Subject: SUMMARY - Reaction Pathway Programs

From: [email-masked] (Joe Golab)
Date: Tue, 15 Jul 1997 16:51:21 -0500

Hi CCL:

Below is the summary of responses to the "retro-synthesis" question
I recently asked.  Thanks to all who have responded.  I have edited
some of the answers and so I take full responsibility for any errors.
If I get any more answers, I will re-post summary.

<< Tue Jul 15 16:50:53 CDT 1997 >>

Execute Summary of Answers

  1) SYNGEN, Jim Hendrickson, Brandeis University
  2) CAMEO, Bill Jorgensen, Yale
  3) SYNTREE, Commerical Software, Vendor?
  4) SYNLIB, Dan Chodosh, may not exist anymore
  5) REACCS, MDL
  6) CAS's reaction data base
  7) Chiron, Steve Hannisan (spl?) of U. of Montreal.
  8) LAHSA, E.J. Corey, Harvard U.
  9) Unknow, Michael Mavrovouniotis, Northwestern
 10) Crossfile, Beilstein

:Joe
 [email-masked]
 (630) 961-7878  <SOCON 231 7878>

______________________________ Original Note __________________________________
Subject: CCL:Reaction Pathway Program
Author:  chemistry-request ([email-masked]) at unix,sh
Date:    7/14/97 4:43 PM

Dear CCL Member:

Do you know of any (engineering, chemistry, biological, etc) program that
given a compound would suggest any and all reaction pathways toward that
compound (no matter how outlandish from a thermodyanmic standpoint)?

For example, given tolune, the program would suggest:

 1) benzene + methane -> toluene
 2) methylcyclohexane -> toluene + H2
 3) methane + heat/pressure -> toluene + H2
 4) ETC.

Perhaps this is really a database that is part of a program.  Any leads
would be gratefully appreciated!  Thanks.

_____________________________Reply Separator_________________________________
Subject: Re: CCL:Reaction Pathway Program
Author:  lchen ([email-masked]) at unix,mime
Date:    7/14/97 5:16 PM

Dear Joe:

Please check the following SYNGEN site:

http://syngen2.chem.brandeis.edu/syngen.html

you may find something interesting you.

-Lingran

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Senior Scientific Programmer
MDL Information Systems, Inc.
14600 Catalina Street
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CA 94577

Phone: (510) 895-1313, Ext. 1305
FAX:   (510) 614-3616

Email: [email-masked]
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_____________________________Reply Separator_________________________________
Subject: Re: CCL:Reaction Pathway Program
Author:  eslone ([email-masked]) at unix,mime
Date:    7/14/97 6:32 PM

Talk to Jim Hendrickson at Brandeis University.  He has a program called
SynGen.
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_____________________________Reply Separator_________________________________
Subject: Re: CCL:Reaction Pathway Program
Author:  dsmith ([email-masked]) at unix,mime
Date:    7/14/97 9:12 PM

Joe:

I am not familiar with any program that will suggest ALL reaction
pathways... there are just way too many possibilities, which is why we
still have synthetic organic chemists.

You are probably familiar with Bill Jorgensen's CAMEO program (I hope I
have the name correct), which can suggest 'reasonable' synthetic routes to
various types of compounds and functionality.  There is also a commercial
program (not that Bill doesn't sell his programs, ;)) called SYNTREE (I
believe).  There were some papers about this at either the last ACS
National meeting in San Francisco or at the Midland, MI, ACS Regional
meeting in May.  I can look for more information if you wish, but I am at
home and just finishing up a vacation while I write this.

Regardless, both of these programs use a combination (I believe) of data
bases and "expert" algorithms to select likely reactions.  I don't know of
anything that will give you all possible routes, except perhaps an
aggressive undergraduate who has just finished his/her organic final exam.

There was also SYNLIB that came from the late Dan Chodosh... I don't know
if anyone picked up that program so I can't tell you if it still exists.
This was purely data base based and matched based on user-defined
descriptors, if I remember correctly from my postdoc days.  MDL REACCS and
CAS's reaction data base are two others that come to mind.

I would also love to hear from anyone else about similar programs.  Please
post to CCL rather than just to Joe.

Doug Smith

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_____________________________Reply Separator_________________________________
Subject: Re: CCL:Reaction Pathway Program
Author:  Willie ([email-masked]) at unix,mime
Date:    7/15/97 1:12 AM

Joe,

Two programs that can do retrosynthetic analysis,
1. Chiron, from Prof. Steve Hannisan (wrong spelling?) of U. of Montreal.
2. LAHSA, from prof. E.J. Corey of Harvard U.

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_____________________________Reply Separator_________________________________
Subject: RE: Reaction Pathway Program
Author:  RICHEYFA ([email-masked]) at unix,mime
Date:    7/15/97 6:12 AM

Hi, Joe,

I had a similar question when looking for new routes to commodity
chemicals.  I found references to techniques for making expensive
[usually pharmaceutical] chemicals which would take a target structure
and elaborate[!] multistep pathways from known precursors.  I think one
was E.J. Corey's group's product.  At least one of these gave
synthetically viable guesses for transformations so probably weeded out
a lot of the thermodynamically infeasible routes.

I haven't pursued this very far but was left with the feeling that there
was a lot of work in the 80's and the only thing that has survived
outside academe has been the pharmaceutical part.  I may be wrong in
this.

I never did summarize my work but if you are interested I can send you
references with brief comments.

I wanted this approach to automate the cataloging of possible synthetic
routes including finding the ones that I'd overlook because of my
particular chemical background.

Forrest Richey

Union Carbide Corporation
Technical Center
Bldg 740 Room 4107
S. Charleston, WV 25303
(304)747-4964

Two things happen when you reach fifty, and if I could remember one, I
wouldn't worry about the other two.

_____________________________Reply Separator_________________________________
Subject: Reaction Pathways
Author:  burkhart ([email-masked]) at unix,mime
Date:    7/15/97 9:00 AM

Hi Joe,

If I'm not mistaken, Prof. Bill Jorgensen's group @Yale worked
on a program called CAMEO. As I remember it, they were trying
to use it as a reaction chemistry "assistant"--but I'm not
sure how far they got.

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_____________________________Reply Separator_________________________________
Subject: Re: CCL-Reaction Pathway Pro
Author:  mnliebman ([email-masked]) at unix,sh
Date:    7/15/97 9:59 AM

RE>CCL:Reaction Pathway Program              7/15/97

Joe
try contactine Michael Mavrovouniotis at Northwestern- [email-masked] I
think
Michael
271 7190
_____________________________Reply Separator_________________________________
Subject: Your e-mail to CCL
Author:  pierre ([email-masked]) at unix,mime
Date:    7/15/97 10:14 AM

Dear Joe,

I received a copy of your e-mail attached at the end of my reply. You may
remember that we talked on the phone a few month ago. Although my answer is
obviously biased by the fact that I work for MDL, my experience after 9
years working with the large pharma and chemical industries in Europe and in
the US is that there seems to be no good way to have a prediction program. A
lot of companies have tried, and they have ended up licensing our databases
or other  (like Beilstein Crossfire). The advantage they have found in our
system, compared to other database systems, (especially since we introduced
ISIS, the client server system we provide now) is the flexibility of our
querying interface. You can search not only on exact reactions, but also on
things like " find an example of a reaction where this fragment is formed".
Or "find an example of a reaction using these conditions where a fragment is
unaltered".

As an example, to address your query below, we would draw the toluene, and
define it as a product, and then we would perform a search known as
"structure as product not as reactant, or "sub-structure as product, not as
reactant". Which basically defines that the toluene has to be formed during
the reaction. You could also refine the query by specifying certain classes
of reactions you do not want (list catalysts that are expensive etc).

Running the query you use as an example on our databases leaded to 113
reactions out of 107 publications. The query was exclusively dealing with
the toluene as product, no substituted toluene was allowed. In some of these
reactions the benzene is a by product, and probably a lot of them are
dealing with cleavage from a larger structure, but these reactions could
still be of interest, you would have to judge.

>> [Parts of Original Message Edited/Deleted] <<

Sincerely

Pierre Allemand Ph.D.
Senior Account Manager

>-- END

-- 

:Joe
 [email-masked]
 (630) 961-7878  <SOCON 231 7878>

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 | You can pick your friends but you can't pick your nose. |
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---

From: [email-masked] (Kevin P. Cross Ext. 3192)
Date: Thu, 17 Jul 1997 10:53:56 -0400

Folks,

Joe has done a nice job gathering and summarizing
information about retro-synthesis planning programs.
I would like to have this conversion move in a slightly
different direction.  A lot of these programs have been
around for a long time yet it seems that none has really
caught on in the market place.

What are peoples opinions on why these programs are not
routinely used for synthesis planning today?

I have a few questions to start out:

Do they give too many hypothetical answers but not practical?
Do they give too many answers (or repetative answers - same substructure)?
Is the software too difficult to use without a lot of training?
Does the software fail to reveal anything new to trained synthetic chemists?
Is it too expensive or run on the wrong platforms?
Does it lack integration with reaction data, availability, etc?
Is it too time consuming to run for many users?

What can be done to make these programs more useful?

Many thanks in advance,
Kevin

===================================================
Kevin P. Cross, Ph.D.
Senior Associate Research Scientist
Chemical Abstracts Service
(614)-447-3600 Ext. 3192
[email-masked]
===================================================

---

From: "Douglas A. Smith Ph.D." <[email-masked]>
Date: Thu, 17 Jul 1997 12:34:31 -0400

To give my personal response to Kevin's questions:

>routinely used for synthesis planning today?

Basic answer is that synthetic organic chemists tend to know the literature
pretty well for the types of reactions and transformations they routinely
need.  So, unless you run into trouble and can't do what you want/need,
there is little incentive to going to a computer, running a program you may
not be too familiar with or that may be difficult to use, and getting
alternatives.  Furthermore, the typical attitude (again, speaking as one
who did synthesis and ran a synthesis group for many years) is "Try it.
Just because it worked/didn't work in the literature doesn't mean it
will/won't work on your compound!"  Furthermore, a typical approach is to
try two or three reactions/reagents at a time, then compare the results for
ease and yield.

>Do they give too many hypothetical answers but not practical?

Probably the opposite it true.  Then the bench chemist must read all 100+
answers, down select him/herself, and try a few anyway.

>Do they give too many answers (or repetative answers - same substructure)?

Same answer as above.

>Is the software too difficult to use without a lot of training?

It sure used to be.  SYNTREE, from what I remember, had a reasonable GUI
under Windows.  I don't know about MDL's software.  Also, many of these
programs came out of the old VAX era, which is a horror for bench chemists
used to MacIntosh or now days Windows GUIs.

>Does the software fail to reveal anything new to trained synthetic chemists?

Isn't this always the case in any expert system?  And these programs are
truly expert systems, typically rule based (e.g. CAMEO, LAHSA).  It is not
trivial to develop a non-rule-based system.

>Is it too expensive or run on the wrong platforms?

See above for my limited knowledge answer.

>Does it lack integration with reaction data, availability, etc?

In my experience, all this is available.

>Is it too time consuming to run for many users?

Yes.
>What can be done to make these programs more useful?

Ah, the good and important question.  I wish I had the answer, I could make
a few bucks!

Doug Smith