Boger, Burke, Haq. JACS, 2010, ASAP. DOI: 10.1021/ja9097252.

Figured it out already?  I bet it caused a few scratched-heads in Dale Boger’s group when, having made the published structure for Sultriecin, things didn’t tally-up.  We’ve discussed quite a few reassignments here over the years, but the majority are antipodal stereoclusters, or isomerisations at worst.  In this case, even the molecular formula was wrong!  The group may well have been suspicious before this point, though, as the related fostriecin, cytostatin and phospholine all contain the phosphate-mono ester that eventually replace the sulfate group initial assigned.  Their journey in reassigning this centre is best read in the pdf, but the synthesis is pretty damned good too!

First up is a fairly simple coupling of an acetylene and an acyl chloride.  Now, I would have cracked-out the BuLi in this case – but not Boger, who used a bit of palladium catalysis.  This certainly has an advantage from a ‘mildness’ point of view, but I not sure why it was necessary.  Perhaps the acetylide could have reacted with the furan?  BTW, it’ll come as no surprise to those readers who know their coupling reactions that the reference given is a Sonogashira paper.

I’m only really mentioning that coupling in passing, as the interesting reaction is one that follows after a pair of reductions.  The freshly installed hydroxy-furan was coaxed into a ring expansion using just a little base, and some NBS.  No explanations or further information here, but it is a nice method!  With the left-hand-side looking pretty much ready, it was time to tackle the other half, containing a rather precarious looking triene.  However, before you try to combine a whole load of Suzuki/Stille methods for it’s construction, have a look at Richard Taylor’s approach – opening of pyrilium tetrafluoroborate with an alkyl lithium to generate the dienal (is that a word?).  A bit of dibromoolefination using carbon tetrabromide and triphenyl phosphene completed the triene, with only a little reduction required to furnish the desired bromo-coupling partner.  What a sweet way to configure your olefins.

Then, predictably, came the coupling itself, using a rather surprising approach of lithium/halogen exchange, and then addition into the aldehyde partner.  This had the advantage of conferring a pretty decent diastereomeric ratio on the new hydroxyl group, something unachievable in the Suzuki disconnection I’d have been planning.  It’s pretty brave, though, as the lithiate looks pretty prone to rearrangement.  At least it’s not skipped-conjugation…

A really neat piece of synthesis coupled to a remarkable reassignment.  I’m amazed that this error was made by the isolation team – the fact that sulphate and phophate-mono-esters are equal in mass is well known.  A little ³¹P NMR would have been soooo diagnostic!

Gin, Perl, Ide, Prajapati, Perfect, Duron. JACS, 2010, ASAP. DOI: 10.1021/ja910831k.

When I see targets containing guanidine moieties these days, I immediately think of David Gin, which goes to show how much he owns that motif just now.  Looking back into the murky past of Tot Syn, an earlier post covered Gin’s synthesis of Batzelladine A, which was fairly guanidine-tastic.  This bad-boy only has one, but with a bit of “anticancer, anti-HIV, antifungal, and Ca²⁺ ion channel blocking [activity]“, that grant-form presumably filled itself, especially at MSKCC.  However, this compound does have previous, and if you had to guess, you’d guess Overman, right?  And you be correct.  And his synthesis features a Biginelli condensation, so how ya gonna beat that, Gin?

Well, through a trio of beautiful cyclisations, as it happens.  The first comes from combination of two quite elaborate starting materials, which were actually easier to come-by than one might imagine.  The skipped ene-yne was produced via a Wittig and a primary-iodide displacement, reducing the compound to two small, asymmetric building-blocks and an acetylene.  The other fragment, containing the precarious-looking carbodiimide, was produced in a second efficient route – three steps from literature material.  One step I hadn’t seen before was the synthesis of the carbodiimide by condensation of a isocyanate onto an azide using a bit of triphenylphosphine to reduce to an amine beforehand.  Neat.  Anyway, one these fragments were in-hand, combination (using a fair-old excess of the carbodiimide) resulted in a pretty efficient cyclisation onto the thioimidate, producing the guanidine-containing aminopyrimidine.

This [4+2] approach has some history, but Gin’s implementation was particularly neat as it worked well on a heavily elaborated system.  This allowed them to quickly remove the interesting silyl-ish protecting group on the imine (ammonium fluoride did that quite nicely without molesting the TBS groups).  Treatment of the now-free imine with gold (III) chloride allowed a second cyclisation onto the nearby acetylene, neatly forming the second pyrimidine, and providing an exocyclic olefin with the correct geometry.  This also stands as a somewhat rare example of metal-catalysed hydroamination of alkynes.  But they were far from done here – that unsaturated system was perfectly set for an addition reaction, which is exactly what happened after treatment with tosic-acid.  Gin doesn’t comment on the stereoselectivity here, so I guess we have to assume that the spirocyclisation was entirely selective for the desired tetrahydrooxepine

Bolting-on the greasy side-chain only took a couple more steps, rounding of a rather neat synthesis, building a complex ring-system with admirable ease.

Shibasaki, Kanai, Shimizu, Shi, Usuda. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.200906678. ; Shibasaki, Kanai, Kuramochi, Usuda. Org. Lett., 2004, 6, 4387. DOI: 10.1021/ol048018s. 

Three amazingly tough targets completed in (almost) as many months – you can’t tell me that total synthesis is stifled.  Hyperforin has been staining the white-boards of many a lab for decades – the isolation (reported in Antibiotik…) was way back in ‘71, and has resisted synthesis until now.  Shibasaki himself has been working on it for quite a while, as you’ll have seen in the header – a key Org. Lett. was published in 2004 where he describes the asymmetric synthesis of the cyclohexanone.  Lets step in there…

Two papers aren’t actually enough to cover this work – one has to grab the SI to see how Shibasaki made the key diene for the asymmetric Diels-Alder. I think it’s work a brief look, as the synthesis has a particularly neat cuperate addition to an acetylene.  This procedure allowed them to trap the enolate formed from this with acetyl bromide, forming a beta-keto ester, containing a tetrasubstituted alkene, rather easily.  Certainly no-doubt better than the ropey Knovenagel-type condensation I would have attempted…

A few more steps were required to complete the substrate, turning it into something that reminds me of Danishefsky’s diene.  Anyway, tickling this with a bit of Lewis acid (optimised in that Org. Lett.) with a C-2 symmetric  ligand results in a extremely well controlled Diels-Alder reaction, setting two stereocenters, one of which was quaternary.  A really neat solution to the cyclohexanone, allowing an efficient elaboration strategy to finish the ring.  C-1 was set by simple de-silylation, removing both TIPS groups, reforming the ketone.  A few steps later, C-5 was set by kinetic enolate formation (favouring C-5 over the now more congested C-1), and trapping with prenyl bromide to add the second prenyl group.

Working with that cyclohexanone certainly helped much of the stereochemical control, but by the time the group were installing the second quaternary center, things were clearly becoming much more difficult.  A regio/chemo/diastereoselectivity issue seems extremely likely if one were to continue forming enolates, so the group changed tack, and went in for the rearrangement approach.  O-alkylation, installing an allyl group using NaHMDS and allyl bromide nuked the C-1 asymmetry, but that was inconsequential, as the Claisen rearrangement reinstated it as the desired quaternary center, with exceptional efficiency and control.  Look to the paper for a transition-state model – I couldn’t face redrawing it…

The terminal olefin that has just been installed certainly looks conspicuous, so there’s no surpise that is was up for a bit of transformation next.  An extremely selective hydroboration /oxidation sequence turned it into the corresponding aldehyde, using my favourite boron species (doesn’t everyone have a favourite borane? No?  Just me?…), disiamyl borane.  Using just a little ethanolic base, this did the simple aldol to form the remaining quaternary centre with ease.

Things were definately looking up at this point – three bastard-hard stereocenters installed, two prenyl groups in, and only a bit of oxidation / prenylation to do.  And add to this a massive stroke of luck – I quote: ‘Cleavage of the MOM ether under acidic conditions proceeded with concomitant protection of the homoprenyl group at C8 to give 21. This unplanned selective protection was desirable because the reactive homoprenyl group caused side reactions at a later metathesis stage.’ A unexpected as this was, it clearly still took quite a bit of work, as three recycles were required to achieve a two-thirds transformation.

However, at this point Lady-Luck (or whatever you think really controls your reactions – my firm belief is in the phase of the moon) stuck two-fingers up at the group, and made oxidation of the ‘bridge’ next to impossible.  A simple oxidation of the ketone to it’s unsaturated cousin was done by silyl-enol-ether formation and a bit of palladium.  From then, one would hope for a selective epoxidation on this electronically disparate olefin, and a bit of Lewis-acid controlled delivery of the required alkyl (prenyl) group, leaving oxygenation in the right place.  However, a glance at the SI for the Angewandte reveals that they basically tried every possible method to no avail.  Three different basic-peroxide preps, TBHP with Triton B, and even a bizarre prep using BINOL, triphenyl arsene oxide, a lananide, some TBHP and seieves didn’t work.  Google assures me that the Japanese for bollocks is kudara n !, but I have no idea how to pronounce this.  However, I imagine this may have been mentioned…

The route that was eventually triumphed used a rather neat vinylogous Pummerer rearrangement; however, creation of this substrate took twelve steps from my previous structure, so clearly was a method of last recourse.  Still, triumph it did, using the how-to-fuck-up-your-Swern-Oxidation type conditions we’ve all been warned about.  And I think a 65% yield and stunning d.r. are worth the effort!

The last bit of chemistry I’m showing is a final rearrangement, using a bit of palladium to encourage a intramolecular allyl transfer.  This presumably involves a pi-allyl co-ordinated palladium complex which collapse after rearrangement, controlled by a thermodynamic urge for C-allyl over O-allyl.  Very neat, and needing only a (rather low yielding) metathesis to finish that final prenyl group.

Take a deserved bow, folks – I’m officially in awe.

Lee, Kim, Choi, Ha, Kim. BOMCL, 2010, 20, 409-412. DOI: 10.1016/j.bmcl.2009.10.016.

The Tot. Syn. bull-shit detector is at eleven just now, having just read Derek Lowe’s post on Piperkadsin C.  This natural product was isolated by Kang Ro Lee of Sungkyunkwan University in a assay-guided chromatographic separation of isolates from Piper kadsura (Piperaceae).  It doesn’t take much more than a glance to see that something seems very wrong with this structure, as it seems to contain a bridged cyclobutene, partially containing a dieneone.  From a chemical stability aspect, this is scary enough, but the real concern is of course in the sterics.  I’ve done some very simple MM2-minimisations in Chem3D:

I’ll ask the geeks chaps in our comp-chem office to try and do something a bit more meaningful tomorrow.  In the meantime, have a look at the NMR data in the SI.  Having trouble finding it?  I did too, ’cause all we’ve got is the tabulated data in the main paper.  Really, I thought all isolations came with scans of the actual NMR data?

I’m still wading through the assignments, and trying to match the ¹³C data with predicted data in ChemDraw (which is pretty good in ¹³C).  But what strikes me is the fact that a search of the PDF has no hits for words like, uh, butane or butene or even frickin’ strain.  Seriously, WTF?!

Part II

Okay, my colleague, James, has done a bit of proper 3D modelling for us (and also provided some tips for modelling) – I quote:

For the sake of all thing decent in comp chem you really should dump the chemdraw 3D stuff and use something decent!!  These were done using omega 3D, the minimisation of all confs produced with MM3, the images are of the lowest energy conf.  Aside from the method, one complaint with the chemdraw images is that you can’t see which are single and which are double bonds

One approach that is slightly preferable is to use a free demo of a commercial tool like corina (a farily industry standard 2D to 3D converter)

http://www.molecular-networks.com/online_demos/corina_demo

1. Select your mol in chemdraw and do Edit -> Copy As -> Smiles

2. Paste the smiles into the above web page, download the results into whatever free viewer you like (pymol is my favourite freeby) and generate some images.

If you get problems, put all explicit H’s in the mol in chemdraw and corina will behave better, I’m not too sure if the simple web app will handle things without H’s.

8th of February – more modeling

I’m currently not well disposed to the bloody French, but I’ll consider one chap and his colleague - Yoann Coquerel & M. Rajzmann – who have added to the modeling work above, and done some proper, AM1 (semi-empirical) and DFT (ab inito) calculations on the proposed structure of Piperkadsin C.  I quote:

We have performed AM1 calculations on the proposed structure of piperkadsin C and a possible alternative structure. Note that we have not been through the reported characterization data to propose the alternative structure, and it may not be realistic at all given the reported data; we just used it as a reference point. Remarkably, the molecule looks stable, although its enthalpy of formation is much higher than the proposed alternative structure. To confirm these results, we have performed DFT calculations on a simplified analogue, and the results are similar. It may be noticed that the results obtained by both methods are very similar, but the AM1 method required less than 5 second on my laptop. If some people are interested, we can continue this study to determine the energy profile of the transformation from the proposed structure of piperkadsin C to the alternative one. Feel free to ask.

The result of their labours can be seen in the lovely graphic below:

(Click for an even bigger image)

Thanks, chaps!

Kerr, Karadeolian. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.200906632.

It’s always going to be a tough situation for the article I blog following something like Palau’amine, but this short and sweet synthesis by Michael Kerr of the University of Western Ontario (in the other London – which I visited in ‘95) is as good as can be.  The rationale for it’s investigation is also pertinant, as it turns out that Isatisine A is a moderately active HIV isolate (EC₅₀ of 38 ?m).  A secondary interest in the isolation was that there was a little confusion, as the compound that reluctantly streaked out of the final column (it’s been one of those weeks) was the syn-acetonide.  This was initially thought to be the target, but resulted from eluting the column in acetone…

The synthesis starts with a damned neat reaction; a Johnson tetrahydrofuran synthesis, using a cyclopropane, an aldehyde and a little Lewis acid.  This reminds me of a lot of recent work with gold; the similarity clearly comes from the fact that most gold complexes are just fancy Lewis acids.  Full details on the reaction are found in a recent JACS, here.  The mechanism involves an “intimate ion pair pathway“, something I like the sound of.  I can just imagine the two halves of the cyclopropane sitting down with a nice pinot noir, a couple of steaks and a Richard Curtis film… More sersiously, read the JACS.

Kerr seems to be disappointed in the  diastereoselectivity of this reaction as the result was a 11:1 mixture of the -cis :-trans. I’d be happy enough, but no matter, as it’s improved later in the synthesis.  With two chiral centres fixed, it was time to functionalise the THF.  The suspicious looking differentiated malonate was up for it’s starring role next, as the benzyl ether was predictably ’saponified’ by hyrodgenation, and fitted up with a allyl ester.  This could then be decarboxyated using palladium, resulting in a 2,5-dihydrofuran.  As you can all guess at this point, dihydroxylation with substrate controlled conditions (methanesulfonamide, NMO, OsO4) provided a pair of stereocenters, protected up.  The tosyl group was then removed from the indole using magnesium metal in methanol – conditions I’ll have call for soon.  (For those that haven’t been there, tosyl groups, whilst easy to apply to the amine of your choice, can be a bastard to remove.  I’ve had all sorts of problems after trying sodium naphthalamide, shit-loads of neat acid, and even the new Sodium-on-silica stuff.  Grrrr.)

This left them set for the appendage of an indole, allowing with a bit of oxidation.  In two steps, they form an epoxide on the existing indole, which was attacked by the free alcohol (which looks kinda remote, but this is a cisoid THF).  The resulting aminal is perfectly set to be C3-indole alkylated, requiring only a little acid to facilitate this.  In practice, the reaction was initially favouring the incorrect epimer, but leaving it lying around in acid allowed an equilibration to occur, giving a 3:1 ratio in favour of the desired isomer after 24h.  If one is prepared to spend a bit of time reading the lit, perhaps a bit of Tot. Syn., listening to Spotify and certainly a few coffee (adding up to 42h), a more satisifying 6.3:1 ratio is to be had, with concommitant lactamisation, and delivery of the protected natural product.  Neat work, folks.

Baran, Seiple, Su, Young, Lewis and Yamaguchi. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200907112.

Y’know, I was kinda hoping for a bit of break between blog-posts this winter, as the amount of online publications tends to tail-off around the year-end.  However, not only have the publications been thick-’n'-fast (got quite a lot of material to get through), but up pops palau’amine.  I really did think that Angewandte would hold-off until sometime in early 2010, but here it is – and it lives up to Baran’s reputation.  I mean that in every sense, as in some ways there’s a slight dissapointment, as he has a way of making the synthesis look to obivious, too easy.  However, it was undoubtedly a challenge; Baran states that ‘the synthesis of palau’amine has thus far eluded organic chemists despite the dozens of Ph.D. theses… Many well-founded and logical plans to secure the peculiar trans-5,5 core of [palau'amine] in our laboratory resulted in unfortunate outcomes‘.  This goes some-way to explaining the brevity of this blog post, but I intend to follow-up this post with a quick review of other routes that have been attempted in other labs.

Cutting to the chase, the problem with palau’amine has always been the 5,5′-fused system.  For about ten years, this was thought to be in a cisoid-configuration, but a recent publication by Baran and Kock reconfigured this as trans.  This both helped and hindered synthesis, as whilst trans-5,5′-fused systems are more difficult to make, it brought the target far closer to that of it’s siblings, such as the axinellamines (more on that soon). Anyway, on with the synthesis of our favourite apostrophied natural product.

The starting point to the chemistry should be familiar to regular readers – hark back to Baran’s 2007 synthesis of the axinellamines, and a familiar intermediate crops up.  Using very similar chemistry to that used in the earlier synthesis, Baran’s first move was to install the sole hydroxyl group using silver(II)-picolinate.  This stereo- and chemoselective transformation targets only the secondary amine, and remains un-molested in the subsequent synthesis.  From there, building a second 2-aminoimidazole was done by simply adding cyanamide in brine – rationalised by the propensity in other solvents for the secondary chloride to be displaced.  Presumably have a load of chloride ions in solutions favours the desired side of that equilibrium.  Bromination of the new aminoimidazole provided a functional handle for the next fragment coupling – a masked pyrrole synthesis.  Estchewing more modern methods using palladium (which failed when attempted) to perform a direct coupling, Baran did an alkylation to complete the C-N linkage, followed by a series of acid-mediate methanol eliminations to give the aromatic heterocycle, conveniently with the free acid functional group.

Next up, and completing the synthesis (!!!) are the final three reactions.  A bit of hydrogenation using palladium acetate – conditions new to me – in a hydrogen atmosphere reduced the azide groups to a pair of primary amines.  Treatment of the amino-acid system with a bit of EDC/HOBt formed a macrolactone, presumably favouring the nine-member ring over the ten.  This macrocycle, dubbed ‘macro-palau’amine‘ by Baran was the key to his synthesis, as the addition of a bit of acid promoted a transannular cyclisation between amide-nitrogen N-14 and imine C-10.  Astoundingly, this reaction was selective for the trans-configured 5,5′-fused system, and thereby completed the synthesis of palau’amine.

Now that’s a damn nice piece of work.  But I’m eagerly waiting for the full paper, which I’m sure will put this synthesis in context, as then we’ll have a better idea of what didn’t work.  That is perhaps the legacy of palau’amine – confounded logic, and ultimately the triumph of human endeavour.  So what’s next?

Ley, Francais, Leyva, Etxebarria-Jardi. Org. Lett., 2009, ASAP. DOI: 10.1021/ol902676t.

For those UKian readers out there, there’s a fittingness to my posting a Cambridge paper following an Oxford last week.  Having spent a bit of time at both, it’s hard for me to pick a particular allegience, but I guess I have to go light blue, and congratulate the boys for their dug-in performance at Twickenham a few weeks back.  But I am particularly lucky to have been at both, as their approach to organic chemistry was so markedly different.  Both universities might be perpetually mentioned in the same breath (or word, the horriffic OxBridge, cause of many a confused tourist in Uxbridge), but the departments couldn’t be more different.  Simply consider the staffing rosters: Ox Cam.  And that difference will only get more dramatic in the near future, as Steve Ley heads for the retiral office (something I’m still uncertain of…).  However, he’s a long way from done, as this new Org. Lett. points out.

Bongkrekic acid is a scene of much synthetic action, with an early triumph by Corey, and a less satisfying effort by Ley last year.  In this paper, Ley admits that their previous effort was somewhat crippled by an ill-fitting methodology, and that this most recent synthesis is an attempt to right this.  And quite success it is too, focusing on using the best methods available for each coupling.  The retro outlines that this paper is indeed coupling-tastic, using quite a few pots from Strem.  But what was often more interesting is how the group made the coupling precursors, with a particular emphasis on installing vinyl iodides.  First up is actually a vinyl-stannane, installed using a stereoselective Piers hydrostannylation, nabbed from this JOC paper.  But what was of more interest to me is a simple piece of convergence I haven’t read before – concommitant deprotection of a TBS ether and oxidation directly to the acid using Jones reagent.  Neat.

And we’re into our first vinyl iodide synthesis, and it’s a prep I’ve used before.  You take your acetylene in hexane, bang in some DiBAL-H, and vac-off the solvent.  The DiBAL-H, meanwhile, has added across your triple-bond in a hydro-alumination, and you isolate this vinyl-alane – not a particularly nice species.  This is then quenched by addition of iodine in THF (better hope it’s dry), giving a pretty decent yield of vinyl iodide, stereoselectively.  This was all well-and-good when I was doing this on a small scale in the lab at Cambridge, but when I moved for my industrial placement at AstraZeneca, the lab-saftey people went nuts, so I ended-out getting a custom synthesis done at their expense…

One iodine isn’t enough here, though – a gem-diiodide (looks real-stable, right?) was formed by oxidising the alcohol to the aldehyde, and then adding hydrazine and iodine.  The details are apparently in this 1970 J. Aust. Chem. paper, but I don’t have access – anyone like to elaborate?

Okay, time to couple something – and using what Ley refers to as the Stille-Migita coupling.  Using CuTC in Stille type couplings is something I’ve written quite a bit about, but I’d always attributed the reaction name to Liebeskind.  A difference is that in most of the Liebeskind work, copper is the sole metal, whereas Ley uses a spot of palladum too.  He also uses a phosphonate base, and explains it’s role as that of tin scavenger.  I wonder if it a) makes the reaction smell less evil and b) allows for a less-streaky column.  One can only hope…

Time to make another vinyl iodide, and this time the chemistry is old school.  Using diethyl methyl malonate (which smells so nice it’s really difficult not to eat it…), a little base and some iodoform, a displacement of one iodine seems to be order of the day.  Following this with a bit more base, and we get a decarboxylation, saponification (of the remaining ester) and elimination, binning the penultimate iodine and generating the vinyl iodide.

This little fragment was coupled up in a Suzuki coupling, quickly generating a diene and finally getting the group ready for a bit of non-flatland chemistry.  Their intention was to do an asymmetry propargylation, and they opted for an Indium mediate reaction using Singaram’s chemistry, which uses an ephedrine-like ligand to provide asymmetry.  The resulted in a cracking yield, but also a disappointing enantiomeric ratio.  The group managed to boost this with some of Greg Fu’s work, using a planar-chiral DMAP-ferrocene catalyst (commercially available) to do a non-enzymatic resolution.  More about that in this Chem. Comm.

And now we get to the final coupling, a Sonogashira using a vinyl-iodide.  Typical conditions using a bog-standard palladium source and similarly common copper salt resulted in a rather neat yield of the enyne.  However, what they desired was of course the E,Z-diene, so a bit of reduction was in order.  The most obvious choice, Lindlar catalyst, failed, giving the group a bit of a headache.  I’ll presume that a few sets of conditions were examined for this reduction, as their success with copper/silver activated zinc seems a little obsure.  I’d have tried diimide, but they didn’t ask me…

It did work, though, giving them a very respectable yield of the desired product (the tri-methyl ester of the natural product), along with some of the undesired Bongkrekic Acid.  Separation at this stage, followed by saponification (without any isomerisation) gave the group a portion of each natural product, rounding-off a cracking read and an interesting synthesis.

More of a post-ette than a full post, this tasty little nugget was found buried amongst effective reposts and updates.  Out there to give you a freaky sense of de ja vous are full papers on kendomycin, spirastrellolide, nakiterpiosin… finding something new was an effort!

What we’ve got here are a pair of closely related synthese of some poly hydroxylated piperidenes; notable for their glycosidase inhibitory effects.  Huh, I hear you say (actually, probably not – there are plenty of med-chemists reading this!) – glycosidase inhibitors have been notable in both anti-cancer and HIV therapies.

The first reaction worth considering is a bis-epoxidation and in-situ opening to provide four stereocenters in one pot.  The chemistry is racemic, but does an excellent job otherwise, garnering a useful yield and excellent diastereoselectivity.

The second reaction I liked followed on directly after this.  Taking the freshly installed alcohol and mesylating under standard conditions results in a trans-annular ring closure, as the proximal amine displaces the mesylate to give an aziridine.  In the formation of the mesylate, chloride is of course displaced (soaked-up by the triethylamine).  But it now comes to the fore, opening the aziridine to complete a formal ring contraction and provide a functional handle.

A bit of silver was sufficient in hydrolysing the primary chloride, setting the group very close to the target, and demonstrating a neat sequence of reactions to produce a heavily functionalised piperidine.

Yeah, I’ve not posted in a bit… Cephalostatin 1 is going into Chemistry World next month, but this months is also worth a read.  Darren Dixon’s synthesis of Nakadomarin A contains quite a few interesting transformation, and is very succinct.

Corey, Brown. Org. Lett., 2009, ASAP. DOI: 10.1021/ol9025793.  . Corey, Behforouz, Ishiguro. JACS., 1979, 101, 1608–1609. DOI: 10.1021/ja00500a048. 

Again, it’s been a while since I blogged, and this time the excuses are two-fold.  First of all, I moved home recently to the leafy London suburb of Surbiton (saaf-wess, for natives…), and have been without my computer, interweb access and beer, all three of which are required for blogging.  However, more critically, there’s been a real dearth of total synthesis in the ASAPs, so much so that this paper isn’t even a formal synthesis (not in the title at least).

What we have here is a Corey Org. Lett. examining an interesting array of asymmetric catalysis.  Primarily, the paper discusses ‘highly enantioselective Diels-Alder reaction with an acetylene equivalent to produce chiral-bridged dienes‘.  However, it turns-out that these bridged dienes are also active ligands in a second asymmetric process, ‘enantioselective addition of vinyl or aryl groups to unsaturated ketones‘.  It’s this second reaction that is the centre-piece of this post, as it leads to an intermediate found towards the back of the Corey filling cabinet room, early in a 1979 synthesis of the title compound.  So this is really just an excuse to look at that paper, but it’s always good to read prime-time Corey.

So first up is this new-fangled asymmetric addition chemistry, using a ligand (12) produced earlier in the paper.  This bad-boy coordinates to the rhodium catalyst, allowing delivery of the aryl (or vinyl) boronic acid as a net reduction.  Interesting points are the vanishingly low catalyst (and ligand) loading, as well as the opportunity to produce the ligand in-situ, developing a rather special cascade-type reaction.

Moving to the total synthesis, a reaction I’d virtually forgotten was used to transform the methyl ketone into the corresponding carboxylic acid.  It’s rather mild, requiring only room-temperature and six hours, and produces a product several steps faster than than might otherwise be construed.  The free acid was then chlorinated to the acid chloride, and a bit of Lewis-acid allowed ring-closure onto the proximal aryl position.  A bit of alkylation with TOSMIC (hydrolysing the nitrile and methylating) and methyl iodide provided enough carbon to get on with things.  A key reaction was de-methylation of the phenol, as this promted gamma-lactone formation. Exhaustive hydrogenation using Nishimura’s catalyst did for the benzene ring, establishing three stereocenters with control presumably arising from the lactone bridge.

Job done, the lactone was opened, reduced and tosylated, providing a nice leaving group.  Treatment of the cyclohexanone with base can then, of course, deliver two enolates, with thermodynamically more stable preferred, as internal alkylation with this gives the carbon skeleton of the target.  However, using LDA over-turns this preference, and results in cyclobutane formation.

A few more steps were required to install the isonitrile, but with no problems.  Neat work from a prof at the top of his game.