Ma, Zi, Yu. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.201002299.

Why make one natural product when you can make two just as easily?  Or three in this case, but the headline syntheses are the Galbulimima Alkaloids GB-13 and GB-16 – notable members of a family that is getting some serious attention in pharma – one analogue is currently in phase III trials.  With all that potential, it’s not surprising that these beasties have seen quite a bit of synthetic attention; indeed, GB-13 was one of the first syntheses I blogged about! Another popular member is himgaline, with two (1, 2) previous blogging efforts here.  Adding to the wealth of chemistry here is going to take quite a bit of talent, so it’s luck that Dawei Ma can bring the goods.

Ma’s approach was to work towards these targets from a common, late-stage precursor, and to build complexity as non-linearly as possible.  One thing I really appreciate about his work and this paper is his synthesis of the smaller fragments, as he describes the synthesis from the commercial precursors rather than literature intermediates.  Perhaps he’s done this as the routes are really quite neat.  Starting with 3-aminobutan-1-ol, a condensation with 1,3-cyclohexanedione gave the bicyclic intermediate after a displacement-cyclisation.  Reduction of the enone under fairly forcing conditions gave the cis-decalin-type structure, generating a pair of stereocenters and allowing completion of a complex, key intermediate in only five steps.

A second intermediate was called into existance using only one more step.  A literature intramolecular asymmetric conjugate addition was able to build a fairly busy cyclohexane, which, after a selective reduction, could be esterified to give the desired lactone with ease.

Unifying these two fragments wasn’t without it’s problems – stereoselectivity being the major issue, as the group could only acheive a 3.5:1 d.r.  However, this was actually irrelevant, as the two diastereomers were taken through a fairly busy elimination / epimerisation / reduction sequence to get to their final goal.

A few steps later, they were ready to make that ring-system even more complex!  Working with a ketone and an enone, treatment with samarium diiodide did a reaction I wasn’t too surprised to learn.  I’d seen the SmI₂ mediate coupling of ketone before, so it’s not really much of a stretch to see this happen in a ‘conjugate’ sense when working with an enone.  The process was completed by a quick DMP oxidation to complete the majority of GB-13 (two more steps required).

Harking back to one of my earlier posts (the Evans’ synthesis of Himgaline), Ma also sees that GB-13 was isolated along with an equibrilating isomer, 16-oxo-Himgaline, in which the piperidine nitrogen adds into the enone.  The reversible process can be fixed by reducing the resulting ketone – something both the groups completed by addition of a bit of triacetoxysodium borohydride.  No yield is given by Ma, so I presume his result concorded with Evans.

Very nice stuff, and a well-written paper

Watanabe, Sumiya, Ishigami. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.201002505. [No SI available]

As much as biological activity is a great rationale for working on a molecule, I do like it when a group does the chemistry for the chemistry.  To quote Watanabe, ‘Although urechitol A itself exhibited no biological activity, its unique tetracyclic structure prompted us to investigate its synthesis‘.  And when a group can make such an interesting molecule without too much resource, why not?  Key, of course, was building that fascinating cycloheptane, featuring not one, but two oxa-bridges.  Their plan was to build this using a [4+3] cycloaddition between a furan and a silyloxyallyl cation – a reaction that could create one of either of the oxa-bridges.  Through a little experimentation (which is unfortunately not published), the route shown was favoured, as it was far cleaner.

The reaction, by it’s nature, lead to a racemic product, but three new stereocenters can’t really be sniffed at, especially as the product is so obviously suited for the target.  Again, the paper is a bit light on details – it’d be nice to know why tickle-four was the optimum Lewis acid, but there are a few reference [1 - a nice Organic Syntheses prep, 2, 3].  Their reasons are summarised by an avoidance of some unidentified crap – perhaps not the most scientific of explanations…

Moving on from here, the molecule is nicely functionalised, allowing the group a lot of freedom for their next move.  They decided to install the other oxygen bridge, and to do this via an epoxidation.  Using the simplest methods such as mCPBA were ‘less effective‘ – and a bit of base was needed to prevent decomposition, presumably arising from protonation of the epoxide and rearrangement.  Interestingly, that’s exactly what they did next – a bit of pTSA in methanol promoted opening of the epoxide and a decent yield of the tricyclic structure.

A few oxidations, and a couple Grignard additions (all stereoselective in their favour) later, and the group were ready to do the final work on the target.  Using the Lemieux–Johnson conditions (yes, that’s the name for this!), a stereoselective oxidation and DHP formation installed the final ring.  A little hydrodge tied things off, and completed a rather neat synthesis.  Now, if only they could find some biological activity.  Even milli-molar cytotoxicity….

This month’s Chemistry World column is Aplykurodinone 1, a rather neat Danishefsky synthesis.

Shair, Liau, JACS, 2010, ASAP DOI: 10.1021/ja104575h.

After wading through the Heathcock paper last week, I’m glad that today’s topic of discussion is a little shorter and easier to read.  (Seriously, part of me hates reading paper older that the 90′s as the style used in the schemes and figures is so difficult to follow.  Some of those 1960′s JACS papers are a real slog to get through – but worth it, normally….)

The target of choice today is Fastigiatine, a member of the Lycopodium alkaloid family, a popular target these days.  Two reason for that – 1. tasty biological activity checks the right boxes on the grant applications and 2. a complex, strained ringsystem makes for high impact publications.  What’s not to like?  Fastigiatine in particular is a tough cookie to crack, as additional complexity has resulted in a tightly-packed pentacyclic ring-system – something Matt Shair hoped to crack with a biosynthetically inspired synthesis.

The first reaction to catch my eye is the rather busy mixed cuperate addition into a malonyl cyclopropane.  I haven’t checked, but you can be fairly sure that Aldrich don’t carry these particular species, so it’s a good thing that their syntheses are fairly short.  The cyclopropane takes four steps from epi-chlorohydrin, so isn’t too bad, whilst the masked cyclohexenone was produced from the corresponding vinyl iodide (itself a five-step procedure).  See the SI for full details on these.  Combination of the two resulted (unsurpisingly) in opening of the cyclopropane to generate bulk of the substrate for the next important step.

The substrate in question certainly looks reactive enough, with two olefins along with that rather sensitive looking ketal.  Surprise (!) – a bit of acid unmasks the ketone, promoting a formal [3 + 3] cyclisation.  I’ll leave it to Matt to explain their thoughts: “…7-endo-trig intramolecular conjugate addition to form the C6-C7 bond, tautomerization to secure the C12 stereocenter, and finally a transannular aldol reaction to form the C4-C13 bond.”  Damn neat work.

Impressive as this was, the group actually targeted an even shorter route – one in which the nosyl protecting group was removed prior to cyclisation.  They hoped that this would be free to react with the ketone, resulting in an initial iminium ion formation, completing the whole ring system in one cascade.  However, the free amine was a reactive little beastie, preventing them from following this plan.  This left then with the final pyrollidine ring to install before retiring to the pub – a plan dispatched by firstly methylating the now-free amine, the using the tried-and-tested method of heating the crap out of it.

The group speculate that this process occurs firstly by retro-aldol to cleave the C4-C13 bond, then iminium ion formation and transannular Mannich reaction, using much of their original ideas.  To complete the target, the group were left with just a carboxylation of the tert-butyl ester and an acetylation to finish a really sweet synthesis and a fine read.

Jung, Chang, Org. Lett., 2010, ASAP DOI: 10.1021/ol1009762.

Although the number of actual steps in a formal synthesis is (or at least should be) smaller than in a full total-synthesis, I often feel that the actual work is harder.  Afterall, one is directly comparing ones work with that of another researcher, and in this case Michael Jung has got his work cut-out.  There aren’t many professors whose work is truly that daunting, but Clayton Heathcock is one of them. Jung’s work intercepts the Heathcock synthesis eight steps from then end of the total synthesis, so is certainly a very worthy addition to the literature – and does things asymmetrically, which is  notably absent from the former paper.  However, the overall strategy is shared between the papers – using cycloaddition/alkene chemistry to build that complex ring-system, starting with the 6,5-bicycle.

Jung’s approach was to use some rather novel cyclopropane chemistry to trigger a cycloaddition – but first he had to build his cyclopropane fragment.  The difficult thing here is that it needed to be a single enantiomer, so he chose to use a modified chiral auxiliary to get going.  A Corey-Chaykovsky reaction was used to install the three-member-ring, leaving the group with only a simple hydrolysis in methanol to complete the malonate group and free the cyclopropane.

This fragment was put to work immediately in a tasty Michael addition into a known cyclohexenone, promoted by triflimide. Not only did this reaction form a carbon-carbon bond, but a new stereocenter was installed, and the required silyl enol ether was formed too.  Following this, a methylenation of the ketone (which looks to be a tetchy reaction) provided the substrate for the key cyclopropane chemistry.  Treating this loaded intermediate with a bit of Lewis acid promoted a Mukaiyama-like collapse of the silyl enol ether, which adds into the cyclopropane, thereby completing the 6,5-system and providing a pair of stereocenters.

Importantly, it also provides a useful functional handle (in the form of the malonate), allowing the group to quickly converge with Heathcock after a microwave-assisted decarboxylation.  Rather than just concluding here, I thought I’d have a look back at the Heathcock paper:

Heathcock, Blumenkopf, Smith, J. Org. Chem., 1989, 54, 1548. DOI: 10.1021/jo00268a015. 

Heathcock set the precedent, working with a molecule very similar to that of Jung.  A little Wittig chemistry creates a diene, which undergoes a 5-exo-trig cyclisation to build the cyclopentane, featuring the same exocyclic methylene as Jung.  The catch here is the ester side-chain – Jung’s innovative route places this one methylene group further away from the ring system.  This is key, as Heathcock then needs four more steps to do the same thing (effectively a Arnt-Eistart homologation).

This is where the routes converge, but for Heathcock, targeting the first total synthesis, the work was a long way from done.  Completing a larger nine-member cyclic amine was next on the agenda, using nothing too spectacular to achieve this.  However, the final cyclisation to complete the molecule really is very neat, so here it is in its fineness:

Impressive work by all involved, and due praise to Jung for bringing some neat chemistry to this tasty natural product.

Nicolaou, Chen, Kang, Ng, JACS, 2010, ASAP DOI: 10.1021/ja102927n.

Another popular target today; a last month I wrote a piece in Chemistry World about the first two syntheses of this target, and only a month later, up-pops Nicolau and Chen’s effort.  If nothing else, that’s a whole-lotta funding gone into this target, so it’s no surprise that it’s a pretty biologically active beastie. To quote KCN, ‘…potent and selective growth inhibitory (GI) activities against renal cancer cells‘ is the order of the day, so it’s worth all this effort.  The first two syntheses, published by Ma and Echavarren respectively, use similar gold-mediated cyclisations to build the stereochemically busy 5,7,5- system, using quite different routes to get there. However, Nicolaou and Chen do something rather different.

The paper is divided into two routes; an initial racemic synthesis, and then a later enantioselective formal synthesis.  However, I’m starting with the crux of the synthesis, and their introduction of asymmetry.  The chemistry works by forming a reactive oxopyrilium species from the cyclohexenone, cunningly flattening the molecule, removing those racemic stereocenters.  This exotic beastie then does a [5+2] cycloaddition with the acrylate – in this case bearing a chiral auxiliary.  Creating three new stereocenters in one reaction is quite a challenge, and the paper discusses the development of the chemistry in some detail.  Ultimately, the group couldn’t convince the reaction to give them any more than about a 40% yield, and in the case of the enantioselective chemistry, they were limited to 30% as a 2:1 mixture of diastereomers.

Separation of the diastereomeric mixture was possible, though, leaving two separate pots of enantiomers after removal of the auxiliary.  However, the stereocenter at C-8 looked fairly acidic, and therefore fragile, so the group had to use a rather convoluted reduction/oxidation approach over four steps to achieve what was effectively a transesterification.

A few steps later and the group had introduced a further stereocenter by reduction, and introduced a pendant olefin via elimination.  They then did a palladium-mediated reaction I don’t see very often – a Wacker oxidation.  This provided the desired methyl ketone in excellent yield, and set them up for a nice Robinson Annulation with the cycloheptanone.  Given that there are a couple of modes of reaction for this compound, a yield in the high 70s is pretty respectable, and completes the carbon skeleton of the 5,7,5- ring system.

The next few reaction are what makes this synthesis particularly neat in my opinion.  The enone moiety was reduced in a pair of reaction, firstly tackling the ketone using sodium borohydride and the only Lanthanide I’m ever going to handle.  Then goes the alkene using Crabtree’s catalyst (at a slightly pricey loading…).  Bang – three stereocenters using substrate control and a bit of hydrogen.

The last reaction is yet another that I had to look at for a little while before it clicked (and I felt like an idiot).  After forming the Weinreb amide from the ethyl ester, treatment with methyl lithium gave the group a methyl ketone.  A little peracid then did a Baeyer-Villigar oxidation, forming an ester such that the group were left with an acetate protected hydroxyl.  Neat stuff…

…but is it better than the two preceding syntheses?

Siegel, Yuan, Chang, Axelrod, JACS, 2010, 132, 5924 DOI: 10.1021/ja101956x.

It’s finally time to examine the second synthesis of Complanadine A, and I have to say that this route couldn’t be further removed from the Sarpong synthesis.  Of course Siegel’s route takes advantage of the dimeric nature of the target, but it’d be more worrying if he didn’t.

The synthetic action begins with a rather nice alkylation. Starting with a unsymmetrical cyclohexanone, alkylation could have occurred on either (or both) sides of the carbonyl.  By using a sulfide, the deprotonation is favoured on their preferred side – but the utility of the sulfide doesn’t stop there.  Treating the product with a bit of oxidant results in oxidation of the sulfide, and eventual elimination to give the cyclohexenone – all rather neat.

Rather conspicuous in all this is the stereo-defined methyl group, having played no role in the chemistry so far.  However, in a two step procedure, the group were able to do a very nice functionalisation of the olefin, effectively adding a molecule of acetonitrile over the double-bond, setting two new stereocenters.  I presume that this reaction works by firstly deprotonating the silylated acetonitrile, which would then do a Michael-type addition to the enone.  A bit of fluoride then takes-care of the remaining TMS group, and allows the group to separate the mixture of stereoisomers received.  Forty-five percent isn’t amazing over two steps, but this is a pretty neat way to add a C-2 fragment.

Functionalisation of the remaining ketone over a few steps is what takes us to the next intermediate, in which the group have cyclised-round the pendant acetate onto a amine to build a protected piperidine – which unsurprisingly looks a lot like the aliphatic fragment of the monomer.  The group’s ambitious plan was to unite two of these fragments whilst building the remaining pyridine moieties – really quite different to Sarpong’s route.

The protocol was step-wise – after completing the bicyclic monomer, the first of their cobalt mediated annulations installed only one pyridine.  Using a protected diyne, the Co-mediated chemistry (a formal [2+2+2]) could have two realistic regioisomeric products, but by tuning the SM, and choosing the right solvent system, they were able to get a very respectable yield.  I guess this kind of chemistry isn’t enormously removed from the Pauson-Khand reaction – something that brings back mechanistic nightmares from my undergrad…

In an ideal world, I’m sure the group would have liked to simply add a bit more of the monomer, and allow it to snap-around the remaining TMS-acetylene.  However, this doubley silylated SM was unreactive, and required a little tinkering.  Removing both TMS groups produced a SM that was too reactive, and seemed to be eaten-alive in the reaction, so they had to go the Goldie-locks route and use a single TMS group.  This produced a reactive-enough SM, but they got the wrong regioisomer.  After what the paper terms ‘significant experimentation‘, the group found that using a formyl protecting group on the monomer, and a little triphenyl phosphine, they achieved an impressive success.

The group state that this reaction ‘warrants further study‘ – something I hope they have success with, as this is a pretty impressive bit of work.  And so was the rest of the synthesis!

Sarpong, Fischer. JACS, 2010, 132, 5926 DOI: 10.1021/ja101893b.

It’s quite hard to explain the phenomenon of simultaneous publication to people outside of chemistry, ’cause it simply isn’t easy to rationalise.  This is now twice in as many months, as Englerin A took my fancy in this month’s Chemistry World.  I’ve never been in the situation of working on a target with rival groups bearing down on me, but it must be quite punishing (I took the slightly easier option of working on a target that 1. had been made >30 times and 2. had it’s first synthesis in the 1960s…).  The Sarpong and Siegel groups made it to JACS within days of each other, but the ribbon goes to the Sarpong group, so I’m covering their efforts first.  Both syntheses show some similarity – the dimeric nature of the target almost requires this – but this aside, the routes are rather different. Lets see how the hold-up together…

Sarpong starts with the good stuff; a pretty remarkable cascade, starting with perchloric acid (thanks for the correction!), which hydrolyses the enamine-type system to provide a ketone which reacts as its enol tautomer.  They then add a protected cyclohexenone (6 step literature synthesis), which is deprotected in-situ, forming the corresponding imine which goes on to react with the enol.  A further reaction with the imine follows, with the cascade finally terminating with an enamide formation, completing two rings and the bulk of the Complanidine monomer, N-desmethyl ?-obscurine.

The dimerisation of this molecule is rather neat.  Treatment of the 3,4-dihydropyridinone with lead acetate results in an oxidation to the pyridinone; a new reaction to me, but not particularly surprising.  I wonder if one could substituted that nasty lead for a bit of hypervalent iodine – perhaps a little BAIB could do that oxidation.  Anyway, it gets them to the next step in good yield, ready for triflation of the amide.  This provides a neat handle for palladium chemistry, but they need a partner for that reaction.  This was done easily – by reducing half of their material to the pyridine, and borylating in the 3-position using a little iridium catalysis and boron pinicolate (67% over two steps).

Coupling of the two halves was no problem – including the final deprotection, the finished the synthesis in a 42% yield.  Very well executed.

Bradshaw, Bonjoch, Etxebarria-Jard?´. JACS, 2010, ASAP. DOI: 10.1021/ja101994q.

It’s been a while since I wrote about a synthesis from Spain, so it’s nice to return with a rather sweet synthesis from the labs of Josep Bonjoch and his compatriot, Ben Bradshaw. Their efforts have been focused towards a sub-set of diterpenoids produced by Aspergillus, in which the decalin ring junction contains a pair of quaternary carbons.  That’s a pretty significant challenge by itself, but the rest of the decalin in subsituted in an all cis- arrangement, making for a pretty tricky system.  Perhaps this is why there have been no reported syntheses!

The Spanish team’s approach hinges on a rather tasty piece of methodology executed in the first few steps of the campaign.  Using a rather complex-looking proline/BINOL derivative, they were able to perform an asymmetric Robinson annulation, requiring only 1 mol% base catalyst.  This produced the Wieland-Miescher ketone product in an excellent yield and enantiomeric excess, allowing them to proceed directly to a conjugate addition.  Using the usual cuperate conditions, they completed quaternarisation of the decalin in only three steps and in impressive yield.

A selective ketone protection / methylenation / deprotection sequence later, they were ready to functionalise the decalin.  A key synthetic handle was enone-functionality, installed using Nicolaou’s hypervalent-iodine prep.  This might not be a stunning yield, but in terms of route-efficiency, you can’t beat it.  However, IBX at 70C is somewhat of a concern…

A futher methyl group was appended using an interesting approach of enolisation followed by Eschenmoser’s salt.  Reduction then provided the desired methyl group in the correct orientation.  Rather neatly, they then moved the oxygenation around the ring by reducing the ketone and displacing with an aryl-selenide.  Treatment of this with mCPBA allowed the usual sigmatropic rearrangement to occur, where the conformation of the ring allowed for a nicely diastereoselective reaction.  Interestingly, this reaction only performed well when the solvent was wet…

Even-more selenium chemistry was used to install a further enone (I feel sorry for the other workers in this lab – I hope the fume-hoods were up to the task!!), leaving them perfectly set for addition of the indole moiety.  The group admit that they did a screen of Lewis-acids in the lab, and that for no-reason-in-particular, zirconium tetrachloride was the winner.  This lead to the all-cis arrangement required in the target – with an interesting deprotection of the pendant acetate using KF in ethanol.  Anyone done that chemistry before?

Getting to the target took a futher four steps – oxidation of the primary alcohol and methylenation provided a handle for metathesis to complete the prenyl group, followed by deprotection of the remaining TES group.

All things considered, this is a really neat synthesis and a cracking implementation of some powerful methodology.  The best thing is that their methodology fits pretty much perfectly – it isn’t shoe-horned into the synthesis like we see in many other papers.  The only catch is that the route is entirely linear – something that I think is unavoidable with this target, so of no real consequence.

Apologies for the lack of blogging, friends.  This has in part been due to a lack of free time, but also to my computer going BANG.  A wisp of smoke and an horrendous smell indicate a ‘knackered’ power supply, so it’s going to be a little while longer before I’m back in action again. In the mean time, do read my CW article from last month – Polycavernoside A.  No surprises for guessing what next months CW piece will be – those intreguingly similar publications of Englerin A (one and two).