🧵 I won’t wade too far into the debate du jour re: the Nobel and Hajos (who is alive), Parrish, Eder, Sauer, and Wiechert. But maybe a slight aside on the Hajos-Parrish ketone and its slightly larger cousin, the Wieland-Miescher ketone. 1/
The Hajos-Parrish and Wieland-Miescher ketones have had a big impact on steroid synthesis. They’re still central to teaching organic synthesis in the first year of grad school (AFAIK). 2/ en.wikipedia.org/wiki/Wieland%E…
It’s not clear to me that the asymmetric Hajos-Parrish and Wieland-Miescher ketone syntheses were, by themselves, enough to unlock the tumblers of the organocatalysis universe. Otherwise, why did it take another ~30 years to get around to it? 3/
Anyway, on to the point of the story. It’s 1998 and I’m taking the second semester of the graduate organic synthesis course at Columbia. Sam Danishefsky is teaching, filling the board with steroid total syntheses, one after another, entirely from memory. 4/
Danishefsky pauses midway, turns, and remarks: “If one is unfamiliar with the Wieland-Miescher ketone, one cannot be considered a player. Of course, even if one does know the Wieland-Miescher ketone, that doesn’t make one a player. But if you don’t, then you aren’t.” 5/
(That’s it. That’s the story.) /end
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The molnupiravir discussion last week revealed to me a woeful gap in my nucleoside prodrug knowledge. Spurred on by @GusTheChemist, I've been working to close that gap.
Never be ashamed to admit when you don't know something. These are the best opportunities to learn! 1/4
Gus got my reading rolling with this review on phosphate and phosphonate prodrugs. Putting that first phosphate on in vivo is slow, so having it already present is a strategy. 2/4 pubs.acs.org/doi/10.1021/cr…
Here's another review that's more general and spends considerable time on various ester prodrugs, including amino acid esters. 3/4 jpharmsci.org/article/S0022-…
Time for another PK tweetorial, this time featuring a deeper dive on the not-so-mystical art of human dose prediction. 1/
I’ve argued previously that human dose is the master optimization parameter in medicinal chemistry. Like death, it can’t be cheated. All variables come together in this one number. 2/
This earlier thread talks about some of these things at a higher level and is worth a review. 3/
🧵By request, here we go with another PK tweetorial, this time on the free drug hypothesis. 1/
References up front. A great one on how to properly use plasma protein binding (PPB) to interpret PD/efficacy data and NOT use PPB as an optimization parameter. This paper is a true classic. I’ll never be able to fully repay the debt I owe to it. 2/ nature.com/articles/nrd32…
I support our group with early human dose prediction. Not the fancy, need-tons-of-software and a DMPK pro kind. Just the kind that uses some basic algebra. HDP is a unifying concept for med chemists. It’s the master optimization parameter, and it can’t be easily cheated. 1/
Here’s a wonderful paper from AstraZeneca that speaks to this conceptual framework - this isn’t something I invented. The concept has been around for years. Required reading! 2/ pubs.acs.org/doi/10.1021/mp…