(-)-Nakadomarin A
Total Synthesis of (–)-Nakadomarin A
David A. Evans et. al., J. Am. Chem. Soc., 2013, Just Accepted [PDF] [SI] [GROUP]
DOI: 10.1021/ja404673s
At first glance I didn't think that the appearance of another nakadomarin A synthesis in JACS a couple of days ago was too remarkable, but when I saw Dave Evans' name on it I have admit that I did raise an eyebrow. Although Dave is a living legend within the organic chemistry community, I had believed that his group had wound down to almost nothing, and I certainly wasn't expecting to see any new total syntheses from his group any time soon. And without an oxazolidinone in sight.
Of course, I’m not too surprised that people are still interested in making nakadomarin A; along with the rest of the manzamine alkaloids it's been pretty popular over the last decade and I think that the field is still waiting for a 'final' synthesis. With potent cytotoxic, antibacterial and anti-microbial activity nakadomarin might be a little more exciting that the average natural product in terms of biological profile, but I suspect it’s the alluring structure and that unusual juxtaposition of small, medium and large rings that keeps synthetic chemists coming back for more. Certainly enough well-known groups have spent published work relating its synthesis. The double bonds in the two largest rings are just begging for an RCM-based approached, but it turns out (as with manzamine A), that this strategy is not as easy as it looks on paper. In fact, back in 2011 when I was considering a blog post on the (then) latest synthesis by Zhai, I made this graphic to illustrate the flaws with disconnection.[1] It might be a little dated now:[2]
Evans decided to avoid opening that particular Pandora’s box and instead make both these potentially troubling rings as early as possible, breaking the molecule into two fragments with one larger ring in each. The two components were then to be united in a Lewis-acid mediated formal [4 + 2] reaction as shown below.[2] The group was pretty sure that the one existing stereocentre on the azocine ring junction would limit the approach of this pseudo-dienophilic component to one of two possible trajectories. It was hoped that the tendency of carbonyl dipoles to oppose one another—like in the famous Evans Aldol reaction—would cause the desired (bottom) approach to be somewhat more favoured.
Guest Post: Pentacycloanammoxic Acid
Today's guest post is from Siddharth Yadav, an enthusiastic young chemist from somewhere in India. Enjoy!
I found B.R.S.M. when I was searching the web for the synthesis of cubane by Philip Eaton and was much delighted by the way the material was presented and interpreted, although a quick glance through B.R.S.M. showed me that this blog is not actually centred on compounds like cubane but rather on natural compounds (with their asymmetric carbons and stuff). So, I decided to write up a post on a compound that is much strained like the unnatural compounds but is indeed a naturally occurring chemical – pentacycloanammoxic acid.
It all started when a guy named Damste discovered some unique lipids in some rare bacteria known as ‘Anammox’ (derived from Anaerobic Ammonia Oxidation) bacteria. These tiny guys oxidize ammonia and nitrite ions to liberate nitrogen gas and water, but during this conversion they produce hydroxylamine and hydrazine; two very damaging and membrane permeable intermediates! So as an SOS, these guys have a lipid bi-layer made of pentacycloanammoxic acid, which is denser than average membranes (dense enough to keep hydroxylamine and hydrazine at bay; hence avoiding their diffusion into the cytoplasm and preventing cellular damage).
Now to the really interesting part – structural determination of this ‘unique’ lipid gave a rather odd looking architecture! In fact they found two such lipids with slightly different structures. Much to the delight of the synthetic community; E. J. Corey and Vincent Mascitti jumped on the challenge for a total synthesis for pentacycloanammoxic acid. Any guesses why Corey and Mascitti didn’t choose the other acid?
(-)-Neothiobinupharidine
I've not written all that many total synthesis posts this year, not for a dearth of interesting work, but more a lack of free time. I started writing this one about six months ago (!), and I guess most of you have probably seen this paper already, but I think it’s pretty cool so I decided it’d be worth finishing. Now featuring my new favourite piece of punctuation, the em dash!
Synthesis of (−)-Neothiobinupharidine
Ryan A. Shenvi et al., J. Am. Chem. Soc., 2013, 135, 1209 [PDF][SI][GROUP]
DOI: 10.1021/ja310778t
The first of the rather wacky looking nuphar alkaloids were actually isolated back in the 60s by Achmatowicz (of Achmatowicz reaction 'fame'), the family has now grown to a fair size, as you can see from the borrowed figure below. No-one paid them much attention for a while, as they weren't very bioactive, looked quite intimidating, and everyone was probably too busy psyching themselves up to make vernolepin anyway.[1] However, a recent report that they selectively kill off melanoma cells (via a mechanism that no-one’s worked out yet), combined with a pretty cool biosynthetic proposal by LaLonde, was enough for Shenvi to spend a little time working out a synthesis.
BRSM is Two Years Old Today!
I had completely forgotten that today was my 2nd anniversary as a blogger until my girlfriend sent me this photo a bit earlier:
Apparently, as there were no number 2 candles (cf. last year), she instead made two cakes (possibly setting a dangerous precedent in the process!).
I can't believe that it's that time again – I've now been talking to the internet for two whole years! It's been really busy period for me in real life but in contrast a quieter one for BRSM. Although I've written 5 papers,[1] I've only managed 44 blog posts in the past 12 months, which is unfortunately quite a bit short of the one-a-week target that I try to aim for. How people like Derek, CJ and See Arr Oh write so much decent stuff, I don't know!
I still think of this a total synthesis blog—after all, it began with me reading a Totally Synthetic post one day and thinking "I could do that!"–but it seems that the posts that get the most hits tend to be the ones based on random observations or conversations with friends. For example, here are my top posts of 2012-13 (In descending order of pageviews):
1. Where Did It All Go Wrong? – I probably wrote this in about 10 mins after glimpsing a ridiculously misassigned structure in J. Nat. Prod., but a link from Derek probably helped this to the top.
2. Drugs I Shan’t Be Taking This Week 1: 2,4-Dinitrophenol – I really have no idea why people keep reading this. It must be high on some Google search!
3. And Now For Something Completely Different 4: Wikipedia Fun – Based on the chance tea time observation that my PhD supervisor is outranked on Google by a number of golfers and DJs with the same name. I think that occasional commenter Martyn (of gyrofaunal fame) did most of the legwork for this one.
4. Superlatives 3: The Longest Polyene – A friend emailed me a photo (thanks, James!), which I posted.
5. A Birthday Surprise for K. C. Nicolaou – Inspired by a drunken conversation in a pub.
Not a single scheme in sight – I am constantly surprised by what you guys will read!
While I'm reminiscing, I'd like to thank this year's three guest authors: my long-time benefactor DrFreddy, who promised me a post 'about teenage love, the Greenwich Observatory and TNT' that he surprisingly was able to deliver; Brandon from ChemTips, who wrote about Hanessian's recent full paper on pactamycin; and Siddharth Yadav, whose post on pentacycloanammoxic acid will be up later in the week. Conversely, I also wrote my first ever guest post, which attempted to give some practical advice for the Birch reduction, over at ChemTips. I also contributed a little bit to Blog Syn, by mostly failing to reproduce other people's work. I hope that we'll find a way to get that site going again!
I'd also really like to thank everyone who has gave me advice for my imminent move to the US whether it was in person, on twitter, or via the recent mini-carnival that Jess and Freda organised. Hopefully I'll catch up with some of you one day!
Finally, thank you all for reading and commenting! I don't know what a couple of years in the US will do to my ability to spend hours messing around on the internet, but hopefully I'll keep this thing up for another year!
1. This claim would be a lot less impressive if I told you where we sent them...
I’m Unemployed And It’s Awesome
I don't like to apologise too much for things I do (or more often don't do) on here, because, well... it's not like you pay me anything. That said, I am sorry things have been so quiet around here for the last couple of months. It's been a hectic end to my postdoc, but I'm able to kick back for a couple of weeks at least before I head over to the USA. I'll try and write a few posts before then. And after. In the meantime, here's a talk I wrote for a group meeting at the start of the month on the topic of Felkin Ahn selectivity. We've been revising 'basic' topics, and I was amazed how much I've forgotten Maybe this'll be useful to someone.
Yes, I did steal that image from Dave Evans' notes...
Here it is: Substrate Control in Acyclic Systems BRSM (2 mb)
And Now For Something Completely Different 7: XKCD-style Venn Diagrams
Update 03/04/2013: Chemjobber made a few!
Thanks to a recent xkcd comic I've just discovered a wonderfully concise new way to communicate – non-overlapping Venn Diagrams:
For example, here's a statement my boss made last week expounded thus:
I quite enjoy the contradiction between the visual simplicity of displaying information in this way and the fact that it's actually a lot more effort to construct these than write a sentence that conveys the same information, as well as their highly inefficient use of space. There's just something kind of amusing about them. Or I think so, anyway.
Give it a go, and share any good (chemistry related) ones you can think of in the comments. I've just put one in a talk I'm writing on acyclic stereocontrol for a group meeting; I'll let you know how that goes down next week!
And Now For Something Completely Different 6: Green Chemistry
Most of the credit for this one goes to occasional commenter Martyn!
Is it just me, or will green chemistry journals publish anything these days? For example, check out this paper published this morning in the Journal of Sustainable Agitation:
Unpowered Mechanical Stirring of Reaction Media Using Renewable Stirring Fish (RSFs). [PDF]
I couldn't make this stuff up!
Woodward Wednesday 6: Reserpine (Part 2/2)
Okay, this second post is a lot later and a fair bit shorter than I had hoped it would be, but it's been a crazy and not entirely pleasant month. Enjoy!
In the previous Woodward Wednesday post I showed you guys the first half of Woodward's epic total synthesis of the popular bioactive natural product reserpine. If you didn't catch that when it came out, go and check it out, because I'm just going to carry straight on where it left off. Here goes!
And Now For Something Completely Different 5: The Merck Index Challenge
Sorry things have been so quiet around here; it's been a hectic month! Here's something silly born of an unusual conversation over coffee.
The office microwave: unnecessary chemophobia?
The Merck Index, along with Fieser and Fieser's Reagents for Organic Synthesis, Greene’s Protective Groups, March’s Advanced Organic Chemistry and Amarego’s Purification of Laboratory Chemicals is one of those books that any self-respecting organic research group will have a copy of. It’s an iconic reference work, although its usefulness has definitely waned in recent decades with the rise of the internet, Scifinder/Reaxys/Chemspider and Wikipedia. As Derek reported before Christmas, it was recently acquired by the RSC, who have just released an updated edition. I mostly use mine to pass the time waiting for NMRs to run, or when I need a more reputable reference than Wikipedia for a paper or report.[1] However, all of that changed last week when a tea break conversation sparked a bizarre new game: The Merck Index Challenge.
Anyone who’s ever flicked through a copy will probably have noticed that amongst all the drugs, solvents, salts and plants there are a number of… aberrant… entries. For example, Whiskey. And Lard.[2] And Raspberries. And Quorn. And Milk. Thus, the question arose: could a meal be constructed using only ingredients from the Merck Index? Better yet, could one manage three courses?
Guest Post: Pactamycin (Hanessian, 2012)
To mix things up a bit, I've traded posts with Brandon from Chemtips, who's going to be telling you a bit more about Hanessian's pactamycin work in this special guest post. If you head over to his blog you can read my advice to anyone attempting a Birch reduction. Anyone else interested in guest blogging here or swapping posts, please contact me! Enjoy! -BRSM
Today’s target, pactamycin, is an excellent example of just how creative evolution can be. Densely functionalized and almost unique (the authors put forward several loosely related structures), this Streptomyces metabolite is characterized by six contiguous stereogenic centres. First isolated in the early 1960’s, pactamycin binds strongly to the 30S fragment of the ribosome and is toxic to both mammalian and bacterial cells [1]. Briefly considered a potential anticancer agent, the natural product was ultimately shelved over safety concerns.
The first total synthesis of pactamycin was published by Hanessian et al. in Angew. Chem. Int. Ed. Eng. back in 2011, but I’m going to base most of this post on a follow-up publication in J. Org. Chem., which details some of the trials and tribulations encountered during the long synthesis [2]. The ACIE paper has also been discussed over at Synthetic Nature.