A selection of interesting "reactions" from around the lab...

Happy Hanukkah and Thanksgiving Eve to all, here in the Baran lab, we have a lot of pretty mundane reactions running on a day to day basis, but sometimes things get weird. Here's a few of my observations that I've managed to photodocument. As for the details of these reactions - I'll let those that ran them chime in if they care to. 

[...Click through to see some photos...]

iBooks on your Mac desktop/laptop

I guess this blog entry could be called "The Portable Chemist's Consultant Part 4” (see Part 3 here).

First off, we have a new book update (Version 2.4), as listed in Open Flask and on the book's website.

Secondly, with Apple’s new Mavericks system, iBooks can be used on a desktop or laptop. I have placed some screenshots below to show how the iBooks looks like on the computer screen.

Normally the iBooks page looks like this:

When you place your mouse cursor on the left hand side of the page, a little arrow appears, which you can click to go to the preceding page. Same thing for the right hand side of the page to go to the following page.

When you place your mouse cursor on the top part of the page, many icons appear: the book icon (it opens your iBooks library), the bullet point icon (it shows the book's table of contents in a side pop-up), the notes icon (it shows notes or study cards), the search icon (it finds text, media, notes, or a page number) and the bookmark icon (it adds or removes a bookmark).

 And finally, when you place your mouse cursor on the bottom part of the page, you will get a “back button” on the bottom left corner of your screen.

I actually think the iBooks program is faster on the computer than on the iPad—so check it out!

--Yoshi

Bitters-Free Baran Modification of the Bourbon Old-Fashioned

All right, Andre, I'll bite. Now that I know what I'm supposed to do, I figure I'll tell the internet about the Baran Lab modification of your bourbon old-fashioned, which I suppose will be retired in short order.

Hallucinogens

I recently presented a group meeting on Hallucinogens and Phil wanted me to do a little write-up to promote it.  As a brief overview, I cover different classes of hallucinogenic natural products and synthetic compounds.  It starts with a historical overview of the hallucinogenic natural and synthetic compounds.  Then I cover pharmacology and synthesis of a variety of structurally unique hallucinogens.  You can read the group meeting for all of the details on that, but what I wanted to cover here is some of the interesting legal and social issues surrounding research with hallucinogenic compounds.

New Balloons

Although I have long believed balloons to be mostly ineffective (in a laboratory setting), sometimes I use them for the placebo effect. In fact, I've made the following claims to our lab: 

1. Balloons are permeable to O₂!  
Source - Knowledge accrued through chemistry - Ni(0). 

 2. Balloons are not permeable to moisture!  
Source - Knowledge accrued through chemistry.  

3. How do I really be air free in the lab? 
-Degassing by argon sparging (15m) or freeze pump thaw? I've never seen a real difference here... the rumor is freeze-pump-thaw is more effective... (but sparging worked fine for Ni(0).) 
-The solvent system solvents are oxygen free. I used to pull fresh ether straight from the solvent system and wash my Ni(cod)₂. 
-Schlenk flasks and use proper shlenk technique 
-Use the golvebox 

4. Remember, most of what we (BaranLab) do isn't that O₂ sensitive, so don't worry too much. (However, we do a lot that needs to be water free!) 

5. But Dane, you've got 3 balloons in your hood right now! 
-yes, I know, they make me feel emotionally stable; we stir our homogenous reactions too, which is also unnecessary.

 It is with all this in mind that I say: these new balloons are sweet as hell.

Reflecting on Yield, and the Need for a Qualitative Assessment of Reactions

Here's some thoughts:

1. I categorize all reaction yields qualitatively. 

What does this mean? Generally speaking, I don't really believe in yields other than 0%, 25%, 50%, 75%, or quantitative. I also sometimes break this down as 1.) Doesn't work, 2.) Works a little, 3.) Goes halfsies, 4.) Pretty alright, 5.) The bomb diggity. Now, I might conform to the standards of society and report a 62% yield for a publication or presentation, but for the purposes of a practicing-academic-chemist-grad-student, my breakdown is good enough. I readily acknowledge that this view of looking at yields is generally flawed, but it gets the job done on a day-to-day basis.

2. I don't record yields on reactions less than 10 mg.

This isn't entirely true. If I've rigorously run a reaction, and then repeated it, I'll believe a yield on 10 mg scale. But generally speaking, there are too many ways for the yield to go wrong: trace solvent, water, silica, or dust? add 10-20%. Did any manipulation of the material? subtract 10-20%. If I do record a yield on this scale, its most likely going to be as defined in section 1, rounded to the nearest 25%. 

3. TLCs of reactions in SI

Why doesn't anyone do this? We record our TLCs in our notebooks and report R_f in the SI. But in my opinion, the TLC is the most important qualitative and rapid way to assess a reactions "goodness." If your reaction has an 75% yield, and an R_f = 0.40, but an inseparable side product at R_f = 0.37, then I hate your reaction (but I'll still use it if I need it). This is useful qualitative data! Far more useful than melting point. Believe it or not, you can optimize reactions on tiny scale by TLC alone. Its not ideal, but it definitely works when material is scarce.

4. Yield ranges on multiple scales

Reported at 95%! Awesome! Except, maybe that was the best yield you got out of 15 experiments, the reaction usually sits around 75% (and once you got a 30%). Maybe you know the reason for variabliliy (great! put it in the discussion), maybe you don't (thats ok too). Do good science: report yield ranges on multiple scales. If its not possible because its the front line of your 72-step linear synthesis, I forgive you. If its a methodology on simple starting materials, no excuses. 

5. Yield is not important.

I'm use hyperbole for effect. But honestly, my yield doesn't ever really matter, in total synthesis there are two quantities of material: enough and not enough. There is a need in the literature to deemphasize the importance of yield. Its been said before that emphasizing yield is bad. If it were me, I would do so in favor of honest reporting of pros and cons of reactions, with a discussion of more qualitative aspects: ease of running and purifying, cost of catalysts, etc.

Those are my thoughts. Have a discussion. Or not. Now if you'll excuse me, I've got some scale-up to get back to. 

On Data Integrity

By now, we've all seen Amos Smith's editorial on data integrity in Organic Letters.

Photo from lab cleanup.

Deep beneath the sash

BBr₃ oozes forth.
WTF, Sure/Seal™?

iBooks will be coming to your Mac laptop this Fall

I guess this short blog entry could also be called "The Portable Chemist's Consultant Part 3" (see Part 2 here).

First off, we have a new book update (Version 2.3), as listed in Open Flask and on the book's website.

Secondly, Apple has announced a new OS X platform, OS X Mavericks, which will allow the use of iBooks on a laptop! So for those of you who own Apple laptops but who don't want to get an iPad, you will be able to read this book sometime in the Fall.
 
And lastly, Angewandte's book review is out, here. Thanks Angewandte!
 
--Yoshi

Ingenol: Behind the scenes

Disappointment, frustration, excitement, setbacks, thrill, and success. It has been a roller-coaster ride, but finally the reward is here. A total synthesis of ingenol from our lab was published online today. The chemistry is all described in the paper, so I will not go into too much detail here. However, I want to highlight some of the key reactions and hurdles we had to overcome to finally being able to publish this work.

Our synthesis starts from commercially available and cheap (+)-3-carene, and in five steps we get to the substrate for the first key reaction, the Pauson-Khand. In order to get enough of the Pauson-Khand product, we needed to optimize this reaction quite a bit, but we can run it on gram-scale now as shown below.

Gram-scale Pauson-Khand reaction

1,2-Addition of MeMgBr to the carbonyl group of the P-K product gives us the so-called cyclase phase end-point.

Happy Christian with 1 gram of cyclase-phase endpoint

The oxidase phase also consists of seven steps, in which we install the four hydroxyl groups and rearrange the tigliane skeleton to give the desired ingenane skeleton.

The most troublesome, frustrating, and time-consuming problem to overcome was the pinacol shift to give the ingenane skeleton.

After 8 months of desperation, numerous shift reactions in one form or the other, a lot of disappointing results, and a ridiculous amount of NMR time to figure out what we got from all these reactions, we still couldn’t get the desired product. In fact, we actually almost abandoned the whole route because we just couldn’t get that shift to work the way we wanted. Eventually, we agreed to start designing another route to ingenol, if we could not get the shift to work by November 1st, 2012.

You may call it insane luck, but on October 24th 2012 we finally hit the sweet spot and got the reaction to work on a model substrate and about a week later on the real system. What a relief! Finally we could move on.

Comparably, the last steps of the synthesis were a much smoother ride. An allylic oxidation, a deprotection, and an elimination step later we eventually had a tiny amount of our first natural product, 20-deoxyingenol, just before Christmas of 2012. About a month later, we finally made ingenol for the first time.

However, it took us another 6 months of optimization and scale-up to get the end result, which was published online on Science Express today.

Especially, the reductive alkylation of the chloro-ketone needed some serious optimization. Initially, we tried to prepare big quantities of the methyl ketone itself which turned out to be very difficult to prepare and handle. We had some really painful weeks where we would run this reaction almost everyday and get out nearly nothing. At some point, Phil suggested to run both steps - reductive methylation and aldol reaction - in one pot (!) without isolating the methyl ketone itself. Initially we had a hard time imagining that this would work but after some optimization we finally arrived at the one-pot methylation aldol procedure.

Frustration after another failed attempt at the reductive methylation

What do you do if you almost go nuts? You do stuff like drawing your team-mates.

Here is Christian’s artistic interpretation of Steve and myself.

So what’s up next? We are currently collecting data for an upcoming full paper, which will cover the side reactions and failed approaches. Furthermore, we are focusing on making analogs of ingenol for pharmacological testing. The key intermediate, the cyclase phase end-point, which is our branch point for analog syntheses is being scaled–up in conjunction with our collaborators at LEO Pharma, developers of Picato® (an ester of ingenol).



Whoever is reading this post, if any, please feel free to comment and ask us questions about the synthesis. We will be more than happy to answer them and give you more insights.

Cheers

Scientists Love Adverbs or: What Would This Look Like for Organic Chemists?

Over on his blog, bioinformatician Neil Saunders wrote up a nifty little analysis of adverbs in scientific manuscripts. I wonder how it would look if he had only looked at chemistry papers.

Lab tacos day!!!

Here are some pictures from the beautiful sunny day...with a lot of beers, tacos and sports.

My patriotism is vastly superior to that of Young Brando's

Disclaimer: This isn't from today, according to my camera I took this picture on 3/26/2011. Based on this date, its possibly a copper (II) sulfate wash, but more likely an aqueous workup from a stoichiometric nickel reaction. As for why its three phases, not sure after 2 years. I never had a reason to show anyone this picture until I saw Brando's. Later internet world,  I'm off to a BBQ soon.

The Most Patriotic Thing I Can Do From Here

Happy Fourth of July, everybody. I hope you're enjoying burgers and hot dogs or something.

Paying it Forward

Paying it Forward: Inspired by my Apprentice

                When I started in organic chemistry, my mentor agreed to train me on one condition.  That is, that I would unselfishly share all of the skills and knowledge that I obtain with other chemists – so called “paying it forward”.  I always wondered when or if I would be in the position to pass on the skills, tips, and hood tricks that I have collected over the years to an apprentice. I wasn’t sure if or when I’d be a mentor but I just hoped I would do a good job.  After all, I would be teaching someone habits and skills that they will most likely carry with them throughout their career – it’s a big responsibility!  Recently, the time came for me to share my skills and knowledge with a bright young mind.

                For the past couple months, I have had the pleasure of working with a very special young man, Jason Ge.  Jason is a high school student here in San Diego at Westview High School. But he isn’t an ordinary student by any means.  Jason has represented the US in the prestigious International Chemistry Olympiad and can write the mechanism of the Boger Pyridine Synthesis with his eyes closed (No, I’m not kidding!).

                Last week, I came to know that Jason has started his own non-profit organization called “catalyst4success”.  Each day, Jason and his team of fellow high school students travel to surrounding elementary, middle, and high schools where they teach youngsters about chemistry and perform live chemistry “magic shows.”  Thus, Jason is “paying it forward” too.

                Catalyst4success  has reached over 10,000 students this year – just amazing!  They have traveled up and down the coast and have dedicated themselves to reaching as many students as possible. Jason and his team fund the organization through donations but the funds come mostly out of their own pockets.  I didn’t write this posting intended to be a call for donations but “What’s $20 anyway?”  This is a chance for you to “pay it forward” too! You can donate at their website catalyst4success.org – there is a donate tab on the top right of the homepage.

                I was planning on teaching Jason about the importance of being a good mentor and role model to others at the end of his internship…..but it looks like he’s got that one covered.  I hope that Jason will be inspired at the end of his time here – I know that he has inspired me!

Website: catalyst4success.org

Check out this video: http://youtu.be/3wbIP_jWF0s

               

I Took My Mom to See Science Live

“Are you wearing heels?” I asked, and my mother nodded. “Mom, trust me, you don’t want to wear them in lab. You should switch them to some flats.” And she did, rather begrudgingly. My mom was visiting me a few months ago, and for whatever reason, decided that it would be a good idea to experience a full day in a chemistry lab. Not a very good start, I thought, but at least she was sensible enough to wear a comfortable shirt and a pair of jeans.

What's your favorite journal?

Organic Letters is my favorite journal. There are a number of reasons why, and herein I will try and coerce you to take my stance.

The beauty of a continuously updated electronic book

I guess this blog post could be called "The Portable Chemist's Consultant Part 2" (see part 1 here). The reason for the existence of this blog post is three-fold: 1) to write about the advantages of an electronic book that is continuously updated; 2) to show you how to update this book once you have it on your iPad; and 3) have a history of updates on this page so that you can check back to see when the next update comes out. 

Somebody Tell Me What These Numbers Mean

Or, a completely unscientific survey of total syntheses published in JACS in the last 30 or so years.

Who wants to be a heterocyclic millionaire?

In case you didn't know, Phil has been teaching a Heterocyclic Chemistry class here at Scripps since 2005. This course consists of approximately two dozen 1.5-hour lectures. Other than the students, there are many Scripps postdocs and industrial chemists auditing this class (25-30 people from local companies are sitting in each time). Phil discusses traditional topics such as pyridines, pyrroles, furans and indoles as well as more specialized topics such as benzodiazepines and alkaloid biosynthesis. The industrial chemists are also encouraged to bring in their personal chemistry problems and write it up on the chalkboard before class for "free consulting" from Phil (avoiding IP-sensitive functional groups and side chains, of course!). This course wraps up with a fun class quiz under the title of "Heterocyclic Millionaire" where Phil brings out his best Regis impersonations.

(Read on to see the midterm yourself!)

Mechanisms, End of April

Well, its Monday morning and the hoods are down at The Scripps Research Institute. Here's a picture of the lab sitting in the hall, reading papers. I decided it was high time to post the past two week's mechanisms.

 
April 20, 2013:

April 27, 2013:

Answers inside.

On Benzene

Figure 1. Snaaaaaakeeeee, a snaaaaaakeeeee!

Ahh benzene! Europeans fear it, I love the smell of it, and it can look like a snake (Figure 1)! What isn't there to love? Not to mention its qualities as a solvent, and its utility in the azeotropic removal of water from ethanol. But what I'm here to discuss today is how we draw benzene (dude, lets be honest, the Armstrong benzene is fantastic). This came up over coffee a few years ago and I decided to formalize it a little bit. If you want to play along, go ahead and draw a benzene yourself, don't think too hard, but pay attention to how you draw it. Twenty-five graduate student and postdoctoral chemists were surveyed for this blog post and the results were compiled and analyzed for your pleasure (after the jump).

Mechanism, Apr. 13, 2013

As usual, click onward for the solution.

The difluoroethylator?

Over the past few years our laboratory has become interested in the radical functionalization of heterocycles. This started with arylboronic acids as radical precursors but recently developed into alkylsulfinate chemistry. The latest addition to our list of commercialized reagents is sodium difluoroethanesulfinate (DFES-Na), a difluoroethylating agent.

According to Sigma-Aldrich, DFES-Na sold out of stock within 1 week of being listed, and due to the incredible demand, they are targeting multi-kilo quantities. Metric tons of DFES-Na will likely be needed in the next 10 years. This is, of course, exciting news for us but we would also like this blog post to be exciting for you as well. So, we have put up another video. This one is about Qianghui (first author of the paper describing DFES-Na) running a difluoroethylation reaction and hopefully after watching this video, you will be running your own difluoroethylation, too!

 

Mechanism Apr. 06, 2013

Onward for the answer!

The Portable Chemist's Consultant

This is my first ever blog entry, let alone the Baran lab blog but on all blogs web-wide. I thought this would be a suitable entry to celebrate this landmark of mine. I (Yoshi) came to the Baran Lab in 2007 and obtained my PhD last year but I'm staying here longer for a pet project of mine. And Ana's. And most importantly for those of you who visit this page for Baran lab news: Phil's vision. Case in point: we have been writing a book mostly on heterocyclic chemistry and today is our official launch date. The book is called "The Portable Chemist's Consultant." This is not a hardcover book but is only offered on the iBookstore; we also have a website dedicated to it.  While you can find the book itself and the sample book in the former, and cool graphics and a comments page in the latter, on this blog I decided to put up a quick video of myself talking through the features of this electronic book while holding up my iPad. 

   

Here is an impromptu video taken by Phil using his iPhone... he just stormed into my working area, brought me into his office and said "let's take a video of you talking about the interactive features of this book. Starting... now." 

Maybe one day I'll take a better version of this video that has my iPad on a more stable platform and without me stuttering, but for now this will do. I just wanted to showcase here that this is a highly interactive book with all sections hyperlinked to each other and all references hyperlinked to the original literature source on the internet. As well as a lot of Phil Baran videos for those of you who are not fortunate enough to be in San Diego to attend his heterocycles class (which started today, coincidentally... or not). Check it out!  --Yoshi

Baran Lab to move to Wyoming

In light of recent blog posts, we would like to formally announce that our lab is moving to an abandoned home depot somewhere in rural western Wyoming.

Young Brando is "excited to have two full hoods to himself," and Taycoh said, "with the new space and low overhead costs, we should be able to have a lab of two- to three-hundred students."

The ATF will be providing funding for new research on the novel chemoselective syntheses of ethan-1-ol and ethan-2-ol.

Phil's children's love of adorable farm animals may have influenced the move.

Stay tuned for more information!

A Taxol synthesis is simple

I got the results back from NSF fellowship application today. I didn't get the fellowship, but that doesn't matter. Something funny was that one of the reviewers said my “proposed project looked simple or at least written that way.”

I’m the chump working on the taxane project. The overall goal is in the figure below. You might have seen the Nature Chemistry paper where we described the construction of the taxane skeleton. My project involves multiple C-H oxidation transformations on this skeleton en route to Taxol. Simple, right?

I’m not here to toot my own horn or rally up a pity party, but I think every chemist familiar with synthetic organic chemistry will agree this endeavor is somewhere between crazy difficult and flat-out impossible. No one would claim it looks simple. Then why is this NSF reviewer judging my application if they don’t see the difficulty of this project?

To be clear, I wouldn't care if I scored “excellent” on everything and still didn't get the fellowship. There are many people deserving of this award, and who am I to say I deserve it more than anyone else? Also, there are plenty of reasons to not fund me or this project. My problem is that reviewers are unqualified to judge my “intellectual merit” if they don’t know the basic frontiers of my field. I guess the moral of the story is don’t assume people know why your science is hard. Be very explicit. This problem probably applies to some extent to other award applications and even applying for a job.

Column Chromatography....seems silly now.

Last month the team at Eisai responsible for the commercial scale synthesis of Halaven (easily the most complex drug molecule produced entirely by chemical synthesis) published a series of papers (theres three links there) detailing the development from the medchem route to process.  While these papers are a must read from the standpoint of using total synthesis to solve a supply need, this post is only peripherally related.

Early on in the synthesis of one of the pieces of the western half of the molecule the group does a chromatographic resolution of a racemic alcohol using 'simulated moving bed chromatography'.

Mechanism Mar. 16, 2013

Solution after the jump!

The Press Corpse

The press scribble scribble every half-truth spoke then shoot it round the country like an April Fools joke

Why not a semisynthesis?

What is a typical experiment in the Baran lab?

Ever wonder what a jelly bean does in organic solvent? Now we know.