The Return of Dylan Stiles

Just as we thought that Dylan Stiles, formerly the host of blog.tenderbuton.com, was a dead and buried blogger he returns. Check his post on how to make pure nepetalactone (aka Kitty Crack) in your kitchen out here. D!

Asymmetric synthesis of vinylcyclopropanes

Apologies for the sluggish posting. Life is more complicated than usual as I've moved from one research group to another and as many of you will know this essentially means that you are working in two groups for a while. Finalising old stuff, cleaning up and writing papers on one topic whilst trying to start new projects in another lab....somewhat stressful and time consuming. Anyway, enough moaning. As you can see from the previous post I've sacked my fellow bloggers as they weren't blogging. So now it's all down to me (which it was anyway). I've been meaning to post this stuff since I read the paper in late December 2006. I have had a long lasting affair with cyclopropanes, in particular cyclopropane amino acids so I was very pleased to see this paper by Deng et al., DOI: 10.1021/ja056751o. These guys from Shanghai are doing some real cyclopropane magic using some easily obtainable camphor-derived sulfur ylides:The work is very throrough and makes up an 11 page JACS paper (not including any experimental). Many chemists would probably have split this work up in two papers. It's really nice to see these guys decided to stick the whole story in one paper. In brief these guys discover that they can make trisubstituted vinyl-cyclopropanes in high yield, diastereoselectivity and enantioselectivity. Moreover, they can make both enantiomers of cyclopropane selectively by switching from endo- to exo-sulfur ylides. This table from the paper illustrates how sweet this stuff is:Only "problem" here is that they are using stoichiometric sulfur ylide. However, they address this by developing a catalytic ylide cyclopropanation. The yields are not as impressive and the ee's are down to 50-80%. Still pretty cool and I bet these guys are working hard to improve the catalytic system. Finally, they decide to pull off a short and high yielding formal total synthesis of a known cyclopropane amino acid.
Obviously, they are making both enantiomers as well as both enantiomers of a diastereoisomer. And here I'm messing around trying to improve my lousy dr's on the racemic synthesis of the same target. Crap! D!

You're fired

Dear Steve and Chris: You're fired, both of you. Your license is revoked. All privileges have been suspended. Pack up your stuff and leave! D!

The Mannich Reaction revisited

The Mannich Reaction (Carl Ulrich Franz Mannich, 1877-1947) is yet another one of those reactions that look brilliant on paper. However, I have on many occasions heard chemists attempting the reaction moan a fair bit to say the least. The major problem seems to be that the reaction is sluggish requiring heating/reflux to get anywhere and that the reagents (and desired product) start polymerising. You can find Mannich's original paper here: Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, p. 647. There is a detailed entry in Wikipedia on the reaction for those not familiar with it. A good alternative to the classic Mannich conditions is to use Eschenmoser's salt which I've seen used successfully in a number of total syntheses. Anyway, recently a PhD student in my lab was bitching about his Mannich Reaction. He left the lab, did some reading and came back with this nice JOC Note by A. Erkkila and P. M. Pihko, DOI: 10.1021/jo052529q. When he started using this stuff all his problems were solved. Fortunately, he sorted all this out right before I had to do my first Mannich Reaction. It also worked as a charm for me so I warmly recommend this simple, and efficient Mannich protocol.

Now Erkkila and Pihko are quite concerned about reaction times because they are thinking of industry applications. However, for the average chemist that does a lot of work overnight (whilst at home in bed) it isn't essential that it's done in 1 hour. We found that if you do these reactions overnight no heating is required and the products are of very high purity. Very clean reactions indeed. Here's four examples from the paper:

As it turns out the chemistry works really well for most systems using catalyst 1. However, some aldehydes require catalyst 2 to give a good result, eg. entries 3 and 4. The only compounds tested in this paper that failed completely were aldehydes that exist predominantly in a hemiacetal form, eg. 5-hydroxy-valeraldehyde. So there you have it. Maybe something you should consider giving a go next time it's alpha-methylenation time. D!

Chemistry Blogs

I've received some emails from people wanting me to link to their blogs and web sites and also had some people ask me why I don't provide links to certain chemistry blogs. The blogs on the lists are the ones I like and visit regularly. I have decided not to link to blogs were there is to much bitching and slander going on, in particular if the blogger is anonymous. And then there's obviously all the stuff that I still haven't had the time to check out. I've just added two new blogs this weekend that I would recommend. Organometallic Current is a great blog with detailed paper reviews and lots of mechanistic stuff. If you like your Palladium you should check it out. Also A Synthetic Environment is an excellent blog. This blog is looking at some more historic and equipment related topics which are quite entertaining. Check, check, cccheck it out man.... D!

Revenge of the NMR tube

Well I guess it had to happen to someone sooner or later. It appears that I applied slightly too much pressure when I was sticking the lid on my NMR tube the other night. As a result the tube snapped and proceeded to go straight through my glove and into my finger. Now that's obviously annoying but can be fixed with band aid. However, when the tube had finally embedded itself in my finger it decided to snap for the second time. In other words I had a piece of NMR tube thoroughly buried in my finger. This is not the sort shit you want to happen to you at 11 pm on a Monday. Trying to fish the glass out myself only resulted in pain and blood everywhere so off to the hospital. Fortunately, the hospital is only a short walk from the Chemistry Department. After waiting for an hour amongst screaming people on various drugs and/or totally shit faced with blood coming out of various openings I was attended by a very nice Doctor. She told me straight away that X-ray was no good for glass so she would have to dig around for the glass bits. At this point I would like to say thank you to whoever it was that came up with anesthetics. Anyway, after some serious digging and cutting a big chunk of NMR tube was extracted. This is what my finger looked like at 1.30 am when I was finally out of the Emergency room.
No my fingers weren't really blue. I have no idea why it keeps uploading the picture like this but it looks kind off cool and scientific. Anyway, it really wasn't particularly dramatic and if it wasn't for the glass I would never have gone to the Emergency Room. I have always heard that impaling yourself with an NMR tube is a particularly common accident amongst chemists. Nevertheless, I'm the first casualty that I know off. Does anyone else know of similar incidents? Finally, I have to say that there wasn't really anything I could have done to prevent this from happening. I used a brand new tube and applied a minimum amount of pressure when putting the lid on........just got unlucky I guess. And by the way what are people thinking off getting drunk and on drugs on a Monday. Save it for the weekend people. D!

Tethered aminohydroxylations Donohoe stylie

Back in 2002 I started on a project where we considered using the Sharpless asymmetric aminohydroxylation (AA) as a key step. However, the anticipation of major regioselectivity issues and the success we experienced using the Sharpless asymmetric dihydroxylation meant we abandoned this approach entirely. However, I clearly remember sitting at my desk drawing a tethered version of the AA reaction where the amine was attached to an allylic alcohol as a carbamate. I'm sure that hundreds of other guys where drawing similar stuff and scratching their heads, however, Timothy Donohoe, from Oxford University decided to put the pencil down and get some students to get on with it. I completely missed the first paper that came out in 2001 in Chem. Commun. (DOI: 10.1039/b107253f) and only picked up on what they were doing when they published a paper on their TA work in JACS in 2002 (DOI: 10.1021/ja0276117). Ever since I have been following the Donohoe groups progress closely. The reason that I'm posting this now is because they finally nailed the reaction down in a recent Org. Lett. paper (DOI:10.1021/ol070430v). Anyway, let's get down to business. Firstly, it's important to realise that the TA reaction isn't asymmetric. It is however, a stereospecific, stereo-, regio- and chemoselective process. In other words if you start with optically active substrates you are laughing. Here's the condensed version of the story so far:

(1) Donohoe et al., Chem Comm, 2001, pp 2078-2079 (DOI: 10.1039/b107253f)
TA of acyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 41 to 61%. Here's a really nice example with a diene:

(2) Donohoe et al., JACS, 2002, pp 12934-12935 (DOI: 10.1021/ja0276117)
TA of cyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 50 to 83%. Works for 6,7 and 8-membered rings but only 5-membered rings with exocyclic double bonds undergo aminohydroxylation. Here's another nice example making a protected amino-sugar:

(3) Donohoe et al., Org. Lett., 2004, pp 2583-2585 (DOI: 10.1021/ol049136i)
TA of chiral acyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 57 to 74% with excellent syn-selectivity. Some very impressive examples of TA reactions in this paper, for example:

(4) Donohoe et al., JACS, 2006, pp 2514-2515 (DOI: 10.1021/ja057389g)

Finally, they manage to get rid of hypochlorite and NaOH by attaching a mesitylsulfonyl substituent to the carbamate nitrogen. As a consequence catalyst loading can go down to 1%, yields have improved (69-83%) and homo-allylic carbamates have become viable systems. Check this homo-allylic TA out:Nice stuff innit and it gets better.

(5) Donohoe et al., Org. Lett., 2007, pp. 1725-1728 (DOI: : 10.1021/ol070430v)

And finally the climax. This is the final, and very recent paper, from the Oxford lab. Previously some of the TAs just didn't work (with the mesitylsulfonyl N-substituent) for no apparent reason. So they screen a bunch of different N-leaving groups and discover that things take off big time when pentafluorobenzoyl is attached to the carbamate. Catalyst loading is now permanently down to 1 mol%, yields are up (71-98%) also for difficult homo-allylic substrates, and it works for both cyclic and acyclic systems. Here's a nice homo-allyic example:

So it took about 6 years to develop this methodology to the point where I believe it will start finding wide spread use in synthesis. I'm itching to try one of these for myself and I'm desperately looking for an excuse. If anyone has tried running some of these Donohoe TAs I would very much like to hear any comments - is it really as good as it looks on paper? D!

Monkeys

Yes, yes, yes I know Curly Arrow hasn't exactly been a hive of activity lately. Trust me it isn't because I spend my evenings sipping red wine and watching the sun set. There's a post in the making on tethered amino-hydroxylations so come back tomorrow and check it out. Until then have a look at this most interesting Monkey Distribution Map.

You'll notice that neither Europe nor North America has any monkeys. Where I used to work we saw many similarities between PhD students and monkeys (except monkeys have better lives). However, this is clearly not reflected on this map. Anyway, serious stuff tomorrow. D!

Tempo Oxidations Part II

I've previously mentioned the TEMPO/BAIB combo for oxidising alcohols to carboxylic acid. A very smooth and mild oxidation. Back when we discussed this particular reaction we had a brief discussion about stopping this reaction at the aldehyde stage. This is indeed what this particular reaction type was developed for originally and so when I recently had to oxidise a primary alcohol to an aldehyde I thought I'd give it a go. By chance Delfourne et al. (DOI: 10.1021/jm0308702) had previously made the same compound using a TEMPO oxidation. Too easy! According to the procedure the product was obtained in quantitative yield and purification wasn't required! This particular procedure involves a crazy cocktail of reagents. This is what I did:Fortunately, all the ingredients are reasonably affordable. Mixing it all up and adding the alcohol gives a biphasic reaction mixture that looks a bit like Schweppes Orange:
However, unlike Delfourne et al. my final product wasn't clean after a simple work up. Succinimide was simply precipitating everywhere and hence some silica was required. In the end a filtration through a silica plug proved sufficient to give clean product on a reasonably large scale (18 grams) in excellent yield (97%). So despite the fact that a simple work up wasn't sufficient to clean the product up this is an easy to do reaction that I would recommend to anyone who's tired of stinky old Swern. D!

Fun with singlet oxygen

So finally I'm back fresh and invigorated after numerous bottles of awesome South Australian Wine. I'd like to recommend Primo Estate/Joseph, Kay Brothers, Pertaringa and Leconfield/Richard Hamilton in McLaren Vale and Langmeil, Rockford and Richmond Grove in Barossa Valley. Anyway, first day back at work I did a photolysis as we often do were I work. In other words a diene is irradiated in the presence of oxygen and a triplet sensitiser (in this case Rose Bengal). I love this reaction because it's absolutely beautiful. Check it out man:
Now the above reaction is obviously totally irresponsible and was only on for less than a minute so that I could take the picture. We are dealing with a fancy piece of glassware that has oxygen bubbling through it whilst two flood lamps are hammering photons away generating singlet oxygen and in the process heating the fume hood up big time. Hence, aluminium foil on the bottom of the hood is required to literally avoid a melt down and I'll be hooking a pump up that sends ice water through the cooling jacket. Moreover, I'm synthesising an endoperoxide - AAaARRRrGGGHhHh PEROXIDE - yeah I know but they are really quite stable. In fact our friends at the defence force haven't been able to blow them up so we aren't too worried. However, to avoid any nasty surprises we try not to make more than 5-10 grams of endoperoxides at any time. So as I said totally irresponsible hence I proceed to wrap this beautiful reaction up in two blasts shields covered in aluminum foil, pull the sash down and hook a cooling box/pump up to the glass ware and the final set up looks like this:
Well at least I know it's beautiful behind all that plastic and aluminium foil. This particular day I was doing the following photolysis:

Reactions of this type generally work quite well giving yields in the 40-70% range and since dienes are easily accessible using classic Wittig chemistry we consider making endoperoxides quite trivial. So why was I making this particular endoperoxide? Well if I told you I would have to kill you. There should be a paper coming out later this year featuring amongst others this particular endoperoxide turning into a supa cool cyclopropane in one (yes one) synthetic step so keep your eyes open for that paper. Some of you are probably wondering what Rose Bengal is. Behold the halogenated beast:We tend to use the bis-triethyl ammonium salt (as shown) because it is nicely soluble in organic solvents such as dichloromethane. D!