"But...This Synthesis Goes Up to Eleven!"

Have you had fun reading through all the hilarious send-ups on the Twitter hashtag #HonestChemTitles? This tag tries to dig down to the subtext behind highfalutin words and strange symbols, uncovering the hidden motivations behind scientific papers. And...it's a hoot.

Remember the tweet that kicked off this brouhaha? A harmless convergent synthesis of some Lycopodium alkaloids. Kudos to @AlexFGoldberg for highlighting the authors' rather overblown title:

Classic children's literature;
my first exposure to superlatives

Amazingly, that 10-word title is 30% superlatives and 30% chemistry, with a smattering of conjunctions and articles to connect them. As others pointed out, how do you measure "elegantness," anyway? And when does a total synthesis cross the line from concise to exceedingly so; can anything more than a one-stepper be really succinct?

Sort through the paper with a grammarian's fine-toothed comb; one wonders if it wasn't run through some sort of excitement thesaurus, perhaps to get people really stoked about these routes.

Here's all the intense words and expressions I found:

Diverse
Useful
Unique
Challenging
Efficient
Complete
Direct
Achieved
Accomplished
Value
Exceedingly concise and convergent
Attractive

...and that's just in the first paragraph, folks.

Nigel Tufnel (Christopher Guest), ca. 1984

Honest opinion? Aside from the goofy title and superlatives liberally sprinkled into the text, the chemistry seems solid. Nothing's breathtaking - setting an early quaternary center through steric control is nice, and telescoping the three steps before the desired tetracyclic dione works well - but there's no "killer reaction" for me in this paper. The NMRs are clean, and the synthesis represents a decent improvement over existing methods.


Thus, I'd like to accept this publication into the "Spinal Tap Synthesis" category, so-named for the hard rock auteurs profiled in 1984's This is Spinal Tap, the tongue-in-cheek rock mockumentary. If you've never watched the movie, I won't spoil it, but I highly recommend the sequence in the middle where Nigel Tufnel, the vapid, misunderstood lead guitarist, obsesses over a "special" amp he designed that "goes to 11."

Fits this paper to a T.

Spot-Checking Antibacterials in PLoS One

Update (April 17) - Commenters here and at Derek's place have set off alarm bells to potentially doctored spectra. Stay tuned...
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Ever looked at a molecule and thought something was just...off?

A little while ago, I browsed through the latest edition of PLoS One, the open science journal. I don't often go there for chemistry publications, but curiosity struck, so I typed, "antibacterial NMR" (I think) into the search box. Up came this paper, from 2013, announcing:

1. A novel alkaloid, xinghaiamine A, isolated from a marine bacterium, that...
2. Had novel structural features, such as a sulfoxide and acenaphthylene ring, rarely seen, and...
3. That showed decent lead activity against MRSA strains (2.7-5.5 uM MIC).

First thought: "Wow!" Second thought: "If this is so great, why is it buried in PLoS One?"

Then I happened to look at the proposed structure for this potential panacea:

Jiao, Zhang, Zhao, Hu, Suh, PLoS One, 2013

[Rubs eyes in disbelief].

Sulfonylated "ladderane" substructure.
A (4,7) disubstituted acenaphthylene bridge.
A previously-unknown-to-science (and virtually unknown to SciFinder) 4-4-5-6 ring system.
Can that really be correct?

Naturally, I made a model of one "half" of the presumed dimeric molecule:

Xinghaiamine A, pseudo-axial conformation,
assumed diastereomer of the (4-4-5-6) ring system.
The red circles are supposed to be bonded together...

I've taken apart and reassembled this molecule a few times, and can't seem to access any diastereomer that 1) looks energetically minimized, and 2) can actually have the acenaphthylene bridge the way the authors specify without "strain energy" popping out the plastic bonds.

Perusing the analyticals in the Supporting Information, I'm puzzled by a few more bits:

Jiao, Zhang, Zhao, Hu, Suh, PLoS One, 2013

The IR, briefly addressed in the text as suggestive of "[the] presence of a sulfoxide functional group" due to the 1082 cm^-1 band, but contains peaks suggestive of:

• alcohols, primary amines: 3383 cm^-1 band
• heteroaromatics: 743, 846 cm^-1 band

The published 1H NMR has no peak labeling or integration (tsk, tsk).

That the COSY shows only one set of strong H/H correlations out of the 6 posited protons on the conjugated ring, which should not fit with the proposed structure. Nor should the seeming high symmetry of the ring fit with the proposed substitution.

--

Readers, what do you make of this? What kept this out of a more mainstream chemistry journal? 

Do you agree with the assigned structure? (Am I just shouting in the wind here?)

April 17 - Uh-oh...check out these anonymous commenters' finds on Derek's blog:

Potential editing of the H/H COSY

...and the HMBC

The Pterodactyl Flies Again

I'll admit it: I was a bit bummed out to read B.R.S.M.'s tweet regarding Totally Synthetic's untimely demise:

As a young pup, I cut my teeth in a few guest posts over at Paul's place. Since I saw a sexy, streamlined version of one molecule go by in Org. Lett. last week, I decided to do a (memorial? celebratory?) post in true Tot Syn style.

Folks who've read the other syntheses might agree with me that the trigonoliimines, as drawn by Tambar, resemble a terrifying pterodactyl:

Respectfully stolen from Tot Syn

Both Tambar and Movassaghi aimed for asymmetric syntheses, and started from a [2,2] fusion point between differentially-functionalized tryps. They're aiming to make the whole lot (Trig A-C), so this semi-biosynthetic approach makes sense. But Hao's latest paper sets its sights squarely on (all together now!) the (6/5/7/5/6/6) core of Trig A - sadly, a much "flatter" molecule with less 'dinosaur' character. But, the target still shows moderate antiviral activity, so the group reasons a shortened synthesis may expedite analog generation.

Hao aims to use two fairly well-known reactions to join his tryptamines: a modified Strecker, followed by a Houben-Hoesch cyclization. First, the group pops open a methoxylated, phthalamide-protected Trp precursor using CuCl under oxidative conditions (the 'cool' kids use blue LEDs now). Now they've set the stage for the really short racemic synthesis:

Initial TMS-promoted imine condensation with the aryl ketone sets up a CN alkylation, which cyclizes on the nearby formamide (probably through an isonitrile). Now here comes a 7-membered Houben-Hoesch ring closure, which they perform in a one-pot prep due to instability of the methoxy-Strecker intermediate. Basic workup, followed by hydrazine deprotection / cyclization, produces Trigonoliimine A, in a respectable 35% yield (4 steps, 3 pots).

Godspeed Dr. Docherty, wherever you are...

Update: Neil posits that Paul is still alive and well, and writing for Chemistry World.