The New Clayden pp. 694 – 756

There’s not much new to say about Chapter 28, on retroSynthetic analysis, since the first edition.  Given the general disrespect that monster syntheses seem to engender today,.  Here’s a repeat of  what I wrote about the chapter years ago.

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.

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.
Here are some notes a questions on the first chapter of heterocyclic chemistry.  The chapter explains why they react the way they do to electrophilic and nucleophilic aromatic substitution.  Pretty obvious is you remember about electronegativity, where the orbitals are, and old fashion resonance structures stabilizing positive and negative charges.  Clear as a bell, so there aren’t many notes and questions.

p. 725 — “Pyridine is a weak base with a pKa (for its conjugate acid) of 5.5”  Why not say the pkaH of pyridine is 5.5?

p. 728 — What is Cl-CO2-Et and how do you make it?

p. 731 — How do you make Br3- ??? Pyridine + HBr + Br2 ??

p. 739 – Epibatidine — [ Proc. Natl. Acad. Sci. vol.  100 pp. 11092 – 11097 ’03 ] The frogs don’t make the stuff — it’s from the insects and plants that they eat — then they ship it to their skin.   It’s an even more fantastic explanation than jumping genes or convergent evolution.

p. 744 — The sulfur ylid chemistry converting a ketone to oxirane is found on p. 665.

p. 744 — I always wondered what tetrazoles were doing in so many drugs.  Now I know — they are substituting for COOH, as their pKa is the same (about 5). 

p. 745 — How to make a single carbon atom (while taking your life in your hands) — fantastic.  Kudos to the chemists who did this — presumably they are still intact.   I well remember the terror I had of diazomethane when I worked with it back in the 60s. 
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