Hi Greg
>
> I should have provided a bit more context around what the current
behavior
> is, or at least what it's supposed to be. Sorry I forgot that.
My fault - I should have (re)read the manual (I thought it seemed a bit
familiar..!)
> Currently, when creating a reaction from rxnSMARTS,
inversion/retention is
> handled by looking at the relative stereochemistry of atoms in the
reactants
> and products.
>
> If they're different you get inversion (apologies for the extremely
bogus
> example "reaction"):
>
> In [13]: rxn = AllChem.ReactionFromSmarts("[C@:1]>>[C@@:1]")
>
> In [14]: ps =
rxn.RunReactants((Chem.MolFromSmiles('F[C@](Cl)(Br)I'),))
>
> In [15]: Chem.MolToSmiles(ps[0][0],True)
> Out[15]: 'F[C@@](Cl)(Br)I'
>
> In [16]: ps =
rxn.RunReactants((Chem.MolFromSmiles('F[C@@](Cl)(Br)I'),))
>
> In [17]: Chem.MolToSmiles(ps[0][0],True)
> Out[17]: 'F[C@](Cl)(Br)I'
>
> and if they're the same you get retention:
>
> In [7]: rxn2 = AllChem.ReactionFromSmarts("[C@:1]>>[C@:1]")
>
> In [8]: ps =
rxn2.RunReactants((Chem.MolFromSmiles('F[C@](Cl)(Br)I'),))
>
> In [9]: Chem.MolToSmiles(ps[0][0],True)
> Out[9]: 'F[C@](Cl)(Br)I'
>
> In [10]: rxn3 = AllChem.ReactionFromSmarts("[C@@:1]>>[C@@:1]")
>
> In [11]: ps =
rxn3.RunReactants((Chem.MolFromSmiles('F[C@](Cl)(Br)I'),))
>
> In [12]: Chem.MolToSmiles(ps[0][0],True)
> Out[12]: 'F[C@](Cl)(Br)I'
>
>
> This much feels logical to me, though of course it can be changed if
there's
> disagreement.
It sort of does to me too, but I can't shift the sensation that there
might be a can of worms here - more on that in a moment...
> If you call the reaction with non-chiral starting material, you get
non-chiral
> ouput:
>
> In [20]: rxn3 = AllChem.ReactionFromSmarts("[C@@:1]>>[C@@:1]")
>
> In [21]: ps = rxn3.RunReactants((Chem.MolFromSmiles('FC(Cl)(Br)I'),))
>
> In [22]: Chem.MolToSmiles(ps[0][0],True)
> Out[22]: 'FC(Cl)(Br)I'
>
> This is probably also ok; it certainly reflects what would happen in
the lab (er,
> at least I think it does).
Just to be a pedant for a moment (but actually, this could be important
later) - this is actually calling the reaction with *chiral* (albeit
presumably racemic) starting material
> So far so good. We've got inversion of stereochemistry and retention
of
> stereochemistry. There are two cases left: resolution/creation and
> scrambling.
>
> One obvious thing to do here would be:
>
> [C@:1]>>[C:1] scrambling
> [C:1]>>[C@:1] resolution/induction
>
> This is where my extremely bogus example starts to make things more
> difficult to understand, so here's a more real example of the
induction case:
> [#6:1]/[C:2]=[C:3](/[#6:4])>>[#6:1][C@H:2](Br)[C@H:3](Br)[#6:4]
>
> Seem right?
<<Can of worms alert 1!!>> At first sight this seems perfectly ok(?) -
as long as we accept that we know what we mean by the (R) flags on the
carbons (by my reckoning we probably mean syn addition of Br2 across a
double-bond?). But - problems of symmetry and atom priorities aside(!)
- what do I do if I want to employ the same transformation but with no
absolute stereo-control (ie if I don't have the same wonder-catalyst)?
At the moment I guess there is no way to represent relative
stereochemistry in the absence of an enhanced stereochemistry model?
This brings me on to the main can of worms sensation - and I think it
may revolve trying to service both real and 'virtual/fake' reactions in
the same system, as well as some obvious concerns about enhanced
stereochemistry. So some examples / questions:
1. I have a super-useful enzyme that will only hydrolyse (R)-esters (or
more precisely I should say it won't hydrolyse (S)-esters). So:
CC[C@H](C)C(=O)OC>>CC[C@H](C)C(=O)O ## R gets hydrolysed
CC[C@@H](C)C(=O)OC>>CC[C@@H](C)C(=O)OC ## S doesn't
CCC(C)C(=O)OC>> ## Oh dear, what do we want to happen here? I know what
my enzyme will do - but we do have to assume that we are implying a
racemic mix (it gets more worrying if we might mean a single, but
unknown, enantiomer, or we might know nothing at all - we're back to
enhanced stereochemistry again!)
CCC(C)C(=O)OC>>CC[C@H](C)C(=O)O.CC[C@@H](C)C(=O)OC ## So this is
what the enzyme would do - because we have treated the chiral centre as
a racemic mix - essentially expanding out to:
CC[C@H](C)C(=O)OC.CC[C@@H](C)C(=O)OC>>CC[C@H](C)C(=O)O.CC[C@@H](C)C(=O)O
C
The problem with this is that it doesn't fit with the existing rSMARTS
nomenclature for retention and inversion, because the absolute
stereochemistry of the starting material affects the outcome of the
reaction! But I guess my enzyme reaction above would be represented as
something like
[C@:1][C:2](=[O:3])[O:4]C>>[C@:1][C:2](=[O:3])[O:4]H
But we would have to (a) assume now that '@' in the starting material
only matched (R), and (b) treat incoming racemates intrinsically as
two-component mixtures of (R) and (S) to then apply the transformation
to just the (R) and add the (S) starting material to the products...
2. I am a database admin, and I want to transform some mis-assigned
racemates to the (S) enantiomers
Eg CCC(C)C(=O)OC>>CC[C@@H](C)C(=O)OC
But extending the concept of treating racemates intrinsically as (R)/(S)
mixtures, does this mean I should apply:
[C@:1][C:2](=[O:3])[O:4]C>>[C@@:1][C:2](=[O:3])[O:4]C
Which (if again we accept absolute stereo-matching in the rSMARTS) would
convert any (R) stereocentres to (S) - including those in the racemates
in our set of interest. So the desired behaviour, but is it intuitive?
3. I want to epimerise a chiral centre alpha to a carbonyl to the more
stable 'anti' arrangement relative to an adjacent chiral centre
C[C@H]1CCN(C)C(=O)[C@H]1C>>C[C@H]1CCN(C)C(=O)[C@@H]1C ## Inversion
example when we start with the less stable 'syn'
C[C@H]1CCN(C)C(=O)C1C>>C[C@H]1CCN(C)C(=O)[C@@H]1C ## Same output,
but starting with a racemic centre
C[C@H]1CCN(C)C(=O)[C@@H]1C>>C[C@H]1CCN(C)C(=O)[C@@H]1C ## No change if
we start with the anti arrangement
But in all cases I am only bothered about relative stereochemistry, not
absolute... And I need to be able to make
CC1CCN(C)C(=O)C1C>>C[C@H]1CCN(C)C(=O)[C@@H]1C
mean "take the mix of 4 diastereomers and give the two trans ones" (not
the one R,S one). Enhanced stereochemistry again?!
I'm sort of wondering whether the complexity and pain of enhanced
stereochemistry introduction would actually make handling reaction
stereochemistry simpler? Or am I just confusing things with 'edge'
cases (I don't think so...)? But this does all feel like a mine field
that others must have trodden already!
My head hurts and I'm going for a lie-down! : )
James
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