte Brehm, Darryl S. Pickering, Birgitte Nielsen, Tommy Liljefors,
Rasmus P. Clausen, Tommy N. Johansen and Povl Krogsgaard-Larsen.
Danish University of Pharmaceutical Sciences
Organic and Biomolecular Chemistry, 2, 206-2132004,
http://www.rsc.org/CFmuscat/intermediate_abstract.cfm?FURL=/ej/OB/2004/B310450H/index.htm&TYP=ADV

/Jeremy
Received on 2004-09-12 - 17:26 GMT