Back in 1994, we published the crystal structure of the molecule below (X=H), a putative anti-malarial drug called halofantrine. Little did we realise that a whole area of organo catalysis based on a thiourea catalyst with a similar motif would emerge a little later. Here is how the two are connected.
Archive for the ‘Interesting chemistry’ Category
Connections in chemistry. Anti-malaria drug ↔ organocatalysis.
Thursday, July 5th, 2012Streptomycin: a case study in the progress of science.
Monday, May 28th, 2012Streptomycin is an antibiotic active against tuberculosis, and its discovery has become something of a cause célèbre. It was first isolated on October 19, 1943 by a graduate student Albert Schatz in the laboratory of Selman Waksman at Rutgers University. I want to concentrate in this post on its molecular structure. Its initial isolation was followed by an extraordinarily concentrated period of about three years devoted to identifying that structure, culminating in a review of this chemistry in 1948 by Lemieux and Wolfram.[cite]10.1016/S0096-5332(08)60034-X[/cite] This review presents the structure as shown below (left). The modern rendering on the right is based on a crystal structure done in 1978.[cite]10.1098/rspa.1978.0047[/cite]‡
Surprises (?) in the addition of HCl to a carbonyl group.
Thursday, May 24th, 2012HCl reacting with a carbonyl compound (say formaldehyde) sounds pretty simple. But often the simpler a thing looks, the more subtle it is under the skin. And this little reaction is actually my prelude to the next post.
Reductive ozonolysis: the interesting step.
Monday, May 7th, 2012The mechanism of the reaction of alkenes known as ozonolysis was first set out in its modern form by Criegee. The crucial steps, (a), (b) and (d), are all pericyclic cycloaddition/eliminations. The last step (e) is known as reductive ozonolysis, and this step is often treated as an afterthought, part of the work-up of the reaction if you like (it is not illustrated in Criegee’s review for example). Here, I will attempt to show that it is actually a very interesting mechanistic step.
The Dieneone-phenol controversies.
Monday, April 30th, 2012During the 1960s, a holy grail of synthetic chemists was to devise an efficient route to steroids. R. B. Woodward was one the chemists who undertook this challenge, starting from compounds known as dienones (e.g. 1) and their mysterious conversion to phenols (e.g. 2 or 3) under acidic conditions. This was also the golden era of mechanistic exploration, which coupled with an abundance of radioactive isotopes from the war effort had ignited the great dienone-phenol debates of that time (now largely forgotten). In a classic recording from the late 1970s, Woodward muses how chemistry had changed since he started in the early 1940s. In particular he notes how crystallography had revolutionised the reliability and speed of molecular structure determination. Here I speculate what he might have made of modern computational chemistry, and in particular whether it might cast new light on those mechanistic controversies of the past.
Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions.
Sunday, April 22nd, 2012Astronomers who discover an asteroid get to name it, mathematicians have theorems named after them. Synthetic chemists get to name molecules (Hector’s base and Meldrum’s acid spring to mind) and reactions between them. What do computational chemists get to name? Transition states! One of the most famous of recent years is the Houk-List.
Spotting the unexpected. The hydration of formaldehyde.
Monday, March 12th, 2012In my previous post I speculated why bis(trifluoromethyl) ketone tends to fully form a hydrate when dissolved in water, but acetone does not. Here I turn to asking why formaldehyde is also 80% converted to methanediol in water? Could it be that again, the diol is somehow preferentially stabilised compared to the carbonyl precursor and if so, why?
Spotting the unexpected. The trifluoromeric effect in the hydration of the carbonyl group.
Friday, March 9th, 2012The equilibrium for the hydration of a ketone to form a gem-diol hydrate is known to be highly sensitive to substituents. Consider the two equilibria:
An orbital analysis of the stereochemistry of the E2 elimination reaction
Saturday, February 4th, 2012The so-called E2 elimination mechanism is another one of those mainstays of organic chemistry. It is important because it introduces the principle that anti-periplanarity of the reacting atoms is favoured over other orientations such as the syn-periplanar form; Barton used this principle to great effect in developing the theory of conformational analysis. Here I explore its origins. (more…)