Back again

Well, been away for quite a while (more than 1 month since last post), but it has been very busy time. I just got my second child and just starting to get back to my normal groove (with some deviations). Hopefully I will be able to keep writing about more chemistry soon. Going to have a presentation on total synthesis, going to post it here when I am done.

My little Vincent Thiago

And he looks a bit angry here

I am trying to plan a reaction in which I incorporate a sulfonamide in the last step of the reaction. I need the conditions to be mild and the yields to be good. I found a paper by Mayer et al. in which the reaction conditions I want may be used:

Sulfonamide/aniline, KOt-Bu, NMP, allylchloro{1,3-bis(2,6-di-propylphenyl)imidazol-2- yilidine]
palladium(II) (IPr•HCl•Pd), Pd(dppf)Cl2•CHCl2,

What I see as a problem is the imidazol Pd(II) salt that is used. Is actually the first time I see it and they use it in 20% amounts along with Pd(dppf)Cl2•CHCl2 and I have a hard time understanding why. I have to find something more general or an explanation for this...

On the other hand, there are many other methods to go. Wang et al recently (2012) published a paper were mild reaction conditions were used. This method is very similar to an older paper by Wei et al (2005) in which they use an aminoacid as a ligand stabilizing the copper reagent.

Of course, the group of Buchwald et al. have Pd-methods that can be used, and in an earlier paper, they stress the importance of using a bulky P-ligand for the reaction to work (here are some examples with amides, and one example with sulfonamide working with chlorides).


An update. Tried out all these reactions, but the one that worked best was an old protocol using Pd(OAc)2 and the ligand Xantphos and Cs2CO3 (s) as the base in THF:Toluene (1:1) at 120 °C. Got almost 80 % product after a very easy purification procedure.

Synthesis of Cyanthiwigin U

Cyanthiwigin U is a challenging molecule to synthesize, and is the topic of tomorrow's synthesis seminar. Cyanthiwigin U is a diterpenoid which is isolated from both fungal and marine sources. It contains a cyclohepta[e]indene ring system, and has no less than 5 stereocenters, a real synthetic challenge.

In this paper, Phillips and Pfeiffer shows a very beautiful approach to synthesize Cyanthiwigin U. It all begins with the synthesis of an endo-acrylisoborneol. The authors used a synthetic strategy presented by Palomo et al. Lithiated methoxyallene is reacted with (1R)-(+)-camphor (1) using THF as solvent at -30 °C and TMEDA as metal ligand. The intermediate (2) is then hydrolyzed in 1M HCl, yielding the desired enones (3, 4 or 5 in the scheme 1 below).

Scheme 1. Taken from Palomo's publication

Through

In  Phillips and Pfeiffer's paper, the endo-acrylisoborneol is then reacted with alkene 6 via a metathesis using Grubb's catalyst (7). The product is a substrate (8) which is next used as a Diels-Alder precursor.

Conditions: (1) 5 mol % Grubbs catalyst (7), 93%

The precursor 8 was then reacted with 1,4-dimethylcyclohexadiene in acidic media (2 equiv TfOH) at -78 °C provided the Diels-Alder product (9, a bicyclo[2.2.2]octene).

Conditions: (2) 1,4-dimethylcyclohexadiene, TfOH (2 equiv), -78 °C, 70%

The cyclization between 8 and 1,4-dimethylcyclohexadiene occurs through a Diels-Alder cyclization. 

Reacting product 9 with CAN (Cerium Ammonium Nitrate), removes the borneol group through a radical reaction. This procedure is also described by Palomo et al. in an earlier publication.

Conditions: (3) CAN, aqueous MeCN, 82%.

The carboxylic acid and pivalic ester are thereafter reduced to the alcohols using LiAlH4. The product is then  subjected to a Swern oxidation to yield the corresponding aldehydes.

Conditions: (4) a) LiAlH4, THF, reflux, 16h, 99%. b) (COCl)2, DMSO, Et3N, 84% 

The dialdehyde 11 is trated with vinylmagnesium bromide. The formed alcohols were re-oxidized
using Dess-Martin periodinane, providing the bis-enone 12. The bis-enone 12 was then exposed to Grubb's catalyst 7, under an atmosphere of ethylene, providing 13.

Conditions: (5) a) Vinylmagnesium bromide, CeCl3. b) Dess-Martin Periodinane. (6) 20 mol% 7, ethylene, Toluene

So, I did not quite get it at the beginning what was going on between 12 and 13, but I tried to make a drawing to understand it better. Here it is:

So the Grubbs catalyst open up the ring's alkene, and from there, it could either make the 7-membered ring first and then the 5-membered ring right after. It could also be the other way around. The important thing is that the alkene in the ring is opened first.

And it is very late right now so I will pause here and continue tomorrow or when I have some more time to write.

Peace & Luv

BJJ, Monday 20101008

Today Åke went through two techniques that can be used when your opponent is turtling.

The first one, an important detail: when you are putting your foot underneath his armpit, make sure your heel is underneath or tightly pushed to your opponent's chin. This will allow the lock-down to be easily set-up.

 The second one is a bit different and in my opinion somewhat easier to execute than the first one (the first one feels a bit riskier, especially when the foot is going underneath the armpit).

We also warmed up with some take-down techniques, but I did not captured them on film ://. I am planning to go on Wednesday again if nothing unplanned happens at home :))

Peace and luv

Photoshoot on a beautiful autumnday

Yesterday Sunday  I went with Julia and Miranda to Botaniska trädgården in Uppsala. It was a very beautiful  day perfect for photography, so we decided to take some pictures. What I most like about the autumn are the colorfulness of the leafs. They are still a little bit too green but we managed to find some spots  where they went from green to yellow and red. Here are some of the picts:

Miranda is quite good at taking pictures. I gave her my very very old camera. A Minolta Z1, which was one of the first digital cameras I ever had. She loves to experiment with it

And here is Julia in front of the "Orangeriet" 

Miranda, of course, wanted to have some pictures of her own. The tree which Julia is standing in front of was had really fantastic colors. I do not think I really nailed it on that picture though ://; its still a good one... 

 And last, both playing with the leafs...

Well, that is it for today... now I have to write about the BJJ training :). Tomorrow, I'll try to write about a very interesting synthesis. Peace and luv...

BJJ Training Sunday 20101007

Today, Kristofer substituted Henke as instructor and the warm up was quite tuff... so, after an exhausting warm-up, we practiced some techniques from the guard (two). The first one is aimed to take control of your opponent's upper-body and set-up triangles or omoplatas. I guess it is possible to set-up sweeps whit a little bit more of practice from this position. Well, here it comes:

The second technique was a sweep from guard. I use it a lot after failing an armbar, but it is also very good as a technique of its own.

Well, planning to go tomorrow to practice some more. Will put those techniques here as well :)

BJJ Training, 20121003

Today Nils went through some De la Riva techniques. The language, as usual is Swedish.

The first video below just shows a set-up for De la Riva guard:

Next, this is one sweep from De la Riva guard. It is quite important to really hold the foot to make the sweep work properly, but please correct me if I am wrong...

And last, another "sweep" you can use from De la Riva to take your opponents back. I could not make it work but I know there people there who makes it work pretty well. 

Hell... I am tired. Enough for today.

Chemistry Problem Set #1

At work, every Wednesday we have a problem set to solve. I will try to solve them and write down the solution here (I will loose my papers if I write them down on a paper-block, here I can always go back and look).

So, the target molecule for this week is (1)

(1)

It did not look like something difficult, especially if you think about the parent scaffold (2)

(2)

So, I started to think how to make the parent scaffold (2) and then go back to the target. So, retro-synthetically I was thinking that you would need to have 2-(aminomethyl)aniline and react it with some kind of carbonyl with good leaving groups (like L1-CO-L2). Some brainstorming and google search gives me CDI (carbonyldimidazole)

Anyway. They usually are not happy with one-step answers, but want you to go further back. So, how to make the 2-(aminomethyl)aniline? Well. I guess you could do something like having a bromide where the aminomethylgroup is (i.e. having a bromomethyl instead of amino, and yea, the aniline should be a nitro group which can be reduced with iron dust). Well, they say one image says more than 1000 words and it is very truth in chemistry. This is the route I would choose:

a) AIBN, NBS in CHCl3. b) NH3 in... something aprotic. Maybe neat NH3 (?). c) Reduce the NO2, Fe-dust in ethanol and NH4Cl is quite normal to use here. Or  Zn(Hg) in HCl

Well, I guess there are other routes. I found this papers (here and here) in which other routes are conducted (and the molecule looks a bit different).

Do not have much more time now so I will have to do the rest later :).

And here is the rest of the exercise. So, the target molecule can be synthesized in a different way. Here is a short retrosynthetic analysis

And the mechanism for this is a one-pot reaction (click on the image to see it clearly), but you can also isolate the imidine and then react it with the nitromethane

One thing I was wondering for my self... why does the methoxi do not attack the imidine carbon? I have to check the paper and see what they say about it (do not have the paper with me at the moment)

BJJ training

So, today's BJJ was quite fun. A lot of people are coming to practice and it seems like Hilti Uppsala is growing :).

We did some techniques from butterfly guard. Got only two of them on video. The first one is a armlock/armbar from butterfly.

The one we did looks like this:

And here is another variant I found on youtube (I guess you can find as many different variants as there are grain of sand in the sea):

Last technique was a triangle from butterfly. I would personally never go for this one as a first option, but I think is good to know.

Hell, I am to tired to write anything about these techniques but I just want to go back and remember the details in a near future. Time for me to sleep, have to work tomorrow :))

Photo session

Today I got to take some photos of my friends' little son. He is 5 months old and we only had a very short amount of time to take the photos, but I was very happy with the results. Here are two of them:

The little guy showed a lot of patience, and it is the first time I have a photo session with a baby. It is hard as hell to make them look at the camera or to get them to pose as you would like... but hell it is worth the time :). I used my reflective screen (silver) and my flash (SB900, Nikon) together with a 50 mm f1.8. The aperture was set to f2.2 most of the time. I do not know what is the best aperture to use, but had a hard time to focus correctly using f1.8 (he moved to much).

Well, I just send all of the picts to my friends... lets hope they like :))

Eschenmoser's Salt

On monday, just gonna start easy on the lab. Going to make some kind of alkylation using Eschenmoser's salt (N,N-Dimethylmethyleneiminium iodide), which is a hygroscopic crystalline substance having a melting point of 240 °C (although I have seen everything from 117 °C and 147 °C as melting points, but this is the one you find at Sigma and other serious producers).

Safety Information

Symbol	GHS07
Signal word	Warning
Hazard statements	H315-H319-H335
Precautionary statements	P261-P305 + P351 + P338
Personal Protective Equipment	dust mask type N95 (US), Eyeshields, Gloves
Hazard Codes	Xi
Risk Statements (Europe)	36/37/38
Safety Statements (Europe)	26-36

It is used to prepare compounds of the type RCH2N(CH3)2, and is very compatible with enolates, enolsilyl ethers and ketones. The mechanism of reaction is quite simple, and I have seen many different solvents and bases being used (like Et3N and Dichloromethane, or Et3N in acetonitrile).

Lägg till bildtext

Now, the salt we have at the lab is quite old and dirty, so I have some different alternatives:

• Buy a new bottle
• Recrystallize the dirty compound
• Synthesize new salt
• Use it as it is

Of coure, I'll go for re-crystallization of the outdated compound. But, to synthesize some more should be quite easy:

Well, so I guess I will have to recrystallize then....

Uppdate,

So, I said I was planning to recrystallize the salt. I did not manage to find a proper solvent for recrystallization so I opted to test the salt as it was, since I supposed I would get some product and then I could purify it. I was quite wrong. I did run the reaction (in dry Acetonitrile, reflux) and got a by-product in HUGE amounts. This by-product had a molecular mass of 12 a.u. higher than the expected compound. So, of course, a carbon was added to my molecule somehow.  

I got curious to know what this was and started to purify the stuff and run NMR (H, C, COSY, HSQC, HMBC) to see what the hell was happening. It turned out that there was a big amount of decomposed Eschenmoser's salt (i.e., it had decomposed to formaldehyde). So what was happening was that the formed product was subjected to a second enolization, which resulting in the attack of formaldehyde present in the mixture. Apparently, there is a publication about this reaction and would I have come around this problem 15 years ago, I would have invented a new methodology 8-)).

Reaction of arylketone with Eschemoser's salt

So, I really had to purify the salt, and the best way was actually to run a bulb-to-bulb. I crushed the salt (with a mortar) and put the temperature at 80 °C and the pressure at 8 mbar. It did the trick. All paraformaldehyde sublimated. Raising the temperature to 95 °C resulted in slow sublimation of the Eschenmoser salt. I did this quite quickly and I do not think those temperatures are optimal, but the product was pure enough for my purposes. Now the reaction is running and I hope I can get some pure product by tomorrow :))

BJJ training 20120926, techniques from half-guard

So, today Wednesday Nils was the instructor. He is quite good attacking from the half-guard and just being annoying with his sweeps from any guard. So, he shares with us three different techniques he uses. I know two of them will be very useful for me anyway. The language on the video is Swedish and it is just a bit shaky, but hell... what you gonna do.

So, in this technique is quite important to know. Is like a basic form the half-guard (I am not very good from half-guard though ://). Very important is to really lock his leg with your "free leg" and grab the back of your opponent really tightly. If your opponent manage to avoid the first sweep (which most people with some BJJ experience do), then the second sweep is very useful and works very well (see the clip at 2:10 approx to see the second technique).

Here is the third technique.

A little bit more unusual and I have actually never had to use it. But might be good to know, you could bait your opponent to go to that position. 

Design of Experiments (DoE)

Well, there is a lot of discussion whether to use DoE on method development when working in organic chemistry or not. According to me, you should use it as fast as you can. I mean, the industry has adapted to this quite well and it is now a standard procedure so I do not understand the reluctance from academics to adapt to this powerful tool. There is an excellent article by Torbjörn Lundstedt et al. about DoE (here).

One major reason I like DoE is, I guess, doe to my engineering background. As an engineer, you like graphs, you like correlations and you like computers. DoE offers all of this and assist you in your work. In the paper to which I linked (see above), they address some of the common objections from people reluctant to use DoE. Here is a summary of the normal arguments people use to avoid using DoE (that I have heard my self, there are many more for sure)

“Why Bother When the Results Are Blindingly Obvious?”

Personally I think there is a lot of ego in this kind of statements. Of course you have to have an idea of what will work and what wont work, but given the fact that chemistry is affected by so many parameters (temperature, time, pressure, reagents, rate of addition, catalyst, solvent, concentration, pH, etc), it is worthwhile to try a small screening design at the beginning of any project. At the end, all information might be used and the effect of a given variable can be calculated .

Many people expect DoE to provide miracle results. But, visualize that one-factor-at the time is the counterpart of running with boots, DoE is the counterpart of running with proper running shoes. Having to run is a pain in the *ss no matter the shoes you choose, but you cannot deny that is h*ll more easy to run with Asics Gel-Scout than using a pair of gothic boots.

What If We Miss a Factor? Will My DOE Work Not Be Wasted?

If you miss a factor using DoE, you will probably miss it using the usual approach (one factor at a time). With DoE you can actually use Lack of Fit tests and residual analysis  which may help you find that missing variable (with a little bit of thinking and analysis).

Other stuff you may hear are that the resources are limited. But, using this argument just proves that you have missed the whole point of DoE, it is designed to minimize costs and the amount of experiment that have to be performed in order to find optimal responses. The thing is that you see in beforehand the amount of material that will be "wasted". Changing one-factor-at-the time, you waste while you progress and at the end, you do not realize that the amount of material used just surpassed the amount of material that would be needed to make a screening design and an optimization.

So, I do not have so much more time to use here. I may be wrong in some points, but my advice for them who are new at DoE in method development are (besides reading the papers above)

• Search the literature. Remember, four weeks in the lab will save you four hours in front of the computer (or library).
• Start with a screening design. What parameters are important? (usually, temperature and solvent have to be included...)
• Do not forget to try to minimize the number of variables used. Sometimes using A, B and C (three variables) is just as meaningful as using ratios of these factors (i.e. A/B and C/B, which give you two variables instead of three)
• When you are done with the screening design and have found the most important variables, is time to optimize. Response surface design is usually the way to go.

Well, the reason I posted this is because of a little bit of frustration I feel due to the almost non-existent use of DoE at academic organic chemistry labs, while this is a method that is a must out in industry. I have been striving to work with it as much as I possibly can, and one day, I hope it will be a tool as frequently used as an analytical HPLC. 

First Post and Presentation

Well, I guess it is time to try to keep track of myself and what I am doing. This is by no means meant to instruct anyone in anything, but the idea is for me to keep myself busy and improving. If I can share some ideas with someone else it is just a bonus for me.

I will post stuff about chemistry (mostly problems I encounter and hopefully the solutions I find), photography, Brazilian Jiu-Jitsu and I guess some philosophical and political stuff.



So, who am I? Well, if you are asking that in a professional way, here is my CV. The rest of this text will be very informal.

I am a Colombian/Swedish citizen, living in Sweden since I was 14 years old. I was born in Pereira, a medium-sized city in Colombia which is known as the capital of the coffee triangle (the other two cities are Manizales and Armenia).

Since 1996 I have been living in Sweden. I started in a small city called Flen, and in 1997 I moved to Stockholm (the city who chose to call it self "the capital of Scandinavia" and pissed off the people of  Oslo (I guess Copenhagen is to confident of its real position to argue about niceties).

Anyway, in 2001 I decided to become a Chemical Engineer and moved to Uppsala, where I met my wife Julia. In 2006 we got our lovely daughter Miranda and another little baby is on its way at the moment (planned to november 2012) .

Well, lets go back in time a bit. Before finishing my studies, I decided  to become a medicinal chemist, and my grand plan was to end up working in scale-up or process development. Therefore, at the end of 2006 I chose to start my Ph.D. studies at the Department of Medicinal Chemistry, also in Uppsala, supervised by Prof. Mats Larhed. I had the opportunity to work in the area of Palladium catalyzed coupling reactions (publications here, here, here, here and here) and HIV-protease and integrase inhibitors (publications here and here respectively).



I get a lot of questions about how it is being a Ph.D. student in organic chemistry. First of all: I did never consider myself to be a student. Of my five years of education, I only had to go three courses, the rest of it was plain work. What I  most enjoyed was the possibility of driving your own projects. It is like having your own mini-coorporation. You learn a lot about planning, finding information and applying it to real case scenarios. Moreover, you get the opportunity to really understand a subject to its core and to test own theories. If sometimes I wanted to test a new purification technique, no problem, go ahead. If it did not work, well, I always tried it at least three time before giving up. Most of the times I got it right after a few modifications that suited my style of work better. Being a Ph.D. is like being a child again; a curious child. You are allowed to test and try whatever you like (almost), as long as you manage to keep delivering results from your main projects.

One of the things I loved the most as a Ph.D. student, and that I will miss now that I have defended, is the teaching. Some people detest this, but I just loved it. It is quite satisfying having a big crow of students in front of you smiling because you managed to explain reaction mechanisms, trends and patterns in a way they understand. One of the most important things about teaching is, in order to make a good job, you actually have to understand the subject pretty well. Planning the lectures/seminars/labs gave you the opportunity to discover your weaknesses and go fix them. Moreover, most students are very fun and outgoing.


Well, I guess I will finish here for now. I will continue posting less about me and more about chemistry, photography and BJJ in no especial order.

Peace

// Alejandro