Retrosynthetic analysis and Moliere

Chapter 30 of Clayden, Greeves et. al. concerns retrosynthetic analysis, but what in the world does this have to do with Moliere?  Well, he wrote a play called Le Bourgeois Gentilhomme back in 1670 and played the central character, Monsieur Jourdain, himself in its first performance (before king Louis XIV).  Jean Baptiste Lully, one of the best composers of the time (Bach hadn’t been born yet) wrote the score for it and also played a role.  M. Jourdain was a wealthy bourgeois gentilhomme who wanted to act like those thought better (e.g. the nobility) at the time.  So he hired various teachers to teach him fencing, dancing and philosophy. The assembled notables watching the play thought it was a riot (did not the French invent the term, nouveau riche).  He was taught the difference between poetry and prose, and was astounded to find that he’d been speaking prose all his life.

So it is with retrosynthetic analysis and yours truly. Back in ’60 – ’62 we studied the great syntheses that had been done to learn from the masters (notably Woodward).  Watching him correctly place 5 asymmetric centers in a 6 membered ring of reserpine was truly inspiring.  Even though Corey had just joined the department, the terms retrosynthetic analysis and synthon were nowhere to be found.  The term is almost a tautology, no-one would think of synthesizing something by making an even more complicated molecule and then breaking it down to the target.  So synthetic chemists have been speaking retrosynthetic analysis from day 1 without knowing it. 

Probably the reason that things have become so formalized, is that we have many more reactions at our disposal presently.  Silyl enol ethers and lithium enolates were not in evidence back then (as I recall) — although we spent a lot of time with aldols, Diels Alder’s and Claisen’s back then.   One of the things I hope to acquire reading Clayden (and probably others) is the ability to read the syntheses of today and enjoy them, the way I do an unfamiliar string quartet.  Synthesis back then was an art form, and apparently it still is.  People question its utility (I wonder what Woodward would say), but just how do you use a string quartet? Grooving on the entries in TotallySynthetic.com etc. is still probably a year (and 700 pages of Clayden) away, if not longer. 

The blog is almost a year old, and it’s time to get things categorized, so you can find what you’re interested in without paging back, or Googling it.  I hope to do this in the next month or so (assuming life doesn’t intervene).

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Comments

  • Wavefunction  On June 20, 2010 at 10:28 pm

    If you want to get into the heart and brain of the master synthesizer and sample his delicious creations, do check out the book on him; Robert Burns Woodward : Architect and Artist in the World of Molecules by Benfey and Morris

  • J-bone  On June 21, 2010 at 2:15 pm

    Do people really question the utility of total synthesis? I’ve seen lively discussion about what molecules are worth pursuing or whether certain routes are elegant/worth spending time on, but never whether or not total synthesis has value.

  • luysii  On June 21, 2010 at 4:56 pm

    Wavefunction: Not quite there yet. I found some of the problems at the end of Ch. fairly tricky.

    J-Bone — they certainly do. I tried to find an old post (I think it was on the late lamented ChemBark — when people were criticizing some total synthesis which took a decade (I think was about two years ago), comparing it to how Woody Allen felt in Sleeper, when he woke up 200 years in the future and was told that cigarettes and hamburgers were good for you. I wondered what Woodward would have said.

  • J-bone  On June 22, 2010 at 8:57 am

    Wow, that’s really disappointing. Where do these people think the next generation of drugs are going to come from? Not to mention new developments in materials for things like OLEDs, or even improvements in our existing technologies.

    As I said earlier, I’ve seen some complaints about the way things are approached, but not necessarily the whole field. There are some rumblings that pursuing certain targets has become a waste of resources and grad student/postdoc time. Brevetoxin for example. Throw enough people at it and it WILL get synthesized. But will anything useful to society come from that? Total synthesis has also advanced to a point that now people are beginning to critique the elegance of the synthesis. You can’t just throw Lego blocks of two or three carbons together until you get Taxol. It is imperative to use clever reactions/conditions to build the framework in order to garner respect from others in the field (read the comments on any of the Phil Baran’s syntheses on Totally Synthetic for example)

  • Wavefunction  On June 22, 2010 at 2:11 pm

    Retread, you easily have the capacity to appreciate Woodward’s early papers. The reagents and reactions were very simple by today’s standards but were still beautifully employed. You certainly don’t need to get to the end of Clayden before doing this! The book I am quoting also has a lot of very interesting Woodward history. Definitely worth purchasing.

  • luysii  On June 22, 2010 at 5:59 pm

    Wavefunction — perhaps I do, but the problem is getting sidetracked, which has happened too many times since I started reading organic chemistry 2 years ago.

    One question. At reunions, the chemistry department had a reception for the old grads who’d majored in it. The one thing I’d found frustrating about Clayden was the ‘magic’ associated with inorganic ions, so I asked the chair for an organometallic reference, and he suggested the latest version of Hegedus (3rd) “Transition Metals in the synthesis of Complex Organic Molecules”. So I bought it, and there on p.3 is a list of the transition metals, but only the middle 8 of the d orbitals, leaving out Scandium and Zinc in the first row, Yttrium and Cadmium in the second row, etc. etc. What’s going on ?? ??. Is it the empty or filled d shell that excludes them.

  • luysii  On June 28, 2010 at 1:46 pm

    J-Bone, for some negativity about total synthesis, see the following http://pipeline.corante.com/archives/2010/06/28/maitoxin_its_on_all_right.php

  • J-bone  On June 29, 2010 at 8:32 am

    Thanks for the update luysii, I’ve been following that post too. Actually, it’s been comments on Nicolaou’s most recent syntheses that were on my mind in my original post. Most of the recent criticisms seem to be that he’s wasting money and resources on a target that will never make it anywhere near a clinical trial, so what’s the point? Aside from being able to tell people you made it, which people obviously aren’t interested in anymore.

    I did see a couple of people mention that total synthesis was a pointless endeavor, but most of them were in the context of there being no jobs afterwards for these students, which also smacks of truth.

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