Page 130 - Chiral Separation Techniques

4.5 3D Structure Database Searches 107

centers, aromatic ring centers, lipophile centers, etc. These will be assumed to rep-
resent the types of interactions that the sample is likely to have at the CSP receptor
sites. Once potential CSP active sites have been identified, the user can propose dif-
ferent enantiophores, which are complementary to the sites and since, may be con-
sidered as CSP receptor-based queries. The main purpose of this enantiophore build-
ing is then to locate in CHIRBASE the potential structures that can fit into a given
CSP receptor.
This technique has been used to track conceivable enantiophores of the Whelk-O
1 CSP ((3R,4S)-4-(3,5-dinitrobenzamido)-3-[3-(dimethylsilyloxy)propyl ]-1,2,3,4-
tetrahydrophenanthrene) which was prepared in 1992 by Pirkle and Welch [22]. As
seen in Fig. 4-7, a Whelk enantiophore should contain two ore more of the follow-
ing molecular properties:

aromatic center (π-π interaction)
hydrogen-bond donor center
hydrogen-bond acceptor center
dipole-dipole stacking
The hypothetical enantiophore queries are constructed from the CSP receptor
interaction sites as listed above. They are defined in terms of geometric objects
(points, lines, planes, centroids, normal vectors) and constraints (distances, angles,
dihedral angles, exclusion sphere) which are directly inferred from projected CSP
receptor-site points. For instance, the enantiophore in Fig. 4-7 contains three point
attachments obtained by:
projecting a point at a 3 Å distance along a line that is perpendicular to an aro-
matic ring plane. This point is surrounded by an exclusion sphere (1.5 Å in diam-
eter) to exclude atoms within this sample space.
projecting a point along the direction of a hydrogen at a 3 Å distance from the
hydrogen bond donor site.
The distances then retrieved between the enantiophore points are exactly based on
the actual receptor-site information, and so well justify the expression of “CSP
receptor-based query” quoted above. It is well recognized today that samples that are
resolved on a common CSP receptor do not systematically bind with analogous
functional groups. Many CSPs often present multiple modes of chiral recognition
mechanisms. For this Whelk CSP study, we have elaborated the following simple
enantiophore queries (Fig. 4-8) using the exposed strategy:

Query 1: contains two aromatic groups. The «A» (any) atoms mean that we allow
the retrieval of heterocyclic systems.
Query 2: an aromatic group and a hydrogen-bond acceptor center. R1 is a complex
generic group (not detailed here) which delimits the search to all groups
that provides lone-pair electrons to the hydrogen bond.
Query 3: an aromatic group and a hydrogen-bond donor center.
Query 4: one aromatic group and an amide group.
All these queries have at least one lipophilic aromatic group.