Cubanes! Get Your Cubanes, Here!

A cube of med-chem cubanes**

It's not often you see drug candidates advanced with cubane substructures.* A collaborative group from the UK branch of AstraZeneca and Oxford University aims to change that: a report in Organic Letters indicates they've produced gram-scale quantities of cubane derivatives with common med-chem handles already "baked in."

Starting from a 1,4-cubane diester, Burton, Davies, and Wlochal take turns elaborating each side into thiazoles, beta-diketones, nitriles, amine salts, and ynones. Though more cautious readers might expect the cubed synthons to go up in smoke, they actually seem to survive fairly rigorous conditions - boiling water, phosphoryl and oxalyl chloride, TMS triflate, LDA.

I'd be most interested to hear from any readers who integrate these new building blocks (sorry, couldn't resist!) into their research. It's hip to be...cubic.

* On Twitter, CJ (rightly) points out that the authors could have done some DSC (stability) and solubility assays, just to put minds at ease that these synthons really could be integrated into a drug campaign.

**Not a real substance (but wouldn't that be something???)

Coming Soon: Free Online MedChem Course

(Looks like I get the same emails as Chemjobber does!)

Prof. Erland Stevens of Davidson College will be offering an introductory medchem course through EdX:

The seven-week course starts on March 10^th.  Each week has about 1 hour of video and a number of accompanying web pages.

The course is strictly an introduction.  A short syllabus is below.

Week 1 – brief history of medicinal chemistry, introduction to drug development process and regulatory approval

Week 2 – proteins (enzymes and receptors) as drug targets, enzyme inhibition, ligand-receptor binding theory

Week 3 – pharmacokinetics (compartment models, Vd, clearance)

Week 4 – metabolism, phase I, phase II, prodrugs, genetic variability

Week 5 – drug-target complementarity, drugs as part of chemical space, chemical libraries

Week 6 – lead discovery, screening, filtering hits by metrics/structural alerts/predicted PK, SOSA, natural products

Week 7 – lead optimization, functional group replacements, isosteres, directed libraries, peptidomimetics

The overall goal of the course is to get a student up to speed to watch a medicinal chemistry lecture (and maybe even ask a question at the end).

**If anyone signs up and completes this course, I'd love to get their impressions of it for a follow-up post!

BuLi: Not Just a Base Anymore

When do you reach for that bottle of n-butyllithium at the back of the fridge? Making anions, sure, but BuLi's also great at ripping off halogens, destroying esters, alkylating imines, or swapping lithium for other metals (see: Sn, Zn, B, Cu, etc...).

What about using BuLi as an off-the-shelf cross-coupling partner? Sure, sounds like a methyl-ethyl-butyl-futile joke gone too far, but there're quite a few of those aryllithiums in catalogs nowadays...

Looks like Ben Feringa's got you covered. In Nature Chemistry, his group reveals that slow addition of a diluted organolithium to an aryl or vinyl bromide mixed with some electron-rich Pd(0) precatalysts provides alkylated products with high selectivity. At room temp. In one hour. In the presence of chlorides, esters, free alcohols, and all sorts of things that usually gum up the works. Zoinks!

I'll admit it - As someone who's spent a decent part of my life trying to glom one carbon onto another (grumbling while I purified yet another organotin or boronate), these initial results look promising. I'm sure they're furiously working on the alkyl-alkyl (sp3) coupling as we speak - good luck, that one's gonna be a lot harder.

P.S. Kudos for a well-thought-out Supporting Info section, too. The authors discuss their optimization process almost "stream-of-consciousness"-like, letting you vicariously learn the chemistry along with them.

R.I.P. Jerome Horwitz, Medicinal Chemist

Multiple news outlets (NYT, SciAm, Karmanos) now report the passing of Jerome Horwitz, 93, a career medicinal chemist behind AIDS drugs such as AZT (1964), stavudine (1966), and dideoxycytidine (1967). Most obituaries focus on two facets from his life:

1. His invention of AZT, a drug so synonymous with AIDS treatment that it's been mentioned in raps, novels, and Broadway shows.
2. His perceived failure to patent his antiviral molecules, thus "costing" him and Wayne State University millions in revenue realized instead by Burroughs Wellcome (later GSK). 

First report of AZT, J. Org. Chem. 1964, p. 2076*

I want to take a slightly different tack on Horwitz's career. For my money, he met all the criteria for a successful career in organic chemistry. He published >100 articles and book chapters; not a one-trick nucleoside pony, Horwitz's work covered sterols, acridines, tetrazoyl ylides, epoxide rearrangements, and analogue development of anticancer drug XK469. He had a fifty-year career as a professor at two universities. His work led to (at least) three approved drugs.

He even has a statue installed at Detroit Medical Center.

Even more interesting, he accomplished nearly everything in his career while staying in one place: Michigan. He jumped outside (briefly) to Illinois for a postdoc at Northwestern, but all other schooling and professional work came from in and around Detroit. It's amazing to me, given how much I and others have moved around for a career in science, that his tenure in one metro area lasted for a lifetime.

*Side note: When I look up old papers, I enjoy seeing who else I recognize among the authors in the same issue. 1964 must have been quite heady - in the same issue with AZT, we have papers by Nakanishi, H.C. Brown, Bill Dauben, Alfred Blomquist, and John Baldwin.

Synthonix Rings Up an Advertising Coup

Gotta hand it to 'em: Synthonix sure can print a convincing ad!

One of these things is not like the others! Credit: Synthonix, Inc.

The Wake Forest, NC company has taken out a few full-page ads in C&EN: clean, simple black structures on white backgrounds, illustrating the wide variety of oxetane, azetidine, and spiro-heterocycles intended for stitching into med-chem lead molecules. But their latest ad, a portion of which is shown here, takes the cake.

As any Linnaean taxonomist can tell you (*Kings Play Chess On Fat Grey Stools, anyone?), classification runs deep in the scientific blood. When you consider the sheer number of organic molecules that can exist (10^60 potential molecules of 500 MW or less?!), please forgive the namers for getting a little punchy. Molecules garner nicknames based on their appearance (propellanes, cubanes), their smell (putrescine, cadaverine), or other chemists (bullvalene)!

The naming convention for small, 5-membered heterocycles proceeds thusly: start with Latin or English names of the heteroatom, and add "ole" to the end (rhymes with "pole" or "coal," not like Olé!).

Phosphorus? = phosphole. Sulfur? = thiazole. And arsenic...?

(I'll let you figure that one out)



 (*Kingdom, Phylum, Class, Order, Family, Genus, Species...Bio 101 FTW!)