Hi Greg,
> I've got a question for the community about how chirality should be
handled in reactions.
> This morning I managed to fix one of the outstanding reaction
stereochemistry problems in the RDKit: the loss of chirality when one
bond to a stereocenter is to an unmapped atom. Here's a quick demo of
the new behavior (not yet checked in; there are still a couple things to
be cleaned up):
>
> In [7]: rxn = AllChem.ReactionFromSmarts('[C:1]-O>>[C:1]-S')
> In [8]: ps = rxn.RunReactants((Chem.MolFromSmiles('F[C@H](O)Cl'),))
> In [9]: Chem.MolToSmiles(ps[0][0],True)
> Out[9]: 'F[C@H](S)Cl'
>
> It seems nice to be able to preserve chirality in these cases.
> The question that comes up is: "*Should* we be preserving chirality in
these cases?". The change makes it impossible to indicate a reaction
that scrambles stereochemistry. That doesn't seem right.
> So... the question to you guys: How should stereochemistry
inversion/retention/loss be indicated in Reaction SMARTS?
Good question - and let me be the first to jump in, feet first, without
thinking enough! : )
Instinctively, I would say it would be good to (a) scramble
stereochemistry if not otherwise specified - at least this way we
default to losing information rather than risking keeping incorrect
information; (b) use a flag at each centre if we want to retain
stereochemistry (what about '@'?); (c) use another flag if we want to
invert (and, inventive I know, what about '@@'?).
So in the above example, let's say I want to always invert (eg to
represent an SN2 reaction) - the rSMARTS could then be something like
[C:1]-O>>[C:1@@]-S, and the example input above would give F[C@@H](S)Cl
out.
The same output with no specification could give FC(H)(S)Cl and, of
course, achiral input would always give achiral output - regardless of
the flag in the rSMARTS.
> Bonus points to anyone who can explain to me how the
inversion/retention flags in RXN files should be handled. At the moment
the RDKit uses what's in the products and ignores them in the reactants.
Something like the above? (I told you I hadn't thought about it enough!)
Kind regards
James
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